piperidines and Alzheimer-Disease

Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.

Topics: Alzheimer Disease; Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Heterocycles and their derivatives hold an important place in medicinal chemistry due to their vast therapeutic and pharmacological significance and wider implications in drug design and development. Piperidine is a nitrogen-containing heterocyclic moiety that exhibits an array of pharmacological properties. This review discusses the potential of piperidine derivatives against the neurodegenerative disease Alzheimer's. The incidences of Alzheimer's disease are increasing nowadays, and constant efforts are being made to develop a medicinal agent for this disease. We have highlighted the advancement in developing piperidine-based anti-neuronal disease compounds and the profound activities of some major piperidine-bearing drug molecules with their important target site. This review focuses on advancements in the field of natural and synthetic occurring piperidines active against Alzheimer's disease, with emphasis on the past 6 years. The discussion also includes the structure-activity relationship, the structures of the most promising molecules, and their biological activities against Alzheimer's disease. The promising activities revealed by these piperidinebased scaffolds undoubtedly place them at the forefront of discovering prospective drug candidates. Thus, it would be of great interest to researchers working on synthesizing neuroprotective drug candidates.

Topics: Alzheimer Disease; Humans; Neurodegenerative Diseases; Piperidines; Structure-Activity Relationship

Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated.. In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine.. Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment.. AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data.

Topics: Acetylcholinesterase; Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Dementia; Galantamine; Humans; Indans; Parkinson Disease; Perfusion; Phenylcarbamates; Piperidines; Rivastigmine

Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most prevalent cause of dementia. In spite of the urgent need for more effective AD drug therapy strategies, evidence of the efficacy of combination therapy with existing drugs remains unclear.. To assess the efficacy of combined drug therapy on cognition and progress in patients with AD in comparison to single agent drug therapy.. The electronic databases MEDLINE and EMBASE were systematically searched to identify relevant publications. Only randomized controlled clinical trials were included, but no limits were applied to language or time published. Data were extracted from May 27th until December 29th, 2020.. Three trials found that a combination of ChEI with additional memantine provides a slight benefit for patients with moderate to severe AD over ChEI monotherapy and placebo. However, a further 4 trials could not replicate this effect. One trial reported benefits of add-on. Additional memantine in combination with ChEI might be of slight benefit in patients with moderate to severe AD, but evidence is ambiguous. Longer trials are needed. No major cognitive benefit is missed, if solely appropriate ChEI monotherapy is initiated.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Humans; Indans; Memantine; Piperidines

Donepezil is a first-line drug for the treatment of Alzheimer's disease (AD). However, there are no meta-analyses on efficacy and safety of high-dose versus standard-dose donepezil in the treatment of moderate-to-severe AD.. We searched for randomized controlled trials (RCTs) from 1993 to May 2021 PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases. The outcomes of the meta-analysis included cognitive function, global assessment, and the incidence of adverse events and serious adverse events.. Five RCTs (2974 people) were included in this meta-analysis. The improvement of cognitive function was significant among the patients with the treatment of high-dose donepezil [SMD = 0.12, 95% CI: 0.03 ~ 0.22;. High-dose donepezil is more effective than standard-dose donepezil in improving cognitive function of the elderly with moderate-to-severe AD. However, more attention should be paid to patients with heart problems when high-dose donepezil was used.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Alzheimer's disease (AD) is a kind of neuropsychiatric illness that affects the central nervous system. In this disease, the accumulation of amyloid-beta increases, and phosphorylated tau (P-tau) protein is one of the ways to treat this disease is to reduce the accumulation of amyloid-beta. Various studies have demonstrated that pharmacological approaches have considerable effects in the treatment of AD, despite the side effects and challenges. Cholinesterase inhibitors and the NMDA receptor antagonist memantine are presently authorized therapies for AD. Memantine and Donepezil are the most common drugs for the prevention and therapy of AD with mechanisms such as lessened β-amyloid plaque, affecting N-Methyl-D-aspartate (NMDA) receptors. Diminution glutamate and elevated acetylcholine are some of the influences of medications administrated to treat AD, and drugs can also play a role in slowing the progression of cognitive and memory impairment. A new pharmacological approach and strategy are required to control the future of AD. This review appraises the effects of memantine, donepezil, rivastigmine, and aducanumab in clinical trials, in vitro and animal model studies that have explored how these drugs versus AD development and also discuss possible mechanisms of influence on the brain. Research in clinical trials has substantial findings that support the role of these medications in AD treatment and ameliorate the safety and efficacy of AD therapy, although more clinical trials are required to prove their effectiveness.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal, Humanized; Donepezil; Indans; Memantine; Patents as Topic; Piperidines; Rivastigmine

Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Humans; Indans; Nanotechnology; Piperidines; Plants, Medicinal; Rivastigmine

Patient characteristics may predict the progression of Alzheimer's disease (AD) and may moderate the effects of donepezil.. To build a personalized prediction model for patients with AD and to estimate patient-specific treatment effects of donepezil, using individual patient characteristics.. We systematically searched for all double-masked randomized controlled trials comparing oral donepezil and pill placebo in the treatment of AD and requested individual participant data through its developer, Eisai. The primary outcome was cognitive function at 24 weeks, measured with the Alzheimer's Disease Assessment Scale-cognitive component (ADAS-cog). We built a Bayesian meta-analytical prediction model for patients receiving placebo and we performed an individual patient data meta-analysis to estimate patient-level treatment effects.. Eight studies with 3,156 participants were included. The Bayesian prediction model suggested that more severe cognitive and global function at baseline and younger age were associated with worse cognitive function at 24 weeks. The individual participant data meta-analysis showed that, on average, donepezil was superior to placebo in cognitive function (ADAS-cog scores, -3.2; 95% Credible Interval (CrI) -4.2 to -2.1). In addition, our results suggested that antipsychotic drug use at baseline might be associated with a lower effect of donepezil in ADAS-cog (2.0; 95% CrI, -0.02 to 4.3).. Although our results suggested that donepezil is somewhat efficacious for cognitive function for most patients with AD, use of antipsychotic drugs may be associated with lower efficacy of the drug. Future research with larger sample sizes, more patient covariates, and longer treatment duration is needed.

Topics: Alzheimer Disease; Antipsychotic Agents; Bayes Theorem; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

The aim of the present systematic review (SR) was to provide an overview of all published and unpublished clinical trials investigating the safety and efficacy of disease-modifying drugs targeting synaptic plasticity in dementia. Searches on CT.gov and EuCT identified 27 trials (4 phase-1, 1 phase-1/2, 18 phase-2, 1 phase-2/3, 1 phase-3, 1 phase-4, and 1 not reported). Twenty of them completed, and seven are currently active or enrolling. The structured bibliographic searches yielded 3585 records. A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. We used RoB tool for quality analysis of randomized studies. Efficacy was assessed as a primary outcome in all studies except one and the main scale used was ADAS-Cog (7 studies), MMSE and CDR (4 studies). Safety and tolerability were reported in eleven studies. The incidence of SAEs was similar between treatment and placebo. At the moment, only one molecule reached phase-3. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib.

Topics: Alzheimer Disease; Benzamides; Bryostatins; Humans; Levetiracetam; Neuronal Plasticity; Piperidines; Pyridines; Thiazoles

Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer's disease (AD) has also attracted the attention of many pharmaceuticals due to its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep inducer. Recently, a combination of donepezil with other agents has displayed better desirable results in managing several disorders, including the most common Alzheimer's disease (AD). This study involves all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets and mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combination therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for treating multiple pathological disorders. To the best of our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.

Topics: Alzheimer Disease; Antineoplastic Agents; Antiviral Agents; Clemastine; Computational Biology; COVID-19 Drug Treatment; Dipyridamole; Drug Repositioning; Humans; Hydroxychloroquine; Lenalidomide; Machine Learning; Neoplasms; Neuroprotective Agents; Piperazines; Piperidines; Protein Kinase Inhibitors

The actual standard treatment for mild-to-moderately severe Alzheimer's disease only attacks its symptoms. Masitinib is a potent and selective phenylaminothiazole-type tyrosine kinase inhibitor which is currently in Phase III studies for the treatment of Alzheimer's disease (AD) with the aim of modifying its evolution and with multiple pharmacological targets such as inhibition of mast cells activity, inhibition of microglia activation, modulation of Aβ and Tau protein signaling pathway and prevention of synaptic damage. Here, we review the preclinical and clinical studies that investigated the administration of masitinib treatment in monotherapy in AD. All research studies revealed positive effects concerning the cognitive functions in AD and generally with good safety and tolerability.. Lay abstract In the 21st century, life expectancy has increased a lot in developed countries but so has the number of people who are diagnosed with Alzheimer's disease (AD). AD causes a decline in brain function over time and is the main cause of death and disability in elderly people. Current treatments only improve the symptoms of the disease but do not cure or stop the disease getting worse. For this reason, new treatments are being developed including the drug masitinib which is in Phase III in clinical trials. Masitinib protects specific brain and nervous system cells from being damaged by the disease. Results from current research into masitinib suggest that it can improve cognitive processes in AD patients. This article summarizes results from masitinib clinical and preclinical studies.

Topics: Alzheimer Disease; Benzamides; Cognition; Humans; Piperidines; Protein Kinase Inhibitors; Pyridines; Thiazoles

Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Neurodegenerative diseases are amongst the leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the coming years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly, there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggregation, neuroinflammation and cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzamides; Central Nervous System; Dasatinib; Humans; Molecular Targeted Therapy; Multiple Sclerosis; Myelin Sheath; Nerve Tissue Proteins; Neurodegenerative Diseases; Oligodendroglia; Parkinson Disease; Piperidines; Proto-Oncogene Proteins c-fyn; PrPC Proteins; Pyridines; Receptors, N-Methyl-D-Aspartate; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets; tau Proteins; Thiazoles

Behavioral and psychological symptoms of dementia are symptoms of disturbed perception, mood, behavior, and thought content that occurred frequently. These symptoms, which include apathy, depression, anxiety, psychosis, agitation, and aggression, can serve as predictors of and early clinical diagnostic markers for Alzheimer's disease (AD) and are common precipitants of institutional care. Agitation and psychosis are associated with accelerated disease progression and increased tau phosphorylation in patients with AD. Current guidelines recommend the use of second-generation antipsychotics for the treatment of agitation and psychosis in AD, but only after first-line non-pharmacological interventions and for no longer than 12 weeks because long-term use of these drugs is associated with an increased risk of mortality and an increased frequency of cerebrovascular events. Therefore, new antipsychotic drugs with improved efficacy and safety are needed as an alternative to current antipsychotic drugs. In this report, we discuss some of the most relevant advances in the field of agitation and psychosis in AD and focus on the recent positive clinical evidence observed with two new antipsychotics drugs: brexpiprazole and pimavanserin. Brexpiprazole is a receptor partial agonist (D2, D3, 5-HT1A), receptor antagonist (5-HT2A/B, α1B/α2C) according to the neuroscience-based nomenclature. Two recent phase III clinical trials have shown that brexpiprazole 2 mg/day is effective for the treatment of agitation in patients with AD and has an improved tolerability and safety profile compared with currently available second-generation antipsychotics. Pimavanserin is a receptor antagonist (5-HT2A, 5-HT2C) that has been given market authorization for psychosis occurring in Parkinson's disease. Recent phase II studies suggest that this drug is effective in AD patients with more severe psychosis, although further long-term studies are needed to better define the efficacy and long-term safety profile of pimavanserin for the treatment of psychosis in AD.

Topics: Alzheimer Disease; Antipsychotic Agents; Anxiety; Humans; Piperidines; Psychotic Disorders; Quinolones; Thiophenes; Urea

To evaluate the clinical evidence for traditional medicines (TMs) used in East Asia on measures of cognition in Alzheimer disease, determine the effect sizes at different time points for the TMs and pharmacotherapies, and assess the tolerability of the TMs.. We searched 12 databases in English, Chinese, and Japanese for eligible randomised controlled trials that compared orally administered TMs with pharmacotherapy and reported cognitive outcomes. Meta-analyses were conducted for Alzheimer's Disease Assessment Scale-cognitive subscale and/or Mini-Mental State Examination (MMSE). Mean differences and 95% confidence intervals were calculated to evaluate treatment effects.. Thirty randomised controlled trials met inclusion criteria. Twenty-nine compared TMs with donepezil. Single studies provided comparisons with galantamine, rivastigmine, or memantine. There were no significant differences between the TM and donepezil groups at 12 or 24 weeks for Alzheimer's Disease Assessment Scale-cognitive subscale or MMSE. Improvements over baseline were significant for MMSE at 12 and 24 weeks within the TM and donepezil groups and remained significant at 1 year. Effect sizes were reduced in the 3 double-blind studies. At 24 weeks, donepezil 10 mg/d generally produced greater improvements in MMSE than 5 mg/d. Tolerability reporting was incomplete and inconsistent between studies.. The results suggested that the clinical benefits of the TMs were not less than donepezil at comparable time points, with both groups showing improvements. However, lack of blinding in most studies and other design and measurement issues are likely to have resulted in overestimation of effect sizes in both groups. Further well-designed studies are needed.

Topics: Alzheimer Disease; Asia, Eastern; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Humans; Indans; Medicine, Traditional; Memantine; Nootropic Agents; Piperidines; Plant Extracts; Rivastigmine

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Molecular Structure; Piperidines; Structure-Activity Relationship

Alzheimer's disease is the most common cause of dementia in older people. One approach to symptomatic treatment of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by blocking the action of the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. This can be done by a group of drugs known as cholinesterase inhibitors. Donepezil is a cholinesterase inhibitor.This review is an updated version of a review first published in 1998.. To assess the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease; to compare the efficacy and safety of different doses of donepezil; and to assess the effect of donepezil on healthcare resource use and costs.. We searched Cochrane Dementia and Cognitive Improvement's Specialized Register, MEDLINE, Embase, PsycINFO and a number of other sources on 20 May 2017 to ensure that the search was as comprehensive and up-to-date as possible. In addition, we contacted members of the Donepezil Study Group and Eisai Inc.. We included all double-blind, randomised controlled trials in which treatment with donepezil was administered to people with mild, moderate or severe dementia due to Alzheimer's disease for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two different doses of donepezil were compared.. One reviewer (JSB) extracted data on cognitive function, activities of daily living, behavioural symptoms, global clinical state, quality of life, adverse events, deaths and healthcare resource costs. Where appropriate and possible, we estimated pooled treatment effects. We used GRADE methods to assess the quality of the evidence for each outcome.. Thirty studies involving 8257 participants met the inclusion criteria of the review, of which 28 studies reported results in sufficient detail for the meta-analyses. Most studies were of six months' duration or less. Only one small trial lasted 52 weeks. The studies tested mainly donepezil capsules at a dose of 5 mg/day or 10 mg/day. Two studies tested a slow-release oral formulation that delivered 23 mg/day. Participants in 21 studies had mild to moderate disease, in five studies moderate to severe, and in four severe disease. Seventeen studies were industry funded or sponsored, four studies were funded independently of industry and for nine studies there was no information on source of funding.Our main analysis compared the safety and efficacy of donepezil 10 mg/day with placebo at 24 to 26 weeks of treatment. Thirteen studies contributed data from 3396 participants to this analysis. Eleven of these studies were multicentre studies. Seven studies recruited patients with mild to moderate Alzheimer's disease, two with moderate to severe, and four with severe Alzheimer's disease, with a mean age of about 75 years. Almost all evidence was of moderate quality, downgraded due to study limitations.After 26 weeks of treatment, donepezil compared with placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog, range 0 to 70) (mean difference (MD) -2.67, 95% confidence interval (CI) -3.31 to -2.02, 1130 participants, 5 studies), the Mini-Mental State Examination (MMSE) score (MD 1.05, 95% CI 0.73 to 1.37, 1757 participants, 7 studies) and the Severe Impairment Battery (SIB, range 0 to 100) (MD 5.92, 95% CI 4.53 to 7.31, 1348 participants, 5 studies). Donepezil was also associated with better function measured with the Alzheimer's Disease Cooperative Study activities of daily living score for severe Alzheimer's disease (ADCS-ADL-sev) (MD 1.03, 95% CI 0.21 to 1.85, 733 participants, 3 studies). A higher proportion of participants treated with donepezil experienced improvement on the clinician-rated global impression of change scale (odds ratio (OR) 1.92, 95% CI 1.54 to 2.39, 1674 participants, 6 studies). There was no difference between donepezil and placebo for behavioural symptoms measured by the Neuropsychiatric Inventory (NPI) (MD -1.62, 95% CI -3.43 to 0.19, 1035 participants, 4 studies) or by the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scale (MD 0.4, 95% CI -1.. There is moderate-quality evidence that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12 or 24 weeks with donepezil experience small benefits in cognitive function, activities of daily living and clinician-rated global clinical state. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total healthcare resource costs. Benefits on 23 mg/day were no greater than on 10 mg/day, and benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose, but the rates of withdrawal and of adverse events before end of treatment were higher the higher the dose.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

The vesicular acetylcholine transporter (VAChT), a presynaptic cholinergic neuron marker, is a potential internal molecular target for the development of an imaging agent for early diagnosis of neurodegenerative disorders with cognitive decline such as Alzheimer's disease (AD). Since vesamicol has been reported to bind to VAChT with high affinity, many vesamicol analogs have been studied as VAChT imaging agents for the diagnosis of cholinergic neurodeficit disorder. However, because many vesamicol analogs, as well as vesamicol, bound to sigma receptors (

Topics: Alzheimer Disease; Animals; Humans; Neurodegenerative Diseases; Piperidines; Radiopharmaceuticals; Structure-Activity Relationship; Vesicular Acetylcholine Transport Proteins

Currently, five pharmacotherapeutic options are available to treat Alzheimer's disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials. Areas covered: This article provides a risk-benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy. Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer's disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Humans; Indans; Memantine; Piperidines; Randomized Controlled Trials as Topic

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in elderly people. Considering the multifactorial nature of AD, the concept of multi-target-directed ligands (MTDLs) has recently emerged as a new strategy for designing therapeutic agents on AD. MTDLs are confirmed to simultaneously affect diverse targets which contribute to etiology of AD. As the most potent approved drug, donepezil affects various events of AD, like inhibiting cholinesterases activities, anti-Aβ aggregation, anti-oxidative stress et al. Modifications of donepezil or hybrids with pharmacophores of donepezil in recent five years are summarized in this article. On the basis of case studies, our concerns and opinions about development of donepezil derivatives, designing of MTDLs, and perspectives for AD treatments are discussed in final part.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Drug Discovery; Humans; Indans; Ligands; Molecular Docking Simulation; Oxidative Stress; Piperidines

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.

Topics: Alzheimer Disease; Clinical Trials as Topic; Dementia; Humans; Mental Status and Dementia Tests; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Treatment Outcome; Urea

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Drug Therapy, Combination; Galantamine; Humans; Indans; Memantine; Piperidines; Rivastigmine

The prevalence of Alzheimer's disease (AD) continues to rise, while treatment options for cognitive impairment are limited. Acetylcholinesterase inhibitors (AChEIs) aim to provide symptomatic benefit for cognitive decline, however these drugs are not without adverse events (AEs). The safety profile of each drug must be taken carefully into consideration before being prescribed, as new dosages and formulations have recently been approved. Areas covered: Donepezil, galantamine and rivastigmine are the three AChEIs approved for the treatment of varying stages of AD. Numerous clinical trials and post-marketing studies have evaluated the safety of these medications. This article will review the safety, efficacy and tolerability of these drugs in treating AD. Topics including pharmacovigilance databases, concomitant drug interactions, prescribing cascades, and treatment discontinuation are also covered. Expert opinion: AChEI use in those with mild, moderate or severe AD provide modest improvements in cognition, function and behavior. The pharmacological treatment of AD using AChEIs is associated with generally mild AEs. Differences in drug formulations should be taken into account when determining the most appropriate route of administration for each individual. Furthermore, discontinuation of AChEIs must be carefully monitored as it may be associated with worsening cognitive impairment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Drug Interactions; Galantamine; Humans; Indans; Piperidines; Rivastigmine; Severity of Illness Index

This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD), and global functions.. PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments.. Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p < .001), BPSD (g = -0.878, p < .001) and global functions (g = -0.585, p = .004). Gradual titration of memantine plus a fixed dose and gradual titration of donepezil as well as a fixed dose and gradual titration of memantine resulted in limited improvements in cognitive functions(g = 0.371, p = .005), BPSD(g = -0.913, p = .001), and global functions(g = -0.371, p = .001).. Both in the 24th week and at the final evaluation point, the combination of donepezil and memantine led to greater improvement in cognitive functions, BPSD, and global functions than did donepezil alone in patients with moderate to severe Alzheimer Disease.

Topics: Alzheimer Disease; Donepezil; Drug Therapy, Combination; Humans; Indans; Memantine; Nootropic Agents; Piperidines

Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid β, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Progression; Donepezil; Early Diagnosis; Humans; Indans; Neuroprotective Agents; Nootropic Agents; Piperidines; Time Factors

The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with β-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-β-secretase or τ-antiaggregation activity.

Topics: Alkaloids; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Humans; Indans; Inhibitory Concentration 50; Piperidines; Rivastigmine; Tacrine

Cholinergic transmission loss is one of the major features in Alzheimer&#039;s Disease (AD). Acetylcholinesterase inhibitors (AChEI) are moderately active in AD. α7nAChR (alpha-7 nicotinic acetylcholine receptor), encoded by CHRNA7 (Nicotinic Cholinergic Receptor Alpha-7 gene), is involved in the cholinergic neurotransmission and AD pathogenesis. α7nAChR is a putative receptor of amyloid beta (Aβ). The complex α7nAChR-Aβ is found in neuritic plaques and AD cortical neurons. In normal physiologic conditions, α7nAChR-Aβ interaction leads to receptor activation. Genetic polymorphisms (SNPs) of CHRNA7 and/or CHRFAM7A (fusion gene containing CHRNA7 partial duplication) may be a possible susceptibility trait to dementia, potentially useful to identify high risk or responder individuals. CHRFAM7A-2-bp deletion or CHRNA7 SNPs (rs1514246, rs2337506, rs8027814) seem protective factors in different forms of dementia including AD.. Correlation between(SNPs) of CHRNA7 and/or CHRFAM7A and cholinesterase inhibitors in AD.. Literature review.. Among the leading AD therapeutics, Donepezil (DP) and galantamine (AChEI) induce upregulation of α7nAChR protein levels, protecting neurons from degeneration. Patients carrying rs8024987 (C/G) or rs6494223 (C/T) respond better to AChEI. In the caucasic population rs6494223 TT subjects are 7-15% of the total. α7nAChR upregulation induced by DP is higher in lymphocytes from TT subjects than in CC or CT as well as calcium uptake.. The correlation between genetic and functionality data may have an impact on several aspects of disease presentation and therapy, helping in prediction pattern of AD presentation and treatment efficacy. As a consequence it may lead to better patients quality of life and longer periods of self- sufficiency. Moreover, it may contribute to clarify AChEI mechanisms of action.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Gene Expression Regulation; Humans; Indans; Male; Pharmacogenomic Variants; Piperidines; Polymorphism, Single Nucleotide; Treatment Outcome; Up-Regulation

Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Ligands; Piperidines; Tacrine

With the ever-growing geriatric population, research on brain diseases such as dementia is more imperative now than ever. The most prevalent of all dementias is Alzheimer's disease, a progressive neurodegenerative disease that presents with deficits in memory, cognition, motor skills, and a general decline in the quality of life. The social and economic burden associated with Alzheimer's disease is tremendous and is projected to grow even greater over the coming years. There is a specific need to elucidate and improve the treatments available, not only to alleviate the symptoms related to dementias such as Alzheimer's but also to prevent the formation of the disease. This is an effort that can be expedited and made more efficient by utilizing an animal model such as the zebrafish. This paper reviews the utility of zebrafish in Alzheimer's research by examining research on a sampling of the treatments available for the disease, specifically donepezil, memantine, and methylene blue. The human model and the shortcomings of the rodent model are also discussed.

Topics: Alzheimer Disease; Animals; Dementia; Disease Models, Animal; Donepezil; Humans; Indans; Memantine; Methylene Blue; Piperidines; Rodentia; Species Specificity; Zebrafish

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders encountered in clinical practice. Whilst dementia has long been synonymous with AD, it is becoming more widely accepted as part of the clinical spectrum in PD (PDD). Neuropsychiatric complications, including psychosis, mood and anxiety disorders, and sleep disorders also frequently co-exist with cognitive dysfunctions in AD and PDD patients. The incidence of such symptoms is often a significant source of disability, and may aggravate pre-existing cognitive deficits. Management of AD and PDD involves both pharmacological and non-pharmacological measures. Although research on pharmacological therapies for AD and PDD has so far had some success in terms of developing symptomatic treatments, the benefits are often marginal and non-sustained. These shortcomings have led to the investigation of non-pharmacological and novel treatments for both AD and PD. Furthermore, in light of the diverse constellation of other neuropsychiatric, physical, and behavioural symptoms that often occur in AD and PD, consideration needs to be given to the potential side effects of pharmacological treatments where improving one symptom may lead to the worsening of another, rendering the clinical management of these patients challenging. Therefore, the present article will critically review the evidence for both pharmacological and non-pharmacological treatments for cognitive impairment in AD and PD patients. Treatment options for other concomitant neuropsychiatric and behavioural symptoms, as well as novel treatment strategies will also be discussed.

Topics: Alzheimer Disease; Animals; Antiparkinson Agents; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Exercise Therapy; Galantamine; Humans; Indans; Memantine; Parkinson Disease; Piperidines; Rivastigmine; Sleep Wake Disorders; Treatment Outcome

Comparative evidence for efficacy and safety of second-generation cholinesterase inhibitors (ChEIs) is still sparse.. The purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild-to-moderate Alzheimer's disease (AD).. We conducted a systematic review for published articles and included randomised, double-blind, placebo-controlled trials and head-to-head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta-analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions.. Among the 21 trials included, network meta-analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS-Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety.. Our analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild-to-moderate AD.

Topics: Aged; Alzheimer Disease; Bayes Theorem; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Galantamine; Humans; Indans; Male; Middle Aged; Network Meta-Analysis; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Alzheimer's disease (AD) is a progressive condition that affects cognition, function, and behavior. Approximately 60-90% of patients with AD develop neuropsychiatric symptoms (NPS) such as hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep disturbances, appetite and eating changes, or altered sexual behavior. These noncognitive behavior changes are thought to result from anatomical and biochemical changes within the brain, and have been linked, in part, to cholinergic deficiency. Cholinesterase inhibitors may reduce the emergence of NPS and have a role in their treatment. These agents may delay initiation of, or reduce the need for, other drugs such as antipsychotics. This article summarizes the effects of donepezil, a cholinesterase inhibitor, on the NPS of dementia with emphasis on AD and dementia with Lewy bodies.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Lewy Body Disease; Piperidines; Psychotic Disorders

Alzheimer's disease (AD) is the most frequent progressive neurodegenerative disease. Cholinergic dysfunction is one of the major pathological alteration, although depletion of cholinergic neurons is caused by the well-established toxicity of the beta-amyloid plaques and neurofibrillary tangles. Cholinergic dysfunctions are consequences of the decrease in acetylcholine synthesis and release, and altered function of muscarinic and nicotinic cholinergic receptors. In addition, a direct correlation between cholinergic alteration, amyloidbeta production and tau phosphorylation, two main AD-pathology hallmarks, has been identified.. In the present review we focused our discussion on the identification of new allosteric or bitopic ligands able to modulate the cholinergic receptor activity. Moreover drug delivery methodology (nanoparticeles, liposomes, etc.) that might contribute to drive the drug in the brain, reducing their toxicity and potential side effects have been also discussed.. Many drugs are currently in use for AD (e.g. donepezil, rivastigmine etc.) and several of those in development such as muscarininc and nicotinic agonists, target specifically the cholinergic system; the main mechanism aims to rescue the cholinergic dysfunction, to reduce neurotoxic protein accumulation and improve the cholinergic impairments responsible of the cognitive deficits. Promising approaches aim to either improve drug delivery into the brain or develope new compounds targeting known or new molecular pathways. Nanoparticles and liposomes are also described as new nanotechnology tools that overcome traditional routes of administration, with a particular focus on their employment for compounddelivery that targets the cholinergic system. Ultimately, a new fields of research is emerging as the use of induced pluripotent stem cells, a technology that allows to obtain cells directly from the patients that can be propagated indefinetely and differentiated into the susceptible neuronal subtypes. This may significantly contribute to improve the understanding of AD pathological processes and enhance current AD pharmacology beyond the cholinergic dysfunction.. From the topics discussed in the present review, emerges that the combination between pharmacological studies and nanotechnological approaches for drug delivery and the identification of new specific models may largely enhance and improve the therapeutic strategies for different neurological disease including AD.

Topics: Allosteric Regulation; Alzheimer Disease; Animals; Donepezil; Humans; Indans; Ligands; Neuroprotective Agents; Piperidines; Receptors, Cholinergic; Rivastigmine

Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzamides; Benzodioxoles; Brain; Disease Models, Animal; Humans; Mice; Neurons; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-fyn; PrPC Proteins; Pyridines; Quinazolines; Receptor, Metabotropic Glutamate 5; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Synapses; Thiazoles

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Donepezil; Drug Discovery; Galantamine; Humans; Indans; Molecular Targeted Therapy; Piperidines; Rivastigmine; Structure-Activity Relationship

Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in psychopharmacological research topics. During this period, we identified a number of novel regulatory mechanisms that control the prefrontal dopamine system through functional interaction between serotonin1A and dopamine D2 receptors or between serotonin1A and σ1 receptors. Our findings suggest that strategies that enhance the prefrontal dopamine system may have therapeutic potential in the treatment of psychiatric disorders. We also found that environmental factors during development strongly impact the psychological state in adulthood. Furthermore, we clarified the pharmacological profiles of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine, providing novel insights into their mechanisms of action. Finally, we developed the female encounter test, a novel method for evaluating motivation in mice. This simple method should help advance future psychopharmacological research. In this review, we summarize the major findings obtained from our recent studies in mice.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dopamine; Drug Discovery; Environment; Female; Galantamine; Indans; Male; Mental Disorders; Mice; Molecular Targeted Therapy; Motivation; Piperidines; Psychopharmacology; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1D; Receptors, Dopamine D2; Research; Rivastigmine

Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer's dementia, addressing respectively, the cholinergic and glutamatergic dysregulation which underlies or results from its pathophysiology. To alleviate the pill burden and swallowing difficulties associated with the condition, a fixed drug combination of extended-release memantine and donepezil was developed. This combination was shown to be both bioequivalent to the components administered separately and could be administered sprinkled over soft food. The mode of action, pharmacokinetics, clinical efficacy and safety and tolerability of the combination are discussed together with the wider, often conflicting trial literature of combination versus monotherapy with memantine and ChEIs, their meta-analyses and treatment guidelines.

Topics: Alzheimer Disease; Donepezil; Drug Therapy, Combination; Humans; Indans; Memantine; Piperidines; Practice Guidelines as Topic

Differential responses to donepezil treatment in patients with Alzheimer's disease (AD) have been observed in clinical practice. It remains controversial whether, and to what extent, individual variation in the genes responsible for drug metabolism (CYP2D6) or those associated with AD pathogenesis (APOE) modulate the response to donepezil treatment.. The aim of this study was to better understand the potential link between donepezil treatment response and CYP2D6 or APOE polymorphisms.. We performed a meta-analysis based on data collected from 1266 donepezil-treated AD patients, and evaluated the association of CYP2D6 or APOE polymorphisms with treatment effectiveness.. No significant difference was observed in the responder rate of donepezil treatment between the normal function CYP2D6 alleles group and the decreased/non-functional group [odds ratio (OR) 1.34, 95 % confidence interval (CI) 0.5-3.58; p = 0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response to donepezil treatment (OR 1.52, 95 % CI 1.14-2.03; p = 0.005). For the specific CYP2D6 single nucleotide polymorphism rs1080985, patients who carried the G allele had a significantly higher risk of poor response to donepezil treatment. After adjusting the data based on APOE genotype, it was observed that only individuals bearing both the APOE-ε4 allele and the rs1080985-G allele showed a significant increase in the frequency of treatment non-response (OR 1.73, 95 % CI 1.07-2.09; p = 0.03). No independent effect of APOE polymorphism on donepezil clinical responses was found (OR 1.08, 95 % CI 0.85-1.38; p = 0.53). Lastly, in a subgroup analysis based on ethnicity, all results remained consistent.. The CYP2D6 genotype may be potentially effective for predicting the response to donepezil treatment in AD patients.

Topics: Alzheimer Disease; Animals; Apolipoproteins E; Cytochrome P-450 CYP2D6; Donepezil; Humans; Indans; Nootropic Agents; Pharmacogenetics; Piperidines; Polymorphism, Single Nucleotide

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease. Patients with severe AD often require assistance with daily functioning and have a substantially higher probability of admission to nursing homes compared to the general population.. Medications approved by the US Food and Drug Administration for the treatment of severe AD include the cholinesterase inhibitors (ChEIs), donepezil (10 and 23 mg/day) and rivastigmine (transdermal patch, 13.3 mg/24 hours), and the N-methyl-D-aspartate receptor antagonist memantine (immediate- and extended-release formulations). This article will review the efficacy, safety, and tolerability data of these agents in the treatment of severe AD. Issues related to combination therapy, neuropsychiatric symptoms, and treatment discontinuation are also discussed.. AD therapeutics provide benefits on measures of cognition, functioning, behavior, and global status even in the severe stages of AD. Combination therapy with memantine and ChEIs may provide additive benefits compared with ChEI monotherapy. Decisions regarding discontinuation of these medications should be made on a case-by-case basis, with some evidence suggesting that discontinuation may worsen cognition and functional impairment. It is recommended that patients entering the terminal stages of AD discontinue all medications not necessary for comfort.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Humans; Indans; Memantine; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Transdermal Patch

Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the

Topics: Adolescent; Adult; Alzheimer Disease; Biological Availability; Cholinesterase Inhibitors; Cognition; Delayed-Action Preparations; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Middle Aged; Nootropic Agents; Piperidines; Severity of Illness Index; Young Adult

For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Data Mining; Databases, Factual; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Exercise Therapy; Humans; Indans; Memantine; Piperidines; Species Specificity; Systems Biology; Systems Integration; Translational Research, Biomedical

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once-daily sustained-release 23-mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose-response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild-to-moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Male; Piperidines

Alzheimer's disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell-glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment.

Topics: Alzheimer Disease; Animals; Benzamides; Humans; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Thiazoles

The purpose of this systematic review was to review the current place in therapy of the 4 medications, donepezil, rivastigmine, galantamine, and memantine, approved for the treatment of Alzheimer disease (AD) since the publication of Phase III trials.. A systematic literature search of MEDLINE and EMBASE was conducted for articles published in the past 10 years. The search was performed using the following Medical Subject Headings and text key words: Alzheimer's disease, treatment, donepezil, galantamine, rivastigmine, memantine, dementia of the Alzheimer's type, and dementia.. Studies that evaluated new doses, indications, and dose formulations remain a large part of the current literature. Donepezil gained approval for the treatment of severe AD and became available in a 23-mg/d dose formulation. Rivastigmine became available in a patch formulation. Memantine became available as an extended-release capsule. Use of a combination product formulation was recently approved, memantine extended release/donepezil. Controversy among clinicians remains regarding when to initiate therapy, appropriate duration of therapy, and how and when to discontinue the treatment of AD.. Only drugs that affect cholinergic function have shown consistent, but modest, clinical effects, even in late-phase trials. There is a need for a better appreciation of the various risk factors and drug targets for the treatment of AD. The wide range of targets makes it unlikely that affecting only 1 of those targets (eg, cholinergic function or N-methyl-d-aspartate) will lead to a more than minimally effective treatment option, regardless of when a treatment is started and discontinued. There is substantial opportunity for the continued growth and development of drugs and clinical trial expansion for the treatment of AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials, Phase III as Topic; Donepezil; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Piperidines; Rivastigmine; Treatment Outcome

In this article, we review and repropose our hypothesis of the endogenous appearance of anticholinergic activity (AA) in Alzheimer's disease (AD). First, we introduce our previous articles and speculate that, because acetylcholine (ACh) regulates both cognitive function and inflammation, downregulation of this neurotransmitter causes upregulation of the inflammatory system. AA then appears endogenously with the production of cytokines and the downregulation of ACh in AD. To support our hypothesis, we present a female AD patient whose AA was considered to occur endogenously through her AD pathology. Her serum anticholinergic activity (SAA) was positive at her first visit to our memory clinic, was negative at the 1-year and 2-year follow-up visits, and had become positive again by 3 years. We speculate that the initial positive SAA was related to her AD pathology plus mental stress, and that her SAA at 3 years was related to her AD pathology only. Consequently, we believe that 2 patterns of SAA positivity (and therefore AA) exist. One occurs when the downregulation of ACh reaches a critical level, and the other occurs with the addition of some other factor such as medication, induced illness or mental stress that causes AA to affect AD pathology. Finally, we consider the pharmacotherapy of AD based on the proposed hypothesis and conclude that cholinesterase inhibitors can be used to prevent rapid disease progression, whereas N-methyl-D-aspartate receptor antagonists should be reserved for the treatment of AD that is already in a stage of rapid progression. We also propose a staging schema for patients with AD.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Cholinergic Antagonists; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Memantine; Piperidines

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Combinations; Humans; Indans; Memantine; Piperidines; Receptors, N-Methyl-D-Aspartate

Neuropsychiatric symptoms are common in Alzheimer's disease (AD) and other neurodegenerative disorders. Recent progress has been made with clinical trials, advancing new therapies for psychosis in Parkinson's disease (PD), agitation in AD, and apathy in AD. Definitions have emerged for agitation and apathy in patients with cognitive impairment, facilitating recruitment of clinical trial populations. Progress in clinical trial design and the agents being assessed promise to advance therapies for disabling symptoms and improve quality of life for patients and caregivers.

Topics: Alzheimer Disease; Apathy; Citalopram; Clinical Trials as Topic; Cognition Disorders; Humans; Mental Disorders; Piperidines; Research Design; Therapies, Investigational; Treatment Outcome; Urea

An 86-year-old man was admitted with a 3-day history of melaena and syncope. He was haemodynamically compromised and anaemic on presentation. His only medical history was mild Alzheimer's disease diagnosed 6 months prior. For this, he was on donepezil, a cholinesterase inhibitor (ChEI), with a recent dose increase 3 months earlier. After fluid resuscitation with packed red cells, an endoscopy was performed, which showed an acute duodenal ulcer. This was treated with a high-dose proton pump inhibitor. The patient recovered well and was discharged on donepezil with the addition of a gastro-protective proton pump inhibitor. In view of other absent risk factors of upper gastrointestinal haemorrhage, donepezil was the likely causative agent. ChEIs are associated with frequent side effects and increased hospitalisation due to central and peripheral increase in acetylcholine. With this case report, we review the literature of side effects related to ChEIs, where the mechanisms of action, complications and appropriate management are discussed.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Duodenal Ulcer; Endoscopy; Gastrointestinal Hemorrhage; Humans; Indans; Lansoprazole; Male; Piperidines; Proton Pump Inhibitors; Syncope

A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10 mg (Namzaric™) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28 mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil-treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents.

Topics: Alzheimer Disease; Clinical Trials, Phase III as Topic; Drug Combinations; Humans; Memantine; Nootropic Agents; Piperidines

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Models, Molecular; Molecular Structure; Piperidines

Alzheimer's disease (AD) is a neurological disorder and is the most frequent type of dementia among elderly people. Donepezil, rivastigmine, galantamine, tacrine and memantine are the US Food and Drug Administration approved oral drugs used in the treatment of AD. Quantitation of these drugs in various biological matrices and monitoring them in long-term treatment is essential to titer the dose of these drugs and ensure patient compliance. This review provides a comprehensive account of various HPLC and LC-MS/MS assays, which have been successfully employed to measure the drug levels in various biological matrices arising from preclinical and clinical studies. In addition, this review collates various considerations such as internal standard selection, extraction schemes, matrix effect, selectivity evaluation and optimization of mass spectrometric conditions to enable the development of sound bioanalytical methods for quantitation of Alzheimer's drugs. Overall LC-MS/MS methods have proven to be the choice of bioanalytical method for the quantification of Alzheimer's drugs in both preclinical and clinical studies. In conclusion, important features of LC-MS/MS methodology for Alzheimer's drugs include shortened analysis time, increased throughput, selectivity and lower cost of analysis.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Galantamine; Humans; Indans; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Tandem Mass Spectrometry

The role of currently available drugs for Alzheimer's disease (AD) has been controversial, with some national formularies restricting their use, and health economists questioning whether the small clinical effects are economically worthwhile.. To estimate the efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of AD.. Double-blind, placebo-controlled, with random assignment to a cholinesterase inhibitor or memantine trials were included into the pooled studies.. Cognitive effects were significant for all drugs, ranging from a -1.29 points mean difference (95% CI -2.30 to -0.28) in the 20 mg daily memantine trials to -3.20 points (95% CI -3.28 to -3.12) in the 32 mg daily galantamine group. Only memantine had no effect on the Clinicians' Global Impression of Change scale. No behavioral benefits were observed, except for -2.72 (95% CI -4.92 to -0.52) in the 10 mg daily donepezil group and -1.72 (95% CI -3.12 to -0.33) for 24 mg daily galantamine trial. Only 5 mg daily donepezil had no effect on the function outcome. Compared with placebo, more dropouts and adverse events occurred with the cholinesterase inhibitors, but not with memantine.. Cholinesterase inhibitors and memantine are able to stabilize or slow decline in cognition, function, behavior, and global change.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

To investigate whether there is a difference in the treatment effect of donepezil on cognition in Alzheimer disease between industry-funded and independent randomised controlled trials.. Fixed effects meta-analysis of standardised effects of donepezil on cognition as measured by the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive subscale.. Studies included in the meta-analyses reported in the National Institute for Health and Care Excellence (NICE) technical appraisal 217 updated with new studies through a PubMed search.. Inclusion criteria were double-blind, placebo-controlled trials of any length comparing patients diagnosed with probable Alzheimer disease (according to the NINCDS-ADRDA/DSM-III/IV criteria) taking any dosage of donepezil. Studies of combination therapies (eg, donepezil and memantine) were excluded, as were studies that enrolled patients with a diagnosis of Alzheimer disease associated with other disorders (eg, Parkinson's disease and Down's syndrome).. Our search strategy identified 14 relevant trials (4 independent) with suitable data. Trials sponsored by pharmaceutical companies reported a larger effect of donepezil on standardised cognitive tests than trials published by independent research groups (standardised mean difference (SMD)=0.46, 95% CI 0.37 to 0.55 vs SMD=0.33, 95% CI 0.18 to 0.48, respectively). This difference remained when only data representing change up to 12 weeks from baseline were analysed (industry SMD=0.44, 95% CI 0.34 to 0.53 vs independent SMD=0.35, 95% CI 0.18 to 0.52). Analysis revealed that the effect of funding as a moderator variable of study heterogeneity was not statistically significant at either time point.. The effect size of donepezil on cognition is larger in industry-funded than independent trials and this is not explained by the longer duration of industry-funded trials. The lack of a statistically significant moderator effect may indicate that the differences are due to chance, but may also result from lack of power.

Topics: Alzheimer Disease; Cognition; Donepezil; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Research Support as Topic; Treatment Outcome

Donepezil is a highly selective acetylcholinesterase inhibitor and one of the only four drugs currently approved for treatment of Alzheimer's dementia. Providing high bioavailability and a very long half-time, donepezil is regarded as effective and well tolerable in Alzheimer's disease patients, even in difficult clinical conditions such as hepatic or renal impairment. It moderately improves cognitive and global functioning scores in patients with mild to moderate Alzheimer's disease over the course of 6 - 12 months, with open-label extension studies suggesting effects of even longer duration.. We summarized relevant pharmacokinetic, pharmacodynamic, clinical trial and neuroimaging data of donepezil. A literature search was performed in the PubMed database; articles published until October 2013 have been considered for this review. Moreover, references from original work and reviews have been searched for further relevant literature.. Donepezil is one of the most frequently prescribed anti-dementia drugs. The recent additional approval of the 23 mg formulation will expand its use in patients with moderate to severe Alzheimer's disease. After numerous Phase III study failures of novel disease-modifying drugs for Alzheimer's disease, donepezil is likely going to stay a first-line therapeutic option in Alzheimer's disease in the upcoming years.

Topics: Alzheimer Disease; Animals; Biological Availability; Cholinesterase Inhibitors; Donepezil; Half-Life; Humans; Indans; Piperidines; Severity of Illness Index; Time Factors; Treatment Outcome

We herein report an 81-year-old woman with Alzheimer's disease (AD) in who donepezil, a cholinesterase inhibitor (ChEI), caused cervical dystonia. The patient had a two-year history of progressive memory disturbance fulfilling the NINCDS-ADRDA criteria for probable AD. Mini-Mental State Examination score was 19/30. The remaining examination was normal. After a single administration of donepezil (5 mg/day) for 10 months, she complained of dropped head. Neurological examination and electrophysiological studies supported a diagnosis of cervical dystonia. Antecollis disappeared completely at 6 weeks after cessation of donepezil. Dystonic posture can occur at various timings of ChEI use. Physicians should pay more attention to rapidly progressive cervical dystonia in ChEI-treated AD patients.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dystonia; Female; Humans; Indans; Piperidines; Postural Balance

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cholinesterase Inhibitors; Cognitive Dysfunction; Dementia; Disease Progression; Donepezil; Education, Medical, Continuing; Galantamine; Humans; Indans; Lewy Body Disease; Nootropic Agents; Peptide Fragments; Phenylcarbamates; Piperidines; Positron-Emission Tomography; Reference Standards; Rivastigmine; tau Proteins; Tomography, Emission-Computed, Single-Photon

Studies have examined the effects of anti-dementia drugs on gait performance. No structured critical evaluation of these studies has been done so far. The objectives of this study were (1) to perform a qualitative analysis of all published studies on changes in stride time variability (STV) with anti-dementia drugs among patients with Alzheimer disease through a systematic review, and (2) to quantitatively synthesize anti-dementia drug-related changes in STV.. An English and French MEDLINE search was conducted on November 2013, with no limit of date, using the Medical Subject Headings term "pharmaceutical preparations" combined with "delirium", "dementia", "amnestic", "cognitive disorders" AND "gait" OR "gait disorders, neurologic" OR "gait apraxia". Fixed-effects meta-analyses were performed to compare STV before and after the use of anti-dementia drugs, and to compare the final STV among participants in intervention and control groups.. Of the 110 originally identified abstracts, four studies (i.e., one assessing galantamine, one donepezil, one memantine, and one memantine and acetylcholinesterase inhibitors) were included in the qualitative review, and three studies in the quantitative synthesis. Results were mixed, as two studies showed significant between-visit improvements (i.e., decrease in mean value) in STV, while one study did not, and the last one reported mixed results. In the meta-analysis, there was no difference between intervention and control groups (summary mean difference of final STV = -0.38 % [95 % confidence interval -1.14 to 0.37]) and no before-after difference in the intervention group (summary mean difference of STV = 0.66 [95 % confidence interval -0.17 to 1.49]).. Our findings showed inconclusive effects of anti-dementia drugs on STV.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Gait; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Piperidines

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cholinesterase Inhibitors; Donepezil; Drug Discovery; Galantamine; Humans; Indans; Magnetic Resonance Imaging; Memantine; Neurofibrillary Tangles; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Tomography, Emission-Computed, Single-Photon

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Topics: Aging; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Pharmacogenetics; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine

Randomized clinical trials have evaluated the efficacy of acetylcholinesterase inhibitors (AChE-Is) and memantine across a wide range of Alzheimer's disease (AD) severity. However, these drugs are prescribed and reimbursed according to precise upper and lower cut off scores of cognitive tests.. To verify whether the efficacy of pharmacological treatment had any dependence on the severity of dementia in AD patients.. Published English-language randomized, placebo-controlled trials evaluating the efficacy of AChE-Is or memantine at any dose, over any length of time, in patients with any severity of dementia due to AD were included. Cognitive, behavioral, and functional outcomes were extracted from each study and multiple outcomes from the same trial were pooled to obtain a unique indicator of efficacy for cognition, functional impairment, and behavioral and psychological disturbances. The existence of a relationship between size of the treatment effect and severity of dementia, measured with the Mini-Mental State Examination, was determined using parametric and non-parametric correlation analyses.. Both AChE-Is and memantine had significant effects on cognition. Functional and psycho-behavioral outcomes were reported less frequently but also showed significant efficacy of treatment. High heterogeneity among studies was found within and between the different drugs. The efficacy of all drugs except memantine was independent from dementia severity in all domains. Memantine effect on functional impairment was better in more severe patients.. The modest beneficial effects of anti-dementia drugs on cognition are independent from dementia severity. Memantine is more effective on functional incompetence only in severe patients.

Topics: Aged; Alzheimer Disease; Behavior; Cholinesterase Inhibitors; Cognition; Data Interpretation, Statistical; Disability Evaluation; Disease Progression; Donepezil; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

To provide healthcare professionals with a comprehensive assessment of donepezil 23 mg and its role in treating Alzheimer's disease (AD), the Donepezil 23 mg Expert Working Group (EWG) convened in June 2011 to critically evaluate the clinical trial database for this higher dose formulation and the members' clinical experience with its use. Discussions were based on a large, 6-month, phase 3 clinical trial in patients with moderate to severe AD that compared continuing donepezil 10 mg/day versus switching to 23 mg/day. In this trial, donepezil 23 mg/day demonstrated significantly greater cognitive benefits (mean change in Severe Impairment Battery score, 2.11 points; P < 0.001). Prespecified analyses showed that benefits were significant irrespective of concomitant memantine use. The EWG considered integrating these new data into clinical practice approaches. Dementia severity, tolerability of the 10 mg dose, and need for additional therapy were key selection criteria, as was monitoring of gastrointestinal side effects, as consideration of titration strategies is an important aspect of implementation. The EWG concluded that donepezil 23 mg is an efficacious therapy for moderate to severe AD, with or without concomitant memantine, extending the treatment opportunities available to manage moderate to severe AD dementia. EWG guidelines offer assistance to clinicians in choosing and implementing treatment options.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Patient Selection; Piperidines; Practice Guidelines as Topic

Topics: Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nitric Oxide; Piperidines; Stimulation, Chemical; Vasodilation

Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Communication Disorders; Donepezil; Galantamine; Humans; Indans; Outcome Assessment, Health Care; Phenylcarbamates; Piperidines; Rivastigmine

At present, there may be over 210,000 people with Down syndrome (DS) over the age of 55 in the United States (US) who have significant needs for augmented services due to circumstances related to ordinary and/or pathological aging. From 1979 through 2003, the birth prevalence of DS rose from 9.0 to 11.8 (31.1%) per 10,000 live births in 10 representative US regions. This increase, largely due to women conceiving after age 35, portends an ever-growing population of people with DS who may be subject to pathogenic aging. Whereas Trisomy 21 is one of the most widespread genetic causes of intellectual disability (ID), it still is one of the least understood of all genetic ID syndromes. While longevity in people with DS has improved appreciably in as modest a period as 30 years, age-specific risk for mortality still is considerably increased compared both with other people with ID or with the typically developing population. The penetrance of the phenotype is widely distributed, even though a consistent genotype is assumed in 95% of the cases. Some, but not all body systems, exhibit signs of premature or accelerated aging. This may be due to both genetic and epigenetic inheritance. We now know that the long-term outcome for people with DS is not as ominous as once contemplated; a number of people with DS are living into their late 60s and 70s with few if any major signs of pathogenic aging. Alzheimer's disease (AD), a devastating disease that robs a person of their memory, abilities and personality, is particularly common in elder adults with DS, but is not a certainty as originally thought, some 20% to 30% of elder adults with DS might never show any, or at most mild signs of AD. DS has been called a mature well-understood syndrome, not in need of further research or science funding. We are only beginning to understand how epigenetics affects the phenotype and it may be feasible in the future to alter the phenotype through epigenetic interventions. This chapter is divided into two sections. The first section will review typical and atypical aging patterns in somatic issues in elder adults with DS; the second section will review the multifaceted relationship between AD and DS.

Topics: Adult; Aging; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Female; Humans; Incidence; Indans; Intellectual Disability; Male; Metabolic Syndrome; Middle Aged; Nootropic Agents; Oxidative Stress; Peptide Fragments; Phenotype; Piperidines; Prevalence; Telomere Shortening; Treatment Outcome; United States

Topics: Alzheimer Disease; Dementia, Vascular; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Treatment Outcome

The drugs currently available for the treatment of Alzheimer's disease and other dementias can provide limited symptomatic improvement. The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA-receptor antagonist memantine have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior in patients with disease severity ranging from mild to severe. Among the acetylcholinesterase inhibitors, transdermal rivastigmine causes fewer gastrointestinal side effects than the oral formulation. Whether adding memantine to an acetylcholinesterase inhibitor is more effective than an acetylcholinesterase inhibitor alone remains to be established; clinical trial results have been mixed. None of these agents have been shown to stop or reverse the underlying neurodegenerative process.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Rivastigmine

Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage.. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD.. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007-2012.. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of "adequacy and representativeness." Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24-52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Memantine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Numerous approaches have been explored to treat individuals with Alzheimer's disease (AD). General approaches include the following treatment; treatment of cognitive symptoms, slowing decline, delaying onset of disease, and primary prevention. 2011 is the new era for the drug therapy for AD in Japan, because three anti-dementia drugs, galantamine, rivastigmine and memantine, were admitted to use for AD in addition to donepezil. Donepezil, galantamine and rivastigmine has been developed based on cholinergic hypothesis that acetylcholine (ACh) acts a chief neurotransmitter as a cognitive neurotransmitter. Donepezil a specific acetylcholinesterase inhibitor (AChEI). Galantamine acts as an allosteric potentiating ligand of nicotinic acetylcholine receptors in addition to the function of AChEI. Rivastigmine increase acetylcholine in the cholinergic synapse by inhibition of both AChE and butyrylcholinesterase. Recent study shows that these anti-dementia drugs afford symptomatic effect and also act as disease-modifiers which inhibit neuronal death and abnormal amyloid-beta deposition. These effects can slow the rate of decline of the disease. While in the past many of our attempts have been to treat secondary symptoms or improve the cognitive deficits, future attempts are likely to focus on slowing the rate of decline, delaying the onset of appearance, or preventing the disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinergic Neurons; Cholinesterase Inhibitors; Donepezil; Drug Discovery; Galantamine; Humans; Indans; Molecular Targeted Therapy; Neuroprostanes; Phenylcarbamates; Piperidines; Rivastigmine

Randomized controlled trials (RCTs) provide safety and efficacy data for regulatory approval of antidementia drugs, but offer limited data regarding real-world effectiveness. Long-term observational controlled studies (LTOCs) extend our understanding by providing longitudinal data across multiple stages of Alzheimer's disease (AD).. Comparisons of strengths, limitations, evidence level, and results for monotherapy (cholinesterase inhibitors) and combination therapy (cholinesterase inhibitors + memantine) in RCTs versus LTOCs were made.. Similar to RCTs, LTOCs have shown that both monotherapy and combination therapy are associated with slower cognitive and functional decline. Combination therapy is associated with better cognitive outcomes and greater delays in time to nursing home admission versus monotherapy or no treatment. Persistent antidementia drug treatment is associated with slower decline in cognition, daily function, and global severity, even in patients with advanced disease.. LTOCs provide complementary evidence regarding effectiveness of antidementia therapy over many years, a time course relevant to AD management. These findings also provide compelling arguments in favor of using LTOCs to estimate effectiveness, risk-benefit, and costs of AD treatments.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Dopamine Agents; Evidence-Based Medicine; Humans; Indans; Memantine; Nootropic Agents; Piperidines; Prevalence; Randomized Controlled Trials as Topic

Clinical studies and post hoc analyses have investigated the use of combination therapy for the treatment of Alzheimer's disease (AD). We review the evidence for the short- and long-term efficacy of combination therapy in AD.. The review is based on a search of the PubMed database to identify relevant articles concerning combination treatment with memantine and cholinesterase inhibitors (ChEIs).. In patients with moderate-to-severe AD, combination treatment with the N-methyl-d-aspartate receptor antagonist memantine and the ChEI donepezil has produced significant benefits in cognition, function, behavior, global outcome, and care dependency, compared with donepezil treatment alone. Data from long-term observational studies support these findings. Compared with ChEI monotherapy, combination treatment slowed cognitive and functional decline (a 4-year sustained effect that appeared to increase over time) and reduced the risk of nursing home admission. Preclinically, the combination of N-methyl-d-aspartate receptor modulation and acetylcholinesterase inhibition has been shown to act synergistically, which may explain the observed clinical effects of combination treatment.. Treatment with memantine/ChEI combination therapy in moderate-to-severe AD produces consistent benefits that appear to increase over time, and that are beyond those of ChEI treatment alone.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Drug Therapy, Combination; Humans; Indans; Memantine; Piperidines; Severity of Illness Index; Treatment Outcome

Donepezil is the first cholinesterase inhibitor widely used for the treatment of Alzheimer's disease (AD). Its pharmacological actions are straightforward, enhancing cholinergic activity both in the brain and systemically, with a long-enough half-life to allow for once a day dosing. Its efficacy has been approved for use in mild-to-moderate AD stage for improvement of symptoms for 10 years, and now it is also approved for use in severe stage.. This review article will offer a 10-year perspective on the use of donepezil in clinical practice against AD and related disorders. In addition to discussing the information from randomized clinical trials and from the drug monograph, this article will seek to facilitate the clinical development and clinical use of the next generation of drugs for AD.. Adjustments about expectations and safe use of donepezil were made over time based on such clinical experiences. Offering a cholinesterase inhibitor to patients with mild-to-moderate AD clearly showed advantages. If well tolerated, donepezil should be continued in the severe stages of AD as long as the patient appears to benefit from a slower clinical decline.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Drug Design; Half-Life; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Severity of Illness Index

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

Topics: Alzheimer Disease; Clinical Trials as Topic; Donepezil; Drug Discovery; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Neuroprotective Agents; Phenylcarbamates; Piperidines; Plaque, Amyloid; Rivastigmine; tau Proteins

Donepezil is a reversible, non-competitive piperidine-type acetylcholinesterase inhibitor (AChEI) that is structurally unique compared with other currently available AChEIs. It was developed as a symptomatic treatment to compensate for the progressive loss of cholinergic signal between neurons, a consequence of neuronal cell loss in the brains of patients with Alzheimer's disease (AD). Clinical trials conducted over the 15 years since the drug was first licensed and available for use in patients with mild to moderate AD (1997) have shown that donepezil is efficacious and well tolerated at all stages of AD, from patients with mild or moderate impairment to those with severe disease. The published literature contains nearly 2000 papers on donepezil, and more than 200 of these articles relate to randomized controlled clinical trials. Trials in patients with mild cognitive impairment (MCI) failed to meet all of their primary objectives, but provided insights into patient selection and the design of trials. Overall, more than a decade of donepezil research has gradually changed attitudes toward therapy of AD from a general belief that no clinically useful treatment exists to the present day understanding that symptomatic therapy may be effective across the spectrum of dementia stages.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

In randomized clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with the placebo group. Patients who receive placebo treatment report a high frequency of AEs, but little is understood about the nature of these. No study has yet analyzed the level of cognitive impairment as a crucial aspect for the AEs reported by patients.. The rates of AEs reported by patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the placebo arms of donepezil trials were compared using a systematic review approach. PubMed was searched with the terms "MCI and donepezil" as well as "AD and donepezil" from January 1989 to December 2010. Nineteen studies fulfilled the selection criteria (3 MCI, n = 783; 16 AD, n = 2,059).. An overall comparison of 81 categories of AEs in the placebo arm of MCI versus AD trials showed that patients in AD trials experienced a significantly higher number of AEs than patients in MCI trials (p < 0.001).. This is the first study showing that AD patients may be at a greater risk of developing AEs than MCI patients. This may be related to a greater presence of somatic comorbidity predisposing them to express emotional distress as physical symptoms and/or to AD patients being frailer and therefore more susceptible to AEs. The phenomena we observed may be interpreted in terms of the "nocebo effect".

Topics: Aged; Alzheimer Disease; Cognitive Dysfunction; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Placebos; Randomized Controlled Trials as Topic

In this work we consider marketed drugs for Alzheimer disease (AD) including acetylcholinesterase inhibitors (AChE-Is) and antiglutamatergic treatment involving the N-methyl-d-aspartate (NMDA) receptor. We discuss medications and substances available for use as cognitive enhancers that are not approved for AD or cognitive impairment, and other neurotransmitter-related therapies in development or currently being researched. We also review putative therapies that aim to slow disease progression by mechanisms not directly related to amyloid or tau.

Topics: Alkaloids; Alzheimer Disease; Amino Acids; Animals; Cholinesterase Inhibitors; Dietary Supplements; Disease Progression; Docosahexaenoic Acids; Donepezil; Drug Approval; Galantamine; Ginkgo biloba; Half-Life; History, 20th Century; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Psychotropic Drugs; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Sesquiterpenes; Vitamin B Complex; Vitamin E

Alzheimer's disease (AD) is common among the elderly; it is responsible for 60-80% of all dementia cases. AD is characterized by cognitive decline, behavioural and psychological symptoms, and reductions in functioning and independence. Because of its progressive neurodegenerative nature and unknown aetiology, the burden of AD becomes increasingly significant in an aging population. Estimates indicate that 35.6 million people worldwide suffered from AD in 2010. By 2030 and 2050, this figure is predicted to increase to 65.7 million and 115.4 million, respectively. Costs will also rise along with the increase in the number of people diagnosed with AD. In 2010, the worldwide costs associated with dementia were estimated to be $US604 billion.. The objective of this study was to conduct a systematic review of current publications dealing with the pharmacoeconomic factors associated with AD medications and to describe the decision-analytic models used to evaluate long-term outcomes.. A systematic literature search was performed to identify articles published between 1 January 2007 and 15 July 2010. The search was also based on a previous systematic review, which included literature up to 2007. Articles were included if they were complete and original economic evaluations of AD and if they were comparative in nature. A quality assessment of the included publications was conducted and relevant information was extracted into tables.. Seven out of 2067 identified articles were included in this systematic review. Four articles evaluated treatment with donepezil, one with galantamine and two with memantine. The studies were conducted in America, Europe and Asia. Five different groups of medications were compared. The incremental cost-effectiveness ratios (ICERs) for the group of patients treated with donepezil versus no drug treatment ranged from a dominant value to 281, 416.13 euros per quality-adjusted life-year (QALY). Patients treated with donepezil versus placebo showed ICERs with a range from a dominant value (not specified) up to 20, 866.77 euros per QALY. Treatment with memantine in addition to donepezil versus treatment with donepezil alone showed an ICER range from a dominant value to 6818.33 euros per QALY. In comparison with the memantine treatment as an add-on therapy, the ICER of memantine monotherapy versus standard care (without cholinesterase inhibitors [CEIs]) ranged from a dominant value to 63, 087.20 euros per QALY. Finally, the economic evaluation of galantamine in comparison with usual care without any AD drugs showed ICERs ranging from 1894.70 euros to 6953 euros per QALY.. The seven identified publications included in this review indicate that treatment with CEIs or memantine seems to be reasonable in terms of clinical effects and costs for patients with AD. Depending on different hypotheses, assumptions and variables (e.g. time horizon, discount rates, initial number of patients in different states, etc.) in the sensitivity analyses, treatment with these drugs seems to be primarily a cost-effective strategy or even a cost-saving strategy. Nevertheless, the results generally are associated with a degree of uncertainty. The comparability of the results from the different economic evaluations is limited because of the different assumptions made.

Topics: Alzheimer Disease; Cost-Benefit Analysis; Donepezil; Dopamine Agents; Drug Costs; Economics, Pharmaceutical; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Piperidines; Quality-Adjusted Life Years

Topics: Alzheimer Disease; Animals; Asthma; Dermatitis, Atopic; Drug Design; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Leukodystrophy, Globoid Cell; Lipocalins; Muscular Dystrophies; Niacinamide; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyrimidines; Rhinitis, Allergic, Perennial; Spinal Cord Injuries; Thiazoles

Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK.. Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009).. Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects.. The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE).. mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities.. Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY.. Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters.. The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Dopamine Agents; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Models, Economic; Phenylcarbamates; Piperidines; Rivastigmine; Technology Assessment, Biomedical

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly. An estimated 5.4 million people in the United States have AD, and its prevalence is expected to increase rapidly in the coming years. Few US Food and Drug Administration (FDA)-approved treatment options for AD are currently available. Donepezil is 1 of only 2 therapies approved in the United States for the treatment of moderate-to-severe AD. In 2010, the FDA approved a higher daily dose of donepezil (23 mg/day) for the treatment of AD in the moderate-to-severe stages based on positive results from a large, global, phase 3 clinical trial that compared switching to donepezil 23 mg/day with continuing treatment with donepezil 10 mg/day. In that trial, no benefit was seen in the co-primary endpoint of global functioning; however, donepezil 23 mg/day provided a small but significant improvement in the cognitive endpoint compared with donepezil 10 mg/day. A subgroup analysis subsequently showed that the cognitive benefits were significant irrespective of concomitant memantine use. Adverse events were mainly gastrointestinal related and were more prevalent in patients receiving the donepezil 23-mg/day dose during the first month of therapy, but were relatively infrequent thereafter. These data indicate that once-daily donepezil 23 mg may be an effective treatment option for patients with moderate-to-severe AD with or without concomitant memantine. This article reviews the rationale for using higher-dose donepezil, the clinical data supporting its use, and some of the practical implications that should be considered by practicing physicians when using donepezil 23 mg/day for patients with AD.

Topics: Alzheimer Disease; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Cholinesterase inhibitors (ChEIs) represent the mainstay of symptomatic treatment in Alzheimer's disease. Three medications belonging to this class are presently widely available. These agents differ in their individual mechanisms of action and pharmacokinetic properties. Switching ChEIs can be a reasonable option in cases of intolerance or lack of clinical benefit.. A systematic literature search of switching ChEIs was conducted, and all studies specifically evaluating this issue were identified. Published consensus guidelines were also searched for recommendations on ChEI switching.. Eight clinical studies are summarized and discussed. All of these studies are open-label or retrospective and they cannot be readily compared because of heterogeneity in design, number of patients, agents used, and endpoints. Switching in most of these studies was done for both "lack of benefit" or "loss of response" after up to 29 months of treatment. Nevertheless, the majority of studies did not include individuals switched for lack of response after several years of treatment. Lack of satisfactory response or intolerance with the initial agent was not predictive of similar results with the second agent.. In light of these findings, we propose the following practical approach to switching ChEIs: (1) in the case of intolerance, switching to a second agent should be done only after the complete resolution of side-effects following discontinuation of the initial agent; (2) in the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter; (3) switching ChEIs is not recommended in individuals who show loss of benefit several years after initiation of treatment.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Practice Guidelines as Topic; Rivastigmine; Treatment Outcome

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

Topics: Acetylcholine; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Delayed-Action Preparations; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Nerve Degeneration; Piperidines; Severity of Illness Index

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Continuity of Patient Care; Donepezil; Humans; Indans; Memantine; Piperidines; Randomized Controlled Trials as Topic

To assess the effects of pharmacological and non-pharmacological interventions on activities of daily living in dementia and the heterogeneity of the applied measurement instruments.. Four Health Technology Assessments (HTA) on dementia are summarized regarding to effects on activities of daily living. These HTA assessed RCTs on ACE-inhibitors, Memantin, Ginkgo and non-pharmacological interventions according to Cochrane standards. An overview over the domains of activities of daily living covered by the applied assessment instruments is provided.. The analysis of 40 RCTs revealed indications of a beneficial effect of Donepezil, small positive effects of Galantamin, Rivastigmin and Memantin, positive effects of caregiver training in only one of five RCTs and no beneficial effects in seven RCTs on validation and reminiscence therapy, cognitive training procedures or activity-based interventions.. The studies demonstrated a very heterogeneous methodological quality with regard to assessment instruments, measurement time points and report of study design and results. Harmonisation in research methods is imperative and further elaborated RCTs must be conducted.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Angiotensin-Converting Enzyme Inhibitors; Caregivers; Donepezil; Galantamine; Geriatric Assessment; Ginkgo biloba; Humans; Indans; Institutionalization; Memantine; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Plant Extracts; Randomized Controlled Trials as Topic; Rivastigmine

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Acetylcholinesterase inhibitors or NMDA glutamate receptor antagonists are currently used for the treatment of AD, but only the former have weak beneficial effects on cognitive function.. The aim of this review is to provide an overview of the main pharmacological features of both current drugs and new compounds which are still under clinical development for the treatment of AD.. The discovery of new drugs acting at the early stage of AD could be considered as a 'medical need' and inhibitors of γ-secretase or monoclonal antibodies against Aβ seemed good options. However, inhibitors of γ-secretase, that is, tarenflurbil or semagacestat, were discontinued due to their lack of cognitive improvement or unacceptable side effects. A careful evaluation of the risk:benefit ratio should be considered for monoclonal antibodies since, by increasing the disaggregation of fibrillar amyloid-β-peptide (Aβ), they could increase the neurotoxicity of soluble Aβ oligomers. In conclusion, the discovery of new drugs efficacious in AD subjects is an ambitious goal, however, and one that will require close, active collaboration by pharmacologists, chemists and clinicians.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Humans; Indans; Memantine; Neurons; Oxidative Stress; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Rivastigmine

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Discovery; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Japan; Memantine; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

The term 'dementia' encompasses a number of neurodegenerative diseases of which Alzheimer's disease (AD) is the most common. Prior to 2003, cholinesterase inhibitors, such as donezepil, were the only class of drugs approved to treat mild-to-moderate AD. In 2003, memantine became the first drug approved by the US FDA to treat moderate-to-severe AD. Currently, both memantine and donepezil are FDA approved for the treatment of moderate-to-severe AD. This article examines the pharmacologic profile of memantine, evidence for memantine's efficacy in moderate-to-severe AD and other dementias, its novel use in other neuropsychiatric disorders and future implications and research directions for memantine.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Dopamine Agents; Humans; Indans; Memantine; Neurodegenerative Diseases; Piperidines

To review the different pharmacological approaches to the cognitive, functional, and behavioural manifestations of Alzheimer disease (AD).. We searched and critically analyzed the most recent relevant literature on pharmacological treatment of AD.. The current pharmacological approach to AD treatment is based on vascular prevention and symptomatic therapy with cholinesterase inhibitors (ChEIs) and memantine, an N-methyl-d-aspartic acid antagonist. Clinical trials of 6- to 12-month duration have shown statistically significant benefits with ChEIs and memantine on cognitive, global, functional, and behavioural outcome measures. In general, these benefits are modest. However, they are dose-dependent and reproducible across studies. Most importantly, these benefits are symptomatic as they do not alter disease course. According to the third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, these agents are considered standard treatment options in AD. We will discuss practical issues related to current pharmacological management, such as setting realistic expectations, management of side effects, switching ChEIs, and the decision to discontinue treatment. The results of clinical trials studying potentially disease-modifying approaches in AD will also be reviewed. Unfortunately, although there remains much promise and enthusiasm, none of these agents has shown consistent benefits, and none are available for use in clinical practice.. Pharmacological options are presently available for the symptomatic treatment of AD. These treatments provide mild but sustained benefits. Before disease-modifying approaches become available, optimizing the use of the available treatment options is crucial.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Galantamine; Humans; Indans; Memantine; Neuroprotective Agents; Neuropsychological Tests; Piperidines

Alzheimer's dementia represents organ failure of the brain. It denotes a clinical milestone that is the result of a pathological process, Alzheimer's disease (AD), which over 1 or more decades has wrought insidious destruction, and finally overwhelmed the brain's capacities to compensate. It is incurable, progressive, and follows an individual pace and course. AD is particularly demanding and devastating to family and caregivers, and patients, all of whom suffer psychologically and emotionally. The cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl- D-aspartate receptor antagonist memantine are approved by the US Food and Drug Administration for AD; they are often used in combination once the disease reaches moderate stages. The relatively good safety profile of these medications, along with their efficacy in alleviating symptoms, is supported by several level-I evidence-grade, short-term, randomized, placebo-controlled trials (RCTs). However, these studies are of limited value in assessing the real-world clinical and economic impact of AD therapies. Long-term, observational studies can provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points. There is now accumulating and convergent evidence from short- and long-term RCTs, longer-term open-label extensions of RCTs, and long-term observational studies that ChEIs and memantine reduce decline in cognition and daily function, and delay nursing home placement. Optimal care in AD is multifactorial; it includes early diagnosis and multidisciplinary care with educational and nonpharmacological interventions, while ensuring safety, treating comorbidities, caring for caregivers, and appropriate initiation and maintenance of combination therapy.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Dementia; Disease Progression; Donepezil; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Time Factors; Treatment Outcome

Every 69 seconds, a person in the United States develops Alzheimer's disease (AD). By 2050, this rate is expected to double. Total direct costs of AD and dementia (AD/D) are estimated at $183 billion, and are expected to increase to $1.1 trillion by 2050. In 2010, unpaid care was valued at an estimated $202 billion. Caregivers of patients with AD are usually family members, and provide up to 70 hours of care per week. By delaying institutionalization of an AD patient, a savings of $2029 per month in direct healthcare costs could be realized; therefore, caregiver support is a significant factor in controlling costs. It is important for those with AD/D to have prescription plans that optimize access to AD/D therapies. Among older adults who previously did not have prescription coverage, 80% are now enrolled in Medicare Part D. Three preferred AD/D agents (donepezil, extended release galantamine hydrochloride, and memantine hydrochloride) have been identified by an expert panel. It is important, given the clinical course of AD, especially with progression to moderate-to-severe disease, that physicians continue to have access to preferred medications as demonstrated through evidence-based clinical evaluations. Many Medicare Part D beneficiaries are subject to a gap in prescription coverage known as the "donut hole," including 64% of patients with AD. Because of the increased out-of-pocket expenditures associated with this coverage gap, some patients stop taking their medication completely or reduce medication use. It is critical to avoid lapses in maintenance therapy, as functional and cognitive abilities cannot be regained. Numerous clinical trials have demonstrated the pharmacoeconomic benefits of appropriate and preferred AD therapies; greater therapeutic availability may lead to better adherence and therefore improved outcomes.

Topics: Age Factors; Aging; Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Galantamine; Health Care Costs; Health Expenditures; Humans; Indans; Medicare; Medicare Part D; Memantine; Piperidines; Psychometrics; United States

Oral cholinesterase inhibitors (ChEIs) are associated with side effects such as nausea and vomiting. The use of transdermal patches for ChEI delivery may help to minimize these problems. The objective of this review was to consider available data from patients switching from oral ChEIs to transdermal rivastigmine treatment, and to suggest practical guidelines for patients wishing to do this. Literature database and reference list searches were performed to identify suitable publications. Data from two clinical trials and a series of open observational studies, in which patients were switched to the rivastigmine patch from oral rivastigmine, donepezil tablets, or galantamine, were evaluated. Adverse events were tabulated. In the studies reported here, nausea was reported in up to 3.2% and vomiting in up to 1.9% of patients switching to the rivastigmine patch from oral rivastigmine. Similar rates (up to 3.8% of patients for nausea and 0.8% of patients for vomiting) were reported when switching to the rivastigmine patch from donepezil tablets, and no nausea or vomiting was reported in a case study of patients switching to the rivastigmine patch from galantamine tablets. Switching regimes used in clinical trials appeared well tolerated. Data support recommendations for patients on high rivastigmine capsule doses to switch directly to the 9.5 mg/24 h rivastigmine patch, while those on lower oral rivastigmine doses should start on the 4.6 mg/24 h patch for 4 weeks before increasing to the 9.5 mg/24 h patch. This latter regimen is recommended for patients on other oral cholinesterase inhibitors if switching is medically indicated or requested by the patient or the caregiver.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Databases, Factual; Donepezil; Female; Humans; Indans; Male; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Rivastigmine

This review describes on comprehensive care for persons with Down syndrome especially in adulthood. Down syndrome is probably believed too special and therefore many clinicians seems to hesitate to attend them or scare to give wrong treatment. Quite a few psychiatrists make diagnoses of psychiatric diseases instead of behavior problems due to environmental effects and give inappropriate and/or unnecessary medication. Special care is needed on (1) muscle hypotonia, (2) characteristic mental development and developmental retardation, and (3) various complications. Complications are not too special and treatment is similar to common diseases. Persons with Down syndrome have many excellences, but maltreatment and/or environment without normalization may lead them psychiatric disorders.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Child; Comprehensive Health Care; Continuity of Patient Care; Counseling; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Psychomotor Disorders; Young Adult

To compare the safety and tolerability of switching patients with mild-to-moderate Alzheimer's disease from donepezil to either rivastigmine capsule or transdermal patch.. Three studies investigated the switch from donepezil to rivastigmine; study US13 was a 26-week, single-arm, immediate-switch study; US18 was a 26-week, sequential cohort study (both studies evaluated rivastigmine capsules 3-12 mg/day); study US38 was a 25-week, randomised, parallel-group, open-label study which investigated switch (immediate or after 7 days' withdrawal) from donepezil to rivastigmine transdermal patch (4.6 mg/24 hr). Safety outcomes included adverse events (AEs), discontinuations caused by AEs and serious AEs (SAEs).. Patient groups receiving rivastigmine patch (n = 261) or capsules (n = 331) had mean +/- SD ages of 77.3 +/- 8.0 and 78.1 +/- 7.8 years, dementia durations of 3.9 +/- 2.6 and 3.6 +/- 2.2 years and Mini-Mental State Examination scores of 18.3 +/- 4.00 and 17.9 +/- 4.4 respectively. Overall, 184 (70.5%) and 276 (83.4%) patients experienced at least one AE, and 23 (8.8%) and 55 (16.6%) patients experienced an SAE with the rivastigmine patch and capsules respectively. Of the patients who experienced an AE, 10 (3.8%) and 109 (32.9%) experienced nausea, and 11 (4.2%) and 80 (24.1%) experienced vomiting with the rivastigmine patch and capsules respectively. Discontinuations because of AEs occurred in 64 (19.3%) patients receiving capsules and 38 (14.6%) patients in the transdermal patch group. The most common reasons for discontinuation with the transdermal patch were application site reaction and disease progression, and nausea and vomiting with the capsules.. The rivastigmine transdermal patch appears to have better tolerability than rivastigmine capsules, with fewer gastrointestinal AEs and discontinuations because of these AEs. Simple daily rotation of patch location will likely reduce the frequency of skin reactions. This post hoc analysis was carried out by Novartis Pharmaceuticals Corporation. Data for the analysis were collected from the US13 study (CENA713B US13), the US18 study (CENA713B US18) and the US38 study (CENA713D US38).

Topics: Administration, Cutaneous; Administration, Oral; Aged; Alzheimer Disease; Blood Pressure; Capsules; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Phenylcarbamates; Piperidines; Pulse; Randomized Controlled Trials as Topic; Respiration; Rivastigmine

In the brain of Alzheimer's patients, the cholinergic neurons innervated the hippocampus and cerebral cortex degenerates before accumulation of beta-amyloid protein. Donepezil, a potent acetylcholinesterase (AChE) inhibitor is reported to rescue neurons from excitotoxic injury in culture. However, there is no evidence to confirm its neuroprotective effect on ACh neurons in vivo. Using olfactory bulbectomy (OBX) mice, we defined the neuroprotective mechanisms of donepezil on the medial septum cholinergic neurons with concomitant improvement of the impaired cognitive function. Bilateral olfactory bulbs of DDY mouse were removed by surgery. After olfactory bulbectomized (OBX), donepezil (1 or 3 mg/kg/day) was administered for 15 days and mouse brain was fixed with paraformaldehyde perfusion at day 18. Then, the neuroprotective effect of donepezil was evaluated by counting the number of Chdine acetyltrans-ferase (ChAT) immunoreactive neurons in the medial septum. The number of ChAT immunoreactive neurons in the medial septum reduced by 40% of that in sham-operated animals. The reduced ChAT positive neurons were restored by donepezil treatments. Consistent with these observations, the cognitive deficits observed in OBX mice were significantly improved by the donepezil treatment. Taken together, donepezil treatment rescues the cholinergic neurons in the medial septum from the neurodegeneration by OBX. We will also discuss the mechanism underlying the donepezil-induced neuroprotection in the medial septum cholinergic neurons.

Topics: Alzheimer Disease; Animals; Choline O-Acetyltransferase; Cholinergic Fibers; Cholinesterase Inhibitors; Donepezil; Hippocampus; Humans; Indans; Mice; Neurogenesis; Neurons; Neuroprotective Agents; Nootropic Agents; Olfactory Bulb; Piperidines; Septal Nuclei

We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in patients with AD.. Based on pre-specified criteria, six studies were selected from among all donepezil clinical trials in AD. Individual items from nine ADL scales used in these trials were mapped to a standardized functional scale comprising 12 domains (six basic, six instrumental); scores were transformed to a 0-100 scale. External validation of this scale yielded a concordance rate of 90.8%. For each domain, mean change from baseline to 24 weeks in the placebo and donepezil groups was compared for the total population and for subgroups stratified by baseline disease severity. Study settings included outpatient, assisted living, and skilled nursing facilities. Participants comprised 2183 patients (donepezil, 1261; placebo; 922) with baseline Mini-mental State Examination (MMSE) scores 5-26.. Significant treatment differences favoring donepezil were observed for five items (two instrumental and three basic). Patients with moderate AD at baseline (MMSE 10-17) demonstrated the greatest treatment effect.. Functional data were successfully pooled using standardizing methodology. A beneficial effect of donepezil treatment on function was demonstrated using this standardized functional scale. Similar analyses from studies with other anti-dementia drugs may help to determine the generalizability of these findings and potentially encourage use of functional assessment as a clinical tool.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Ambulatory Care; Assisted Living Facilities; Disability Evaluation; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Multicenter Studies as Topic; Nootropic Agents; Piperidines; Psychometrics; Randomized Controlled Trials as Topic; Skilled Nursing Facilities

More than 5 million people in the United States are afflicted with Alzheimer disease, a condition that is the seventh leading cause of death in the nation. Lacking definitive disease-modifying treatments, modern care for individuals with Alzheimer disease is necessarily multimodal, combining the use of approved pharmaceutic agents (ie, acetylcholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, antipsychotics), lifestyle and behavioral interventions, and components of palliative care. Some promising experimental treatments are undergoing clinical trials, including immunotherapy to prevent the deposition of β-amyloid, a protein implicated as an etiologic factor in the disease. The authors briefly examine the rationale and methods for screening patients for early indications of the onset of Alzheimer disease. They also describe current and potential treatments for patients with this disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Cognition; Donepezil; Excitatory Amino Acid Antagonists; Humans; Immunosuppressive Agents; Indans; Memantine; Neuroprotective Agents; Phenylcarbamates; Piperidines; Psychological Tests; Rivastigmine; Severity of Illness Index; Tacrolimus

Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined.. Pooled data from 14 randomized clinical studies of donepezil in the treatment of AD (N = 3748) were analyzed to identify predictors of fast decline and determine the effect of donepezil on the risk of fast decline.. Young age and more severe baseline cognitive, global, or behavioral status were identified as independent predictors of faster decline in placebo-treated patients. Multivariate models indicated that donepezil treatment was associated with a 39% to 63% reduction in the risk of faster decline.. These results correspond with previous findings, indicating relationships between age or baseline disease severity and rates of cognitive decline. Furthermore, they suggest that symptomatic therapy for AD could reduce the likelihood of faster decline in treated patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Risk Factors

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Donepezil; Dystonia; Galantamine; Humans; Indans; Male; Piperidines; Syndrome

Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome [DS]. Acetylcholine is a chemical found in the brain that has an important role in memory, attention, reason and language. Donepezil a reversible inhibitor of acetylcholinesterase, which is thought to maintain levels of acetylcholine, and is reported to have some benefits for people with AD in the general population. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population.. To determine the effectiveness and safety of donepezil for people with DS who develop AD.. CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of donepezil as well as experts in the field, to ask about reports of unpublished or ongoing trials.. Randomised controlled trials of participants with DS and AD in which treatment with donepezil was administered compared with a placebo group.. Data were extracted from the published reports of the one relevant study identified.. The one study included in this review is a small (n=30) randomised controlled trial lasting 24 weeks. It was followed-up by an open label study with a crossover design.No significant differences were found on any four validated outcomes including global functioning and three measures of cognitive abilities and behavioural problems. 6 out of 16 carers (37%) of participants on donepezil and 2 out of 15 (13%) on placebo reported improvement. No data were available for day to day skills, institutionalisation, reduction in carers' stress or economic outcomes. Half the intervention group and 20% of the placebo group reported adverse events; two participants left because of adverse events.. To date there is only one small randomised controlled study on the effect of donepezil. This shows, at best, a modest, non statistically significant trend in favour of people with Down syndrome and Alzheimer's dementia who are able to tolerate donepezil (this drug is currently only dispensed in relatively large doses and is contraindicated for those with cardiac and respiratory problems).This study does not provide good evidence on which to base practice. Findings in an open-label follow up to this study suggest possible benefit in some individuals. Further, larger randomised controlled studies with longer-term follow up are required.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are management of Alzheimer's agitation with donepezil; needle-free lidocaine powder for minor painful procedures; psychostimulants in depression; anticoagulation for cancer-related venous thromboembolism; effect of waiting for acute pain treatment on risk of chronic pain; and an update on severe cutaneous reactions associated with medications.

Topics: Alzheimer Disease; Amphetamines; Anesthetics, Local; Anticoagulants; Antidepressive Agents; Depression; Donepezil; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Indans; Lidocaine; Nootropic Agents; Pain; Palliative Care; Phlebotomy; Piperidines; Prescription Drugs; Psychomotor Agitation; Randomized Controlled Trials as Topic; Sertraline; Stevens-Johnson Syndrome; Thromboembolism

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by an insidious onset and slow deterioration in cognition, activities of daily living (ADL), mood stability and social functioning. The cholinesterase inhibitors (ChEIs), developed based on the cholinergic hypothesis, are currently considered to be the best established treatment for AD, although the significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments. Donepezil is a mixed competitive and noncompetitive acetylcholinesterase inhibitor that shows a relative selectivity for acetylcholinesterase inhibitor compared with butyrylcholinesterase. In many clinical trials of donepezil, beneficial effects on standard measures of cognitive function, ADL and behavior have been shown in patients with mild, moderate or severe AD. Although the pharmacological and phamacokinetic profiles of the currently available ChEIs have notable differences that may affect efficacy, the clinical significance of these differences remains hypothetical in the absence of large, randomized trials that compare the ChEIs with each other.

Topics: Alzheimer Disease; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Pharmacologic treatment for patients with Alzheimer's disease (AD) who reside in long-term-care (LTC) facilities is discussed.. The recognition of AD can be problematic in patients residing in LTC who do not have a preexisting diagnosis of dementia. Residents in LTC facilities generally have fewer day-to-day cognitive demands, and, thus, nursing staff or caregivers may not recognize cognitive deficits until the disease is more advanced. The current therapeutic options for the treatment of AD are the cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate receptor antagonist memantine. The ChEIs rivastigmine and galantamine are currently approved for the treatment of mild-to-moderate AD, and memantine is approved for the treatment of moderate-to-severe AD. The ChEI donepezil is presently approved for the treatment of mild, moderate, and severe AD in the United States. Two placebo-controlled trials in nursing-home patients receiving donepezil have been published. In both studies, donepezil appeared to be safe and effective for the treatment of AD in patients residing in LTC facilities. Data from an open-label study suggest that rivastigmine treatment might also provide benefits in nursing-home patients with moderate-to-severe AD. Another study demonstrated that treatment with galantamine might delay the need for transfer from an assisted-living facility to a nursing home. The effectiveness and safety of memantine have been assessed in a subgroup of patients with severe AD residing in LTC facilities. There were no major differences in safety and tolerability between the active treatment group and placebo. The relative and clinical importance of the cognitive, functional, and behavioral changes observed in LTC patients treated with ChEIs and memantine remain to be identified.. Pharmacologic treatment should be recommended for most patients with AD who reside in LTC facilities.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Galantamine; Humans; Indans; Long-Term Care; Memantine; Phenylcarbamates; Piperidines; Rivastigmine

The study aim was to conduct a systematic review of the evidence from randomized, placebo controlled trials related to the efficacy of donepezil, rivastigmine and galantamine in the treatment of behavioral and psychological symptoms of Alzheimer's disease.. Electronic database searches of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were carried out using multiple search terms. Articles included were original publications of randomized, placebo-controlled trials of monotherapy of donepezil, rivastigmine or galantamine that reported a behavioral outcome measure.. 14 studies were identified that matched inclusion criteria. Nine were of donepezil, three of galantamine and two of rivastigmine. Median study treatment length was 24 weeks (range 12-170). Most studies used the Neuropsychiatric Inventory as a behavioral outcome measure although three used specific scales for either agitation or apathy. Four studies were specifically designed to assess behavioral outcomes whilst in the majority of studies behavioral outcomes were only secondary measures. Three studies found statistically significant, albeit modest, differences in the change of NPI total score between drug and placebo. The interpretation of the results of many studies is limited by methodological considerations, including generally low NPI scores at baseline and the investigation of behavioral and psychological symptoms of dementia (BPSD) as secondary outcomes.. The evidence base regarding the efficacy of cholinesterase inhibitors in BPSD is limited, in part due to methodological considerations. In the absence of alternative safe and effective management options, the use of cholinesterase inhibitors is an appropriate pharmacological strategy for the management of BPSD in Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Mental Disorders; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Clinical Trials as Topic; Cognition; Donepezil; Ginkgo biloba; Humans; Indans; Mental Processes; Nootropic Agents; Piperidines; Plant Extracts; Quality of Life

Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety.. Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response.. Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups.. These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Middle Aged; Multicenter Studies as Topic; Nootropic Agents; Piperidines; Placebos; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

The purpose of this systematic review was to compare the safety and tolerability of the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine for treating mild to moderate Alzheimer's disease (AD) patients in routine clinical practice.. Electronic databases (Cochrane Library, Medline, EMBASE; accessed October 2008) and manual bibliographic searches were conducted to identify head-to-head non-randomised studies examining ChEIs for the treatment of AD. Data were extracted by 2 independent reviewers.. Twelve head-to-head studies comparing ChEIs met the pre-specified inclusion criteria; 6 retrospective analyses and 6 prospective cohort studies. Donepezil was the most widely studied treatment and galantamine the least widely prescribed therapy. Fewer donepezil-treated subjects withdrew due to adverse events (AEs) compared with rivastigmine and galantamine-treated subjects. The incidence of gastrointestinal (GI) AEs was lower following treatment with donepezil compared with rivastigmine and galantamine. Non-GI (CNS and cardiovascular) AEs occurred at a low frequency, and had a similar incidence in subjects treated with the different ChEIs.. Subjects with mild to moderate AD treated in routine clinical practice with donepezil were more adherent to pharmacotherapy, and had a lower risk of GI AEs compared with rivastigmine or galantamine. This finding accords with results reported in the randomised clinical trial literature.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.

Topics: Adult Stem Cells; Alzheimer Disease; Animals; Cell Differentiation; Cell Division; Cell Movement; Cell Survival; Cerebral Ventricles; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Mice; Nerve Regeneration; Neurons; Olfactory Bulb; Piperidines

The era of disease modification as a therapeutic option for Alzheimer's disease (AD) is upon us. With dozens of novel drugs in development, there is more need than ever to develop biomarkers that distinguish normal aging from AD and AD from other dementias, track changes over time as disease progresses, and respond to interventions. Future trials will need to weight biomarker outcomes equal to cognitive outcomes especially when the biomarkers are linked to specific mechanisms, such as changes to beta amyloid (Abeta) deposition or brain volume. Since the advent of donepezil as a treatment for AD, new mechanisms of action of this molecule have been discovered. In this perspective, we review trial design and discuss the use of biomarkers by using lessons learned from previous trials conducted with cholinergic therapy.

Topics: Alzheimer Disease; Biomarkers; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Piperidines; Research Design

Whether donepezil provides meaningful benefit to patients with Alzheimer's disease (AD) is controversial, but drug sales annually total billions of dollars. A review of data from published randomized clinical trials (RCTs) found rhetorical patterns that may encourage use of this drug. To create a reproducible observation, the sentences occurring at five specific text sites in all 18 RCTs of donepezil for AD were tabulated, as were study design, sources of financial support, and outcomes that could be compared between trials. Rhetoric in the 13 vendor-supported trials (15 publications) was strongly positive. Three early trials used the motif "efficacious (or effective) ... treating ... symptoms" four times. "Well-tolerated and efficacious" or an equivalent motif appeared 11 times in five RCTs. Nine RCTs referred 15 times to previously proven effectiveness. Seven trials encourage off-label use, for "early" cognitive impairment, severe dementia in advance of the Food and Drug Administration labeling change, or behavioral symptoms. These rhetorical motifs and themes appeared only in the vendor-supported trials. Trials without vendor support described the drug's effects as "small" or absent; two emphasized the need for better treatments. RCT results were highly consistent in all trials; the small differences do not explain differences in rhetoric. At these text sites in the primary research literature on donepezil for AD, uniformly positive rhetoric is present in all vendor-supported RCTs. Reference to the limited benefit of donepezil is confined to RCTs without vendor support. Data in the trials are highly consistent. This observation generates the hypothesis that rhetoric in vendor-supported published RCTs may promote vendors' products.

Topics: Advertising; Aged; Alzheimer Disease; Conflict of Interest; Donepezil; Drug Industry; Drug Utilization; Evidence-Based Medicine; Humans; Indans; Manuscripts, Medical as Topic; Marketing; Nootropic Agents; Piperidines; Psycholinguistics; Randomized Controlled Trials as Topic

Pharmacologic treatments for Alzheimer's disease include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. We reviewed their evidence by searching MEDLINE, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 through 2007 (July) for placebo-controlled and comparative trials assessing cognition, function, behavior, global change, and safety. Thirty-three articles on 26 studies were included in the review. Meta-analyses of placebo-controlled data support the drugs' modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change. Three open-label trials and one double-blind randomized trial directly compared donepezil with galantamine and rivastigmine. Results are conflicting; two studies suggest no differences in efficacy between compared drugs, while one study found donepezil to be more efficacious than galantamine, and one study found rivastigmine to be more efficacious than donepezil. Adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine (relative risk = 1.63 and 1.42, respectively). Indirect comparisons also favored donepezil over galantamine with regard to behavior. Across trials, the incidence of adverse events was generally lowest for donepezil and highest for rivastigmine.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

There is substantial evidence from preclinical studies that cholinesterase inhibitors affect basic processes that have been implicated in Alzheimer's disease (AD) pathogenesis, suggesting that these drugs should have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil, which is the focus of this review.. To summarize the preclinical literature regarding the effects of donepezil on cellular and molecular processes underlying AD. Second, to suggest reasons for the apparent disparity between robust preclinical effects and modest clinical effects of this drug and others in its class.. Articles retrieved from PubMed searches were critically reviewed and selected for relevance to the current topic.. Donepezil has numerous cellular and molecular effects that should influence AD progression.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Evaluation, Preclinical; Humans; Indans; Neuroprotective Agents; Piperidines

Moderate-to-severe stage Alzheimer's disease (AD) is a clinically diagnosable entity that represents a substantial burden to our healthcare system in terms of its prevalence, symptomatology, caregiver stress and economics.. In this paper, we review the data from currently available clinical trials aimed at treatment of this later stage of the disease.. A literature search was performed and published randomized controlled trials (RCTs) in which the majority of the study population consisted of Alzheimer patients in the moderate-to-severe stage were selected for review.. A total of nine RCTs were identified in which the study population consisted of mainly moderate-to-severe AD patients. The results from these studies suggest that memantine and donepezil, individually or in combination, provide measurable global, cognitive and behavioral benefits in AD patients.. Pharmacological treatment of moderate-to-severe AD patients can be beneficial. However, cost-benefit data are limited, and the long-term effects and the optimal duration of treatment as patients continue to progress to more severe stages are unknown and require further investigation.

Topics: Alzheimer Disease; Donepezil; Double-Blind Method; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Placebos; Randomized Controlled Trials as Topic; Rivastigmine; Selegiline; Severity of Illness Index; Vitamin E

Dementia and depression are serious causes of global impairment in the elderly. This review is aimed at finding pharmacological reports from 2007-2008 so as to examine whether new guidance is available to treat these patients.. Studies on Alzheimer's disease and Lewy body dementias show that cholinesterase inhibitors are still first line treatment for these diseases and memantine is indicated in moderate/severe Alzheimer's disease, whereas there is as yet no standard available treatment for frontotemporal dementias. Treatment of depression in the elderly shows the same results as in younger individuals, and cerebrovascular pathology is important for treatment resistance.. There is a need for new drugs that focus on treatment resistant and nonresponder individuals. Most studies are confirmation of previous reported results.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Therapy; Evidence-Based Medicine; Geriatric Psychiatry; Humans; Indans; Lewy Body Disease; Parkinson Disease; Piperidines

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antipsychotic Agents; Brain; Cholinesterase Inhibitors; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Donepezil; Humans; Indans; Neurofibrils; Piperidines; Plaque, Amyloid; Quetiapine Fumarate; Reference Standards; Selective Serotonin Reuptake Inhibitors; tau Proteins

Topics: Aged; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Neuropsychological Tests; Piperidines; Positron-Emission Tomography

Autosomal dominant early-onset Alzheimer disease (EOAD) is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Mutation analysis of the APP, PSEN1 and PSEN2 genes was performed. We herein report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 141 (N141I) of the PSEN2 gene. To our knowledge, this is the first German EOAD patient without a Volga-German ancestry and a positive family history for dementia carries the mutation PSEN-2 N141I. The patient came to our clinic for the first time when she was 47 years old. During the following 3 years, her Mini-Mental State Examination (MMSE) score dropped from 28 to 0. Mild cognitive impairment (MCI) was an early symptom that was already present during the first consultation. The concentration in cerebrospinal fluid (CSF) of tau-protein (1151 pg/ml) was increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (335 pg/ml). Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease and positron emission tomography with (18F) fluoro-2-deoxy-D-glucose (18F-FDG PET) demonstrated glucose reduction left parietal and in the precuneus region. Follow-up MRI and 18F-FDG PET studies showed progression of atrophy of the left entorhinal cortex with relative sparing of the hippocampus and progressive hypometabolism of both temporoparietal lobes and left frontal lobe.

Topics: Age of Onset; Alzheimer Disease; Cholinesterase Inhibitors; Codon; Donepezil; Electrophysiology; Excitatory Amino Acid Antagonists; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Indans; Male; Memantine; Middle Aged; Mutation, Missense; Neuropsychological Tests; Pedigree; Piperidines; Presenilin-2; Radiography; Radionuclide Imaging; Radiopharmaceuticals; tau Proteins; Time Factors; Treatment Outcome

Drug therapy is an important component in the management of AD. The agents discussed do not stop or reverse the disease, but can slow its progression. There are currently 3 AChEIs and memantine available to treat AD. Generally, one agent is started and increased up to a maximum dose. If this agent is not effective or not tolerated, another agent is substituted. Combination therapy with an AChEI and memantine is another option that has shown effectiveness in managing AD. Therapy is generally discontinued if these agents prove to be ineffective or are not tolerated. The decision to stop therapy should involve the resident, family, caregivers, and providers.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Approval; Drug Monitoring; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Neuroprotective Agents; Nursing Homes; Patient Selection; Phenylcarbamates; Piperidines; Prevalence; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Severity of Illness Index; Treatment Failure; United States; Withholding Treatment

Some randomized studies, mostly of short duration, have indicated that cholinesterase inhibitors (donepezil, rivastigmine and galantamine) may have a beneficial effect in Alzheimer's disease, vascular dementia and in dementia caused by Lewy body disease. The benefit of these drugs in clinical practice has not been satisfactorily documented.. Literature collected regularly for many years supplemented by extensive non-systematic searches of Pubmed and Embase.. Only in a few placebo-controlled, double-blind, randomised studies were the patients followed for more than one year. Several clinical tests were performed, among them the Mini Mental Status (MMS)-test, which is the most commonly used test in clinical practice. The three cholinesterase inhibitors led to statistically significant results, although of limited clinical relevance, in various forms of dementia.. Based on the results obtained it could be questioned whether the observed effects are of clinical significance. Only a small proportion of patients with Alzheimer's disease seem to benefit from the cholinesterase inhibitors tested, and it is difficult to predict who will in advance. Treatment should first be evaluated after 2-4 months and subsequently on a regular basis, and accepted clinical tests should be applied.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Dementia, Vascular; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Lewy Body Disease; Phenylcarbamates; Piperidines; Rivastigmine; Time Factors; Treatment Outcome

Although the diagnosis of AD can be devastating, treatment options exist that can slow the disease's progression and allow patients to continue performing ADLs, thereby improving the quality of life for both patient and caregiver. Research is ongoing, and it is estimated by the Alzheimer's Association that finding a treatment that could delay onset by only 5 years could reduce the number of individuals with AD by nearly 50% over the next 50 years (Alzheimer's Association, 2007). Although pharmacotherapy is not yet a cure, it does remain an important part of a total approach to caring for patients and families affected by AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Galantamine; Humans; Indans; Memantine; N-Methylaspartate; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine

An increasing number of studies suggest that current pharmacotherapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The oldest hypothesis explain the cause of the AD is the "cholinergic hypothesis", which states, that AD begins as a deficiency in the production of acetylcholine (ACh). Interactions between the cholinergic and serotoninergic systems are believed to play a role in the mechanism underlying AD. The activation of NMDA receptors and increase in intracellular Ca(++) concentration play key role in the development of neurodegenerative processes. Potassium channels may also be involved in several other steps within the cascade that leads to neurodegeneration. In the development of AD a great role play an imbalance between anabolism and catabolism causes an accumulation of amyloid beta-peptide (Abeta), which is a proposed trigger of the onset of AD. There are various therapeutic strategies in current pharmacotherapy of AD. Major group is inhibitors of acetylcholinesterase--donepezil, galantamine, physostigmine. The new effective treatments of AD are NMDA glutamate receptor antagonist-memantine and potassium channel openers such as retigabine. Experimental study suggest, that neprilisin, a rate-limiting peptidase, decreases neurodegeneration.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Middle Aged; Nerve Degeneration; Piperidines

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Behavioral Symptoms; Choline; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Design; Galantamine; Glutamic Acid; Humans; Indans; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Risk Factors; Rivastigmine

This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

Topics: Alzheimer Disease; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Brain Injuries; Donepezil; Down Syndrome; Humans; Indans; Learning Disabilities; Memory Disorders; Mental Recall; Nootropic Agents; Piperidines; Schizophrenia; Treatment Outcome

The impact of behavioral symptoms associated with Alzheimer's disease is substantial. These symptoms contribute to diminished quality of life for patients and caregivers and increase the cost of care in nursing homes. Early recognition of behavioral symptoms and appropriate treatment are important for successful management. Nonpharmacologic strategies remain the cornerstone of the management of Alzheimer's disease-related behavioral symptoms. However, nonpharmacologic strategies may not be effective for problem behaviors, and pharmacologic intervention may be necessary. Relevant articles were identified through various MEDLINE searches with no date restrictions, with an emphasis on recent studies that used cholinesterase inhibitors and memantine. Additional reports of interest were identified from the reference lists of these articles. To facilitate cross-study analyses in the review of cholinesterase inhibitors and memantine, the database search was limited to randomized, placebo-controlled trials that used the Neuropsychiatric Inventory to assess behavioral symptoms of Alzheimer's disease. Overall, evidence from trials of cholinesterase inhibitors and memantine suggests that when these agents are optimized for the various stages of Alzheimer's disease, they can also prevent the emergence of neuropsychiatric symptoms. Although results from the literature are not uniformly positive, cholinesterase inhibitors have been shown to produce significant improvements in behavioral symptoms in patients with both mild- to-moderate and moderate-to-severe Alzheimer's disease. Evidence also indicates that memantine might be of benefit as an adjunct to long-term cholinesterase inhibitor treatment in patients with moderate-to-severe Alzheimer's disease and that memantine monotherapy may have some beneficial effects on behavior in patients with mild-to-moderate disease. Of importance, although no direct comparisons have been performed, these agents seem to have an improved safety and tolerability profile compared with the frequently used antipsychotic drugs. When nonpharmacologic strategies are deemed insufficient to ease problem behaviors in patients with Alzheimer's disease, treatment with cholinesterase inhibitors, alone or in combination with memantine as appropriate for the stage of disease, may be considered as a first-line option in the early pharmacologic management of Alzheimer's disease-related behavioral symptoms.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Memantine; Mental Disorders; Piperidines; Time Factors

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Evidence-Based Medicine; Geriatric Assessment; Humans; Indans; Mental Disorders; Nootropic Agents; Phenylcarbamates; Piperidines; Positron-Emission Tomography; Rivastigmine; Tacrine

Molecular imaging is a visualization of quantity and dynamics of molecules to understand the process of gene regulation and physiological function of the proteins in living tissue or cells. Examples of the research include the development and application of fluorescent proteins, quantum dots, nanoparticles for optical imaging, micro bubbles for ultrasound, ferromagnetic compounds for MRI and radiopharmaceuticals for positron emission tomography (PET). PET is most promising in this field, because of its high sensitivity of the measurement and easy applicability to humans. In this general remark, the topics will be concentrated on molecular imaging with PET for the diagnosis of Alzheimer's disease (AD) in early stage. 11C-MP4P (N-methlpiperidyl-4-propionate), is a probe for the measurement of acetylcholine esterase (AchE) activity in the human brain by PET. The AchE activities (k3) in early onset AD measured with PET was low in hippocampus, amygdale and wide spread neocortex including parietal and temporal cortex compared to those in age-matched control. The results indicated that the decrease of AchE activities is preceded by the decrease of blood flow. One of the topics in this research field is an imaging of aggregated amyloid Abeta in the AD brain. Kudo et al, screened more than 2,600 compounds and found several good probes for amyloid Abeta imaging, including BF-168 and BF-227. Okamura demonstrated that BF-168 specifically bind to the amyloid plaques in the brain of a transgenic mouse (PS1/APPsw). Furumoto et al successfully labeled BF-227 with C-11, and clinical PET studies using 11C-BF-227 is now ongoing at Tohoku University. Preliminary clinical study revealed that the compound accumulated in the tempo-parietal region of the brain in AD patient, although non-specific accumulation in the thalamus, basal ganglia and white matter was observed. The goal of this project is to detect AD at pre-clinical stage.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Benzoxazoles; Brain; Carbon Radioisotopes; Diagnostic Imaging; Humans; Mice; Molecular Probes; Piperidines; Plaque, Amyloid; Positron-Emission Tomography; Propionates; Thiazoles

With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD) in the coming years, interest is growing in identifying and treating adults at high risk for developing the disorder. Recent research suggests that individuals who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study of cognitive impairment before the diagnosis of AD.

Topics: Adult; Alzheimer Disease; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Time Factors; Vitamin E

Delirium is very common in the elderly. It complicates both psychiatric and somatic disorders and is associated with reduced survival, poor functional results, increased duration of hospital stay, and institutionalization. Diagnosis remains difficult in spite of the improvement of the diagnostic criteria, due to the polymorphism of the clinical signs and fluctuation of vigilance and cognition. Age over 70 and previous cognitive impairment are the main risk factors. Precipitating factors are medical and surgical pathologies, intoxications, especially by therapeutic drugs. Delirium can reveal or complicate a previous dementia. Prevention of delirium and care of the delirious patient require the participation of both the medical and nursing staff.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Confusion; Delirium; Diagnosis, Differential; Donepezil; Humans; Indans; Patient Care Team; Piperidines; Risk Factors

Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?. Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants.. The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed.. Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

Topics: Aged; Alzheimer Disease; Cross-Cultural Comparison; Donepezil; Ethnicity; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Thiazoles; White People

Donepezil hydrochloride is the most widely prescribed drug for Alzheimer's disease (AD). The main mechanism of action through which it influences cognition and function is presumed to be the inhibition of acetylcholinesterase enzyme in the brain; however, donepezil may also impact the pathophysiology of AD at several other points. Officially approved for mild-to-moderate and severe AD, donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD. The pharmacokinetics, pharmacodynamics, safety/tolerability profile and drug interaction properties of donepezil make it an easy and safe agent to use. However, in general, the efficacy of donepezil is limited, and ongoing studies are investigating other agents that may ultimately overtake its present position as the mainstay of anti-AD therapy.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Nootropic Agents; Parkinson Disease; Piperidines

The cholinesterase-inhibitors (AChE-I) donepezil, galantamine and rivastigmine are currently used in the symptomatic treatment of patients with Alzheimer's dementia (AD) and the associated cholinergic deficits as well as those with other forms of dementia. Three aspects were analysed: (1) data on their clinical efficacy, (2) differences between North-American and international studies, and (3) potential publication biases.. Included were data from randomized, placebo-controlled, double-blind parallel group trials on more than 100 patients who had been treated for > or =12 weeks for AD, VaD, dementia with Lewy bodies, dementia with Parkinson's disease or with mild cognitive impairment.. These large published trials support the clinical efficacy of AChE-I in patients with mild to moderate AD and other forms of dementia with regard to cognition and global impression. there was a trend towards greater beneficial cognitive effects in North-American studies, but this was non-significant. There was no evidence of a publication bias.. Published data provide evidence for the clinical efficacy of donepezil, galantamine and rivastigmine in patients with mild to moderate AD. There is no indication that these results are critically influenced by the origin or a bias of the publication.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Publication Bias; Randomized Controlled Trials as Topic; Rivastigmine; Severity of Illness Index; Treatment Outcome

Management of Alzheimer disease is based on drug and nondrug treatments. Specific drug treatment includes acetylcholinesterase inhibitors and memantine. They show moderate efficacy superior to that of placebo for global condition, cognitive disorders, need for care, and behavioral problems, but do not prevent further decline. These treatments remain underused. The efficacy of psychotropic drugs (antidepressants, neuroleptics, and antipsychotic agents) in treating behavioral problems is not well documented. Nondrug activities and interventions have not been sufficiently evaluated scientifically. These involve interventions against the consequences of the disease (loss of autonomy, malnutrition) and helping patients' family caregivers. Among these activities, the best evaluated and most interesting are: educational programs for caregivers, occupational therapy at home, and interventions at home by nurses specially trained as case managers.

Topics: Aged; Alzheimer Disease; Animals; Antipsychotic Agents; Caregivers; Case Management; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dopamine Agents; Excitatory Amino Acid Antagonists; Follow-Up Studies; Forecasting; Health Education; Humans; Indans; Memantine; Mental Disorders; Meta-Analysis as Topic; Nootropic Agents; Occupational Therapy; Piperidines; Practice Guidelines as Topic; Psychotropic Drugs; Randomized Controlled Trials as Topic; Time Factors

The efficacy of acetylcholinesterase (AChE) inhibitors for the treatment of dementia diseases has been established for both key cognitive symptoms and dementia-associated symptoms such as aggressiveness and the ability to perform activities of daily life. Presently three AChE inhibitors are approved for the treatment of mild to moderately severe Alzheimer dementia: donepezil, rivastigmine and galantamine. Rivastigmine is also approved for the treatment of Parkinson's dementia. The three substances differ in their efficacy and their pharmacological properties. AChE inhibitors should be used for long-term treatment. The clinical course should be monitored every six months.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Multicenter Studies as Topic; Neuroprotective Agents; Nootropic Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Time Factors

The literature reporting economic evaluations related to the treatment of Alzheimer's disease (AD) has developed over the last decade. Most analyses have used economic models to estimate the cost effectiveness of drugs for the treatment of AD. This review considers the range of methods used in the published cost-effectiveness literature to model AD progression and the effect of interventions on the progression of AD. The review builds on and updates an earlier systematic review of cost-effectiveness studies on drugs for AD. Systematic and rigorous methods were used to search the literature for economic evaluations estimating the cost effectiveness of donepezil, rivastigmine, galantamine or memantine in AD. The literature search covered a wide range of electronic databases (e.g. MEDLINE, EMBASE), and included literature from the inception of databases up to the end of 2005. The search identified 22 published economic evaluations. An outline and brief critical review of the identified studies is provided, and thereafter the methods used to model disease progression were considered in more detail. The review employs recent guidance on good practice in decision-analytic modelling in HTA to critically review the modelling methods used. Using this guidance, the models are assessed against the broad criteria of model structure, data inputs and assessment of uncertainty and inconsistency. Concerns were noted over the model structure employed in all models. The reliance on cognitive scores to model AD, the progression of the disease, and the effect of treatment on costs and consequences is regarded as a serious limitation in almost all of the studies identified. There are also limitations over the data used to populate published models, especially around the failure of studies to document and establish the basis for the modelling of treatment effects. It is also clear that studies modelling AD progression, and subsequently the cost effectiveness of treatment, have not addressed uncertainty or consistency (internal and/or external) in sufficient detail. Further research is required on more appropriate methods for the modelling of AD progression. In the meantime, future economic evaluations of treatment need to be more explicit on the methods used to model AD, and the data used to populate models.

Topics: Alzheimer Disease; Cost-Benefit Analysis; Disease Progression; Donepezil; Galantamine; Humans; Indans; Memantine; Models, Economic; Phenylcarbamates; Piperidines; Rivastigmine

Donepezil is the most widely prescribed of the cholinesterase inhibitors that has been licensed for the treatment of mild-to-moderate Alzheimer's disease. Evidence from a number of clinical trials suggests that it improves cognitive performance and stabilizes the functional abilities in people with mild-to-moderate Alzheimer's disease. Donepezil increases the amount of the neurotransmitter acetylcholine in the brain, the deficit of which is thought to play a major role in the clinical presentation of Alzheimer's disease. Studies show good safety and long-term tolerability. In addition, donepezil's pharmacokinetic properties make it convenient to prescribe. There are a number of newer drug therapies in various stages of pharmacological development, but donepezil should continue to play a major role in the treatment of Alzheimer's disease for the next few years.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

The efficacy of the acetylcholinesterase inhibitors donepezil, galantamine and rivastigmine for Alzheimer's disease is well-documented by a number of studies. In Germany, the three substances are approved for the treatment of mild to moderate Alzheimer's disease; the glutamate antagonist memantine is approved for the treatment of moderate to severe Alzheimer's disease. The health economical benefit of these medicines is disputed and ultimately depends on the health policy evaluation. However, from the medical perspective, every newly diagnosed case of Alzheimer's disease justifies a therapeutic attempt. In a given case, changing between the three approved acetylcholinesterase inhibitors or memantine may be indicated. Whether a combination of the substances has advantages is currently being tested.

Topics: Activities of Daily Living; Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Dopamine Agents; Drug Therapy, Combination; Economics, Medical; Excitatory Amino Acid Antagonists; Galantamine; Germany; Health Policy; Humans; Indans; Memantine; Meta-Analysis as Topic; Neuroprotective Agents; Nootropic Agents; Parasympathomimetics; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Time Factors

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of anti-alzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the development of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group--dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT(3) receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.

Topics: Alkaloids; Alzheimer Disease; Binding Sites; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Indole Alkaloids; Isoquinolines; Phenylcarbamates; Physostigmine; Piperidines; Propidium; Rivastigmine; Steroids; Tacrine

Topics: Alzheimer Disease; Antipsychotic Agents; Behavioral Symptoms; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Memantine; Piperidines; Receptors, N-Methyl-D-Aspartate

Production of new neurons in the subventricular zone (SVZ) and in the dentate gyrus (DG) continues into adulthood. In this paper, we will review our recent studies on migration and survival of new neurons in the adult mouse brain. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. The precise mechanisms controlling neuroblast migration remain unclear. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia. The majority of these newly-generated neurons die before they are integrated into the neuronal circuit, even under physiological conditions. We found that long-term administration of donepezil, an acetylcholinesterase inhibitor clinically used for the treatment of Alzheimer's disease, promotes the survival of newly-generated neurons in the OB and the DG. Although there are a lot of subjects to be elucidated, understanding the comprehensive mechanism of adult neurogenesis should be useful for developing successful regenerative therapies for neuropsychological diseases in the future.

Topics: Adult; Alzheimer Disease; Animals; Brain; Cell Differentiation; Cell Movement; Cell Survival; Cerebrospinal Fluid; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Ependyma; Humans; Indans; Mice; Neurons; Olfactory Bulb; Piperidines; Regenerative Medicine; Stimulation, Chemical

The M1 muscarinic receptor (M1 mAChR), preserved in Alzheimer's disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, beta-amyloid (Abeta) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective muscarinic agonists AF102B [Cevimeline], AF150(S) and AF267B - i) elevated alphaAPPs, decreased Abeta levels and tau hyperphosphorylation, and blocked Abeta-induced neurotoxicity, in vitro, via M1 mAChR-modulation of kinases (e.g. PKC, MAPK and GSK3beta); ii) restored cognitive deficits, cholinergic markers, and decreased tau hyperphosphorylation in relevant models with a wide safety margin. AF267B decreased brain Abeta levels in hypercholesterolemic rabbits and decreased CSF Abeta42 in rabbits and removed vascular Abeta42 deposition from cortex in cholinotoxin-treated rabbits. In 3x transgenic-AD mice that recapitulate the major pathologies and cognitive deficits of AD, chronic AF267B treatment rescued cognitive deficits and decreased Abeta42 and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR-activation of ADAM17/TACE and decreased BACE1 steady state levels and inhibition of GSK3beta, extending findings from above.. A comprehensive therapy should target all AD hallmarks, regardless of the culprit(s) responsible for the disease. In this context, AF267B is the 1(st) reported low MW CNS-penetrable mono-therapy that meets this challenge. Clinical trials will determine if AF267B may become an important therapy in AD.

Topics: Alzheimer Disease; Animals; Humans; Muscarinic Agonists; Piperidines; Receptor, Muscarinic M1; Spiro Compounds; Thiazoles

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Lactones; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index; Sulfones; Vitamin E

The use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process.. To provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD.. Electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review.. Twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms.. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duration.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Quality of Life; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Therapies for Alzheimer's disease (AD) at present augment the deteriorating cholinergic system, are reasonably well tolerated, and are convenient, given once or twice a day. They may, however, support or oppose endogenous circadian cholinergic rhythms. Drugs with a duration of action longer than a day are at odds with the physiology of the cholinergic system, which is active during the day and quiescent at night. Sleep and the consolidation of daytime experience into memory may be disturbed. Tolerance commonly develops, substantial counterregulatory increases in acetylcholinesterase (AChE) have been measured, and brain AChE inhibition is lower than predicted. Therefore, the duration of action and timing of administration, as they relate to natural cholinergic rhythms, are factors to be considered in optimizing cholinergic AD therapeutics.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Circadian Rhythm; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Sleep; Sleep, REM

To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD.. Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE).. A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken.. For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess. Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cost-Benefit Analysis; Donepezil; Dopamine Agents; Evidence-Based Medicine; Female; Galantamine; Humans; Indans; Male; Memantine; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome; United Kingdom

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors.. The objective of this review is to assess whether donepezil improves the well-being of patients with dementia due to Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease.. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.. 23 trials are included, involving 5272 participants. Most trials were of 6 months or less duration in selected patients. Available outcome data cover domains including cognitive function, activities of daily living, behaviour , global clinical state and health care resource costs. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo on the ADAS-Cog scale (-2.01 points MD, 95%CI -2.69 to -1.34, p<0.00001); -2.80 points, MD 95% CI -3.74 to -2.10, p<0.00001) and for 10 mg/day donepezil compared with placebo at 52 weeks (1.84 MMSE points, 95% CI, 0.53 to 3.15, p=0.006). The results show some improvement in global clinical state (assessed by a clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 24 weeks for the number of patients showing improvement or no change (OR 2.18, 95% CI 1.53 to 3.11, p=<0.0001, OR 2.38, 95% CI 1.78 to 3.19, p<0.00001). Benefits of treatment were also seen on measures of activities of daily living and behaviour, but not on the quality of life score . There were significantly more withdrawals before the end of treatment from the 10 mg/day (but not the 5 mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Two studies presented results for health resource use, and the associated costs. There were no significant differences between treatment and placebo for any item, the cost of any item, and for the total costs, and total costs including the informal carer costs. A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue and anorexia (significant risk associated with treatment) in the 10 mg/day group compared with placebo but very few patients left a trial as a direct result of the intervention.. People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total health care resource costs. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Taking into consideration the better tolerability of the 5 mg/day donepezil compared with the 10 mg/day dose, together with the lower cost, the lower dose may be the better option. The debate on whether donepezil is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice .

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues.. To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.. All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.. The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine.. The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimer's disease. As a consequence of their capability to simultaneously interact with two binding sites of the same biological target (the enzyme acetylcholinesterase in most cases), to expand their interaction in the main binding site of the target molecule, or to interact with two different biological targets of interest in the pathogenesis of the disease, these dimeric or hybrid compounds exhibit an improved pharmacological profile including high affinity interactions, additional non conventional actions or complementary actions, what makes them potential drug candidates for the treatment of Alzheimer's disease. Herein, we review from a structural point of view the main classes of dimeric or hybrid compounds developed for the treatment of Alzheimer's disease, along with the pharmacological profile of the most active compounds.

Topics: Alzheimer Disease; Aminoquinolines; Animals; Binding Sites; Cholinesterase Inhibitors; Cognition Disorders; Heterocyclic Compounds, 4 or More Rings; Humans; Monoamine Oxidase Inhibitors; Piperidines; Structure-Activity Relationship; Tacrine

Alzheimer's disease (AD) prevalence rates in the United States are expected to triple over the next 50 years, a consequence of the overall aging of the U.S. population. Because of the profound and far-reaching impact of AD, this projected increase in prevalence is expected to pose a tremendous challenge. Alzheimer's disease results in the cognitive and functional deterioration of the affected patient, and behavioral disturbances frequently accompany the disease. Furthermore, because of its progressive and debilitating nature, AD takes a dramatic emotional, physical, and financial toll on the patient's primary caregiver. Nonetheless, despite the burden experienced by both patients and caregivers, strategies for minimizing the negative consequences of AD are well characterized. Central to the successful management of AD is the prompt and accurate diagnosis of the disease, with current guidelines calling for a 2-tiered approach in which patients first undergo screening using a brief cognitive assessment tool, followed by a comprehensive battery of physical, psychological, and neurologic tests if signs of possible cognitive impairment are evident upon screening. Once a conclusive diagnosis of AD has been made, the development of a disease management approach targeting the needs of the patient and his or her caregiver becomes a primary concern. Pharmacologic interventions may play an important role in such approaches, as agents such as cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine have been associated with favorable outcomes for patients and caregivers alike. However, in addition to the therapeutic benefits of these agents, associated side effects and potential drug-drug interactions must also factor into decisions regarding the pharmacologic treatment of AD.

Topics: Aged; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mass Screening; Memantine; Middle Aged; Neurologic Examination; Neuropsychological Tests; Patient Care Management; Physical Examination; Piperidines; Practice Guidelines as Topic; Prevalence; Randomized Controlled Trials as Topic; Severity of Illness Index; Stress, Psychological; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Memory; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Therapy, Combination; Estrogen Replacement Therapy; Estrogens; Female; Humans; Indans; Male; Medroxyprogesterone; Menopause; Mental Status Schedule; Piperidines; Prognosis; Risk Factors; Sex Factors

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.

Topics: Acetylcholine; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of Alzheimer's disease. Therefore, one hypothesis is that treatment strategies should address impairments in both systems. Galantamine is an acetylcholinesterase inhibitor that, unlike other acetylcholinesterase inhibitors, has a postulated dual mode of action as a nicotinic receptor modulator. Galantamine has demonstrated long-term efficacy in improving or maintaining cognition, functionality, and behavior in patients with mild to moderate Alzheimer's disease. Memantine, a noncompetitive N-methyl-D-aspartate-receptor antagonist, reduces deterioration in cognition and function in patients with moderate to severe Alzheimer's disease. Pharmacokinetic and pharmacodynamic as well as ongoing observation studies support the concept of adjunctive therapy with memantine in patients with advanced moderate Alzheimer's disease currently treated with an established galantamine regimen. The potential to modulate both acetylcholine and glutamate pathways in Alzheimer's disease presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Severity of Illness Index

Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Topics: Aged; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Male; Molecular Biology; Phenylcarbamates; Piperidines; Plaque, Amyloid; Positron-Emission Tomography; Randomized Controlled Trials as Topic; Rivastigmine; tau Proteins

Donepezil, galanthamine, and tacrine are therapeutic acetylcholinesterase (AChE) inhibitors used for the treatment of Alzheimer's disease. The aim of this paper is to review recent findings on their neuroprotective properties and the mechanisms of neuroprotection against glutamate neurotoxicity in rat cortical neurons. First, the hallmark of neurotoxicity induced by two different glutamate treatment conditions was examined, revealing that acute glutamate treatment (1 mM, 10 min) induces necrotic neuronal death and that moderate glutamate treatment (100 microM, 24 hr) induces apoptotic neuronal death. Next, we showed that therapeutic AChE inhibitors protect cortical neurons from glutamate neurotoxicity in a time- and concentration-dependent manner. We examined the mechanism of this neuroprotective effect and found that the neuroprotective effects against both acute and moderate glutamate treatments are mediated through nicotinic acetylcholine receptors (nAChRs), or more specifically, the effects of donepezil and galanthamine are mediated through alpha4- and alpha7-nAChR. We also showed that donepezil and galanthamine protect cortical neurons against acute glutamate treatment-induced neurotoxicity at steps before, and that tacrine protects at steps after, nitric oxide radical formation. On the other hand, the neuroprotective effects of donepezil and galanthamine, but not of tacrine, against neurotoxicity induced by moderate glutamate treatment were mediated through the phosphatidylinositol 3-kinase-Akt pathway. These findings unveiled the hitherto unknown neuroprotective effects of therapeutic AChE inhibitors and provided valuable insights into its neuroprotective mechanisms. They may very likely form the basis for a novel treatment strategy against Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Cell Death; Cells, Cultured; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Galantamine; Glutamates; Humans; Indans; Neurons; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Piperidines; Rats; Receptors, Nicotinic; Tacrine

So far no causal therapies are available for the treatment of Alzheimer's disease. However, four drugs, namely donepezil, rivastigmine, galantamine and memantine, have been licensed for treating the symptoms of the disease.. To systematically review the efficacy and side-effects of these drugs.. With the help of Pubmed, Medline and the Cochrane Library the literature was searched systematically.. Cholinesterase-inhibitors and memantine do have a beneficial effect on cognition and daily functioning. The effect, however, is limited and the cholinesterase-inhibitors in particular frequently have side-effects.. Treatment with the new anti-Alzheimer drugs demands a careful and realistic approach. The drugs should not be prescribed in isolation but the treatment needs to be embedded in the entire set of currently available psychosocial intervention techniques.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Memantine; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

In Denmark, Alzheimer drugs have been registered since 1997. Three cholinesterase inhibitors (donepezil, rivastigmin og galantamin) are approved mild to moderate Alzheimer's disease and one partial NMDA receptor antagonist (memantin) with the indication moderate to severe Alzheimer's disease. The treatment is symptomatic with a parallel shift of the course. The life expectancy does not seem to be altered. There is documented effect on the cholinesterase inhibitors of up to two years and for memantine for 6 months. New disease modifying agents are under clinical development.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Dementia, Vascular; Disease Progression; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Lewy Body Disease; Memantine; Nootropic Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

As a group, strains of laboratory mice carrying Alzheimer's disease (AD)-related transgenes are currently the most widely studied animal models of AD. Many AD mouse models carrying the same or similar transgene constructs demonstrate strikingly different phenotypic responses to transgene expression, mimicking the apparent genetic complexity of AD pathogenesis seen in the human population. Genetic differences between the numerous mouse model strains used for AD research can significantly affect correct interpretation and cross-comparison of experimental findings, making genetic background an important consideration for all work in mouse models of AD. Furthermore, because of the potential for discovering novel genetic modifiers of AD pathogenesis, the effects of genetic background on AD phenotypes in the mouse can prove a worthwhile subject of study in their own right. This review discusses the implications of genetic modifiers for mouse and human AD research, and summarizes recent findings identifying significant roles for genetic background in modifying important phenotypes in AD mouse models, including premature death, amyloid deposition, tau hyperphosphorylation, and responsiveness to environmental or treatment interventions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Environment; Humans; Mice; Mice, Transgenic; Phenotype; Phosphorylation; Piperidines; Pyridines; tau Proteins

Mild cognitive impairment (MCI) is a clinical syndrome thought to represent the transition between normal function and dementia. This review describes data that support the existence of such a transitional phase, outlines the heterogeneity of MCI and how that has influenced the evolving concept of MCI, and discusses the impact of heterogeneity on recent MCI clinical trials.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Models, Psychological; Neuropsychological Tests; Piperidines; Syndrome; Terminology as Topic; Treatment Outcome

Topics: Alzheimer Disease; Dementia; Donepezil; Estrogen Replacement Therapy; Humans; Indans; Magnetic Resonance Imaging; Mental Status Schedule; Nootropic Agents; Piperidines; Positron-Emission Tomography; Randomized Controlled Trials as Topic; Risk Factors; Sensitivity and Specificity

Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity. They are the only class of compounds known that may pharmacologically separate AMPA subtypes.. This manuscript will review preclinical work on positive AMPA modulators, with clinical examples where relevant.. The activity of these compounds appears to be determined by the AMPA receptor subunit composition. Studies have shown that splice variant and/or subunit combinations change the desensitization rate of this receptor. Also, these subunits are heterogeneously expressed across the central nervous system. Therefore, the functional outcome of different positive AMPA modulators could indeed be different. The origins of this pharmacological class come from hippocampal long-term potentiation studies, so quite naturally they were first studied in models of short- and long-term memory (e.g., delayed match to sample, maze performance). In general, these agents were procognitive. However, more recent work with different chemical classes has suggested additional therapeutic effects in models of schizophrenia (e.g., amphetamine locomotor activity), depression (e.g., forced swim test), neuroprotection (e.g., NMDA agonist lesions) and Parkinson's disease (e.g., 6-hydroxydopamine lesion).. In conclusion, positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

Topics: Alzheimer Disease; Animals; Benzothiadiazines; Cognition; Dioxoles; Humans; Long-Term Potentiation; Memory; Neuroprotective Agents; Piperidines; Protein Subunits; Receptors, AMPA; Schizophrenia

This review was conducted in order to determine the efficacy of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease, and also to determine whether galantamine was a superior pharmacological intervention. Meta-analytic methods were used to analyse the data from eight empirical studies which met the inclusion criteria specified. By finding the mean effect sizes of the treatment on the outcome measures of cognition, it was determined that neither drug was greatly efficacious. However, this result does not necessarily diminish the practical value of the drug. It was also found that galantamine was no better than donepezil at treating cognitive decline in AD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Male; Nootropic Agents; Piperidines; Treatment Outcome

Alzheimer's disease (AD) and vascular dementia (VaD) are both associated with deficits in cholinergic neurotransmission that are amenable to therapeutic intervention. The cholinesterase inhibitor, donepezil, is clinically effective in both AD and VaD. Results from a 10-study metaanalysis of donepezil (5 or 10 mg/day) in AD and a two-study combined analysis of donepezil (5 or 10 mg/day) in VaD are presented to compare patient characteristics and donepezil treatment outcomes. The analyzed studies were randomized, placebo-controlled, and of up to 24 weeks duration. In both AD and VaD, donepezil provided significant benefits compared with placebo on measures of cognition and global function. Placebo-treated AD patients showed a decline in cognition and global function, whereas placebo-treated VaD patients remained stable, suggesting treatment effects of donepezil in VaD were driven by improvement rather than stabilization or reduced decline. More VaD patients than AD patients received concomitant medications. Cardiovascular adverse events were more common in VaD than AD patients but were not increased by donepezil. In conclusion, although there are differences between AD and VaD patients in comorbid conditions and concomitant medications, donepezil is effective and well tolerated in both types of dementia.

Topics: Aged; Alzheimer Disease; Cognition; Dementia, Vascular; Donepezil; Female; Humans; Indans; Male; Multicenter Studies as Topic; Neuropsychological Tests; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Dementia associated with probable Alzheimer's disease (AD) is one of the most common types of dementia. Patients with AD often have cholinergic deficits in association with the disease. The cholinesterase inhibitors donepezil hydrochloride, galantamine hydrobromide, and rivastigmine tartrate are the current mainstays of symptomatic treatment for patients with AD. In clinical trials for all three agents, beneficial effects on standard measures of cognitive and global function have been observed in patients with mild to moderate AD. Although none of the cholinesterase inhibitors has been approved for treatment of patients in advanced stages of AD, all three agents have had beneficial cognitive effects among patients with less severe forms of the disease. The author provides information on recommended dosing for all three medications, noting that cholinesterase inhibitors must be titrated carefully. When administered with caution, galantamine, rivastigmine, and donepezil are generally well-tolerated pharmacologic treatment options. The author notes that, after patients and their caregivers understand that no change in status is considered an "improvement" and a desirable clinical outcome for patients with AD, if no benefits are achieved with the use of one cholinesterase inhibitor, switching to another medication in this class might be beneficial. The author further suggests that the benefits found in cholinesterase inhibitors for patients with AD might also be applicable to patients with other types of dementia such as vascular dementia and dementia with Lewy bodies as cholinergic deficits have been reported in association with these types of dementia as well.

Topics: Acetylcholine; Acetylcholinesterase; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cost of Illness; Dementia; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Severity of Illness Index

The cholinesterase inhibitors (ChE-Is)--rivastigmine, donepezil and galantamine--demonstrated efficacy in large, 6-month, double-blind, placebo-controlled trials, and are widely used for the symptomatic treatment of patients with mild-to-moderate Alzheimer's disease (AD). Over the past few years, data have emerged, suggesting that these agents may have long-term benefits. These data have been summarized in this study, followed by an interpretation of clinical relevance. Data were identified by searches of Medline((R)) and references from relevant English-language articles. The search words 'Alzheimer', 'donepezil', 'rivastigmine', 'galantamine' and 'long term' were used. In addition, recent data presented at international congresses and/or provided by colleagues in this field of research were included in order to ensure maximum topicality. Data are available showing cognitive performance in patients remaining on rivastigmine for up to 5 years (n = 83), donepezil for up to 4.9 years (n = 18) and galantamine for up to 4 years (n = 185). Most of these data come from open-label studies and need to be interpreted with caution. The data appear to suggest that patients, caregivers and physicians will still see some decline on ChE-Is after a period of stabilization, but this may be slower and later than expected if the patients were left untreated. This applies across all domains of AD - not simply cognition - and function can be relatively preserved, even if cognitive scores are falling. Despite the limitations of current data, the information reviewed in this study may help practising doctors assess the long-term value of ChE-Is in this consistently progressive disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Humans; Indans; Long-Term Care; Phenylcarbamates; Piperidines; Rivastigmine

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Community Mental Health Services; Diagnosis, Differential; Donepezil; Family; Female; Humans; Indans; Lewy Body Disease; Male; Memory; Piperidines; Social Support; Tomography, Emission-Computed, Single-Photon

The introduction of new therapies into the clinical arena often requires that prescribing clinicians determine how these new treatments should be integrated into an existing standard of care, typically with little more than clinical trial data to guide them. However, trial outcome measures may not always translate easily into useful information for the practicing physician. Since the publication of dementia treatment guidelines in 2001, new data on Alzheimer's disease (AD) therapies have become available. Notably, memantine has emerged as the first medication indicated for the moderate-to-severe stages of AD. This review summarizes pivotal clinical trial data on memantine in the treatment of moderate-to-severe AD and describes how these results may be interpreted for use in the clinical treatment setting. The studies showed that memantine, both alone and in combination with donepezil, was associated with positive, clinically relevant effects on cognitive and functional ability. Further, memantine in combination with donepezil also was significantly better than donepezil alone in management of behavioral symptoms. This review will conclude with a discussion of how new data on AD treatments will potentially change current treatment parameters.

Topics: Aged; Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Female; Humans; Indans; Male; Memantine; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

Cholinesterase inhibitors and memantine have been shown to improve symptoms associated with AD. Mechanisms of action and the pathophysiologic targets are distinct for the 2 classes, but clinical outcomes demonstrate both medications improve patient symptomatology. In addition, memantine and a ChEI appear to produce an additive effect resulting in a well-tolerated, effective treatment strategy.

Topics: Acetylcholine; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Disease Management; Donepezil; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Galantamine; Glutamic Acid; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Severity of Illness Index; Tacrine; Treatment Outcome

Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.. The terms "donepezil", "rivastigmine", and "galantamine", limited by "randomized-controlled-trials" were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language.. All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality.. 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale--cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws--for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation.. Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Defining the regions of the brain displaying the neuropathological lesions that cause Alzheimer's disease (AD) will facilitate deeper investigation into their pathophysiology. In addition, this would allow the effects of AD treatment to be specifically monitored in those regions. Cognitive decline in AD begins with failings of episodic memory and spatial orientation in patients with very mild AD. Clinical and experimental data show that the brain regions primarily involved in memory impairment early in AD are the hippocampus and the medial temporal lobe. Is it possible to prevent the development of pathophysiology in these regions? The neuroprotective effect of cholinesterase inhibitors has been demonstrated in a number of different models, including protection of cortical neurons in models of oxygen-glucose deprivation and glutamate-induced toxicity, and protection against the effects of hippocampal mitochondrial dysfunction in transgenic mouse models of AD. These preclinical data are supported by extensive clinical data indicating that maximum benefit is gained through early initiation of treatment with donepezil and suggest that the benefits afforded by donepezil may extend beyond those of a purely symptomatic treatment.

Topics: Aged; Alzheimer Disease; Brain; Cholinergic Agents; Cholinesterase Inhibitors; Dementia; Donepezil; Humans; Hypoxia, Brain; Indans; Nervous System; Piperidines

The purpose of this review was to summarize research on the clinical benefits of early treatment for Alzheimer's disease via a focused discussion of data on donepezil. Well-controlled clinical trials demonstrate that donepezil is effective in stabilizing or slowing progressive decline in cognition, function, and behavior. Several studies reveal statistically significant and clinically meaningful advantages to initiating treatment early in the course of the disease. Benefits of donepezil treatment include behavioral stabilization and preserved independence, in addition to slowed cognitive decline. Epidemiologic studies and evidence from histopathology underlie a rationale for treating patients who are cognitively impaired but do not have dementia. Clinical trials in such patients indicate that treating patients with mild cognitive impairment (MCI) may delay the onset of Alzheimer's dementia. Substantial evidence favors initiating treatment early in the course of dementia and reinforces the necessity to assess behavior and activities of daily living to accurately evaluate treatment response. Results of early studies of donepezil in MCI are promising and suggest directions for further research.

Topics: Aged; Alzheimer Disease; Cerebral Infarction; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Today drug therapy of dementia in elderly patients is possible. Owing to a huge increase in the number of elderly people throughout the Western world in the coming years, evidence-based treatment of dementia in this group is needed. The article reviews double-blind, randomized trials on the effect in dementia of donepezil, galantamine, rivastigmine and memantine up to 2003. A total of 27 studies were included. Donepezil, galantamine, rivastigmine and memantine improve cognition and the global level of functioning in mild to moderate Alzheimer's disease (AD). Most evidence exists for donepezil and galantamine. The effect of rivastigmine is best documented in Lewy body dementia (LB). Galantamine, memantine and donepezil may improve cognition in vascular dementia (VD). Galantamine may improve behavioural psychological symptoms of dementia (BPSD). No solid evidence for drug therapy in severe dementia exists. Elderly patients with mild to moderate AD should be offered drug therapy. One should also consider expanding the indication of dementia treatment to LB and VD. An international consensus on what primary efficacy variables to use is needed.

Topics: Aged; Alzheimer Disease; Dementia; Donepezil; Galantamine; Humans; Indans; Memantine; Neuroprotective Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Topics: Alzheimer Disease; Benzodiazepines; Dementia; Donepezil; Galantamine; Ginkgo biloba; Humans; Indans; Memantine; Nootropic Agents; Olanzapine; Phenylcarbamates; Physostigmine; Phytotherapy; Piperidines; Rivastigmine; Selegiline; Tacrine

Donepezil is a selective acetylcholinesterase inhibitor that is widely prescribed for Alzheimer's disease (AD). It has been shown to be of benefit in mild, moderate and severe stages of AD, vascular dementia and dementia associated with Parkinson's disease. Donepezil is absorbed slowly, but completely, from the gut, reaching peak plasma levels in 3-4 h and, with daily dosing, steady-state concentration in 15-21 days. Within a relatively narrow range, there is a linear relationship between dose and pharmacodynamic effects, measured as red blood cell acetylcholinesterase inhibition and clinical efficacy. Donepezil is principally excreted unchanged in the urine, but there is also hepatic metabolism; some of its metabolites may be active. Despite being 96% bound to plasma proteins, it has few interactions with other drugs, and the 5-mg dose can be given safely to patients with mild-to-moderate hepatic and renal -disease. Side effects, which are mainly a consequence of its cholinomimetic mechanism of action, are usually mild and transient. Although donepezil was originally developed to inhibit the breakdown of the neurotransmitter acetylcholine as symptomatic therapy for AD, recent studies raise the possibility of other effects this drug has on the pathogenesis of AD.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

This article reviews the piperidine derivative, donepezil hydrochloride (E2020, Aricept), a reversible central acetylcholinesterase inhibitor currently approved for treatment of mild-to-moderate Alzheimer's disease. Donepezil is well absorbed orally, unaffected by food or by time of administration; it reaches therapeutic levels in doses of 5-10 mg/day and peak plasma concentrations are obtained 3-4 h after oral administration. A single bedtime dose is recommended due to the long elimination half-life of the drug (70 h). Donepezil does not cause liver toxicity or significant drug interactions and is relatively well-tolerated. Initial side effects include nausea, vomiting, diarrhoea, insomnia, muscle cramps, fatigue, anorexia and syncope. Caution is advised in patients with bradycardia. Long-term use of donepezil in AD has been found to delay nursing-home placement and to result in caregiver respite. Donepezil also slows deterioration of cognition and global function in patients with moderate-to-severe AD, with improvement of abnormal behaviours. In addition to AD, donepezil demonstrates significant improvement in cognition, global function and activities of daily living in comparison with placebo-treated patients with vascular dementia and has potential therapeutic benefit for other neurological conditions.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Piperidines; Psychiatric Status Rating Scales; Receptors, Cholinergic; Schizophrenia

Alzheimer's Disease (AD) is the most common cause for dementia in our ageing population, which leads to a slowly progressive, irretrievable ruination of mental function. The destructive, primarily degenerative condition is neuropathologically characterized by the formation of amyloid plaques, neurofibrillary tangles and loss of neurons and synapses as well. Research during the past twenty years revealed early in the disease course a degeneration of cholinergic nuclei localised in the basal forebrain. Impairment of this cholinergic system, which projects into large areas of the limbic system and the neocortex is followed by disturbance of attentional processes and cognitive decline. The link between the cholinergic dysfunction and cognitive impairment has focused large scientific efforts to understand the neurobiology of cognition and to develop therapeutic tools for the fight against Alzheimer's Disease. Acetylcholinesterase inhibitors are currently the best established treatment for this devastating disease. This review describes historical aspects and the vast range of use of cholinesterase inhibitors in traditional societies and industrial nations. Second, the rational basis will be outlined for their development as medication, the so-called cholinergic hypotheses of AD. Third, acetylcholinesterase inhibitors currently available for the treatment of AD will be reviewed. This includes donepezil, galanthamine and rivastigmine. Tacrine, the first acetylcholinesterase inhibitor who became available in 1993 as a treatment for AD, does not play an essential role anymore besides his historical value, because of its hepatotoxicity. Although acetylcholinesterase inhibitors are no cure, these drugs can delay the progress of mental deterioration, reduce neuropsychiatric symptoms and therefore represent a rational therapeutic approach to the treatment of Alzheimer's Disease.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

Topics: Acetylcholine; Alzheimer Disease; Antidepressive Agents; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Haloperidol; Humans; Hydroxyzine; Hypnotics and Sedatives; Indans; Injections, Intramuscular; Physostigmine; Piperidines; Selective Serotonin Reuptake Inhibitors; Tacrine

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Humans; Indans; Mental Processes; Piperidines; Prognosis; Risk; Selegiline; Survival Rate; Time Factors; Vitamin E

Topics: Aged; Alzheimer Disease; Cerebral Cortex; Cholinesterase Inhibitors; Diagnosis, Differential; Diagnostic and Statistical Manual of Mental Disorders; Diet Therapy; Donepezil; Exercise Therapy; Hippocampus; Humans; Indans; Memory; Piperidines; Platelet Aggregation Inhibitors; Psychotherapy; Reference Standards

The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Animals; Behavioral Symptoms; Brain; Butyrylcholinesterase; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Tolerance; Galantamine; Humans; Indans; Piperidines; Rats; Receptors, Nicotinic

Topics: Aged; Alzheimer Disease; Alzheimer Vaccines; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cholinesterase Inhibitors; Donepezil; Drug Design; Endopeptidases; Enzyme Inhibitors; Galantamine; Humans; Indans; Piperidines; Severity of Illness Index

Alzheimer's disease (AD) is the most common etiology of dementia. Its incidence increases with age following an exponential trend of line between 60 and 90 years old. Anti-cholinesterasic drugs reduce modestly AD symptoms. However, they have no basic impact on the pathological evolution of the disease. Memantine offers another therapeutic approach in AD with a dissimilar mechanism of action, confronting neurotoxic effects of glutamate overload. It prevents the elevation of glutamate which destroys cholinergic neurons by inhibiting the N-methyl-D-aspartate (NMDA) receptors. Its clinical efficiency has been demonstrated during 28 weeks with 20 mg/day, in patients presenting moderate or severe AD and mild or moderately vascular dementia. Its use in association with anti-cholinesterasic (donepezil) revealed more interesting results with a significant improvement of cognitive functions and activities of daily live, compared to association placebo-donepezil. We are waiting for results of further lenghter studies, including more, well-defined, patients.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Excitatory Amino Acid Antagonists; Glutamic Acid; Glutamine; Humans; Indans; Memantine; Piperidines

The management of dementia in Alzheimer's disease has dramatically changed since the development of anti-dementia drugs. However, there is limited information available regarding the bio-medical aspects of the differing drugs; particularly relating to adults with intellectual disability. Indeed the information available for the intellectual disabled population is limited to adults with Down syndrome. This review highlights the important pharmacological and clinical aspects of donepezil, rivastigmine, galantamine and memantine and supports the view that such drugs play an important part in the management of dementia in adults with intellectual disability. Future clinical and research issues are discussed.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine

Research into Alzheimer's disease (AD) pathology has identified several underlying disease processes that are potential targets for drug discovery and development. One strategy targets glutamatergic neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptor. Therapeutic intervention with high-affinity NMDA receptor antagonists, such as phencyclidine (PCP) and MK-801, is not practical due to adverse side effects; however, a low-moderate affinity, uncompetitive and strongly voltage-dependent NMDA receptor antagonist, memantine (NamendaTM), is well tolerated and recently has been approved by the U.S. Food and Drug Administration for the treatment of moderate to severe AD. Clinical results support NMDA receptor antagonism as a viable therapeutic strategy for AD and suggest that this novel pharmacologic approach, either alone or in combination with other drugs, is likely to significantly impact the current AD treatment paradigm.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Indans; Memantine; Piperidines; Receptors, N-Methyl-D-Aspartate

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinergic Agents; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Research Design; Rivastigmine

Data were derived from the Cochrane Collaboration meta-analyses of the efficacies of ginkgo, donepezil, rivastigmine and galantamine on changes in cognitive function in patients with dementia and, where necessary, were transformed to standardized mean differences. The proportion of patients discontinuing trials was used as a proxy measure of tolerability. Outcomes were assessed after 6 months of treatment. Trial data for cholinesterase inhibitors were more consistent than those for ginkgo, particularly regarding patient populations and outcome measures. Significant benefits on cognition vs. placebo were seen with donepezil, 5 and 10 mg, rivastigmine, 6-12 mg, and galantamine, 16 and 24 mg. Significant benefit vs. placebo with ginkgo was seen only when all doses were pooled. Similar proportions of patients discontinued treatment with ginkgo and placebo. Cholinesterase inhibitors were also well tolerated, although a significantly greater proportion of patients receiving active treatment discontinued vs. placebo with some doses. An evidence-based medicine approach, taking into account the quality of clinical trials, is essential when assessing the safety and efficacy of medications.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Ginkgo biloba; Humans; Indans; Multicenter Studies as Topic; Neuropsychological Tests; Nootropic Agents; Phenylcarbamates; Piperidines; Plant Extracts; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD).. A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events.. A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration.. Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic

Enhancement of the activity of cholinergic neurons has been regarded as one of the most promising methods for treating Alzheimer's disease (AD). Donepezil is a representative acetylcholinesterase inhibitor (AChEI) and is a great success among the AChEI drugs. AChEIs are being studied for other mechanisms of action, neuroprotective action, and nicotinic receptor enhancement. AD is a type of neurodegenerative disease and AChEIs have been found to be an effective anti-AD medication. AChEI can alleviate the symptoms and delay the progression of AD, but it cannot cure the disease. However, AChEIs are now the subject of a wide range of clinical studies for other diseases, for example, other types of dementia (such as Lewy body disease, cerebral vascular dementia, and Parkinson's disease dementia), and migraine. These drugs are also being studied as a combination therapy, for example, with an antioxidant, SERM, and NMDA antagonist.

Topics: Acetylcholine; Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Design; Humans; Indans; Neuroprotective Agents; Neurotransmitter Agents; Piperidines

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.

Topics: Aged; Alzheimer Disease; Animals; Basal Ganglia Diseases; Bradycardia; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Double-Blind Method; Drug Evaluation; Drug Interactions; Female; Galantamine; Gastrointestinal Diseases; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Memantine; Meta-Analysis as Topic; Mice; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Single-Blind Method; Sleep Wake Disorders; Treatment Outcome

Objective of this systematic review is to determine the level of scientific evidence for the use of Donepezil in Alzheimer's Disease.. Ten randomised controlled double-blind trials testing Donepezil versus Placebo were identified in MEDLINE and EMBASE. All ten trials were included in this systematic review. Following a detailed catalogue of criteria the methodological standard of the ten trials was assessed.. The authors of eight trials postulated statistically significant differences in favour of Donepezil. Unfortunately, the methodological standard of all studies was insufficient. The methodological shortcomings are discussed in detail.. With regard to severe methodological deficiencies the evidence for the use of Donepezil in moderate to severe Alzheimer's Disease is lacking. But even if the trials had been conducted in a methodologically correct way the clinical relevance of the postulated positive results would have to be questioned.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Research Design

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Piperidines

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug-drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single- and multiple-dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug-drug interactions. The incidence of weight loss is very similar between donepezil- and placebo-treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day(-1) or switching to morning dosing can reduce these events to the levels of placebo-treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Piperidines; Sleep Wake Disorders; Weight Loss

No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the alpha4beta2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G(s) proteins. The alpha7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the alpha4beta2 receptor and potentiated NMDA currents with the maximum effect at 1 microM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.

Topics: Alzheimer Disease; Animals; Donepezil; Galantamine; Humans; Indans; Nicotinic Agonists; Nootropic Agents; Piperidines; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

To evaluate the representation of frail older adults in randomized controlled trials (RCTs), and to assess consequences of under representation by analyzing drug discontinuation rates.. A cohort of older adults newly dispensed donepezil in Ontario between September 2001 and March 2002 was constructed using administrative data. A systematic review of the literature identified RCTs of donepezil. Patients dispensed donepezil were then compared to clinical trial subjects. Discontinuation rates were examined for patients with and without potential contraindications to this drug.. There were 6,424 older adults in the Ontario cohort with new claims for donepezil. Ten RCTs evaluating the use of donepezil were identified (n = 3,423). Between 51% and 78% of the Ontario cohort would have been ineligible for RCT enrollment. Patients dispensed donepezil were older (80.3 vs. 73.7 years, p < 0.001) and more likely to be in long-term care (14.1 vs. 7.1%, p < 0.001) than RCT subjects. Overall, 27.8% of the Ontario cohort discontinued donepezil within seven months of initial prescription. Discontinuation rates were significantly higher for patients with a history of obstructive lung disease, active cardiovascular disease, or Parkinsonism.. Fewer than half of the older adults dispensed donepezil in Ontario would have been eligible to participate in the RCTs that established the efficacy of this drug. Discontinuation rates were higher among patient groups not represented in the trials. Clinicians should carefully assess the potential risks and benefits of such drug therapies for older patients with dementia.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Dementia; Donepezil; Female; Humans; Indans; Male; Middle Aged; Ontario; Patient Dropouts; Patient Selection; Piperidines; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic

Topics: Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Cognition; Dementia; Donepezil; Galantamine; Ginkgo biloba; Haloperidol; Humans; Indans; Memantine; Olanzapine; Phenylcarbamates; Physostigmine; Phytotherapy; Piperidines; Risperidone; Rivastigmine; Selegiline; Tacrine; Vitamin E

Alzheimer's disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer's disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer's disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer's disease.

Topics: Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Diarrhea; Donepezil; Drug Interactions; Humans; Indans; Nausea; Piperidines; Treatment Outcome; Vomiting

Topics: Alzheimer Disease; Dementia; Donepezil; Galantamine; Ginkgo biloba; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Physostigmine; Phytotherapy; Piperidines; Rivastigmine; Tacrine

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but donepezil (E2020, Aricept) is safer.. The objective of this review is to assess whether donepezil improves the well-being of patients with dementia due to Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 9 October 2002. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease.. Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated.. Sixteen trials are included, involving 4365 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are unavailable. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo (-2.02 points on the ADAS-Cog scale WMD, 95%CI -2.77 to -1.26, p<0.00001; -2.92 points on the ADAS-Cog scale WMD 95% CI -3.74 to -2.10, p<0.00001)and for 10 mg/day donepezil compared with placebo at 52 weeks (1.84MMSE points, 95% CI, 0.53 to3.15, p=0.006). The results show some improvement in global clinical state (assessed by an independent clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 12 and 24 weeks. Benefits of treatment were also seen on measures of activities of daily living and behaviour. There were significantly more withdrawals before the end of treatment from the 10 mg/day (but not the 5 mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day.A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10 mg/day group compared with placebo and the 5 mg/day group, but very few patients left a trial as a direct result of the intervention.. People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. Although no significant changes were measured on a patient-rated quality of life scales, the instrument used was crude and possibly unsuited to the task. The additional data now available confirm the findings of the previous issue of this review and extend the evidence for the effectiveness of treatment to at least 52 weeks and to those with severe dementia. More evidence is still needed for the economic efficacy of donepezil, but clinical efficacy is confirmed.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

The current recommended standard of care for the symptomatic treatment of mild to moderate Alzheimer's disease is cholinesterase inhibitors. In short- and long-term studies, the 3 cholinesterase inhibitors most commonly used, donepezil, rivastigmine, and galantamine, have demonstrated efficacy in improving not only cognition but also function and behavior in patients suffering from mild to severe cases of Alzheimer's disease and other forms of dementia. However, the benefits of cholinesterase inhibitors in treating the broad spectrum of symptoms associated with Alzheimer's disease are not sustained indefinitely, and the illness continues to progress even while patients are receiving treatment. Additionally, while temporary stabilization may occur, there is typically only a modest improvement from baseline, and side effects from treatment with cholinesterase inhibitors can be too severe for some patients to tolerate. Therefore, additional therapies for Alzheimer's disease still need to be developed that include more tolerable agents with alternative mechanisms of action and broader efficacy.

Topics: Alzheimer Disease; Behavioral Symptoms; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Multicenter Studies as Topic; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

Topics: Alzheimer Disease; Anticonvulsants; Antipsychotic Agents; Carbamates; Donepezil; Galantamine; Ginkgo biloba; Humans; Indans; Nootropic Agents; Phenylcarbamates; Phosphatidylcholines; Physostigmine; Phytotherapy; Piperidines; Rivastigmine; Tacrine; Vitamin E

Several clinical trials have been conducted over a period of many years reporting the benefits of donepezil for Alzheimer disease (AD) patients.. Randomized, double-blind, placebo-controlled stud-ies of 3-6 months' duration have demonstrated significant benefits for 5mg/D and 10 mg/D of donepezil compared with placebo. The results include benefits for cognition, activities of daily living, and abnormal behaviors associated with AD. The benefits are independently detectable by clinicians based upon direct patient assessment with input from a caregiver. Populations studied include mild-to-moderate AD patients, moderate-to-severe AD patients, nursing home patients, and outpatients. Open label studies that took place after the double-blind phase and 1-year double-blind, placebo-controlled trials demonstrated that benefits persist for more than a year. Adverse event (AE) profiles, generated in studies that used a 1-week forced dose titration, show a low incidence of primarily cholinegic AEs such as nausea and diarrhea. There are no significant laboratory AEs or drug interactions. Recent studies have assessed the benefits of donepezil inpatients with ischemic vascular dementia, mild cognitive impairment, and other cognitive disorders.. Donepezil benefits AD patients by improving, stabilizing, or retarding decline of the cognitive, functional, and possibly behavioral features of the disease. The duration of benefits is not known but extends beyond 1 year. The drug is safe and well tolerated.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines

M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjøgren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, in mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in reversal learning. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cell Death; Disease Models, Animal; Down-Regulation; Humans; Memory Disorders; Mice; Muscarinic Agonists; Oxidative Stress; Piperidines; Quinuclidines; Receptor, Muscarinic M1; Spiro Compounds; tau Proteins; Thiazoles; Thiophenes

In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are being investigated in ongoing clinical and experimental studies. Presently available treatments should be initiated early on, and applied as long as needed, which requires the earliest possible clinical diagnosis by the primary-care physician. The results of initial studies reveal an effect of antidementia agents also in mixed Alzheimer's and vascular dementia, as well as vascular and lewy-body dementia. Efforts to obtain approval for these indications are underway.

Topics: Activities of Daily Living; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Controlled Clinical Trials as Topic; Dementia; Dementia, Vascular; Donepezil; Dopamine Agents; Female; Galantamine; Ginkgo biloba; Humans; Indans; Male; Memantine; Meta-Analysis as Topic; Multicenter Studies as Topic; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Placebos; Plant Preparations; Prospective Studies; Rivastigmine; Tacrine; Time Factors

Subcortical Vascular Encephalopathy (SVE) is an increasingly diagnosed disease with an enormous socio-economic impact. SVE leads to a progressive disability with immobilisation because of gait- and postural disturbances and with a progressive subcortical vascular dementia which is composed of cognitive slowing, loss of initiative and forgetfulness. A valid diagnosis has become possible only through a clear improvement in cerebral imaging techniques developed in the eighties. This explains, why so many different and confusing terms exist to describe the syndrome. The pathophysiological basis is a cerebral microangiopathy leading to lacunar infarcts and to diffuse ischemic white matter lesions, often occurring side by side. Taken together, such lesions lead to an interruption of parallel functional prefrontal-subcortical circuits, which are essential for psychomotor function. Neuroradiological methods like computed tomography (CT) and magnetic resonance imaging (MRI) are essential for the diagnosis. The prognosis is rather unfavourable. Several consensus meetings have established clinical and diagnostic criteria, which can serve as a basis for therapeutical trials. This review delineates diagnostic milestones, discusses etiological and pathophysiological mechanisms, and displays therapeutical options.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amantadine; Brain; Carbamates; Clinical Trials as Topic; Dementia, Vascular; Diagnosis, Differential; Donepezil; Dopamine Agents; Gait; Humans; Indans; Magnetic Resonance Imaging; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Pilot Projects; Piperidines; Placebos; Prognosis; Risk Factors; Rivastigmine; Time Factors; Tomography, X-Ray Computed; Walking

Topics: Alzheimer Disease; Animals; Carbamates; Cholinesterase Inhibitors; Cognition; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Rivastigmine

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Female; Humans; Indans; Male; Nootropic Agents; Phenylcarbamates; Piperidines; Practice Guidelines as Topic; Rivastigmine; Treatment Failure; Treatment Outcome

Various drugs have been approved for the treatment of Alzheimer's disease (AD) in the United States and Canada, including donepezil and rivastigmine, although questions remain as to their efficacy, effectiveness, and long-term benefits.. The goal of this study was to conduct a best-evidence synthesis of data on the efficacy and cost-effectiveness of donepezil and rivastigmine in the treatment of AD.. Relevant published randomized controlled trials (RCTs) and Phase IV open-label extension studies (excluding abstracts) were identified through searches of MEDLINE, HealthSTAR, and PsycINFO for the period January 1984 to October 2001. The bibliographies of retrieved articles were searched for additional publications. For inclusion in the best-evidence synthesis, clinical trials had to pass a blinded quality assessment (score > or =5 on the Jadad scale) and use National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria. Economic studies were selected using National Health Service Centre for Reviews and Dissemination criteria for reporting critical summaries of economic evaluations.. Nine RCTs of donepezil and 2 of rivastigmine were identified and met inclusion criteria for the best-evidence synthesis. Eight donepezil trials and both rivastigmine trials included patients with mild AD (Mini-Mental State Examination [MMSE] score, 15-27) or moderate AD (MMSE score, 8-14); 1 donepezil trial included patients with moderate or severe AD (MMSE score, 0-7). In the RCTs of donepezil, the mean decrease in scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was greater with active treatment than with placebo (lower scores indicate less cognitive deterioration). In the RCTs of rivastigmine, ADAS-cog scores decreased over the follow-up period with both active treatment and placebo; however, scores decreased more with active treatment. Three Phase IV studies of donepezil and I Phase IV study of rivastigmine were identified. Their results were consistent with those of the RCTs. Ten economic studies (7 donepezil, 3 rivastigmine) were identified and reviewed. In 4 of the donepezil studies and all 3 rivastigmine studies, use of the drug cost less than a no-drug strategy.. The efficacy data indicate that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD. Patients receiving active treatment will have more favorable ADAS-cog scores for at least 6 months, after which their scores will begin to converge with those of patients receiving placebo. Differences in methodology, types of direct or indirect costs included, and sources of cost data made it difficult to compare and synthesize findings of the economic studies; therefore, the cost-effectiveness data are inconclusive.

Topics: Aged; Alzheimer Disease; Canada; Carbamates; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Humans; Indans; Middle Aged; Multicenter Studies as Topic; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Cholinesterase inhibitors are the 'first-line' agents in the treatment of Alzheimer's disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity. Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation. Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses. In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques. The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to

Topics: Aging; Alzheimer Disease; Biological Availability; Carbamates; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Half-Life; Humans; Indans; Intestinal Absorption; Liver; Phenylcarbamates; Piperidines; Protein Binding; Rivastigmine; Tacrine; Tissue Distribution

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Forecasting; Galantamine; Humans; Indans; Male; Phenylcarbamates; Piperidines; Prognosis; Rivastigmine; Severity of Illness Index; Tacrine; Treatment Outcome

Systematic review of the clinical and cost-effectiveness of donepezil, rivastigmine, and galantamine for people suffering from Alzheimer's disease.. Sixteen electronic databases (including MEDLINE, the Cochrane Library, and Embase) and bibliographies of related papers were searched for published/unpublished English language studies, and experts and pharmaceutical companies were consulted for additional information. Randomized controlled trials (RCTs) and economic studies were selected. Clinical effectiveness was assessed on measurement scales assessing progression of Alzheimer's disease on the person's global health, cognition, functional ability, behavior and mood, and quality of life. Cost-effectiveness was presented as incremental cost per year spent in a nonsevere state (by Mini Mental Health State Examination) or quality-adjusted life-year.. Twelve of 15 RCTs included were judged to be of good quality. Although donepezil had beneficial effects in Alzheimer's patients on global health and cognition, rivastigmine on global health, and galantamine on global health, cognition, and functional scales, these improvements were small and may not be clinically significant. Measures of quality of life and behavior and mood were rarely assessed. Adverse effects were usually mild and transient. Cost-effectiveness base case estimates ranged from 2,415 Pounds savings to 49,476 Pounds additional cost (1997 prices) per unit of effect for donepezil and a small savings for rivastigmine. Estimates were not considered robust or generalizable.. Donepezil, rivastigmine, and galantamine appear to have some clinical effect for people with Alzheimer's disease, although the extent to which these translate into real differences in everyday life remains unclear. Due to the nature of current economic studies, cost-effectiveness remains uncertain and the impact on different care sectors has been inadequately investigated. Further research is needed to establish the actual benefits of acetylcholinesterase inhibitors (AChEls) for people with Alzheimer's disease and their caregivers, the relationship of these changes to clinical management, and careful prospective evaluation of resource and budgetary consequences.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Cost of Illness; Cost-Benefit Analysis; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Quality of Life; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

The tolerability and safety of donepezil HCI in patients with mild to moderate Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920) were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse events, physical examinations and clinical laboratory tests were assessed. A high completion rate (79%) was achieved in these trials. Of the 1,291 patients receiving donepezil only, 142 (11%) withdrew because of an adverse event compared with 43 of the 629 (7%) placebo patients. The most common adverse events included nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting, asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on any laboratory evaluations and was not associated with hepatotoxicity. These results demonstrate that donepezil is well tolerated and has a favourable safety profile at clinically effective, once-daily doses of 5 mg and 10 mg.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic

Alzheimer disease(AD) is characterized as neurodegenerative disease showing impairment of cognitive function, death of neuronal cells, numerous numbers of senile plaques and tangle of neurofilaments. There are two different hypotheses that neurotoxicity of aggregated amyloid beta protein(A beta) and hyperphosphorylation of tau protein are the causes of AD. The dysfunction of cholinergic neuronal system is observed in the early stage of AD. Therefore, the strategy to increase of acetylcholine (ACh) level in brain by using ACh esterase inhibitor is mainstream in the present. We have tacrine, donepezil, rivastigmine and galantamine. Tacrine, the first drug for AD, is replaced by other drugs, because of its hepatic toxicity. Galantamine binds allosteric sites of nicotine receptor and stimulates it in addition to its inhibitory effect on ACh esterase. Metamantine was approved in EU in 2002. It is non-competitive inhibitor of NMDA receptors, and dopamine releaser, which has neuroprotective effect. All of the above drugs improve cognitive function of patients, and they could delay hospitalization for 7 months or more. In the present anti-inflammatory drugs, anti-oxidative drugs and estrogen are under investigation. As anti-A beta therapy, inhibitors of beta -and gamma-secretase, A beta aggregation inhibitors, A beta degradation stimulators and A beta vaccination are possible strategies. The inhibitors of tau protein phosphorylation and activators of phosphates could be that of anti-tau protein phosphorylation. Additionally, it is expected to have the strategies such as neuroregeneration by neurotorophic factors and immunopyline ligands, and supply of neuronal cells by gene therapy and human ES cells.

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Carbamates; Cholinesterase Inhibitors; Donepezil; Drug Design; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; tau Proteins

Mild Cognitive Impairment (MCI) is an emerging concept used to describe memory decline and probably attention disturbances in otherwise intellectually intact individuals. MCI may be considered in 12 to 15 p. 100 of the cases as announcing an Alzheimer's Disease (AD). Although still speculative, the debate concerning the drugs susceptible to normalize symptoms of MCI or to stop conversion to AD must be raised. For that purpose, several long term clinical trials are running (antioxidants, nootropics, anticholinesterasics.) and new molecules in the pipe-line should be assessed in patients with the diagnosis of MCI.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dopamine Agonists; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vitamin E

This review provides an overview of the three most widely used cholinesterase (ChE) inhibitors: donepezil, rivastigmine, and galantamine. Differences in pharmacologic profiles will be discussed, and consideration will be given to how such differences may relate to and influence the clinical efficacy and tolerability of the various agents. In addition to providing cognitive benefits in patients with Alzheimer's disease (AD), growing clinical evidence also suggests that ChE inhibitors can produce favorable and clinically relevant effects on neuropsychiatric/behavioral disturbances and activities of daily living. Furthermore, recent data indicate that these agents may be effective at all levels of disease severity and for all rates of disease progression. The clinical utility of ChE inhibitors in a wider spectrum of dementias which share a common cholinergic deficit, such as Lewy body dementia, Parkinson's disease dementia, and vascular dementia, is currently under investigation. Beyond symptomatic relief, data suggest that ChE inhibitors may also slow the underlying disease process. As clinical and research experience with these agents continues to accumulate, the differences in their effects will become more apparent and will help physicians tailor ChE inhibition treatment to the needs of the individual patient.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dose-Response Relationship, Drug; Galantamine; Humans; Indans; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

Topics: Alzheimer Disease; Clinical Trials as Topic; Cognition Disorders; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Adult; Aged; Alzheimer Disease; Amitriptyline; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Clinical Trials as Topic; Cognition; Cohort Studies; Controlled Clinical Trials as Topic; Dementia, Vascular; Donepezil; Female; Fluoxetine; Galantamine; Haloperidol; Hormone Replacement Therapy; Humans; Hydroxychloroquine; Indans; Middle Aged; Nootropic Agents; Piperidines; Placebos; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Time Factors; Trazodone

A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Design; Humans; Indans; Piperidines; Structure-Activity Relationship

Once the clinical diagnosis of Alzheimer's disease has been made, a treatment plan must be developed. This plan should include cholinesterase inhibitor therapy to temporarily improve cognition or slow the rate of cognitive decline, management of comorbid conditions, treatment of behavioral symptoms and mood disorders, provision of support and resources for patient and caregiver, and compliance with state-mandated reporting requirements for driving impairment and elder abuse. The primary caregiver can be a valuable ally in communication, management of care, and implementation of the care plan. Patient symptoms and care needs change as Alzheimer's disease progresses. In the early stage of the disease, the family physician should discuss realistic expectations for drug therapy, solicit patient and family preferences on future care choices, and assist with advance planning for future care challenges. In the middle stage, the patient may exhibit behavioral symptoms that upset the caregiver and are difficult to manage. When the patient is in the advanced stage of Alzheimer's disease, the caregiver may need support to provide for activities of daily living, help in making a difficult placement decision, and guidance in considering terminal care options. Throughout the course of the disease, routine use of community resources allows care to be provided by a network of professionals, many of whom will be specialists in Alzheimer's disease.

Topics: Advance Directives; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Disease Progression; Donepezil; Humans; Indans; Lorazepam; Patient Education as Topic; Phenylcarbamates; Piperidines; Risperidone; Rivastigmine

Behavioural and psychological symptoms of dementia (BPSD) are among the most distressing manifestations of dementia and result in considerable social and economic costs. Practical, non-pharmacological approaches such as environmental and behavioural changes may provide some benefit for patients in managing mild BPSD. In addition, various pharmacological approaches to treatment have been employed, such as neuroleptics and atypical antipsychotics, which differ in neurochemical target and clinical effectiveness. Growing evidence suggests that the neurobiological basis of BPSD in Alzheimer's disease (AD) and related dementias is a loss of cholinergic neurones and a resultant decline in acetylcholine (ACh) in brain regions which regulate behavioural and emotional responses, such as the limbic system. This cholinergic deficit can be partly corrected by inhibiting cholinesterase enzymes (ChEs). Studies of ChE inhibitors have shown positive effects to improve or stabilise existing BPSD and delay the emergence of new behavioural symptoms. In placebo-controlled studies, donepezil has reported efficacy in non-institutionalised moderate to moderately severe patients over a period of 24 weeks, but has failed to demonstrate efficacy in mild to moderate AD and in institutionalised patients with severe disease. Galantamine has been shown to delay the onset of BPSD in mild to moderate AD patients in one placebo-controlled study, and improve BPSD in a similar study of patients with cerebrovascular disease or probable vascular dementia. Studies with rivastigmine have shown efficacy in placebo-controlled studies of mild to moderately severe AD and in patients with Lewy body variant AD. Institutionalised patients with severe disease also show symptomatic benefits in BPSD with rivastigmine, resulting in a reduction in concomitant psychoactive medication use. Symptom complexes responding to ChE inhibitors appear to differ - all agents improve apathy, depression and anxiety, while rivastigmine additionally improves hallucinations and delusions, possibility as a result of dual inhibition of acetylcholinesterase and butyrylcholinesterase. The presence of hallucinations has been shown to predict response to rivastigmine. Accumulating data from studies of ChE inhibitors suggest that early intervention and long-term treatment, in addition to providing cognitive benefits, improves BPSD and offers potential to enhance quality of life. Differences seen between the agents in terms of eff

Topics: Acetylcholine; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Disease Progression; Donepezil; Galantamine; Humans; Indans; Neuroprotective Agents; Phenylcarbamates; Physostigmine; Piperidines; Rivastigmine; Tacrine; Time Factors; Treatment Outcome

There are many agents in clinical use that manipulate central nervous system levels of epinephrine, dopamine, and serotonin. However, development of pharmacological options to manipulate central acetylcholine systems has lagged behind because of poor penetration of the blood-brain barrier and significant peripheral nervous system side effects. Newer agents have demonstrated some efficacy in the management of behavioral and cognitive side effects in Alzheimer's disease, and preliminary data in traumatic brain injury suggest acetylcholine esterase inhibitors may play a significant role in the treatment of this patient population as well.. In this article, the basic neuroanatomy and pharmacology of the central acetylcholine system are reviewed, along with agents currently available for clinical use.

Topics: Administration, Oral; Adult; Aged; Alzheimer Disease; Brain Injuries; Carbamates; Clinical Trials as Topic; Cytidine Diphosphate Choline; Donepezil; Female; Follow-Up Studies; Humans; Indans; Injections, Intravenous; Injury Severity Score; Male; Middle Aged; Parasympathomimetics; Phenylcarbamates; Physostigmine; Piperidines; Rivastigmine; Severity of Illness Index; Tacrine; Treatment Outcome

Recently advances in understanding the molecular basis of Alzheimer's disease have led to the consideration of the relationship between cholinergic inhibitors and amyloid deposition as a new hypothesis for the future rational design of effective anti-Alzheimer drugs. In the present review, the non-cholinergic functions of acetylcholinesterase (AChE) and the therapeutic potential of peripheral and dual binding site AChE inhibitors in delaying the neurodegenerative process will be discussed.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Binding Sites; Carbamates; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Molecular Conformation; Molecular Structure; Phenylcarbamates; Piperidines; Rivastigmine; Structure-Activity Relationship; Tacrine

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and has become an urgent public health problem in most areas of the world. Substantial progress has been made in understanding the basic neurobiology of AD and, as a result, new drugs for its treatment have become available. Cholinesterase inhibitors (ChEIs), which increase the availability of acetylcholine in central synapses, have become the main approach to symptomatic treatment. ChEIs that have been approved or submitted to the US Food and Drug Administration (FDA) include tacrine, donepezil, metrifonate, rivastigmine and galantamine. In this review we discuss their pharmacology, clinical experience to date with their use and their potential benefits or disadvantages. ChEIs have a significant, although modest, effect on the cognitive status of patients with AD. In addition to their effect on cognition, ChEIs have a positive effect on mood and behaviour. Uncertainty remains about the duration of the benefit because few studies of these compounds beyond one year have been published. Although ChEIs are generally well tolerated, all patients should be followed closely for possible adverse effects. There is no substantial difference in the effectivenes of the various ChEIs, however, they may have different safety profiles. We believe the benefits of their use outweigh the risks and costs and, therefore, ChEls should be considered as primary therapy for patients with mild to moderate AD.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cost-Benefit Analysis; Donepezil; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

Alzheimer's disease is the most common cause of dementia and is characterised by an insidious onset and slow deterioration. The estimated prevalence of Alzheimer's disease for a standard health authority (500,000 people) is about 3330. Current service involves a wide range of agencies, and drug therapy for some patients.. To provide a rapid and systematic review of the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine in the symptomatic treatment of people suffering from Alzheimer's disease.. A systematic review of the literature was undertaken. METHODS - DATA SOURCES: Searches were made of electronic databases, including MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effectiveness, NHS Economic Evaluation Database, National Research Register, Science Citation Index, BIOSIS, EconLit, MRC Trials database, Early Warning System, Current Controlled Trials, TOXLINE, Index of Scientific and Technical Proceedings, and Getting Easier Access to Reviews. All sources were searched over the period covered by the databases up to March/July 2000. Bibliographies of related papers were assessed for relevant studies and experts were contacted for advice and peer review, and to identify additional published and unpublished references. Manufacturer submissions to the National Institute for Clinical Excellence (NICE) were reviewed.. Studies were included if they fulfilled the following criteria: (1) INTERVENTION: donepezil, rivastigmine or galantamine used to treat Alzheimer's disease. (2) PARTICIPANTS: people diagnosed with Alzheimer's disease who meet the criteria for treatment with donepezil, rivastigmine and galantamine. (3) OUTCOMES: measures assessing changes in cognition, function, behaviour and mood, quality of life (including studies assessing carer well-being and carer-input), and time to institutionalisation. (4) DESIGN: systematic reviews of randomised controlled trials (RCTs) and RCTs comparing donepezil, rivastigmine or galantamine with placebo or each other or non-drug comparators were included in the review of effectiveness. Economic studies of donepezil, rivastigmine or galantamine used to treat Alzheimer's disease that included a comparator (or placebo) and both the costs and consequence (outcomes) of treatment were included in the review of cost-effectiveness. Studies in non-English language, and abstracts and conference poster presentations of systematic reviews, RCTs and economic evaluations were excluded. Two reviewers identified studies by independently screening study titles and abstracts, and then by examining the full text of selected studies to decide inclusion. METHODS - DATA EXTRACTION AND QUALITY ASSESSMENT: Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, with any disagreements resolved through discussion. The quality of RCTs was assessed using the Jadad scale and the quality of systematic reviews was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. The quality of economic evaluation studies was assessed by their internal validity (i.e. the methods used) using a standard checklist, and external validity (i.e. the generalisability of the economic study to the population of interest) using a series of relevant questions. METHODS - DATA SYNTHESIS: The clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine were synthesised through a narrative review with full tabulation of results of all included studies. In the economic evaluation, the reviewers assessed whether adjustments could be made to existing models to reflect the current situation in England and Wales. RESULTS - CLINICAL EFFECTIVENESS: (1) Donepezil--three systematic reviews and five RCTs (plus four studies from industry (unpublished data, submitted as commercial in confidence

Topics: Alzheimer Disease; Carbamates; Cost-Benefit Analysis; Donepezil; Galantamine; Humans; Indans; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine

Topics: Acetylcholinesterase; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Donepezil; Free Radical Scavengers; Humans; Indans; Nerve Growth Factor; Piperidines

The four cholinesterase inhibitors now available for treatment of Alzheimer disease (AD) may be most beneficial, especially in the long run, if started early in the course of the disease. This paper reviews the efficacy, pharmacokinetics, metabolism, side effects, dosage, and precautions for the use of these agents, which may produce modest improvements in cognition, behavior, and the ability to perform activities of daily living.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

The number of patients with Alzheimer's disease (AD) and related dementia treated in managed care organizations (MCOs) is increasing, and this trend is expected to continue. Therefore, it is critical that MCOs develop disease management strategies for this population.. To review the literature on the prevalence, costs, and treatment of AD and related dementia.. Review of published articles from MEDLINE and peer-reviewed journals.. Prevalence of AD and related dementia is approximately 5.7% among those aged 65 and older. Prevalence data from claims-based studies of AD in managed care are lower, ranging from 0.55% to 0.83%. Costs for formal care average $27,672 per patient annually, with long-term care being the most costly component. Annual costs for informal care are estimated to be $10,400 to $34,517 per patient. Additional costs associated with AD include lost wages and productivity of patients and caregivers and costs associated with increased morbidity of caregivers. Donepezil treatment is well tolerated and has been extensively tested and evaluated in clinical settings. Early diagnosis and treatment of AD with donepezil has been shown to slow cognitive decline in AD. Although study findings regarding the cost offsets of donepezil-treated patients to date are mixed, there is a growing body of evidence to support the inclusion of this and other therapies into an MCO's AD treatment armamentarium.. It is unlikely that MCOs will escape the increased prevalence and costs associated with AD. Opportunities exist through patient management programs targeted toward early diagnosis, effective use of medications, control of comorbidities, and patient and family support to partially offset these costs while providing quality patient care.

Topics: Aged; Alzheimer Disease; Cognition Disorders; Cost of Illness; Donepezil; Female; Humans; Indans; Male; Managed Care Programs; Medicaid; Nootropic Agents; Piperidines; Prevalence; United States

This is a review of the data available in the literature and the authors' own findings on pathogenetical rationale for the use and clinical study of current treatments for Alzheimer's disease (AD) (synonym: Alzheimer-type dementia). In the past decade many attempts have been made at targeting different links of the pathogenesis of a neurodegenerative process that underlie AD. Several areas of pathogenetical therapy for AD have been developed on the basis of experimental studies and pilot clinical tests. The most developed areas are as follows: various compensatory (replacement) treatments aimed at overcoming neurotransmitter deficit in different neuronal systems that are damaged in AD to a greater or lesser extent; neuroprotective therapy promoting increased viability (survival) of neurons and their plasticity, and vasoactive therapy. Rather new directions of AD pathogenetic therapy, such as antiinflammatory and hormonal therapy along with antiamyloid therapeutic strategies are still under study.

Topics: Aged; Alzheimer Disease; Amino Acids; Aminoquinolines; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dopamine Agents; Estrogens; Ginkgo biloba; Humans; Indans; Memantine; Monoamine Oxidase Inhibitors; Multicenter Studies as Topic; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitter Agents; Nicergoline; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Piracetam; Pyrithioxin; Rivastigmine; Selegiline; Tacrine; Time Factors

Alzheimer Disease (AD) is characterized by the progressive deposition of beta-amyloid in the parenchyma and cerebral microvasculature. The beta-amyloid peptide derives from the metabolism of a larger precursor, Amyloid Precursor Protein (APP). This protein is present in central nervous system, but it is also expressed in peripheral tissues such as circulating cells. An alteration of the APP forms pattern in platelets has been recently reported in AD patients when compared to platelets both of control subjects or non AD patients (NADD). The accuracy of the assay to identify AD is high and decreased levels are found throughout the course of AD with a significant association with severity of symptoms. Moreover, a recent study has demonstrated that AD patients on donepezil (5 mg daily) for 4 weeks displayed two-fold increase in their APPr baseline levels up to normal range. Thus, platelet APP ratio (APPr) holds the potential to be a clinical marker, which might be of helpful and adjunctive value in the diagnosis of AD and in tracking the course of illness, also in the early stages when pharmacological treatment has the greatest potential of being effective.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Biomarkers; Blood Platelets; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines

During the last years, treatment of Alzheimer's disease has improved following a better detection of this disease and, more importantly, following a better knowledge of its physiopathogeny. After years of aspecific symptomatic treatments, acetylcholinesterase inhibitors have been recently released and can be considered as a specific symptomatic treatment. In this pharmacologic class, more practical and less toxic drugs are nowadays available. Treatments of behavioral disturbances have also been recently improved. Nowadays we have to find treatments able to modify the clinical evolution and eventually prognosis of this disease, and even to prevent it for the patients at risk. Nevertheless a simplification of the prescriptions is justified, to the detriment of drugs without any proven activity.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Carbamates; Cholinesterase Inhibitors; Diagnosis, Differential; Disease Progression; Donepezil; Drug Therapy, Combination; Estrogen Replacement Therapy; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Prognosis; Rivastigmine; Treatment Outcome

To compare the effectiveness of second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) with that of the special ginkgo extract EGb 761R in Alzheimer's disease.. Analysis of the effect on cognition with the aid of the ADAS-cog.scale, placebo-adjusted, within six months; statistical evaluation of the effect using the confidence interval for the potential mean improvement.. All medications are statistically significantly superior to placebo. The mean improvement is larger for the cholinesterase inhibitors than for the ginkgo extract. In the statistically unfavorable case, the effect of the cholinesterase inhibitors is still appreciable, but not for the ginkgo extract.. Until the results of direct comparative studies are available, the present results indicate a superior effect of cholinesterase inhibitors over the ginkgo extract in the treatment of mild to moderate Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Ginkgo biloba; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Phenylcarbamates; Phytotherapy; Piperidines; Plant Extracts; Randomized Controlled Trials as Topic; Rivastigmine; Trichlorfon

Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function. The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials, Phase III as Topic; Donepezil; Humans; Indans; Piperidines; Quality of Life; Randomized Controlled Trials as Topic

The role of the cholinergic system with respect to cognitive deficits characteristic of Alzheimer's disease (AD) has led to a number of studies focusing on the development of acetylcholinesterase (AChE) inhibitors as a drug for treating this disease. The earliest known AChE inhibitors, namely, physostigmine and tacrine, performed poorly in clinical trials (e.g., poor oral activity, brain penetration, and hepatotoxic liability). Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action and with manageable adverse effects.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Structure-Activity Relationship

The last decade was very fruitful in neuropharmacology and notably in the therapeutic strategies of dementia and Alzheimer's disease (AD). The amount of data, information and breakthroughs is nevertheless difficult to apply in direct relationship with patients. The present review aims at classifying information according to their origins: epidemiology, clinical trials, neurosciences. A guide for drug prescription in Alzheimer's disease is thus warranted and becomes clearer, sure that, in the next future modifications and new strategies will appear. The main goal of the present review is to summarize the state-of-the-art for a non specialist in AD.

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents useful for the treatment of Alzheimer s disease, glaucoma, myasthenia gravis and for the recovery of neuromuscular block in surgery. To rationalize the structural requirements of AChE inhibitors we attempt to derive a coherent AChE-inhibitor recognition pattern based on literature data of molecular modelling and quantitative structure-activity relationship (QSAR) analyses. These data are summarised from nearly all therapeutically important chemical classes of reversible AChE inhibitors, e.g., derivatives of physostigmine, tacrine, donepezil and huperzine A. Interactions observed from X-ray crystallography between these inhibitors and AChE have also been incorporated and compared with modelling and QSAR results. It is concluded that hydrophobicity and the presence of an ionizable nitrogen are the pre-requisites for the inhibitors to interact with AChE. However the mode of interaction i.e., the 3-dimensional (3D) positioning of the inhibitor in the active site of the enzyme varies among different chemical classes. It is also recognised that water molecules play crucial roles in defining these different 3D positioning. The information on AChE-inhibitor interactions provided should be useful for future discovery of new chemical classes of AChE inhibitors, especially from De Novo design and hybrid construction.

Topics: Alkaloids; Alzheimer Disease; Cholinesterase Inhibitors; Crystallography, X-Ray; Donepezil; Drug Design; Glaucoma; Humans; Indans; Models, Molecular; Myasthenia Gravis; Neostigmine; Physostigmine; Piperidines; Sesquiterpenes; Structure-Activity Relationship; Surface Properties; Tacrine

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.

Topics: Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Crystallography, X-Ray; Donepezil; Humans; Indans; Models, Molecular; Piperidines; Rats; Stereoisomerism; Structure-Activity Relationship

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aspartic Acid Endopeptidases; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Endopeptidases; Hippocampus; Humans; Indans; N-Methylaspartate; Nerve Growth Factors; Nicotine; Piperidines; Tacrine

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Design; Drug Evaluation, Preclinical; Humans; Indans; Nootropic Agents; Piperidines

Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. Onset is usually late in life with increasing impairment of memory, developing gradually into a global impairment of cognition, orientation, linguistic ability and judgement. The clinical course is accompanied by growing disability and dependency on care. One of the characteristic features of the disease is the widely variable rate of progression seen in different patients. Acetylcholine is an important neurotransmitter associated with memory, and abnormalities in cholinergic neurones (including cell loss) are among the many neurological and neurochemical abnormalities that develop in AD. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few side effects.. The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease.. The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'donepezil', 'E2020' and 'ARICEPT'. Medline, PsychLIT and EMBASE electronic databases were searched with the above terms. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomised controlled trials in which treatment with donepezil was administered for more than a day and compared with placebo in patients with Alzheimer's disease.. Data were extracted independently by the reviewers (JSB & DB), pooled where appropriate and possible, and the weighted or standardised mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat data were used.. There are 4 included trials, covering treatment of 12 or 24 weeks duration in highly selected patients. The only information available on one trial (Gauthier 1998) is a conference abstract which reports no usable results. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. The results of three trials suggest a small beneficial effect of donepezil in improving cognitive function: at a 5mg/day dose, improvements measured -2.6 points (95%CI -3.5 -- -1.8) on weighted mean difference, in the midrange of the 70 point ADAS-Cog scale. The results of two trials show some improvement in global clinical state (assessed by an independent clinician) in those treated with donepezil compared to placebo. The patient's own rating of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/d (but not the 5mg/d) donepezil group compared with placebo, which may have resulted in some overestimation of beneficial changes at 10mg/d in progressively declining characteristics, as last available measures were used in analyses. A variety of adverse effects were recorded, but very few patients left a trial as a direct result of the intervention.. In selected patients with mild or moderate Alzheimer's disease treated for periods of 12 or 24 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Piperidines

Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase. Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer's disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients' abilities to perform complex tasks. However, no significant improvement in function was observed with donepezil 5 mg/day in another trial. In the 2 trials of longest duration donepezil (5 and 10 mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of donepezil on patients' quality of life, there are no validated measures of this parameter specific to patients with Alzheimer's disease. Donepezil (5 and 10 mg) significantly reduced caregiver burden. Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with donepezil (10 mg/day in most patients). Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with donepezil 10 mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between donepezil 5 and 10 mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving donepezil (5 and 10 mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug. Conclusions. Donepezil (5 and 10 mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer's disease. Impr

Topics: Aged; Alzheimer Disease; Donepezil; Humans; Indans; Piperidines

One of the most consistent changes associated with Alzheimer's disease (AD) is a deficit in central cholinergic neurotransmission. Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). After oral dosing, DPZ (ID50: 2.6 mg/kg) inhibited brain ChE dose-dependently without any remarkable effect on ChE in the heart and small intestine, whereas tacrine (ID50: 9.5 mg/kg) inhibited ChE equally in the brain and peripheral tissues. Brain microdialysis revealed that DPZ (2.5 mg/kg) enhanced extracellular ACh concentrations in the cerebral cortex and hippocampus in rats. In behavioral studies, DPZ counteracted both the deficit in passive avoidance induced by lesioning of the nucleus basalis magnocellularis (0.125-1.0 mg/kg) and the impairment in acquisition of a hidden-platform water maze task after lesioning of the medial septum in rats (0.5 mg/kg). DPZ also inhibited the scopolamine-induced impairment of radial maze performance (0.5 mg/kg). Placebo-controlled clinical studies of 12- and 24-week treatments of DPZ (5 mg, 10 mg/day) clearly showed an improvement in cognitive scores of probable AD patients.

Topics: Acetylcholine; Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Learning Disabilities; Piperidines

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but E2020 (donepezil, Aricept) is thought to be more specific in its action, and safer.. The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group specialized register was searched using the terms 'donepezil', 'E2020' and 'Aricept'. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with Alzheimer's disease.. Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat (ITT) data were used.. Eight trials are included, involving 2664 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared to placebo (1.9 points on the ADAS-Cog scale, WMD 1.86, 95%CI -2.60 to -1.11; 2.9 points on the ADAS-Cog scale, WMD -2.91, 95% CI -3.65 to -2.16)and for 10mg/day donepezil compared to placebo at 52 weeks (1.7 MMSE points, 95% CI, -2.59 to -0.82). The results of three studies show some improvement in global clinical state (assessed by an independent clinician) in those treated with 5 and 10mg/day of donepezil compared with placebo at 12 and 24 weeks. The patients' own ratings of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/day (but not the 5mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10mg/day A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10mg/day group compared with placebo and the 5mg/day group, but very few patients left a trial as a direct result of the intervention.. In selected patients with mild or moderate Alzheimer's disease treated for periods of 12, 24 or 52 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

Acetylcholinesterase inhibitors (ChEIs) enhance neuronal transmission by increasing the availability of acetylcholine in muscarinic and nicotinic receptors. This effect is believed to be responsible for the beneficial and protective effects of ChEIs on cognition in patients with Alzheimer's disease (AD). Effects of ChEIs on mood and behavior have also been reported. Earlier observations were limited by the exclusive availability of intravenous forms of administration, the short half-life of the formulations, and the high frequency of peripheral side effects. The introduction, in recent years, of better tolerated and less invasive compounds has rekindled the interest in cholinergic central nervous system mechanisms and has given rise to studies in areas other than cognition. The ChEI donepezil has been involved in the largest number of studies and positive reports. Preliminary observations suggest the possible value of ChEIs in the management of behavioral dysregulation, apathy, irritability, psychosis, depression, mania, tics, and delirium and in the diagnosis of depression, panic, and personality disorders.

Topics: Affect; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Mental Disorders; Piperidines

The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Carbamates; Cheirogaleidae; Disease Models, Animal; Humans; Muscarinic Agonists; Neuroprotective Agents; Phenylcarbamates; Piperidines; Receptor, Muscarinic M1; Receptors, Muscarinic; Rivastigmine; Signal Transduction; tau Proteins; Thiazoles

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted into three drugs being registered for the first time in the USA and Europe for this specific indication. All three are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a constant level during a six-month to one-year period of treatment, as compared to placebo. Additional drug effects might slow cognitive deterioration and improve behavioral and daily living conditions. Comparison of clinical effects of six ChEI demonstrates a rather similar magnitude of improvement in cognitive measures. For some drugs, this may represent an upper limit, whereas for other it may still be possible to further increase the benefit. In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment. Recent studies show that in many patients the stabilization effect produced by ChEI can be prolonged for as long as a 24-month period. In order to explain the stabilizing effect of ChEI, a mechanism other than AChE inhibition, based on beta-amyloid metabolism, is postulated.

Topics: Alzheimer Disease; Brain; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Trichlorfon

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines

Although the underlying pathogenesis of Alzheimer's disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks' duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials, Phase III as Topic; Cognition; Donepezil; Drug Tolerance; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

There is reason for optimism about future treatment options for Alzheimer's disease, despite uncertainties about which subgroups of patients will respond to treatment, the magnitude of therapeutic effects, the duration of benefit, and the long-term outcomes from disease-modifying agents. Because Alzheimer's disease is a heterogeneous disorder, the range of treatment responses likely will remain variable. The decision to initiate treatment must be individualized to the therapeutic goals of the patient and his or her caregiver. Advances in the understanding of the pathogenesis of Alzheimer's disease have led to new treatment strategies. Augmentation of cholinergic function through the use of acetylcholinesterase inhibitors with favorable side-effect profiles (e.g., donepezil, possibly metrifonate) can create the potential for improved memory and cognition. Antiinflammatory drugs, estrogen, alpha-tocopherol, selegiline, and ginkgo biloba are the subject of ongoing clinical trials to determine their effectiveness in Alzheimer's disease. Future treatment strategies will likely include a combination of acetylcholinesterase inhibitors and disease-modifying agents. A greater understanding of the pathogenesis of Alzheimer's disease may lead to the development of new neuroprotective agents. The long-term human and social costs, as well as potential benefits, of prolonging the natural course of the disease can only become evident with study of these agents in years to come.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Piperidines; Tacrine

The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).

Topics: Acetylcholine; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Design; Humans; Indans; Piperidines; Rats; Receptors, Cholinergic; Structure-Activity Relationship

Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh) in the forebrain that correlates with brain pathology and cognitive dysfunction. The most promising approach to enhancing central ACh neurotransmission has been the utilization of agents that inhibit cholinesterases which block its catabolism. Initially, the success of this strategy was limited by subtherapeutic levels of acetylcholinesterase (AChE) inhibition, tolerability problems and toxicity of the first agents. Donepezil HCI represents a new chemical class of AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to improve significantly cognition and global function in patients with mild to moderately severe AD, and has demonstrated an excellent tolerability and safety profile. These benefits, as well as a simple, once-daily dosing regimen, make donepezil a viable therapeutic option for AD patients.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Synaptic Transmission

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of new drugs is essential. The application of this information facilitates the design of a rational clinical trial programme and optimizes the chances for rapid and successful clinical development. Upon completion of each development phase, the information obtained must be evaluated critically to maximize the design of subsequent studies. Phase I trials represent the first time the drug is administered in humans and their primary objective is to evaluate the drug's safety and tolerability in man. Phase II trials represent the first time that the drug is administered to the target patient population. The objectives of Phase II trials are to verify the safety and tolerability of the drug in patients, and also to evaluate for the first time the clinical efficacy of the drug. During these phases of development, the use of PK and PD measures is helpful for establishing the therapeutic dose range as well as the suitability of the chosen efficacy measures for use in the pivotal Phase III trials. Here, using several examples of PK and PD data obtained from the clinical development studies of donepezil HCl, the application of these measures on the development of a drug for the treatment of Alzheimer's disease is discussed.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia; Donepezil; Drug Design; Humans; Indans; Nootropic Agents; Piperidines

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Ginkgo biloba; Humans; Indans; Neuroprotective Agents; Nootropic Agents; Phytotherapy; Piperidines; Plants, Medicinal; Selegiline; Tacrine; Vitamin E

The cholinergic hypothesis claims that a decrease of acetylcholine (ACh) in the brain of patients with Alzheimer's Disease (AD) plays an important role in the deterioration of cognitive functioning. This hypothesis has led to extensive research in possible therapeutic approaches towards improving cholinergic transmission in AD patients. The different approaches have focused on the following six strategies: ACh precursors, ACh release, M1, M3, or M4 receptor agonists, M2 receptor antagonists, nicotinic agonists, and acetylcholinesterase inhibitors (AChEI). The aim of this review is to assess the effectiveness of the cholinergic approach for the treatment of AD.

Topics: Acetylcholine; Alzheimer Disease; Animals; Carbamates; Chemical and Drug Induced Liver Injury; Cholinergic Agents; Cholinergic Fibers; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Double-Blind Method; Drug Evaluation, Preclinical; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Nicotinic; Rivastigmine; Tacrine

The rapid growth of the world's Alzheimer's disease (AD) population has resulted in a tremendous financial burden on society, a situation exacerbated by the fact that the funding of health and social services faces increasing restrictions in the coming years. As a consequence, several cost-of-illness studies, aimed at assessing the total costs associated with the care of an AD patient or with individual components thereof, have been conducted, with a view to identifying areas in which costs might be reduced. For example, the Costs of Dementia (CoDem) study, described here, aims to give a profile of the total economic costs of AD in Italy. While this study found the number of Instrumental Activities of Daily Living lost to be the principal predictor of the weekly costs for home care, other studies have reported a correlation between total cost and Mini-Mental State Examination (MMSE) score. The basis for a correlation between cost and disease severity is discussed. Pharmacoeconomics aims to assess the cost effectiveness of interventions that may form part of an overall management strategy in AD. As institutionalization is the largest cost element in the care of any AD patient, efforts at cost containment have focused on maintaining patients at home for as long as possible. The results of studies on a number of interventions, namely, screening, reality orientation therapy, special care units, family interventions, and drug treatment, are discussed, although the costs and, indeed, the long-term benefits associated with many of these remain unknown. Although information concerning costs is essential in health resource allocation, it is also vital that meaningful ways in which to assess quality-of-life issues be developed as the basis for genuine cost-benefit judgments.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Cost of Illness; Costs and Cost Analysis; Donepezil; Humans; Indans; Institutionalization; Italy; Mental Health Services; Neuropsychological Tests; Piperidines; Reality Therapy; Tacrine

Regulatory guidelines in the US and Europe generally require that a drug specifically indicated for treating Alzheimer's disease (AD) must demonstrate an effect upon the core manifestations of dementia. Progressive cognitive and functional losses are the cardinal features of AD. In the US, current guidelines require that new AD treatments show effectiveness on performance-based measures of cognition and on clinician-rated global assessments. Improvement in function is also emphasized in the European guidelines. The primary instruments that have been used to evaluate changes in cognition and global function in most recent AD trials are the cognitive subscale of the Alzheimer's Disease Assessment Scale and a version of the Clinician's Interview Based Impression of Change, respectively. The results from three pivotal trials investigating the acetylcholinesterase inhibitor, donepezil, are used to demonstrate the way in which these tools are used, how to interpret the data they provide, and to determine their overall value in ascertaining efficacy in clinical practice.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Guidelines as Topic; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Donepezil is a specific acetylcholinesterase inhibitor that can improve symptoms in patients with mild-to-moderate Alzheimer's disease; cognitive function is maintained above baseline levels for up to 1 year and normal decline of cognitive function is slowed. The ability of the patient to perform daily activities and neuropsychiatric symptoms may also be improved by donepezil, but data are limited. Donepezil is not expected to alter the underlying neurodegenerative process, and the response to the drug varies between individuals. In the absence of validated instruments to measure quality of life, it is not clear how donepezil affects this parameter. In a US survey of caregivers of patients with Alzheimer's disease who were being cared for at home at the start of the 6-month study period, treatment with donepezil did not increase overall direct medical costs. The acquisition cost of the drug was balanced by reduced institutionalisation costs. Economic analyses using Markov models from the US, UK and Canada suggest that donepezil initiated in the early stages of disease may be effectively cost neutral as a result of patients remaining in a nonsevere state of disease for a longer time.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Costs and Cost Analysis; Donepezil; Drug Evaluation; Economics, Pharmaceutical; Humans; Indans; Markov Chains; New Zealand; Nootropic Agents; Piperidines

In the past decade, significant progress has been made in the understanding and treatment of Alzheimer's disease. Modest success has been achieved using new drugs in treatment of mild symptoms of the disease. Vitamin E, estrogen, and NSAIDs may slow the progression of Alzheimer's disease, but their routine use is not without risk, and there is no evidence that these agents are effective in preventing the disease in asymptomatic people. With our increased understanding of the pathogenesis of Alzheimer's disease, it is likely that the next decade will see further refinement and development of treatment strategies to halt progression and possibly reduce the incidence of disease.

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Donepezil; Estrogen Replacement Therapy; Estrogens; Female; Humans; Indans; Piperidines; Vitamin E

Donepezil is an effective, well-tolerated, and easily administered symptomatic treatment for mild-to-moderate Alzheimer disease (AD). Data from Phase III clinical trials have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil. This favorable safety profile, together with its reported clinical benefits established donepezil as one standard of AD therapy. Vitamin E is one of two anti-oxidant therapies that may help to slow the progression of AD over at least a two-year period. One large-scale clinical trial suggests that it has sufficient benefit and safety to join donepezil as a current standard of AD therapy.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Humans; Indans; Piperidines; Quality of Health Care; Quality of Life; Treatment Outcome; Vitamin E

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Interactions; Humans; Indans; Nootropic Agents; Piperidines

To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug-drug interactions, and the therapeutic issues concerning the use of donepezil in patients with Alzheimer disease.. Published articles and abstracts in English were identified by MEDLINE (January 1985-July 1997) searches using the search terms donepezil, E2020, treatment of Alzheimer's disease, and cholinesterase inhibitors. Additional articles were identified from the bibliographies of the retrieved articles. Data were also obtained from approved product labeling.. The literature was assessed for adequate description of patients, methodology, and outcomes.. Donepezil is a cholinesterase inhibitor that is selective and specific for acetylcholinesterase. It is metabolized by hepatic isoenzymes CYP2D6 and CYP3A4 and undergoes glucuronidation. Information about drug interactions is limited, but a potential for drug-drug interactions does exist, given the route of elimination. Donepezil has a relative bioavailability of 100% following oral administration and is not affected by the presence of food. In 15- and 30-week trials, donepezil was effective in patients with mild-to-moderate Alzheimer disease as shown by improvements on standard assessment instruments (i.e., the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Clinical Interview-Based Impression of Change with Caregiver Input). Adverse effects were comparable with those of placebo, and monitoring of liver function tests is not required.. Donepezil is an effective symptomatic treatment for some patients with mild-to-moderate Alzheimer disease. Although no comparative trials have been reported, donepezil appears to be a safe alternative for tacrine, given its convenient once-daily dosing, minimal adverse effects, and lower total cost.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Monoamine Oxidase Inhibitors; Neuropeptides; Phenylcarbamates; Piperidines; Receptor, Muscarinic M1; Receptors, Muscarinic; Rivastigmine; Spiro Compounds; Tacrine

Topics: Advertising; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Decision Making; Donepezil; Drug Approval; Drug Industry; Editorial Policies; Evidence-Based Medicine; Government Regulation; Health Policy; Humans; Indans; Information Dissemination; Piperidines; Risk Assessment; Therapeutic Human Experimentation; United Kingdom; United States

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Ethics, Medical; Female; Humans; Indans; Male; Memory Disorders; Personal Autonomy; Personhood; Physician-Patient Relations; Piperidines; Quality of Life; Risk Assessment; Self Concept; Truth Disclosure; Value of Life; Withholding Treatment

This article combines data from a clinical trial of donepezil with costing figures to evaluate expected direct costs of care over 5 years after diagnosis of Alzheimer's disease (AD) for patients aged 75 years and over at diagnosis. A Markov model simulates the progression of elderly persons through changing levels of severity. The model compares three treatment regimes for each of two patient groups; mild AD at start of treatment; moderate AD at start of treatment. Patients are followed until 5 years after the start of the treatment. Despite the acquisition costs, use of donepezil is approximately cost-neutral for both 5 mg and 10 mg treatment groups and for patients initially at either mild or moderate states of illness. Expected costs are slightly higher than for the placebo group, but higher expenditure on drugs is partly offset by lower costs of care consequent on treated patients not declining as rapidly as those untreated. The model showed that donepezil patients spent less time in the state of severe dementia, where costs of care are higher. Sensitivity analysis on key assumptions demonstrated that expected costs were highly dependent on discount rate and, more significantly, on the mortality rate.

Topics: Aged; Alzheimer Disease; Cognition Disorders; Cost-Benefit Analysis; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Markov Chains; Models, Economic; Models, Neurological; Models, Psychological; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome; United Kingdom

Psychiatrists are uniquely qualified to provide a variety of important services to patients with Alzheimer's disease and their families and professional caregivers. This paper highlights the role of the psychiatric physician in the differential diagnosis of dementing illnesses. Psychiatrists are also uniquely trained to evaluate and treat the psychiatric symptoms and problem behaviors in Alzheimer's disease. The psychiatrist may be asked to utilize and monitor antidementia compounds as well as to orchestrate functional and competency evaluations. As the leader of the mental health team, the psychiatrist serves as educator and resource provider to patients and their families. Lately, the psychiatrist works closely with caregivers to monitor for and prevent burnout and depression.

Topics: Alzheimer Disease; Attitude to Health; Caregivers; Donepezil; Drug Therapy, Combination; Family Health; Forensic Psychiatry; Humans; Indans; Nootropic Agents; Patient Care Team; Physician's Role; Piperidines; Psychiatric Status Rating Scales; Psychiatry

This article reviews placebo-controlled studies addressing drug efficacy for the cognitive deficits of Alzheimer's disease. Efforts to compensate for the presynaptic cholinergic deficiency in Alzheimer's disease by pharmacologically inhibiting acetylcholine degradation have been successful in several clinical trials. Two cholinesterase inhibitors are available for Alzheimer's disease, and others most likely will soon be available. Cholinesterase inhibitors represent the only therapy currently approved for the treatment of Alzheimer's disease. The antioxidant drugs alpha-tocopherol (vitamin E) and selegiline have been demonstrated marginally superior to placebo for slowing functional deterioration in patients with moderately advanced Alzheimer's disease. Epidemiologic studies suggest protective effects against Alzheimer's disease from postmenopausal estrogen replacement and nonsteroidal anti-inflammatory drugs. Placebo-controlled studies prospectively evaluating the hypotheses generated by these epidemiologic studies are ongoing.

Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Estrogen Replacement Therapy; Humans; Indans; Nootropic Agents; Piperidines; Placebos; Tacrine; Treatment Outcome; Trichlorfon

Therapeutic approaches to the cognitive impairment of dementia are making their way into clinical practice. Clinical pharmacologic approaches toward improvement of cognitive symptoms are discussed, with an emphasis on cholinergic approaches, since they currently appear most promising and since several cholinesterase inhibitors may soon be available for prescribing. As more knowledge is gained about dosing, side effects, and mechanisms of action, these drugs can be prescribed more efficiently. Current research approaches to slowing the rate of cognitive decline are discussed, including the use of antioxidants, monoamine oxidase-B inhibitors, and cholinesterase inhibitors. Drugs that improve cognition may also have effects on behavioral symptoms, severe dementia, and non-Alzheimer's dementia. Evidence suggests that some dementia patients may be particularly responsive to intervention and that other medications may enhance response. Psychosocial interventions may also contribute to prolonging the time to institutionalization.

Topics: Aged; Alzheimer Disease; Antioxidants; Carbamates; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Monoamine Oxidase Inhibitors; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Trichlorfon

This article reviews the current status of therapy with acetylcholine-enhancing compounds in the management of patients with Alzheimer's disease. The focus is on pivotal articles investigating the role of cholinergic augmentation strategies, including precursor loading and acetylcholinesterase (AChE) inhibitors, in the management of cognitive and noncognitive symptoms of Alzheimer's disease. Precursor loading strategies have been for the most part unimpressive. By contrast, studies with AChE inhibitors--tacrine and donepezil--have been promising. For patients in whom hepatotoxicity and gastrointestinal side effects were not problematic, tacrine improves cognitive performance and selected secondary psychiatric symptoms and significantly delays nursing home placement. Donepezil, recently approved for use in mild to moderate Alzheimer's disease, appears to be less toxic and better tolerated than tacrine. It improves performance on cognitive testing and, in one preliminary investigation, demonstrated a sustained drug effect over several years. Therapy with AChE inhibitors provides modest significant symptomatic improvement in patients with mild to moderate Alzheimer's disease.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cholinergic Agents; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Estrogen Replacement Therapy; Estrogens; Female; Humans; Indans; Male; Piperidines; Selective Serotonin Reuptake Inhibitors; Selegiline; Tacrine; Vitamin E

Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BuChE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; Mini-Mental State Examination [MMSE], 10-26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks' duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Donepezil; Double-Blind Method; Humans; Indans; Multicenter Studies as Topic; Piperidines; Randomized Controlled Trials as Topic

Topics: Aged; Alzheimer Disease; Donepezil; Follow-Up Studies; Humans; Indans; Middle Aged; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Diagnostic Imaging; Donepezil; Female; Humans; Indans; Male; Piperidines; Risk Factors; Tacrine

Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment.

Topics: Aged; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines; Rats

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Male; Piperidines; Tacrine; United States

Alzheimer's disease is the most common dementing illness affecting over 4 million Americans. As the population ages, dentists and other health care providers will be faced with the daunting task of managing an increasing number of people with this disease. Currently, there are no definitive medications to treat this disease, although there are a number of recent drugs which may help to alleviate some symptoms. This article reviews the current medical treatment and the dental concerns which face the dentist, patient, and family. Suggestions for dental management are given along with practical recommendations for caregivers.

Topics: Aged; Aging; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Caregivers; Cholinesterase Inhibitors; Dental Care for Chronically Ill; Dentist-Patient Relations; Donepezil; Family Relations; Humans; Indans; Middle Aged; Nootropic Agents; Oral Hygiene; Piperidines; Prevalence; Professional-Family Relations; Tacrine

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of donepezil are reviewed. Donepezil is a synthetic noncovalent reversible inhibitor of acetylcholinesterase (AChE) for the treatment of mild to moderate dementia associated with Alzheimer's disease. In contrast to tacrine hydrochloride, the only comparable agent currently approved by FDA, donepezil exhibits a relatively high degree of selectivity for neuronal AChE as opposed to butyrylcholinesterase. It has a half-life of 60 hours in young adults and 104 hours in elderly patients. In clinical trials, donepezil has been associated with significant improvements in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Interview-Based Impression of Change scores. The most common adverse effects associated with donepezil are nausea, diarrhea, anorexia, and vomiting, which are most likely to occur during dose initiation or adjustment. Hepatotoxicity, a dose-limiting adverse effect that sometimes requires discontinuation of tacrine, has not been reported with donepezil. Donepezil does not appear to interact with theophylline, cimetidine, warfarin, or digoxin. Ketoconazole and quinidine inhibit the metabolism of donepezil in vitro, but there is a lack of clinical data showing that these drugs decrease the clearance of donepezil. The initial recommended dosage is 5 mg daily before bedtime, with a dosage increase to 10 mg after four to six weeks according to the patient's response and tolerance. Donepezil appears to be preferable to tacrine as the initial agent for patients with mild to moderate dementia associated with Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Diarrhea; Donepezil; Drug Administration Schedule; Drug Interactions; Humans; Indans; Nausea; Piperidines

Topics: Adaptation, Psychological; Adult; Aged; Alzheimer Disease; Child; Cholinesterase Inhibitors; Donepezil; Family; Humans; Indans; Piperidines; Visitors to Patients

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Drug Monitoring; Humans; Indans; Informed Consent; Piperidines

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Middle Aged; Patient Selection; Piperidines; Randomized Controlled Trials as Topic

Until recently, few drugs have been available for the treatment of Alzheimer's disease. The first such drug to be launched in the U.K. was the acetylcholinesterase inhibitor, donepezil. The limited published data on donepezil shows only modest cognitive benefit in patients with Alzheimer's disease. The cost of diagnosis and drug treatment, the distressing nature of the disease and the limited evidence available, pose difficult decisions for the introduction of new drugs and the management of this condition.

Topics: Alzheimer Disease; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Contraindications; Donepezil; Drug Interactions; Drug Monitoring; Humans; Indans; Neurons, Afferent; Piperidines; United Kingdom

Therapeutic approaches to treat the cognitive impairment in dementia and to treat slow decline are making their way into clinical practice. Cholinergic agents are currently the most promising treatment, and several cholinesterase inhibitors will soon be available for prescription. As physicians learn more about dosing, side effects, and mechanisms of action, they can prescribe these drugs more efficiently. Evidence suggests that certain patients with dementia may be particularly responsive to such intervention, and other medications may enhance response. Current experimental approaches to slowing the rate of cognitive decline include the use of antioxidants, monoamine oxidase-B inhibitors, cholinesterase inhibitors, and anti-inflammatory agents. Psychosocial interventions appear to help delay institutionalization. Drugs that improve cognition also may affect behavioral symptoms and severe dementia as well as non-Alzheimer dementia.

Topics: Alzheimer Disease; Antioxidants; Carbamates; Cholinergic Agents; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Trichlorfon

The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate.. Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points.. Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups.. The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines

To assess non-inferiority of a donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg in patients with mild-to-moderate Alzheimer's disease; and to compare the efficacy and safety profiles of a donepezil patch 27.5 mg with donepezil hydrochloride tablets 5 mg.. This was a 24-week, multicenter, randomized, double-blind, double-dummy, parallel group, non-inferiority (phase III) study carried out in Japan. The primary end-point was the change in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version from baseline to week 24, with the aim of evaluating the non-inferiority of the donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg.. Of 340 randomized patients, 303 completed the double-blind period. Changes from baseline in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version at week 24 (least squares mean ± standard error) were -0.7 ± 0.4 (donepezil patch 27.5 mg) and 0.2 ± 0.4 (donepezil hydrochloride tablet 5 mg). The difference in the least squares means (95% confidence interval) was -0.9 (-2.01 to 0.14). The upper bound of the 95% confidence interval for the difference between groups was less than the predefined non-inferiority margin of 2.15. The donepezil patches 27.5 mg also had a safety profile that showed good tolerability comparable with donepezil hydrochloride tablets 5 mg.. Non-inferiority on suppression of cognitive decline was shown for the donepezil patch 27.5 mg when compared with donepezil hydrochloride tablets 5 mg in Japanese patients with mild-to-moderate Alzheimer's disease. Geriatr Gerontol Int 2023; 23: 275-281.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Humans; Indans; Piperidines; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Piperidines

In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease.. To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer's disease; and to evaluate safety on switching from donepezil hydrochloride tablets.. This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study.. A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events.. Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Humans; Indans; Piperidines; Treatment Outcome

To explore the effect of resveratrol (RES) combined with donepezil hydrochloride on inflammatory factor level and cognitive function level of patients with Alzheimer's disease (AD).. A total of 90 AD patients treated in our hospital from June 2019 to June 2020 were selected as the study objects and divided into the control group (CG) and experimental group (EG) by the randomized and double-blind method, with 45 cases each. Patients in CG received donepezil hydrochloride treatment, and on this basis, those in EG received additional RES treatment, so as to compare the clinical indicators between the two groups.. Compared with CG after treatment, EG obtained significantly higher good rate, MMSE score, and FIM score (. Combining RES with donepezil hydrochloride has significant clinical efficacy in treating AD, which can effectively improve patients' inflammatory factor indicators, promote their cognitive function, and facilitate patient prognosis.

Topics: Alzheimer Disease; Cognition; Donepezil; Humans; Indans; Piperidines; Resveratrol

Donepezil 23 mg is considered for Alzheimer's disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil.. This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs.. Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (-) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05).. BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs ("Clinicaltrials.gov" No. NCT02550665 registered on September 15, 2015).

Topics: Alzheimer Disease; Body Weight; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Indans; Piperidines; Treatment Outcome

Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the treatment of moderate AD.. To evaluate the effects of donepezil and memantine in relieving BPSD in individuals with moderate AD.. We conducted a prospective, randomized, 6-month clinical trial involving 85 individuals with moderate AD divided into two groups: group 1 (n = 42) was treated with donepezil; group 2 (n = 43) was treated with memantine. We used the Neuropsychiatric Inventory (NPI) to assess the prevalence and severity of BPSD at baseline and after 6 months of treatment with donepezil or memantine.. The two groups' baseline characteristics, including age, sex, mean length of education, and disease duration, were comparable, as were their baseline Mini-Mental State Examination scores. The NPI Total score improved from baseline to month 6 in both groups (P < 0.0001). Analyses of the NPI subdomains revealed that both donepezil treatment and memantine treatment produced statistically significant improvement in all of the NPI domains except euphoria and apathy, for which no improvement was observed after memantine treatment. Both treatments were well tolerated, with mostly mild and transient adverse effects.. Specific drugs for AD, including donepezil and memantine, may be effective in treating BPSD in individuals with moderate AD, with a favorable safety profile.

Topics: Alzheimer Disease; Behavioral Symptoms; Donepezil; Humans; Indans; Memantine; Piperidines; Prospective Studies; Treatment Outcome

Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD).. The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120.. Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Double-Blind Method; Humans; Indans; Parkinson Disease; Piperidines; Treatment Outcome

HTL0018318 is a selective muscarinic M. We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil.. This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics.. AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics.. HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil.. Netherlands Trial register identifier NL5915, registered on 28 October 2016.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Humans; Indans; Piperidines

Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT).. A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus).. A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found.. TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Topics: Alzheimer Disease; China; Cognition; Dementia, Vascular; Double-Blind Method; Humans; Indans; Piperidines; Treatment Outcome

Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression.. ACP-103-019 was a 12-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserin-treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders).. Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = -3.64, t = -4.69, P < .0001) and the CMAI-SF (week six, LSM difference = -3.71, t = -2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI-NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = -3.03, t = -2.44, P = .019).. Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.

Topics: Aggression; Alzheimer Disease; Double-Blind Method; Humans; Piperidines; Psychomotor Agitation; Psychotic Disorders; Treatment Outcome; Urea

Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.. Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD).. Randomized, double-blind, placebo-controlled trial.. Nursing home residents.. Patients with AD psychosis.. Pimavanserin 34 mg or placebo daily for 12 weeks.. The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated.. Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks.. Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Nursing Homes; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Urea

New therapeutic approaches for Alzheimer disease (AD) are needed.. To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD.. Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017.. Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3).. Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded.. Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups.. In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD.. clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Topics: Accidental Falls; Aged; Aged, 80 and over; Alzheimer Disease; Benzylamines; Cholinesterase Inhibitors; Cognition; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Galantamine; Humans; Indans; Indoles; Male; Middle Aged; Piperidines; Rivastigmine; Serotonin Antagonists; Treatment Failure

Pimavanserin is a selective 5-HT. We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553.. Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group.. Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo.. ACADIA Pharmaceuticals.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Nursing Homes; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Treatment Outcome; Urea

Intravenous immunoglobulin (IVIg) has been a candidate as a potential anti-amyloid immunotherapy for Alzheimer disease (AD) because it contains anti-amyloid β (Aβ) antibodies. Although several studies with IVIg in AD have been published, changing levels of Aβ efflux from the brain, or disaggregation of Aβ species induced by immunotherapy, have not been properly investigated. Here, we carried out an open label study of therapy with IVIg in five patients with AD. We collected plasma from a peripheral vein (peripheral-plasma) and from the internal jugular vein (jugular-plasma) to estimate directly the efflux of soluble Aβ from the brain. We also measured high molecular weight (HMW) Aβ oligomers in CSF as a marker to detect disaggregated Aβ. IVIg infusions were well tolerated in the majority of cases. However, one study subject had epileptic seizures after IVIg. Levels of HMW CSF Aβ oligomers in all participants were significantly increased after IVIg. Aβ40 and Aβ42 levels in jugular-plasma were continuously or temporarily elevated after treatment in three of five patients who showed preserved cognitive function, whereas levels of those in peripheral-plasma did not correlate with reactivity to the treatment. Other conventional biomarkers including 11C-Pittsburgh compound B retention were not altered after the treatment. These findings imply that HMW Aβ oligomer levels could be a better biomarker to reflect the anti-amyloid effects of IVIg than conventional Aβ species; moreover, Aβ in jugular-plasma seems to be a more direct and precise biomarker to estimate clearance of Aβ from the brain rather than Aβ in peripheral-plasma.. UMIN000022319.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognition; Donepezil; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Indans; Jugular Veins; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Piperidines; Positron-Emission Tomography; Seizures; Treatment Outcome

Sustained-release, high-dose (23 mg/d) donepezil has been approved for treatment of moderate to severe Alzheimer disease (AD). Based on a previous clinical trial, body weight of less than 55 kg is a risk factor for adverse events with donepezil 23 mg/d treatment in global population.. To clarify whether this finding is consistent across ethnic groups that vary in absolute body mass, we recruited Korean patients aged 45 to 90 years with moderate to severe AD who had been receiving standard donepezil immediate release 10 mg/d for at least 3 months. After screening, we analyzed a final cohort of 166 patients who received donepezil 23 mg/d for 24 weeks to compare the occurrence of treatment-emergent adverse events (TEAEs) between patients with high versus low body mass index (BMI) based on the World Health Organization overweight criteria for Asian populations (23 kg/m).. Treatment-emergent adverse events were reported by 79.45% of patients in the lower BMI group and 58.06% of patients in the higher BMI group (odds ratio, 2.79; 95% confidence interval, 1.39-5.63; χ = 7.58, P = 0.006). In a multivariable survival analysis, the group with lower BMI showed a higher occurrence of TEAEs (hazard ratio, 1.83; 95% confidence interval, 1.25-2.68; P = 0.002).. In Korean patients with moderate to severe AD receiving high-dose donepezil over 24 weeks, TEAEs were significantly more common in those with lower BMI (not clinically overweight), especially nausea. This finding may inform clinical practice for Asian patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Body Weight; Cholinesterase Inhibitors; Delayed-Action Preparations; Dizziness; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nausea; Piperidines; Prospective Studies; Republic of Korea

Alzheimer's disease is a progressive neurodegenerative disease. Although some of the current treatments offer some symptomatic relief, this disease cannot be cured at present. Electroacupuncture may be effective for Alzheimer's disease for cognitive function, but the evidence for its effectiveness is still limited. The aim of this study is to evaluate the add-on effect of electroacupuncture to donepezil for improving the cognitive function of Alzheimer's disease.. A total of 334 participants with Alzheimer's disease will be randomly assigned to either an electroacupuncture combined with donepezil group or a donepezil group with a ratio of 1:1. Participants in the electroacupuncture combined with donepezil group will receive electroacupuncture in addition to donepezil for 12 weeks and will keep taking donepezil for the following 24 weeks. Participants in the control group will take donepezil only. The primary outcome is the change from baseline in the total score of the Alzheimer's Disease Assessment Scale-cognition at week 12. A follow-up will be conducted 24 weeks after the treatment.. We expect to verify the hypothesis that acupuncture in addition to donepezil is better than donepezil in improving the cognitive function of patients with Alzheimer's disease. This trial has a limitation that participant blinding is impossible.. Clinical Trials.gov: ID: NCT02305836 . Registered on 13 November 2014.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; China; Clinical Protocols; Cognition; Combined Modality Therapy; Donepezil; Electroacupuncture; Female; Humans; Indans; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Prospective Studies; Research Design; Surveys and Questionnaires; Time Factors; Treatment Outcome

Recent studies using the mouse model of Alzheimer's disease (AD) have shown that donepezil administration reduces brain amyloid-β (Aβ) accumulation. This study investigated whether donepezil administration can reduce brain Aβ accumulation in human patients with AD. Ten patients with AD underwent two

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Donepezil; Female; Functional Neuroimaging; Humans; Indans; Male; Nootropic Agents; Piperidines; Positron-Emission Tomography; Thiazoles; Time Factors

Alzheimer's disease (AD) is the most common cause of dementia. However, none of medical treatment can stop or reverse the underlying neurodegenerative of AD at present. Acupuncture has attracted more and more attention in recent years due to its efficacy and very few side effects. Lately, a systematic review has thought that the evidence on the effectiveness of acupuncture in improving the cognitive function of AD patients was not powerful enough. Therefore, the aim of this study is to explore the efficacy and safety of acupuncture in patients with mild to moderate AD.. This was a randomized, controlled, parallel-group, exploratory study with 4-week baseline (T0), 12-week treatment phase (T1) and 12-week follow-up period (T2). Patients with mild to moderate AD meeting the included criteria were randomly allocated into either acupuncture or donepezil hydrochloride groups. The acupuncture group(AG) was given acupuncture treatment three times per week and the donepezil hydrochloride group(DG) group was administered donepezil hydrochloride once daily (5 mg/day for the first 4 weeks and 10 mg/day thereafter). Primary efficacy was measured using Alzheimer's disease Assessment Scale-Cognitive (ADAS-cog) and Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus). The second outcomes were measured with 23-Item Alzheimer's disease Cooperative Study Activities of Daily Living Scales (ADAS-ADL. Of 87 participants enrolled in the study, 79 patients finished their treatment and follow-up processes. The ADAS-cog scores for AG group showed obvious decreases at T2 and ∆(T2-T0)when compared with DG group, and significant between-group differences were detected (all p < 0.05). The mean CIBIC-Plus values for the AG group at T1 and T2 were much lower than that for the DG group, and there were significant differences between the two groups (푃<0.05). There were no significant between-group differences in the scores of ADAS-ADL. Acupuncture is safe, well tolerated and effective in improving the cognitive function, global clinical status of AD.. ChiCTR-IOR-17010465 (Retroactively registered on 18 JAN 2017).

Topics: Acupuncture Therapy; Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Mental Status and Dementia Tests; Piperidines; Treatment Outcome

Ethnic diversity between different populations may affect treatment safety and efficacy.. A subanalysis to a global trial (study 326) was carried out to ascertain the safety and efficacy of donepezil 23 mg/day compared with donepezil 10 mg/day in Asian patients with moderate-to-severe Alzheimer's disease. Changes in cognition and global functioning were measured by the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), respectively, at week 24.. Cognitive improvement measured by SIB score was greater with donepezil 23 mg than with donepezil 10 mg (+1.36 vs -1.56]; difference, 2.92). There was no difference between the groups in global function measured by the CIBIC-Plus (3.94 and 3.95, respectively). Overall, 119 patients (82.1%) receiving donepezil 23 mg and 56 (71.8%) receiving donepezil 10 mg experienced ≥1 treatment emergent adverse events (TEAEs). In the donepezil 23 mg group, the incidence of TEAEs was higher among patients of lower weight (<55 kg) at baseline than in those of higher weight (64 of 75 patients [85.3%] vs 55 of 70 patients [78.5%]).. The benefits and risks associated with donepezil 23 mg in Asian patients are comparable to those of the global study population.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Asian People; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Nausea; Piperidines; Severity of Illness Index; Treatment Outcome

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Blood-Brain Barrier; Capillary Permeability; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Spinal Puncture; Time Factors

Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients.. Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine.. Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone.. Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cost-Benefit Analysis; Donepezil; Double-Blind Method; England; Female; Health Care Costs; Humans; Indans; Memantine; Piperidines; Quality of Life; Wales

Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer's disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency.. To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD.. BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo.. Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group.. Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effects.

Topics: Aged; Alzheimer Disease; Anxiety; Apathy; Caregivers; Depression; Donepezil; Double-Blind Method; Female; Glycerylphosphorylcholine; Humans; Indans; Male; Piperidines; Psychotropic Drugs; Severity of Illness Index; Stress, Psychological; Treatment Outcome

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Maximum Tolerated Dose; Middle Aged; Muscarinic Antagonists; Piperidines; Single-Blind Method; Solifenacin Succinate; Treatment Outcome

Donepezil has been used worldwide for the treatment of severe Alzheimer's disease (AD). Whether it is also appropriate for severe AD in Chinese patients remains unknown.. To determine whether donepezil is effective and tolerable for Chinese patients with severe AD.. The present study was a 24-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study conducted at 38 investigational hospitals in China. Patients with severe AD were enrolled in this trial. Patients were randomly assigned in a 1:1 ratio to receive either donepezil or placebo (5 mg for 6 weeks and10 mg for the remaining 18 weeks). The efficacy for donepezil were evaluated by the SIB, the Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-plus) and the MMSE. Safety parameters were monitored throughout.. A total of 313 patients included the donepezil (n = 157) and the placebo groups (n = 156). Donepezil group improved more in SIB scores (least squares [LS] mean difference: 4.8, 95% CI 1.56 to 8.08, p = 0.004) and CIBIC-plus scores (drug-placebo difference: -0.4, 95% CI -0.66 to 0.03, p = 0.04) than placebo groups at Week 24. The MMSE scores between drug and placebo groups did not differ significantly. Twenty-nine patients with serious adverse events (SAEs) were reported in donepezil (n = 11) and placebo groups (n = 18) (p = 0.08). Most SAEs were not considered drug-related.. Donepezil for 24 weeks was more effective than placebo and showed good safety and tolerability in Chinese patients with severe AD. This study supports utility of the drug in severe stages of AD in the Chinese population.

Topics: Aged; Alzheimer Disease; China; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mental Status and Dementia Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's).. Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States.. Four memory care practices within four healthcare systems in the greater Indianapolis area.. Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs.. Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks.. Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event.. 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant.. This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management.. Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Costs; Drug-Related Side Effects and Adverse Reactions; Ethnicity; Female; Galantamine; Humans; Indans; Indiana; Male; Medication Adherence; Piperidines; Rivastigmine

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; 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Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Only a few approved drugs are capable of alleviating the cognitive and behavioural symptoms of people living with Alzheimer's disease (AD). In recent years, however, the number of studies examining the clinical effects of herbal medicines on cognitive function in patients with AD has increased considerably. This study evaluated the long-term effects of a traditional Japanese medicine (Kampo medicine) known as ninjin'yoeito (NYT) on cognitive impairment and mood status in patients with AD over a 2-year period.. Twenty-three patients with mild-to-moderate probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria were included. Each participant had exhibited an insufficient response to treatment with donepezil alone before the start of the trial. Eleven patients received treatment with donepezil alone, and the remaining patients received a combined treatment of donepezil and NYT for 2 years. Patients were assessed by the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version for cognitive function, and the Neuropsychiatric Inventory was used to evaluate the patients' mood status at baseline and every 6 months for 2 years.. The Mini-Mental State Examination results showed no significant differences between the two groups. Significant improvements were observed on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version and the Neuropsychiatric Inventory depression scores of patients who received the combined therapy with donepezil and NYT (Alzheimer's Disease Assessment Scale-cognitive component-Japanese version, 12 months: P < 0.01, 18 months: P = 0.04, 24 months: P < 0.01; Neuropsychiatric Inventory depression, 6 months: P < 0.05, 24 months: P < 0.05).. A 2-year follow-up of patients receiving donepezil and NYT treatment showed an improved cognitive outcome and alleviation of AD-related depression.

Topics: Affect; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depression; Donepezil; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Medicine, Kampo; Panax; Piperidines; Prospective Studies; Severity of Illness Index; Treatment Outcome

We determined the value of hippocampus (Hp) and basal forebrain (BF) volumes for predicting cognitive decline and treatment response in a double-blind, randomized, placebo-controlled phase 4 trial at 28 academic centers (France) in patients with amnestic mild cognitive impairment (MCI) receiving Donepezil 10 mg daily or placebo over 12 months, and 6 months open label follow-up. Outcome measures were the rates of global and domain specific cognitive decline as non-primary efficacy endpoint. The intention-to-treat (ITT) sample analyzed comprised 215 cases. Baseline Hp volume was a significant predictor of rates of change in global cognitive function in linear mixed effects models. This effect was independent of treatment. BF volume was not associated with rates of global or domain specific cognitive decline. Rates of delayed free recall decline were higher in MCI cases treated with donepezil compared to placebo. Only Hp, but not BF volume was a useful predictor of cognitive decline in suspected prodromal AD patients. Both Hp and BF volumes were poor predictors of treatment response, questioning previous approaches on predicting treatment response without placebo control.. clinicalTrials.gov Identifier NCT00403520.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Predictive Value of Tests; Prodromal Symptoms; Treatment Outcome

The purpose of the study is to evaluate whether donepezil (D) plasma concentrations and activity of CYP2D6 and CYP3A4 are associated with the therapeutic response of patients with mild to moderate Alzheimer's disease (AD).. This study comprised 54 patients affected by probable AD in therapy with D 10 mg/daily for at least 3 months. Plasma concentrations of D and its three main metabolites (6DD, 5DD, DNox) were assayed with a novel high performance liquid chromatography (HPLC) technique. Cognitive progression was assessed at baseline and at 9 months of follow-up with the mini mental state examination (MMSE). The activities of the two cytochromes involved in D metabolism-CYP2D6 and CYP3A4-were evaluated according to their metabolic ratios in plasma or urine, after test doses of probe drugs (dextromethorphan and omeprazole).. A significant correlation was found between plasma levels of D and variations in MMSE scores after 9 months of therapy (r (2) = 0.14; p = 0.006). Neither the concentrations of D metabolites nor the metabolic ratios of CYP2D6 and CYP3A4 showed any correlations with cognitive variations. Low CYP2D6 activity and advanced age were associated with high D concentrations. Patients who were treated with CYP2D6 and P-glycoprotein (P-gp) inhibitors also had higher D plasma levels (mean difference = 19.6 ng/mL; p = 0.01) than those who were not.. D plasma concentrations, but not cytochrome phenotyping, are associated with cognitive outcomes in AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cholinesterase Inhibitors; Cognition; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Donepezil; Drug Interactions; Female; Humans; Indans; Male; Phenotype; Piperidines

ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD).. This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).. Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog).. Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.. Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; International Cooperation; Male; Medication Adherence; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD.. To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD).. In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety.. Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil.. SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Delayed-Action Preparations; Donepezil; Double-Blind Method; Female; Humans; Indans; Japan; Male; Mental Status Schedule; Nootropic Agents; Outpatients; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer's disease (AD) susceptibility genes with distinct pharmacogenomic properties.. To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects.. Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer's Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects.. Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder's pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects.. APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Quebec; Treatment Outcome

Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg).. The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.. A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.. In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.. ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinergic Agonists; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Piperidines; Quinuclidines; Thiadiazoles; Treatment Outcome

Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia.. Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness.. The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome.. Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways.. ClinicalTrials.gov identifier: NCT00403520.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Prodromal Symptoms

Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly.. The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient.. The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®.. Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug.. The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

Topics: Adult; Alzheimer Disease; Donepezil; Double-Blind Method; Drug Compounding; Drug Costs; Drug Delivery Systems; Drug Liberation; Drug Stability; Drug Storage; Excipients; Glycyrrhizic Acid; Hardness; Humans; Indans; Mouth Mucosa; Nootropic Agents; Patient Preference; Piperidines; Salvia; Sweetening Agents; Tablets; Taste; Taste Perception

Gait deficits are prevalent in people with dementia and increase their fall risk and future disability. Few treatments exist for gait impairment in Alzheimer's disease (AD) but preliminary studies have shown that cognitive enhancers may improve gait in this population.. To determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic activity, on gait in older adults newly diagnosed with AD.. Phase II clinical trial in 43 seniors with mild AD who received donepezil. Participants had not previously received treatment with cognitive enhancers. Primary outcome variables were gait velocity (GV) and stride time variability (STV) under single and dual-task conditions measured using an electronic walkway. Secondary outcomes included attention and executive function.. After four months of treatment, participants with mild AD improved their GV from 108.4 ± 18.6 to 113.3 ± 19.5 cm/s, p = 0.010; dual-task GV from 80.6 ± 23.0 to 85.3 ± 22.3 cm/s, p = 0.028. Changes in STV were in the expected direction although not statistically significant. Participants also showed improvements in Trail Making Tests A (p = 0.030), B (p = 0.001), and B-A (p = 0.042).. Donepezil improved gait in participants with mild AD. The enhancement of dual-task gait suggests the positive changes achieved in executive function as a possible causal mechanism. This study yielded a clinically significant estimate of effect size; as well, the findings are relevant to the feasibility and ethics considerations for the design of a Phase III clinical trial.

Topics: Aged; Alzheimer Disease; Anti-Dyskinesia Agents; Attention; Cholinesterase Inhibitors; Donepezil; Executive Function; Female; Gait; Gait Disorders, Neurologic; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).. We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).. Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Blood Chemical Analysis; Cognitive Dysfunction; Disease Progression; Donepezil; Female; Heterozygote; Humans; Indans; Longitudinal Studies; Male; Nootropic Agents; Peptide Fragments; Piperidines; Severity of Illness Index; Simvastatin; Vitamin E

Alzheimer's disease (AD) is the most frequent cause of dementia. This work aims to assess the effectiveness of reality orientation (RO), a traditional, extensively documented cognitive enhancement technique, when combined with acetylcholinesterase inhibitors in the treatment of AD. Fourteen patients with AD having mild to moderate dementia receiving standard treatment with donepezil were randomly assigned to control and treatment groups. Patients in the treatment group were submitted to weekly RO sessions for 6 months. Cognitive outcomes were assessed based on scores in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery and the Clock Drawing Test (CDT). Mean CERAD neuropsychological battery, Mini-Mental State Examination (MMSE), and CDT scores improved in the treatment group and worsened in the control group. A number of CERAD neuropsychological battery and MMSE scores were statistically significant. Our findings suggest that RO is a valuable long-term complementary intervention for dementia in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Combined Modality Therapy; Donepezil; Female; Humans; Indans; Male; Neurological Rehabilitation; Neuropsychological Tests; Orientation; Piperidines; Severity of Illness Index; Treatment Outcome

The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD).. A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method.. Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups.. A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Topics: Aged; Alzheimer Disease; Atrophy; Disease Progression; Donepezil; Double-Blind Method; Female; France; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Organ Size; Piperidines; Prodromal Symptoms; Treatment Outcome

To observe the intervention effect of nourishing Xin and Shen method (NXSM) on the cognitive function of mild cognitive impairment due to subcortical small vessel disease (MCI-SSVD).. All 54 MCI-SSVD patients came from Department of Traditional Chinese Medicine, Affiliated Union Hospital of Fujian Medical University from June 2010 to August 2013. They were randomly assigned to the treatment group (28 cases) and the control group (26 cases). Another 33 volunteers were recruited as a healthy control group. On the basis of targeting risk factors of blood vessels, MCI-SSVD patients were treated respectively with NXSM and donepezil hydrochloride, with the therapeutic course of 12 weeks. Neuropsychological scales [mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA)], and Chinese medical dementia syndrome scales were performed in all subjects, and results were compared among groups or intra-group before and after treatment.. MMSE and MoCA scores of the two treatment groups decreased more, when compared with those of the healthy control group (P < 0.05). In particular, MoCA score was significantly decreased (P < 0.01). MMSE and MoCA scores of the two treatment groups increased more after treatment than before treatment (P < 0.05). But there was no statistical difference in MMSE or MOCA score after treatment between the two groups (P > 0.05). Chinese medical dementia syndrome scales decreased more significantly in the treatment group, when compared with before treatment (P < 0.01). But there was no statistical difference in Chinese medical dementia syndrome scales in the control group between before and after treatment (P > 0.05). Visual spatial and executive function scores or delayed recall scores of the two treatment groups increased more, when compared with the same group before treatment (P < 0.05, P < 0.01).. NXSM could effectively improve cognitive functions of MCI-SSVD.

Topics: Alzheimer Disease; Biomedical Research; Cognition; Cognitive Dysfunction; Dementia; Donepezil; Drugs, Chinese Herbal; Humans; Indans; Neuropsychological Tests; Piperidines

Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake.. Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated.. The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments.. An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.

Topics: Adult; Alzheimer Disease; Biological Availability; Cross-Over Studies; Donepezil; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Indans; Male; Memantine; Piperidines

Memantine has been approved by the Food and Drug Administration for the treatment of moderate-to-severe Alzheimer's disease (AD). However, the effect of memantine on patients with mild-to-moderate AD is unclear.. This study is a post hoc analysis of a double-blind clinical trial. Donepezil was used as the standard control treatment. Outcomes included score changes from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a modified 20-item Activities of Daily Living Scale (ADL), the Neuropsychiatric Inventory (NPI), and the Mini-Mental State Examination (MMSE) as well as the score of the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus).. One hundred sixty-seven AD patients with an MMSE score of 10-24 were analyzed. No significant differences in the score changes from baseline to week 24 on all outcomes or the four subscales of the ADAS-cog were observed between the two treatment groups. Donepezil resulted in an improved score for naming ability on the ADAS-cog compared to memantine (p = 0.036), whereas memantine more effectively reduced agitation as measured by the NPI compared to donepezil (p = 0.039).. These findings support the efficacy of memantine for the treatment of mild-to-moderate AD, especially in patients with agitation.

Topics: Alzheimer Disease; Behavioral Symptoms; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Neuropsychological Tests; Piperidines; Prospective Studies; Severity of Illness Index

To explore the efficacy of Chinese herbal formula compared with donepezil 5 mg/day in patients with mild Alzheimer's disease (AD).. Patients with mild AD meeting the criteria were randomized into Chinese herbal formula Yishen Huazhuo decoction (YHD) group and donepezil hydrochloride (DH) group during the 24-week trial. The outcomes were measured by ADAS-cog, MMSE, ADL, and NPI with linear mixed-effect models.. 144 patients were randomized. The mean scores of ADAS-cog and MMSE in both YHD group and DH group both improved at the end of the 24-week treatment period. The results also revealed that YHD was better at improving the mean scores of ADAS-cog and MMSE than DH. Linear mixed-effect models with repeated measures showed statistical significance in time × group interaction effect of ADAS-cog and also in time × group interaction effect of MMSE. The data showed YHD was superior to DH in improving the scores and long term efficacy.. Our study suggests that Chinese herbal formula YHD is beneficial and effective for cognitive improvement in patients with mild AD and the mechanism might be through reducing amyloid-β (Aβ) plaque deposition in the hippocampus.. Chinese Clinical Trial Registry ChiCTR-TRC-12002846.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; China; Cognition; Donepezil; Double-Blind Method; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Piperidines; Treatment Outcome

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Caregivers; Donepezil; Female; Humans; Hypnotics and Sedatives; Indans; Male; Melatonin; Neuropsychological Tests; Nootropic Agents; Nursing Homes; Piperidines; Polysomnography; Pyridines; Risperidone; Sleep Wake Disorders; Treatment Outcome; Zolpidem

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to explore which tests and their measures are able to detect cognitive change after a single dose of donepezil in Alzheimer disease (AD) patients. The aim of this study was to establish the ability of CANTAB tests and their measures to detect cognitive change after a single 5-mg dose of donepezil in treatment-naïve AD patients.. We enrolled 62 treatment-naïve AD patients and 30 healthy controls in this prospective, randomized, rater-blinded study. AD patients were randomized to 2 groups: the AD+ group received donepezil after the first CANTAB testing and the AD- group remained treatment-naïve at second testing. The time period between repeated testing was 4 hours. Parallel versions of CRT, SOC, PAL, SWM, and PRM tests were used.. All groups did not differ according to age, education, gender, or depression (p>0.05). AD+ and AD- groups did not differ according to MMSE. SOC, PAL, PRM, and SWM tests distinguished AD from controls. Eight measures of PAL and PRM had a strong correlation with MMSE (r>0.7). Repeated-measures ANOVA with Bonferroni post-hoc test showed the difference of change in AD+ and AD- groups between first and second CANTAB testing in 7 PAL measures. AD+ and AD- groups differed in the second testing by 7 PAL measures. Four PAL measures differed in first and second testing within the AD+ group.. The CANTAB PAL test measures, able to detect cognitive change after a single dose of donepezil in AD patients, are: PAL mean trials to success, total errors (adjusted), total errors (6 shapes, adjusted), and total trials (adjusted).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Learning; Male; Memory; Neuropsychological Tests; Pattern Recognition, Visual; Piperidines; Prospective Studies; Psychometrics; Severity of Illness Index; Time Factors; Treatment Outcome

Apathy is a common symptom in Alzheimer's disease (AD), but no treatment has proven to be effective, although administration of cholinesterase inhibitors has been associated with moderate improvements in the short term.. This study has compared apathy scores of patients included in "ASCOMALVA" trial treated for two years with donepezil plus a cholinergic precursor (choline alphoscerate), to those of patients receiving donepezil alone with the purpose of assessing if the availability of a higher amount of acetylcholine by combining precursor loading and inhibition of neurotransmitter breakdown would counter apathy in AD.. Apathy was measured at baseline and 3, 6, 9, 12, 18, and 24 months using the apathy subtest of the Neuropsychiatric Inventory in 113 mild-moderate AD patients. Two matched groups were compared: group 1 (56 subjects) treated with donepezil plus choline alphoscerate and group 2 (57 subjects) treated with donepezil alone. Frontal functions were explored by the Frontal Assessment Battery (FAB) at baseline.. Group 1 subjects showed, as a whole, a lower apathy score after 12 to 24 months. The caregiver distress was descreased after 6 to 24 months. Results were unrelated with cognitive scores measured by the MMSE and ADAS-cog test. Subjects with FAB in the normal range had significantly lower scores.. The combination of donepezil with choline alphoscerate is more effective than donepezil alone in countering symptoms of apathy in AD. This suggests that the availability in brain of a higher amount of acetylcholine could affect apathy in AD subjects with spared executive functions.

Topics: Aged; Alzheimer Disease; Apathy; Caregivers; Cholinergic Agents; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Glycerylphosphorylcholine; Humans; Indans; Male; Piperidines; Psychiatric Status Rating Scales; Psychotropic Drugs; Time Factors; Treatment Outcome

ST101, an acetylcholine release agent with efficacy in rodent memory and cognition models, was assessed for clinical safety and efficacy.. A phase 2 double blind, placebo-controlled study enrolled 210 AD patients (MMSE 10-20) on 10 mg donepezil QD. Patients received ST101 (10, 60, or 120 mg QD) or placebo for 12 weeks. The primary endpoint was change in cognitive function measured by ADAS-cog in the modified Intent To Treat (MITT) population and the Per Protocol (PP) population.. Mean ADAS-cog change favored ST101 over placebo in the MITT population (p = 0.0957, one-sided) and in the PP population (p = 0.0434, one-sided, ∼1.5 point drug-placebo difference) comparing all ST101 dose groups combined to placebo. Among secondary and exploratory outcome measures the ADCS-CGIC also showed a beneficial trend (p = 0.0294, one-sided). In a post-hoc analysis, the subgroup with more severe disease (MMSE 10-17) showed a dose response in the ADAS-cog with the greatest efficacy at 120 mg (p = 0.0067, one sided). No significant ST101-related safety concerns were identified.. The study supports the possibility that ST101, in patients receiving a stable dose of donepezil, may provide additional symptomatic benefit in moderate AD.

Topics: Alzheimer Disease; Cholinergic Agents; Cognition; Donepezil; Double-Blind Method; Drug Therapy, Combination; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Spiro Compounds; Treatment Outcome

Previous studies have investigated associations between apolipoprotein E (APOE)-ɛ4 allele status and acetylcholinesterase inhibitor treatment response in patients with Alzheimer's disease. The ability to draw definitive conclusions regarding the effect of APOE-ɛ4 genotype on treatment response has been hindered by inconsistent results among studies and methodological limitations that restrict interpretation of study findings.. To determine whether APOE-ɛ4 carrier status influences the magnitude of change in 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score associated with acetylcholinesterase inhibitor treatment (i.e., donepezil).. Analyses were performed using pooled data from the donepezil and placebo treatment arms of three consecutive, similarly designed, 12-week, multi-national, randomized clinical studies that enrolled patients with mild-to-moderate Alzheimer's disease. Correlations between APOE-ɛ4 carrier status and ADAS-cog scores were evaluated using analysis of covariance.. No appreciable interaction between donepezil response and APOE-ɛ4 carrier status or copy number was detected. Both carriers and non-carriers of APOE-ɛ4 who received donepezil experienced significant improvements from baseline in ADAS-cog score versus placebo (p <  0.05). Change from baseline to final observation in the donepezil treatment group was - 2.95 for APOE-ɛ4 carriers and - 4.09 for non-carriers (p = 0.23). In contrast, non-carriers of APOE-ɛ4 in the placebo treatment group exhibited a greater improvement from baseline versus carriers (-2.38 versus - 0.60, p = 0.05).. Within this population, APOE genotype had no statistically significant effect on cognitive response to donepezil treatment; however, APOE-ɛ4 allele status was associated with a difference in the magnitude of the change in ADAS-cog of placebo-treated patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Genotype; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales

Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease.. In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035.. Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]).. Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.. Medical Research Council and UK Alzheimer's Society.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Donepezil; Double-Blind Method; Female; Homes for the Aged; Humans; Indans; Male; Memantine; Neuropsychological Tests; Nootropic Agents; Nursing Homes; Piperidines; Severity of Illness Index

BACKGROUND Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. MATERIAL AND METHODS Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. RESULTS The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57-2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). CONCLUSIONS The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Prospective Studies; Treatment Outcome

Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of Alzheimer's disease (AD) patients and represent one of the most common reasons for early institutionalization and increase in management costs.. This study evaluated the effects of four drugs (memantine, donepezil, rivastigmine, galantamine) in BPSD in AD patients.. This was a prospective, longitudinal, randomized, open-label, 4-arm, parallel-group, 12-month clinical trial carried out in 177 AD patients. The severity of BPSD was evaluated at baseline and after treatment with memantine (n = 48), donepezil (n = 42), rivastigmine (n = 46), and galantamine (n = 41), by using the Neuropsychiatric Inventory (NPI) and the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scales.. The NPI and BEHAVE-AD total scores improved from baseline to month 12 in all groups. The improvements in both scales were statistically significant in the memantine, donepezil, and rivastigmine groups, but not in the galantamine group. Responder analyses showed that treatment with memantine and rivastigmine resulted in more patients improving on NPI and BEHAVE-AD score, respectively. Agitation/aggression was the NPI item with the highest improvements (significantly versus baseline in the memantine and in the rivastigmine groups), while aggression and anxiety/phobias were the mostly improved BEHAVE-AD items (significantly in the rivastigmine group for both and in the rivastigmine group only for anxiety/phobias). All treatments were well tolerated: most of adverse events reported were transient and of mild-to-moderate intensity.. This study suggests that specific drugs for AD, especially memantine and rivastigmine, may be effective in the improvement of BPSD in patients with mild to moderate AD, without major side effects.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Behavioral Symptoms; Cholinesterase Inhibitors; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Female; Galantamine; Humans; Indans; Longitudinal Studies; Male; Memantine; Mental Disorders; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Rivastigmine

Drug development for Alzheimer disease (AD) is challenged by the success in animal models tested in the Morris water maze (MWM) and the subsequent failures to meet primary outcome measures in phase II or III clinical trials in patients. The human variant of MWM (hMWM) enables us to examine allocentric and egocentric navigation as in the MWM.. It was the aim of this study to examine the utility of a computerized hMWM to assess the effects of donepezil in mild AD.. Donepezil 5 mg/day was started after initial hMWM testing in the treated group (n = 12), and after 28 days, the dose was increased to 10 mg/day. The performance after 3 months was compared to that of a non-treated group (n = 12).. Donepezil stabilized or improved the spatial navigation performance after 3 months, especially in the allocentric delayed recall subtask (p = 0.014).. The computerized hMWM has the potential to measure the effects of donepezil in mild AD. It is a sensitive cognitive outcome measure in AD clinical trials.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Computers; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Pilot Projects; Piperidines; Spatial Behavior

Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzothiazoles; Blotting, Western; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Drug Therapy, Combination; Fluorescence; Follow-Up Studies; Humans; Indans; Physostigmine; Piperidines; Thiazoles; Time Factors

Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antidepressive Agents; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depressive Disorder; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Piperidines; Research Design

In this study we assessed increased cortisol in Alzheimer's disease (AD) patients. The selective 11-β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor ABT-384 blocked regeneration of active cortisol and this tests the hypothesis that intracellular hypercortisolism contributes to cognitive impairment.. In this double-blind, placebo- and active-controlled phase II study we examine the efficacy and safety of ABT-384 given 10 mg or 50 mg once daily, donepezil 10 mg once daily, or placebo for 12 weeks in subjects with mild-to-moderate AD. The primary efficacy end point was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score.. The study was terminated for futility after randomization of 267 subjects. ABT-384 did not improve ADAS-Cog scores or any secondary end point; however, donepezil significantly improved both cognition and functional end points. Overall incidence of adverse events was similar among treatment groups.. ABT-384, when tested at doses associated with complete brain HSD-1 inhibition, did not produce symptomatic improvement in AD.

Topics: Adamantane; Aged; Alzheimer Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperazines; Piperidines; Treatment Outcome

In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow.. We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24.. Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT.. In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Brief Psychiatric Rating Scale; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Cost of Illness; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Prefrontal Cortex; Spectroscopy, Near-Infrared

To evaluate the effect of donepezil, one of the cholinesterase inhibitors, on P300 measurements in patients with Alzheimer's disease (AD) and investigate the relationship between the subfactors of cognitive performance and P300 components.. One hundred outpatients with AD were evaluated for cognitive function (cognitive ability screening instrument) and event-related potentials before and after 22 to 23 weeks of treatment with donepezil (5 mg/day). Twenty age-matched normal control subjects were recruited.. The patients with AD showed prolonged P300 and N200 latency, no significant differences in N100 and P200 components, and poor performance in neuropsychological assessments compared with control subjects at baseline. After donepezil treatment, the patients with AD had reduction in P300 latency at Pz lead, which was associated with a parallel improvement in cognitive function in terms of remote memory, recent memory, visual instruction, and orientation. The pre-post treatment difference of P300 latency significantly correlated with the cognitive ability screening instrument score difference and recent memory score difference, respectively.. The patients with AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The donepezil treatment, which enhances higher-level cognitive processing time, revealed that P300 latency decreases as cognitive capability increases, especially improved in recent memory.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cholinesterase Inhibitors; Cognition; Donepezil; Event-Related Potentials, P300; Evoked Potentials; Female; Humans; Indans; Male; Piperidines

Combined therapy of memantine and acetylcholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD) may be associated with higher benefits than either monotherapy.. This retrospective multicentric study conducted in seven Italian Ambulatory Centers for Dementia assessed the efficacy and safety of memantine 20 mg/day administered for 6 months in addition to an AChEI in AD patients with worsened cognitive functions and behavioral disorders.. A total number of 240 patients (61.7% of women, 38.3% men, mean age 77.9 ± 7.32 years old) who had started treatment with the combination therapy were recruited. At baseline (T0), Month 3 (T1), and Month 6 (T2), cognitive functions were assessed by Mini-Mental State Examination (MMSE), functional dependence by activities of daily living (ADL) and instrumental ADL, behavioral disturbances by the Neuropsychiatric Inventory (NPI), and comorbidities by Cumulative Illness Rating Scale. Adverse events were reported during the study.. MMSE total score significantly increased at Month 6 (p = 0.029 versus month 3) and IADL total score significantly decreased from baseline to endpoint (p = 0.033). There were no significant changes from baseline in mean ADL, despite significant improvements in NPI total score. The mean MMSE total score significantly increased with the combination donepezil + memantine compared to rivastigmine + memantine. The adverse events profile was in line with the expected range of the drugs studied and concomitant therapies. Overall, 17 patients discontinued treatment in the observation time.. Combined treatment with memantine and AChEIs was effective in patients with AD, particularly in slowing cognitive impairment and preventing the onset of agitation and aggression in elderly AD patients.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Comorbidity; Donepezil; Female; Galantamine; Humans; Indans; Italy; Male; Memantine; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Retrospective Studies; Rivastigmine; Time Factors; Treatment Outcome

Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer's disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. The trial has recruited AD patients suffering from ischemic brain damage documented by neuroimaging and has completed 2 years of observation in 113 patients of the 210 planned. Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference group (donepezil + placebo). Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer's Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the different items analyzed. These findings suggest that the combination of choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Antipsychotic Agents; Donepezil; Double-Blind Method; Female; Glycerylphosphorylcholine; Humans; Indans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Piperidines; Severity of Illness Index

ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers.. Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer's dementia.. The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.. The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting.. ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer's dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Histamine H3 Antagonists; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Pyridazines; Pyrroles; Treatment Outcome

In human beings, 5-HT6 receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6 receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease.. For this randomised, double-blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12-19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to-treat analysis). This trial is registered with ClinicalTrials.gov, number NCT01019421.. Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and -0·77 (0·55) in the idalopirdine group (treatment difference of -2·16 points, 95% CI -3·62 to -0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment.. Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here.. H Lundbeck A/S.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzylamines; Cognition Disorders; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Indoles; Male; Nootropic Agents; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Treatment Outcome

The enigmatic etiology of neurodegenerative diseases poses a challenge for the development of novel and efficient drugs. The objective of the present study was to evaluate the efficacy of a polyherbal (test) formulation on cognitive functions, inflammatory markers and oxidative stress in healthy elderly as well as senile dementia of Alzheimer's type (SDAT) patients.. A randomized double-blind placebo- and active-controlled clinical trial was performed in healthy elderly subjects and SDAT patients with an age range of 60-75 years. The polyherbal test formulation along with a placebo was given to healthy elderly subjects while the SDAT patients received either the test formulation containing extracts of Bacopa monnieri (whole plant), Hippophae rhamnoides (leaves and fruits) and Dioscorea bulbifera (bulbils) at a dose of 500 mg or donepezil drug (Aricept) at a dose of 10 mg, twice daily, for a period of 12 months. After every three months, cognitive functions were assessed by determining the mini mental state examination (MMSE) score, digital symbol substitution (DSS; subtest of the Wechsler Adult Intelligence Scale-Revised), immediate and delayed word recall (digital memory apparatus-Medicaid systems, Chandigarh, India), attention span (Attention Span Apparatus-Medicaid systems, Chandigarh, India), functional activity questionnaire (FAQ) and depression (geriatric depression scale) scores. Further inflammatory markers and level of oxidative stress were analyzed using standard biochemical tests.. The trial was performed in 109 healthy subjects and 123 SDAT patients of whom 97 healthy subjects and 104 SDAT patients completed the study. Administration of the test formulation for a period of 12 months was effective in improving cognitive functions in the SDAT patients, when compared to the donepezil-treated group, as determined by the DSS (38.984 ± 3.016 vs 35.852 ± 4.906, P = 0.0001), word recall immediate (3.594 ± 1.003 vs 2.794 ± 0.593, P < 0.0001) and attention span (4.918 ± 1.239 vs 4.396 ± 0.913, P = 0.0208) scores. A significant improvement in the FAQ (11.873 ± 2.751 vs 9.801 ± 1.458, P < 0.0001) and depression (16.387 ± 2.116 vs 21.006 ± 2.778, P < 0.0001) scores was also observed, whereas no significant differences were observed in the MMSE and word recall delayed scores. The level of inflammation and oxidative stress was markedly reduced in the SDAT patients treated with the test formulation when compared to the donepezil-treated group indicating a likely mechanism of action of the test formulation (homocysteine 30.22 ± 3.87 vs 44.73 ± 7.11 nmol/L, P < 0.0001; C-reactive protein [CRP] 4.751 ± 1.149 vs 5.887 ± 1.049 mg/L, P < 0.0001; tumour necrosis factor alpha [TNF-α] 1139.45 ± 198.87 vs 1598.77 ± 298.52 pg/ml, P < 0.0001; superoxide dismutase [SOD] 1145.92 ± 228.75 vs 1296 ± 225.72 U/g Hb, P = 0.0013; glutathione peroxidase [GPx] 20.78 ± 3.14 vs 25.99 ± 4.11 U/g Hb, P < 0.0001; glutathione [GSH] 9.358 ± 2.139 vs 6.831 ± 1.139 U/g Hb, P < 0.0001; thiobarbituric acid reactive substances [TBARS] 131.62 ± 29.68 vs 176.40 ± 68.11 nmol/g Hb, P < 0.0001). Similarly, when healthy elderly subjects treated with the test formulation for 12 months were compared to the placebo group, a significant (P < 0.001) improvement in cognitive measures (MMSE, DSS, word recall delayed but not immediate, attention span, FAQ and depression scores) and a reduction in inflammation (reduction in homocysteine, CRP, IL-6 and TNF-α levels) and oxidative stress levels (reduction in SOD, GPx and TBARS and increase in GSH) was observed. This indicated a protective effect of the test formulation in managing cognitive decline associated with the ageing process.. The results of this study demonstrate the therapeutic potential of this novel polyherbal formulation for the management and treatment of SDAT.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Disease Management; Donepezil; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Plant Components, Aerial; Plant Extracts; Plant Preparations

Difficulty in swallowing tablets or capsules has been identified as one of the contributing factors to non-compliance of geriatric patients. Although orally disintegrating tablet was designed for fast disintegration in mouth, the fear of taking solid tablets and the risk of choking for certain patient populations still exist.. The objective of this study was to develop and characterize orally disintegrating film (ODF), which was prepared using different combinations of polymers, plasticizers and fillers.. Effects of hydroxypropyl methylcellulose (HPMC), polyethylene glycol 400 (PEG 400), glycerin, polyvinyl pyrrolidone (PVP), mannitol and microcrystalline cellulose (MCC) on physical property of ODF formed were studied. The ODF was prepared using the solvent casting method.. Increase in HPMC concentration formed ODF with greater tensile strength. Incorporation of plasticizer (PEG 400 and glycerin) reduced tensile strength but increased elasticity of the ODF formed. PVP increased both tensile strength and elasticity of the ODF. Increase in MCC:mannitol ratio reduced the tensile strength and elasticity of the ODF. Disintegration time of film decreased corresponding to decrease in tensile strength of the film. Formulation R with the optimum tensile strength (13.10 N/mm(2)), bending flexibility (40 times) and disintegration time (41.50 s) was chosen as final formulation. A total of 80% of the drug was released within five minutes and the ODF was stable at least for one year actual condition.. An ODF containing donepezil HCl was developed and characterized. The donepezil HCl ODF has the potential to improve the compliance of Alzheimer disease patients.

Topics: Administration, Oral; Alzheimer Disease; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Donepezil; Drug Stability; Drug Storage; Excipients; Female; Humans; Indans; Male; Medication Adherence; Piperidines; Plasticizers; Polymers; Solubility; Tablets; Tensile Strength; Time Factors; Young Adult

Previous studies with functional magnetic resonance imaging (fMRI) demonstrated a differential brain activity and connectivity after treatment with donepezil in Alzheimer's disease (AD) when compared to healthy elders. Importantly however, there are no available studies where the placebo or control group included comparable AD patients relative to the treated groups. Fifteen patients recently diagnosed of AD were randomized to treatment (n = 8) or to control group (n = 7); the former receiving daily treatment of donepezil during 3 months. At baseline and follow-up, both groups underwent resting-state as well as task-fMRI examinations, this latter assessing encoding of visual scenes. The treated group showed higher connectivity in areas of the default mode network, namely the right parahippocampal gyrus at follow-up resting-fMRI as compared to the control group. On the other hand, for the task-fMRI, the untreated AD group presented progressive increased activation in the left middle temporal gyrus and bilateral precuneus at the 3-month examination compared to baseline, whereas the treated group exhibited stable patterns of brain activity. Donepezil treatment is associated with stabilization of connectivity of medial temporal regions during resting state and of brain efficiency during a cognitive demand, on the whole reducing progressive dysfunctional reorganizations observed during the natural course of the disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Magnetic Resonance Imaging; Memory; Piperidines; Time Factors

Donepezil has been approved, and higher dosages are recommended for the treatment of Alzheimer disease (AD). However, a few studies have reported different cognitive responses in patients with AD treated with donepezil without measuring the concentration.. We evaluated the relationships between the therapeutic responses and plasma concentrations of donepezil in various cognitive domains using the Cognitive Ability Screening Instrument among 37 patients with newly diagnosed mild stage AD taking donepezil 5 mg/d.. Among the 9 cognitive domains in the Cognitive Ability Screening Instrument, the long-term memory domain had the highest improvement ratio (81.1%) compared with the other domains. An increased donepezil plasma concentration [mean (SD), 75.14 (32.16) ng/mL] was significantly associated with the improvement of long-term memory (P = 0.045; odds ratio, 0.959; 95% confidence interval, 0.920-0.999) after adjusting for age, sex, education, and apolipoprotein E genotype.. Although there are some limitations in our study, these findings indicate that a higher concentration of donepezil improves long-term memory in patients with mild stage AD and imply the possible benefits in the advanced stage of AD for relatively preserved long-term memory.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Memory, Long-Term; Nootropic Agents; Piperidines; Prospective Studies; Severity of Illness Index; Treatment Outcome

Treatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response.. A post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed.. Donepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score.. The cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Piperidines; Severity of Illness Index; Treatment Outcome

The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity.. A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated.. Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24.. In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

Topics: Activities of Daily Living; Alzheimer Disease; Analysis of Variance; Cognition Disorders; Donepezil; Double-Blind Method; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

The aim of this study was to evaluate the effect of CYP2D6*10 and APOE polymorphisms on both steady-state plasma concentrations (Cp) and clinical response of donepezil in patients with mild-to-moderate Alzheimer's disease (AD).. A total of 110 Chinese AD patients participated in this study. Patients were treated with 5 to 10 mg of donepezil daily for 6 months. The genotypes of CYP2D6*10 and APOE were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The steady-state Cp of donepezil was measured by high-performance liquid chromatography-tandem mass spectrometric assay method. The cognition of patients was evaluated at baseline and at 6-month follow-up by Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subscale.. At 6-month follow-up, 56 of 96 patients (58.3%) were evaluated as responders and 40 patients (41.7%) as nonresponders to donepezil treatment. A significantly higher frequency of patients with genotypes CYP2D6*1/*10 and *10/*10 were found in responders than in nonresponders (P < 0.05). Besides, patients with CYP2D6*1/*10 and *10/*10 genotypes had higher Cp of donepezil and improved cognition scores than those with CYP2D6*1/*1 genotype (P < 0.05). However, the frequency of APOE [Latin Small Letter Open E]4 carriers and noncarriers showed no difference between the 2 groups (P > 0.05).. AD patients with mutant allele (*10) in CYP2D6 gene may respond better to donepezil than those with wild allele (*1). We did not find the relationship between APOE [Latin Small Letter Open E]4 status and the efficacy of donepezil in our study.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoproteins E; Cognition; Cytochrome P-450 CYP2D6; Donepezil; Female; Follow-Up Studies; Gene Frequency; Humans; Indans; Male; Middle Aged; Mutation; Nootropic Agents; Piperidines; Polymorphism, Restriction Fragment Length

Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD).. Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding.. The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory.. Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Auditory Cortex; Auditory Perceptual Disorders; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Limbic System; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Mental Recall; Middle Aged; Nootropic Agents; Piperidines; Verbal Learning; Young Adult

We attempt to evaluate objectively the regional cerebral blood flow (rCBF) changes during long-term donepezil therapy and the relationship between the clinical response and rCBF change in patients with Alzheimer's disease (AD).. Thirty-one patients with mild-to-moderate AD (11 men, 20 female; mean age, 76.2 ± 6.7 years) were treated with donepezil and underwent brain perfusion single-photon emission computed tomography (SPECT) twice with an interval of 24.5 ± 4.2 months. The rCBF was calculated using 3-dimensional stereotaxic region of interest template, a fully automated each region of interest technique. We compared the differences in rCBF between baseline and follow-up SPECT studies. Moreover, all patients were divided into stabilized (n = 14) and nonstabilized subgroups (n = 17) based on Mini-Mental State Examination (MMSE) score changes and the changes in rCBF were compared between two subgroups.. The mean MMSE score significantly decreased from 20.7 ± 4.6 at baseline to 16.5 ± 6.5 after 2 years. The mean rCBF significantly decreased in the widespread brain regions between the baseline and follow-up SPECT studies. The nonstabilized subgroup showed a significant decrease in rCBF of the parietal and temporal segments compared to the stabilized subgroup.. The progression of cognitive deterioration may be related to rCBF affected by the neuropathologic changes of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Blood Flow Velocity; Cerebrovascular Circulation; Donepezil; Female; Humans; Imaging, Three-Dimensional; Indans; Longitudinal Studies; Male; Middle Aged; Nootropic Agents; Piperidines; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

In addition to inhibiting acetylcholinesterase, galantamine has allosteric-modulating activity at nicotinic receptors. This may make galantamine an attractive option for patients starting treatment for Alzheimer's disease (AD), but also for those who have not benefited from their current therapy. This study explored outcomes in subjects with AD transitioning from donepezil because of insufficient tolerability or efficacy.. Subjects previously receiving donepezil for mild-to-moderate AD were enrolled in a 12-week randomized, open-label study. After screening and a 7-day washout, subjects were randomly allocated to galantamine fast (8 mg/week increments) or slow (8 mg/4 week) titration to 16-24 mg. Efficacy outcomes included the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog/11), Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change - Plus Caregiver's Input (CIBIC-plus) and Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL).. Eighty-six of 89 patients (fast titration, n = 44; slow titration, n = 45) completed the study. At week 12, ADAS-cog/11 score improved from screening by 2.6 and 0.6 in the fast- and slow-titration arms, respectively (overall, -1.6; P = 0.002). MMSE scores improved slightly in both arms (overall, +0.9; P = 0.002). Two-thirds of patients had improvement or no change on the CIBIC-plus at week 12. ADCS-ADL scores did not change significantly from screening in either treatment arm. Galantamine was generally well tolerated; nausea (5.6%) and bradycardia (4.5%) were the most commonly reported adverse events.. Patients in whom donepezil is ineffective or poorly tolerated may benefit from a switch to galantamine.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Galantamine; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Treatment Outcome

Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease.. We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.. Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.. In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Kaplan-Meier Estimate; Male; Memantine; Patient Dropouts; Piperidines; Psychological Tests; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

Throughout the natural progression of Alzheimer's disease (AD), the body mass index (BMI) decreases. This is believed to be brought on by the disturbance in the central lipid metabolism, but the exact mechanism is yet unknown. Adipokines (adiponectin, leptin), hormones produced by the adipose tissue, change glucose and lipid metabolism, and have an anorectic effect through increasing energy consumption in the hypothalamus. The goal of our study was to examine donepezil - an acetylcholinesterase inhibitor (AChEI) currently used in AD therapy -, and to what degree it influences the serum adipokine levels and metabolic parameters of AD patients. During the self-evaluation of 26 clinically diagnosed mild to moderate AD patients, therapy with 10 mg/day donepezil was started according to current protocols. We measured serum adiponectin, leptin, LDL, HDL, trigliceride levels, and BMI and ApoE polymorphism at the beginning of our study, and at 3 and 6-months intervals respectively. All data were analyzed with SPSS 17. In comparison with pre-donepezil therapy values, at the third month interval serum adiponectin levels showed an increasing and leptin levels a decreasing tendency. At the six month interval, adiponectin levels significantly increased (p=0.007), leptin levels decreased (p=0.013), BMI (p=0.001) and abdominal circumference (p=0.017) was significantly lower at 6 months as compared to control values. We did not observe any changes in the lipid profile, and ApoE4 allele carrying showed no association with the parameters. To our knowledge, we are the first to publish that AChEI therapy with donepezil alters lipokine levels, which positively influences the currently known pathomechanism and numerous risk factors of AD. The AChEI treatment-induced weight loss should be considered in the long-term therapy of AD patients.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Appetite; Biomarkers; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Female; Humans; Hungary; Indans; Leptin; Lipid Metabolism; Male; Middle Aged; Nootropic Agents; Outpatients; Piperidines; Polymorphism, Single Nucleotide; Severity of Illness Index; Time Factors; Treatment Outcome; Triglycerides; Waist Circumference

Donepezil is a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease (AD), however its cholinergic adverse side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the adverse side effects caused by donepezil on cardiac rhythm and postural blood pressure changes in elderly patients with Alzheimer Disease.. The ECG parameters including heart rate, PR, QT, QTc interval and QRS duration and postural blood pressure changes were recorded at the baseline and at each donepezil dose level (5 and 10 mg/d). Patients Seventy-one consecutive patients who were referred by primary care centers to a Geriatric Clinic were enrolled and underwent comprehensive geriatric assessment.. Fifty-two subjects completed the study. There were no significant changes relative to the baseline in any of the ECG parameters or arterial blood pressure at any of the investigated dosages of donepezil.. It was demonstrated that donepezil was not associated with increased negative chronotropic, arrhythmogenic or hypotensive effects for elderly patients with Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Arrhythmias, Cardiac; Blood Pressure; Cholinesterase Inhibitors; Donepezil; Electrocardiography; Female; Gastrointestinal Diseases; Heart Rate; Humans; Hypotension; Indans; Male; Nootropic Agents; Piperidines

Previous studies have revealed that functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signal in specific brain regions correlates with cross-sectional performance on standardized clinical trial measures in Alzheimer's disease (AD); however, the relationship between longitudinal change in fMRI-BOLD signal and neuropsychological performance remains unknown.. To identify changes in regional fMRI-BOLD activity that tracks change in neuropsychological performance in mild AD dementia over 6 months.. Twenty-four subjects (mean age 71.6) with mild AD dementia (mean Mini Mental State Examination 21.7, Global Clinical Dementia Rating 1.0) on stable donepezil dosing participated in two task-related fMRI sessions consisting of a face-name paired associative encoding memory paradigm 24 weeks apart during a randomized placebo-controlled pharmaco-fMRI drug study. Regression analysis was used to identify regions where the change in fMRI activity for Novel > Repeated stimulus contrast was associated with the change scores on postscan memory tests and the Free and Cued Selective Reminding Test (FCSRT).. Correlations between changes in postscan memory accuracy and changes in fMRI activity were observed in regions including the angular gyrus, parahippocampal gyrus, inferior frontal gyrus and cerebellum. Correlations between changes in FCSRT-free recall and changes in fMRI were observed in regions including the inferior parietal lobule, precuneus, hippocampus and parahippocampal gyrus.. Changes in encoding-related fMRI activity in regions implicated in mnemonic networks correlated with changes in psychometric measures of episodic memory retrieval performed outside the scanner. These exploratory results support the potential of fMRI activity to track cognitive change and detect signals of short-term pharmacologic effect in early-phase AD studies.

Topics: Aged; Alzheimer Disease; Brain Mapping; Cognition; Donepezil; Dopamine Agents; Female; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memantine; Neuropsychological Tests; Nootropic Agents; Oxygen; Piperidines; Regression Analysis

It is important to detect and prevent Alzheimer disease (AD) at its early stage. Constituting the early stage sign of AD, amnestic mild cognitive impairment (aMCI) has drawn much attention. Studies have shown that donepezil could reduce the AD assessment scale-cognitive subscale (ADAS-Cog) score in MCI patients and improve the patient's attention and speed of response; however, it also has many side effects. Therefore, the authors aim to explore the effects of Chinese herbal medicine for treating aMCI.. To explore the clinical efficacy and safety of Chinese medicine for tonifying the kidney, and resolving phlegm and blood stasis in the treatment of aMCI.. This clinical trial used randomized, double-blind, double-dummy and parallel-controlled design. According to the randomized, double-blind principle, some aMCI patients were randomly divided into Chinese medicine group and donepezil group. Other patients who did not receive any treatment were enrolled as the control. Patients in the Chinese medicine group received oral administration of Chinese medicine, 1 bag/dose, two doses per day, while patients in the donepezil group received donepezil hydrochloride, 5mg/day. Twelve weeks were allocated as the trial period.. After 12 weeks, the Chinese medicine group patients, the donepezil group patients and those patients who did not receive any treatment were accessed using the scores of ADAS-Cog and mini-mental status examination (MMSE).. The ADAS-Cog and MMSE scores of the Chinese medicine group and the donepezil group were both improved from baseline (P=0.001, P=0.000), but the non-treatment group showed no change from baseline (P=0.151, P=0.125); furthermore, there was no significant difference between the Chinese medicine group and the donepezil group. The attention function of the Chinese medicine group was better than baseline (P=0.015), but no change was seen in the donepezil group (P=0.085) at the 12th week. Safety data showed that the occurrence of insomnia, nausea and diarrhea was greater in the donepezil group than in the Chinese medicine group (P=0.002, P=0.005, P=0.000), and both treatments had no influence in participants' vital signs and laboratory examination results.. Both Chinese medicine and donepezil can improve global cognition in patients with aMCI after 12 weeks of treatment. Chinese medicine can also improve attention function and some clinical symptoms in patients with aMCI. Furthermore, Chinese medicine is safe for aMCI patients. Further study is necessary to explore the long-term effect of Chinese medicine for aMCI.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Donepezil; Double-Blind Method; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Middle Aged; Phytotherapy; Piperidines; Treatment Outcome

A large multicenter trial of donepezil 23 mg/day versus donepezil 10 mg/day for moderate-to-severe Alzheimer's disease allowed patients taking concomitant memantine. We evaluated the efficacy/safety of donepezil 23 and 10 mg/day in this trial, with respect to concomitant memantine use.. Prespecified analysis of data from a 24-week, randomized, double-blind trial. Patients were randomized to donepezil doses (23 vs. 10 mg/day) and stratified by concomitant memantine use (yes or no). Efficacy and safety were assessed for each donepezil dose in subgroups taking or not taking concomitant memantine.. At week 24, donepezil 23 mg/day provided significant cognitive benefits over 10 mg/day (p < 0.01) on the Severe Impairment Battery, with or without concomitant memantine (ANCOVA adjusted for baseline score, country and treatment). The higher dose showed no benefit on the global function, Mini-Mental State Examination or activities of daily living measures in either memantine subgroup. Rates of treatment-emergent adverse events (AEs) were higher for donepezil 23 mg/day with memantine (80.7%) than 23 mg/day without memantine (69.7%) or 10 mg/day with/without memantine (66.7/62.0%); across all treatment groups, most events were mild/moderate in severity. Individual rates of serious AEs were low (<1.0%), regardless of concomitant memantine use.. In this population, concomitant memantine use did not alter the response profile of donepezil 23 vs. 10 mg/day. Donepezil 23 mg was generally safe and well tolerated among patients receiving donepezil alone and among patients receiving a combination of donepezil and memantine therapy.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Geriatric Assessment; Humans; Indans; Intelligence Tests; Male; Memantine; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

To evaluate the efficacy and safety of donepezil plus natural hirudin in patients with mild-to-moderate Alzheimer's Disease.. In the 20-week, randomized, open-label and controlled study, 84 patients received either donepezil (5 mg/day for the first 4 weeks and 10 mg/day thereafter) or donepezil plus natural hirudin (3 g/day) treatment. Efficacy was reflected by the change of the total scores of Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Neuropsychiatric Inventory (NPI).. The patients with the donepezil plus natural hirudin treatment showed more significant improvement in the daily activities and the decline of the cognition than those with donepezil treatment. Significant difference was present in the groups since the 8th week. No group difference was found in the NPI change. However, within the hirudin treatment group, more powerful efficacy including NPI assessment was found in the patients with vascular risk factors (VRF) as comparing to with those without VRF. The combination of donepezil and natural hirudin was well tolerated. The dropout rate was greater in the donepezil and natural hirudin (50%) treatment group than in the donepezil (39%) treatment group. Similar result was found in the incidence of adverse events (23.8% vs 19.0%), but there was no statistical difference between the two groups. Adverse events were the most common reason for the dropout. Although hemorrhage and hypersensitiveness were more common in donepezil plus Maixuekang treatment (11.9% and 7.1%) group than in donepezil treatment (2.4% and 2.4%) group, no significant difference was present between the two groups. Economic problem was another important reason for the patients' withdrawal.. Compared with the donepezil treatment in the patients with mild-to-moderate AD, our results suggest that donepezil combined with natural hirudin may improve the treatment effects in the ADL, BPSD and cognition of the patients. Furthermore, this joint treatment is safe.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Hirudins; Humans; Indans; Male; Nootropic Agents; Pilot Projects; Piperidines

Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD.. Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs.. 915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study.. This study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Ambulatory Care; Biomarkers, Pharmacological; Cognition; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by its gradual progression. At present, the cause and mechanism of AD are yet unclear, and there is no effective therapy for treating it. With development of global aging, the prevalence rate of AD is increasing. The life quality of elderly people is affected severely by AD that is ultimately life-threatening. Recently, study on treating AD with traditional Chinese medicine (TCM) has deepened.. To explore the therapeutic effects of a syndrome differentiation-based TCM regime in treating patients with mild to moderate AD for improving cognition, and to evaluate the changes in brain function of AD patients observed by resting-state functional magnetic resonance imaging (fMRI) technique.. Adopting the internationally recognized criteria developed by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association, the clinical trial was conducted on 131 patients with mild to moderate AD from 5 communities and 7 social welfare institutions. Participants were accepted after informed consent was received, and laboratory tests and a head imaging study were conducted. The patients were randomly divided into Chinese medicine group (CMG) (66 cases) or Western medicine group (WMG) (65 cases). Patients in the CMG were treated monthly with Chinese medicine according to syndrome differentiation. Patients in the WMG were treated with donepezil at a dose of 5 mg once daily. The therapeutic course lasted 48 weeks.. The scores of Mini-Mental State Examination (MMSE), Fuld Object-Memory Evaluation (FOM), Block Design (BD) and Digit Span (DS) were used to evaluate the cognitive function; resting-state fMRI was used for observing brain function. The questionnaires and fMRI were performed before and after treatments.. The cognitive functions of the patients in the CMG and WMG were improved after treatment. MMSE score was improved significantly in both groups (P<0.05 or P<0.001). After 48 weeks of treatment, 70.91% patients in the CMG had an improved MMSE score and 20% got worse, however, 55.77% patients in the WMG were improved in MMSE score and 34.62% got worse. Scores of FOM denominator and BD increased significantly in both groups; scores of FOM numerator and DS were also increased in the CMG (P<0.05 or P<0.01). The results of fMRI suggested that both Chinese medicine and donepezil treatment improved the connectivity between posterior cingulated gyrus and specific areas in the brain. The influence range of Chinese medicine primarily impacted on the left parietal lobe, being less than the influence range of donepezil, which primarily affected both sides of frontal lobes.. TCM treatment based on syndrome differentiation is effective in improving cognitive function of patients with mild to moderate AD and increasing the brain function by increasing connectivity between posterior cingulated gyrus and specific areas in the brain.

Topics: Alzheimer Disease; Cognition; Donepezil; Drugs, Chinese Herbal; Humans; Indans; Nootropic Agents; Piperidines

Progressive neurodegeneration in Alzheimer's disease (AD) induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD.. A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added.. Nine rural municipalities in Northern Norway.. 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one-year follow-up.. In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period.. Changes in MMSE sum score.Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test.. MMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo.. In rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results.. ClinicalTrials.gov (Identifier: NCT00443014). EudraCT database (no 2004-002613-37).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Comorbidity; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Norway; Physical Therapy Modalities; Piperidines; Prevalence; Treatment Outcome

To better understand responses in the large number of US-based patients included in a global trial of donepezil 23 mg/d versus 10 mg/d for moderate-to-severe Alzheimer's disease (AD), post hoc exploratory analyses were performed to assess the efficacy and safety in US and non-US (rest of the world [RoW]) patient subgroups. In both subgroups, donepezil 23 mg/d was associated with significantly greater cognitive benefits than donepezil 10 mg/d. Significant global function benefits of donepezil 23 mg/d over 10 mg/d were also observed in the US subgroup only. Compared with RoW patients, US patients had relatively more severe AD, had been treated with donepezil 10 mg/d for longer periods prior to the start of the study, and a higher proportion took concomitant memantine. In both subgroups, donepezil had acceptable tolerability; overall incidence of treatment-emergent adverse events was higher in patients receiving donepezil 23 mg/d compared with donepezil 10 mg/d.

Topics: Aged; Alzheimer Disease; Analysis of Variance; Apolipoproteins E; Donepezil; Dopamine Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; United States

Cholinesterase inhibitors (ChE-Is) are among the drugs more largely used for the treatment of mild-to-moderate symptoms of Alzheimer's disease (AD), but beneficial long-term effects of these compounds on the cognitive, functional, and behavioural symptoms of the disease are small and not always apparent in practice. Preclinical investigations have suggested that association between ChE-Is and the cholinergic precursor choline alphoscerate enhances cholinergic neurotransmission more effectively than single compounds alone. The ongoing clinical trial on the "Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in Alzheimer's disease associated with cerebrovascular injury" (ASCOMALVA) was designed to assess if association of the ChE-I donepezil with choline alphoscerate has a more favourable clinical profile than monotherapy with donepezil alone.. ASCOMALVA is a double-blind multicentre trial that has completed the first 12 months of observation of 91 patients of the 210 planned. Patients were aged between 56 and 91 years (mean 75 ± 10 years) and were included in the protocol with a MMSE score between 15 and 24. Patients with AD diagnosed according to the DSM IV criteria suffer from ischemic brain damage documented by neuroimaging (MRI and CT scan), with a score≥2 in at least one subfield of the New Rating Scale for Age-Related White Matter Changes (ARWMC). Patients were randomly allotted to an active treatment group (donepezil+choline alphoscerate) or to a reference treatment group (donepezil+placebo) and were examined after 3, 6, 9 and 12 months of treatment.. Cognitive functions, patient's daily activities and behavioural symptoms were assessed by the Mini-Mental State Evaluation (MMSE), Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-cog), Basic Activities of Daily Living (BADL), Instrumental Activities of Daily Living (IADL) and Neuropsychiatric Inventory (NPI), of severity and of caregiver distress measures (NPI-F and NPI-D). Patients of the reference group (donepezil+placebo) showed along the course of the 12months of observation, a slight time-dependent worsening of MMSE, ADAS-cog, IADL and NPI-D scores and no changes in the BADL and NPI-F scores. Donepezil plus choline alphoscerate improved compared to donepezil alone the different items analysed except the BADL.. The first results of the ASCOMALVA trial suggest that association of choline alphoscerate to the standard treatment with a ChE-I may represent an option to prolong beneficial effects of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Disorders; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Glycerylphosphorylcholine; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Piperidines; Treatment Outcome

Activities of daily living (ADL) are an essential part of the diagnostic criteria for Alzheimer's disease (AD). A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI) treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy.. This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL) scale, Physical Self-Maintenance Scale (PSMS) and Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models.. After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response.. Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age predicted better cognitive but worse functional response.

Topics: Activities of Daily Living; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Disabled Persons; Donepezil; Female; Galantamine; Humans; Indans; Linear Models; Male; Middle Aged; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms.. Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency × severity) ≥ 3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status.. Of all NPI items, apathy had the highest proportion of subjects scoring ≥ 3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit.. Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Apathy; Brief Psychiatric Rating Scale; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Severity of Illness Index

Donepezil has not been evaluated in Korean patients with Alzheimer's disease (AD) for up to 1 year. The objectives of this study were to evaluate the differential efficacy of donepezil in Korean AD patients with and without concomitant cerebrovascular lesions (CVL).. This study was a 48-week open-label trial of donepezil in patients with probable AD of mild to moderate severity. CVL were evaluated through magnetic resonance imaging (MRI) findings within 3 months. Efficacy analyses were performed for cognitive, behavioral and functional outcome measures.. Concomitant CVL were documented in 35 (30.7%) of the patients on MRI. Seventy-nine (69.3%) of the patients were considered not to have concomitant CVL. The mean Mini-Mental State Examination scores of both patients with and without CVL showed improvement at each evaluation. However, there was no statistical difference in improvement between the groups.. The presence of CVL should not deter clinicians from treating AD with donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Disorders; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Retrospective Studies; Time Factors; Treatment Outcome

To estimate the treatment effects of SB-742457 and donepezil in Alzheimer disease (AD) in a contemporary clinical trial.. Randomized, controlled, parallel-group, exploratory study with a 4-week, single-blind, placebo run-in phase and 24-week, double-blind treatment phase. Primary endpoints were Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog).. One hundred ninety eight subjects with mild-to-moderate probable AD (MMSE scores 12-26) were randomized; 196 were included in the intent-to-treat population (placebo, n = 61; SB-742457 35 mg/day, n = 68; donepezil 10 mg/day, n = 67), and 161 completed. Drug-placebo treatment differences in CIBIC+ score at week 24 were -0.17 (90% confidence interval [CI]: -0.50, 0.16) for SB-742457 and -0.28 (90% CI: -0.61, 0.05) for donepezil. Drug-placebo treatment differences (90% CI) in change from baseline ADAS-Cog score at Week 24 were -0.4 (-2.2, 1.4) for SB-742457 and -1.2 (-3.0, 0.6) for donepezil. All treatments were generally safe and well tolerated.. In this exploratory study, SB-742457 and donepezil were associated with improvements in global function. Treatment effect on cognition for both SB-742457 and donepezil was smaller than those previously observed in previous clinical studies with donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Quinolines; Serotonin Antagonists; Sulfones

To record in real life the appreciation of elderly patients, their caregivers and physicians of a once daily formulation of prolonged release of galantamine in the treatment of mild to moderate Alzheimer's disease.. A prospective, multicenter, observational study was conducted in 128 elderly patients, treated for 6 months with galantamine, donepezil or rivastigmine.. Of the patients treated with galantamine, 82 of the 97 (84.5%) were continuing their treatment after 6 months. These patients reported their condition as improved in 49%, unchanged in 47% and worsened in 4%. Caregivers rated global evaluation as 37% better, 41% unchanged and 22% worse. Physicians rated global clinical impression of change as 46% better, 34% unchanged and 20% worse. Measurements of cognition and behavior remained stable. The appreciation of physicians and caregivers corresponded well (P<0.001). The incidence of serious side-effects possibly related to galantamine was 9.3%, which was not different from that in patients treated with other cholinesterase inhibitors.. In a real life setting, galantamine once daily is safe and is favorably appreciated by patients, their caregivers and physicians.

Topics: Aged; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition; Delayed-Action Preparations; Donepezil; Female; Galantamine; Humans; Indans; Male; Patient Satisfaction; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25-26) indicated improvement versus placebo for AZD3480 20 mg (-1.4, 95% CI: -3.0; 0.2) and donepezil (-1.0, 95% CI: -2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Neuroprotective Agents; Neuropsychological Tests; Piperidines; Pyridines; Time Factors; Treatment Outcome

Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD.. The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both.. The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks.. When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aromatherapy; Cholinesterase Inhibitors; Data Interpretation, Statistical; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Melissa; Middle Aged; Nootropic Agents; Patient Compliance; Piperidines; Plant Oils; Psychomotor Agitation; Quality of Life; Sample Size; Treatment Outcome

Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety.. In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-positive, APOE ε4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE ε4 homozygotes, and the full intent-to-treat population.. No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR).. No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Chemotherapy, Adjuvant; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Rosiglitazone; Thiazolidinediones

Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.. The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).. The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.. The good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Body Weight; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Emergency Services, Psychiatric; Female; Humans; Indans; Male; Piperidines; Severity of Illness Index; Sex Factors; Treatment Outcome

Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Amino Acids; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Neuroprotective Agents; Neuropsychological Tests; Piperidines; Treatment Outcome

To explore the effects of donepezil on the activities of platelet α and β secretases in Alzheimer's disease (AD) patients.. During the period of 2007 - 2010, a total of 76 AD patients received either regular treatment alone or in combination with donepezil (5 mg/d) for a 12-week period. And their effects on ADAS-Cog (Alzheimer's disease assessment scale-cognitive subscale) total and ADL (activity of daily living) scores were measured. The effects of donepezil on α and β secretase activities and sAPPα (soluble amyloid precursor protein α) secretion in AD patients and non-demented patients were detected by fluorescence and Western blot respectively.. After the donepezil treatment, the ADAS-Cog scores of the treatment group decreased versus the control [(5.3 ± 4.4) vs (1.7 ± 1.6)]. And the differences were statistically significant (P < 0.01). And the ADL scores of the treatment group decreased versus the control [(41 ± 7) vs. (48 ± 6)]. And the differences were statistically significant (P < 0.05). As compared with that of pre-treatment (50 ± 6), the differences were statistically significant (P < 0.05). The activity of α secretase increased markedly while that of β secretase decreased markedly versus the controls [(91% ± 9%) vs (64% ± 8%), P < 0.01; (119% ± 11%) vs (178% ± 17%), P < 0.01]. Both had significant statistical differences with those of pre-treatment (both P < 0.01). As compared with the non-demented group (100% ± 12%, P < 0.001), the sAPPα contents of treatment and control groups were (64% ± 14%, P < 0.01) and (26% ± 8%, P < 0.001) respectively.. The administration of donepezil in AD patients improves cognitive functions and daily activities as indicated by the decreased ADAS-Cog total scores and ADL scores through the increased activity of α secretase and the decreased activity of β secretase. The clinical efficacy of donepezil may be attributed to its pharmacological effects on the regulation of platelet secretase activities.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Blood Platelets; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Piperidines; Treatment Outcome

To determine the long-term tolerability and efficacy of donepezil in patients with vascular dementia (VaD).. International, multicentre, open-label, 30-week extension study of two 24-week, randomised, double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age, 74.7 +/- 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease, who were medically stable and had completed one of two double-blind studies. All patients received donepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments were performed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverse events (AEs) and physical and laboratory evaluations.. Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study; 127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6-1.15 points) from double-blind study baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patients who received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group that initiated donepezil treatment during the extension study. Most common donepezil-related AEs were nausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred.. These data suggest that donepezil improves cognition for up to 54 weeks in patients with VaD. Patients initiating donepezil in this extension study did not perform as well on the primary outcome measure as those initiating donepezil in the double-blind study.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales

There is increasing evidence to suggest the possible efficacy of Crocus sativus (saffron) in the management of Alzheimer's disease (AD).. The purpose of the present investigation was to assess the efficacy of C. sativus in the treatment of patients with mild-to-moderate AD.. Fifty-four Persian-speaking adults 55 years of age or older who were living in the community were eligible to participate in a 22-week, double-blind study of parallel groups of patients with AD. The main efficacy measures were the change in the Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Dementia Rating Scale-Sums of Boxes scores compared with baseline. Adverse events (AEs) were systematically recorded. Participants were randomly assigned to receive a capsule saffron 30 mg/day (15 mg twice per day) or donepezil 10 mg/day (5 mg twice per day).. Saffron at this dose was found to be effective similar to donepezil in the treatment of mild-to-moderate AD after 22 weeks. The frequency of AEs was similar between saffron extract and donepezil groups with the exception of vomiting, which occurred significantly more frequently in the donepezil group.. This phase II study provides preliminary evidence of a possible therapeutic effect of saffron extract in the treatment of patients with mild-to-moderate Alzheimer's disease. This trial is registered with the Iranian Clinical Trials Registry (IRCT138711051556N1).

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Crocus; Donepezil; Double-Blind Method; Female; Humans; Indans; Iran; Male; Piperidines; Plant Extracts; Psychiatric Status Rating Scales; Severity of Illness Index

To compare memantine with the most prescribed cholinesterase inhibitor (donepezil) from a clinical viewpoint when administered in early phases of Alzheimer disease (AD), and to find out whether memantine may produce changes in brain metabolite concentrations in comparison with donepezil.. In this comparative rater-blinded parallel group randomized trial we recruited a consecutive sample of patients with probable mild to moderate AD. At baseline we carried out neuropsychological assessment with mini-mental, Clinical Dementia Rating Scale (CDR), Blessed Dementia Rating Scale, Alzheimer's Disease Assessment Scale, cognitive part (ADAS-cog), neuropsychiatric inventory (NPI), and disability assessment for dementia (DAD), as well as (1)H magnetic resonance spectroscopy (MRS) in several areas of the brain. Patients were randomized to receive either donepezil or memantine for 6 months. After this elapse of time we repeated the same procedures and observed the changes in clinical scales (ADAS-cog, NPI, DAD), as well as the changes in metabolite levels in every area of exploration (temporal, pre-frontal, posterior cingulated (PCG), and occipital), especially those of N-acetyl-aspartate (NAA) which is regarded as a surrogate marker of neuronal density.. A total of sixty-three patients completed the trial. We did not see significant differences in clinical scales and metabolite levels between those on donepezil (n = 32) and those on memantine (n = 31). In general, more patients worsened than improved on either of the drugs. The changes in the NAA/creatine ratio in the PCG correlated significantly with the changes in the ADAS-cog (P = 0.004).. Donepezil and memantine have similar modest clinical and spectroscopic effect on mild to moderate AD. MRS could be useful to monitor progression of the disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aspartic Acid; Brain; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Magnetic Resonance Spectroscopy; Male; Memantine; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Protons; Severity of Illness Index; Treatment Outcome

To investigate the tolerability and efficacy of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease receiving concomitant memantine.. Post hoc analysis of a 25-week, randomized, prospective, open-label, parallel-group study. Patients receiving donepezil were switched to rivastigmine patches (4.6 mg/24 h) immediately or following a 7-day withdrawal for 4 weeks (core phase), before titrating up to 9.5 mg/24 h for a further 20-week extension phase. Prior memantine therapy was continued throughout.. Tolerability (adverse events [AEs], serious AEs [SAEs] and discontinuations) and efficacy (cognition, global functioning and activities of daily living [ADLs]) were assessed for the rivastigmine transdermal patch, with or without concomitant memantine.. Overall, 135 and 126 patients received rivastigmine with and without memantine, respectively. Of these, 122 (90.4%) and 118 (93.7%) patients with and without memantine, respectively, completed the core phase; 120 and 114 patients, respectively, entered the extension phase, and 90 (75.0%) and 86 (75.4%) completed the study. The incidences of AEs (73.3 vs. 67.5%) and SAEs (10.4 vs. 7.1%) were both slightly larger in patients receiving concomitant memantine, but the differences were not statistically significant (95% CIs: -5.2, 16.9 and -3.6, 10.1 for AEs and SEAs, respectively). The incidence of gastrointestinal AEs was low in both groups. Discontinuation due to AEs was higher in patients who received memantine (17.0 vs. 11.9%). Changes in cognitive and global function were similar between groups. ADL scores worsened in both groups; significantly more in those treated with memantine.. Use of the rivastigmine transdermal patch in patients on established memantine appears to be well-tolerated, with only modest, non-significant increases in AEs compared with monotherapy, and did not seem to affect cognition or global functioning adversely.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Middle Aged; Neuroprotective Agents; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index; Time Factors; Treatment Outcome

The progression of cognitive deterioration in patients with Alzheimer's disease (AD) is considerably variable. The ability to predict the progression rate is important for clinicians to treat and manage patients with AD. We examined the possible relationship between the rate of cognitive deterioration and regional cerebral blood flow (rCBF) patterns in patients with AD.. We followed 48 patients with AD for an average of 37 months. They were subsequently divided into the rapidly progressing group (n=24) and slowly progressing group (n=24) based on an annual Mini-Mental State Examination (MMSE) score change. Initial and follow-up rCBF were assessed using single photon emission CT (SPECT) and the SPECT data were analyzed by 3D-stereotactic surface projections.. At initial evaluation, the rapidly progressing group had greater rCBF deficits mainly in the parietotemporal and frontal regions, and left posterior cingulate than did the slowly progressing group. When compared with initial SPECT, follow-up SPECT showed a significant rCBF reduction in widespread regions, including parietotemporal and frontal lobes, of the rapidly progressing group, while showed in the scattered and small regions of hemispheres of the slowly progressing group.. Our longitudinal SPECT study suggests a significant association between rCBF deficits in the parietotemporal, posterior cingulate, and frontal regions and subsequent rapid cognitive and rCBF deterioration.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Mapping; Cerebral Arteries; Cerebral Cortex; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disability Evaluation; Disease Progression; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Time Factors; Tomography, Emission-Computed, Single-Photon

The efficacy and safety of the kampo medicine Yokukansan (YKS, TJ-54) in the treatment of behavioral and psychological symptoms of dementia (BPSD) were investigated in patients with Alzheimer's disease (AD) in an open-label study. This study included 26 patients who had been diagnosed as having AD and were not treated with donepezil hydrochloride. These patients were administered YKS (7.5g/day) for four weeks to investigate the changes in neuropsychological test results and care burden in the period from the start to completion of the study treatment. The Neuropsychiatric Inventory (NPI) was used for evaluation of BPSD, the Mini-Mental State Examination (MMSE) for evaluation of cognitive functions, the Zarit burden interview for evaluation of the caregiver's burden, Disability Assessment of Dementia (DAD) for evaluation of activities of daily living (ADL) and Self-Rating Depression Scale (SDS) for evaluation of the caregiver's depression. No significant change was seen in MMSE and DAD after four weeks of treatment, but the mean NPI total score decreased significantly. Furthermore, among the NPI subscales, a statistically significant decrease in score was not seen, however, a clinically significant decrease was seen in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior. No significant changes were seen in caregiver's burden after four weeks of treatment. No serious adverse reactions to YKS were observed. The results of this study suggested that YKS may be an effective and well-tolerated drug in the treatment of BPSD in AD patients.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Behavioral Symptoms; Donepezil; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Mental Status Schedule; Neuropsychological Tests; Nootropic Agents; Piperidines; Statistics, Nonparametric

A formula (formula F) was prepared to counteract oxidative stress (OS) in the brain. The formula contained the most common antioxidants and was intended to: (a) protect proteins, lipids, DNA and proteoglycans from oxidation (carnosine, coenzyme Q(10), vitamin E, vitamin C, beta-carotene, selenium, L-cysteine and ginkgo biloba); (b) reduce homocysteine (HCy) blood levels (vitamins B(6), B(9) and B(12)), and (c) sustain the pentose phosphate cycle in circulating cells (vitamins B(1), B(2) and B(3)). Formula F contained low doses of each antioxidant component and was administered in a two-phase ampoule. A cohort of 52 patients (21 males and 31 females) affected with moderate probable AD (according to NINCDS-ARDA and NINCS-AIREN criteria) already being treated with donepezil (5 mg/day for at least two months) was randomly divided into two groups, and followed for 6 months. A double-blind design was used in which 26 cases were treated once a day with formula F plus donepezil, and the other 26 with placebo plus donepezil. The level of OS was measured on the basis of a d-ROMs test (which measures plasma hydroperoxides), plasma HCy and glutathione, and percentage of sickle erythrocytes. The two patient groups were comparable for all variables (age, sex, concomitant diseases, ApoE epsilon4, MMSE II score, OS, antioxidant reserve and sickle erythrocytes). Forty-eight subjects completed the trial. Significant decreases in OS and HCy were only observed when there was an increase in glutathione (in erythrocytes) and a decrease in sickle erythrocytes in patients treated with formula F. The MMSE II score remained almost the same in the group treated with donepezil and placebo, whereas some significant improvements were found in the group treated with donepezil plus formula F.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Bisphenol A-Glycidyl Methacrylate; Cholinesterase Inhibitors; Cohort Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Homocysteine; Humans; Indans; Male; Models, Biological; Oxidative Stress; Piperidines; Polyurethanes; Proteoglycans; Reactive Oxygen Species; Time Factors; Treatment Outcome

Cognitive and functional decline define the transition from moderate to severe Alzheimer's disease (AD); however, specific relationships between deteriorating cognition and functional abilities are less well characterized. Such relationships are important in care planning and understanding patient needs. Objectives of this post hoc analysis of data from a multicenter randomized double-blind placebo-controlled study were to describe changes in Severe Impairment Battery (SIB) scores over 6 months in patients with moderate to severe AD (MSAD), including an assessment of donepezil treatment on SIB scores, and to potentially identify a cognitive transition point associated with predicted functional disability.. The study comprised 290 patients with MSAD (standardized Mini-Mental State Examination score, 5-17) treated with donepezil 5-10 mg/day or matching placebo. Measurements were SIB, Functional Rating Scale, and Disability Assessment for Dementia.. The largest decline in ability to perform basic activities of daily living (bADLs) occurred in placebo-treated patients with a baseline SIB score of approximately 70. Changes were reduced in the donepezil-treated group.. This post hoc exploratory analysis suggests that a transition point between moderate and severe AD exists at a SIB score of approximately 70 and is associated with predictably declining bADLs.

Topics: Activities of Daily Living; Alzheimer Disease; Cognition; Disability Evaluation; Donepezil; Double-Blind Method; Humans; Indans; Nootropic Agents; Piperidines; Severity of Illness Index

The aim of this 12-week, open-label study was to determine the safety and efficacy of donepezil in participants with Alzheimer's disease (AD) residing in assisted living facilities (ALFs). Participants received 5 mg donepezil daily for 6 weeks followed by 10 mg daily for 6 weeks. Primary and secondary outcomes were change from baseline in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory 8 (NPI-8) scores, respectively. Safety was assessed by adverse events (AEs) and laboratory tests. Of the 97 participants, 76 completed the study. Mean MMSE score (18.7 at baseline) improved 1.8 points (P < .0001) at study end. Total NPI-8 score improved 1.8 points (P = .043). The most frequent AEs were nausea and diarrhea. Donepezil improved cognition and behavior and was safe and well tolerated. The results suggest a need for proactive screening and diagnosis of AD and support the value of treatment and use of donepezil in participants residing in ALFs.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Assisted Living Facilities; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor.. The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD.. This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for > or =12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements.. The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0-138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Delta in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Delta in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs -1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication.. In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Piperidines; Severity of Illness Index

to determine the efficacy of cognitive stimulation therapy (CST) in the treatment of neuropsychiatric symptoms in patients with Alzheimer's disease.. a randomized, controlled, rater-blind clinical trial.. the military sanatorium.. thirty-two patients with mild to moderate Alzheimer's disease exhibiting marked neuropsychiatric symptoms were included in the study.. all 32 patients were randomly assigned to a cognitive stimulation therapy group (n = 16) or a control group (n = 16) for 10 weeks.. the efficacy measures included the Mini Mental State Examination and the Neuropsychiatric Inventory.. patients receiving cognitive stimulation therapy showed a greater improvement in the Neuropsychiatric Inventory total score (mean change - 2.06 points versus 0.00 points, t = -4.766, P<0.001) and in the Mini Mental State Examination total score (mean change 0.81 points versus -0.19 points, t =3.106, P =0.004) compared to control at week 10. Analysis of the individual Neuropsychiatric Inventory domains revealed a statistically significant benefit for cognitive stimulation therapy-treated patients in the areas of apathy (mean change -1.06 points versus -0.31 points, P =0.017) and depression/dysphoria (mean change -0.50 points versus 0.06 points, P =0.047). There were no statistically significant benefits for cognitive stimulation therapy-treated patients in the other individual Neuropsychiatric Inventory domains or in the caregiver distress score.. cognitive stimulation therapy has significant efficacy in lowering apathy and depression symptomatology and in the Mini Mental State Examination in patients with mild to moderate Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Behavioral Symptoms; China; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Combined Modality Therapy; Donepezil; Executive Function; Female; Humans; Indans; Male; Memory, Short-Term; Piperidines; Single-Blind Method

A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR.. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+).. At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%).. No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoproteins E; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Edema; Female; Genotype; Humans; Hypoglycemic Agents; Indans; Intelligence Tests; Interview, Psychological; Male; Middle Aged; Nasopharyngitis; Piperidines; PPAR gamma; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Our aim was to perform a secondary analysis of a 12-month-long, non-blind, multi-centre prospective cost-of-illness study. The analysis assessed the effect of donepezil on cognitive functioning and the performance of patients with possible or probable Alzheimer's disease, compared to that of other drugs for dementia.. A sample of 700 patients took part in the study (76.8 ± 6.6 years of age, 67.3% females): 600 (31.4% drug-naive) received donepezil and 100 (9% drug-naive) were given other drugs for dementia.. The mean variations corrected by the baseline values and the centre of the total scores on the Folstein minimental test, the clinical dementia rating and Blessed dementia rating scales at 12 months were significantly lower in patients treated with donepezil: -1.23 ± 3.41 versus -2.26 ± 3.07 (p = 0.006), 0.20 ± 0.68 versus 0.39 ± 1.03 (p = 0.014) and 1.28 ± 3.31 versus 2.04 ± 2.84 (p = 0.027), respectively.. This secondary analysis shows that the deterioration in the cognitive functioning and performance of patients with the passage of time is slower with donepezil than with other drugs for dementia in routine medical practice. Since these results were observed in a post hoc analysis, formal prospective clinical trials should be conducted to confirm these findings.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cost of Illness; Donepezil; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Spain

Acetylcholinesterase inhibitors (i.e. donepezil) are known to benefit Alzheimer's disease (AD) patients. However, the combined effects of acetylcholinesterase and cognitive stimulation therapy (CST) are still debated. The present study examined their combined effects on the progression of cognitive decline in AD.. The present study was a non-randomized controlled study and included two groups of patients with AD (i.e. CST group and control group). The CST group consisted of 31 patients with AD who received donepezil and weekly, 30-min CST sessions over the course of 7 weeks. The control group consisted of 18 patients who received only donepezil. Changes in cognitive abilities were assessed with Hasegawa's Dementia Scale-Revised (HDS-R) and were statistically analyzed by repeated-measure analysis of variance (anova).. ANOVA showed a significant group × time interaction effect on the HDS-R score. HDS-R scores for the CST group increased significantly during the intervention period, whereas the scores for the control group did not increase. Differences between the means of pre- and post-test HDS-R scores were significantly different between the groups; scores were significantly higher for the CST group than the control group. The groups differed significantly in the proportion of subjects whose score increased by more than four points on the HDS-R (Fisher's exact test, P < 0.05; 8 patients (25.8%) in the CST group and none (0.0%) in the control group).. These results suggest that CST is one of the important non-pharmacological treatment strategies for patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Combined Modality Therapy; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Mathematics; Neuropsychological Tests; Piperidines; Problem Solving; Reading; Verbal Learning

The aim of the present study was to determine the efficacy, side-effects and tolerability of blonanserin for treating refractory behavioural psychological symptoms of dementia (BPSD). The present study was a 12-week, prospective, structured clinical trial of blonanserin for the treatment of BPSD. The degree of cognitive function, activities of daily living score, and the degree of BPSD were determined using the Mini-Mental State Examination (MMSE), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI) and the Rating Scale for Aggressive Behaviour in the Elderly (RAGE). The severity of extrapyramidal symptoms was assessed using the Drug-Induced Extrapyramidal Symptoms scale (DIEEPS). Five patients were enrolled. These patients met the NINCDS-ADRDA criteria. The patients were prescribed more than two kinds of existing antipsychotic drugs and were considered refractory cases; the drugs were discontinued because they were ineffectual and side-effects appeared. Each drug was prescribed independently for at least 2 weeks. The mean changes (at baseline and at the last week, respectively) in the MMSE (12.25, 9.25), in the DAD (6.5, 6.75), in the RAGE (5.5, 5.3) and in the DIEEPS (0.5, 1.5) were minimal. The mean changes in the NPI were two or fewer points. Some side-effects (one gait abnormality and one pneumonia) were observed. The results of this preliminary study show that blonanserin does not have adequate efficacy for the treatment of refractory BPSD.

Topics: Aged; Aged, 80 and over; Aggression; Alzheimer Disease; Basal Ganglia Diseases; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Humans; Japan; Male; Mental Disorders; Mental Status Schedule; Neuropsychological Tests; Piperazines; Piperidines; Prospective Studies; Psychometrics; Receptor, Serotonin, 5-HT2A; Treatment Outcome

Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.. In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.. The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).. Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Endpoint Determination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Patient Compliance; Piperidines; Severity of Illness Index; Treatment Outcome

The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients.. AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively.. The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Brain; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Galantamine; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment.. AD patients (n = 421) were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study).. Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain.. The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease.

Topics: Aged; Algorithms; Alzheimer Disease; Analysis of Variance; Apolipoproteins E; Cognition; Donepezil; Factor Analysis, Statistical; Female; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Time Factors; Treatment Outcome

Six individuals with probable Alzheimer's disease (AD) participated in a phase 1 study employing a repeated measures, parallel baseline design testing the hypothesis that error-free experience during word production practice combined with an acetyl cholinesterase inhibitor would improve confrontation naming ability. While acetyl cholinesterase inhibitors are safe and delay cognition decline associated with AD, improvement over baseline cognition is less evident; clinically significant cognitive deficits persist and progress. Both animal and clinical research strongly implicate acetylcholine in learning, a form of neuroplasticity. In clinical practice, however, people with AD are given cholinergic medications without concomitant systematic/targeted retraining. In this study six participants with probable AD and taking donepezil participated in targeted word production practice using an errorless learning strategy. Results showed that combining behavioral enrichment training and an acetyl cholinesterase inhibitor resulted in significant improvements in verbal confrontation naming of trained items for three of six participants. Differences in baseline dementia severity, living conditions, and medications may have influenced the training response. Detection of substantial treatment effects in 50% of subjects suggests further language treatment studies in AD in combination with an acetyl cholinesterase inhibitor are warranted and provide useful information on inclusion/exclusion criteria for use in subsequent studies.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Behavior Therapy; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Treatment Outcome

A 6-month, randomized, double-blind, placebo-controlled study was extended to evaluate long-term safety and efficacy of donepezil in community-dwelling Japanese patients with severe Alzheimer's disease (AD).. 189 patients were enrolled from the double-blind study into a 52-week, open-label extension study. After a 2- to 8-week washout, donepezil was escalated within 6 weeks to 10 mg/day. Main outcomes were Severe Impairment Battery (SIB), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale for severe AD (ADCS-ADL-sev) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). Safety parameters were monitored throughout.. Overall, mean change from extension study baseline in SIB scores improved until week 24; however, scores were influenced by prior treatment during the double-blind study and by length of washout. Patients treated with donepezil retained some treatment benefits after a washout of 2-4 weeks but lost all treatment benefits after a washout of 4-8 weeks. There was no change in ADCS-ADL-sev or BEHAVE-AD scores. Adverse events were consistent with the known donepezil safety profile.. Donepezil is effective and safe for symptomatic treatment of severe AD for at least 1 year. Patients who receive donepezil 10 mg daily with little or no interruption achieve the best long-term outcome.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Nootropic Agents; Piperidines

Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD).. Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day.. Early phase I clinical trial.. 15 healthy older adults; 14 older adults with mild Alzheimer's disease.. Single acute dose of 5mg donepezil.. Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring.. A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing).. The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Humans; Indans; Male; Maze Learning; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Piperidines; Psychometrics; Reproducibility of Results; Research Design; Sensitivity and Specificity

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cilostazol; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Phosphodiesterase Inhibitors; Pilot Projects; Piperidines; Tetrazoles

This randomised, double-blind exploratory trial was undertaken to compare treatment effects and tolerability of EGb 761(R), donepezil and combined treatment in patients with AD and neuropsychiatric features.. We enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, scored below 36 on the TE4D, a screening test for dementia, below 6 on the Clock-Drawing Test (CDT) and between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery. They scored at least five on the 12-item Neuropsychiatric Inventory (NPI). EGb 761(R) (240 mg per day), donepezil (initially 5 mg, after 4 weeks 10 mg per day) or EGb 761(R) and donepezil combined (same doses) were administered for 22 weeks.. Changes from baseline to week 22 and response rates were similar for all three treatment groups with respect to all outcome measures (SKT, NPI, total score and activities-of-daily-living sub-score of the Gottfries-Bråne-Steen Scale, Hamilton Rating Scale for Depression, CDT and Verbal Fluency Test). An apparent tendency in favour of combination treatment warrants further scrutiny. Compared to donepezil mono-therapy, the adverse event rate was lower under EGb 761(R) treatment and even under the combination treatment.. These exploratory findings helped to develop three hypotheses that will have to be proven in further studies: (1) there is no significant difference in the efficiency between EGb 761(R) and donepezil, (2) a combination therapy will be superior to a mono-therapy with one of both substances and (3) there will be less side effects under a combination therapy than under mono-therapy with donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Bulgaria; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Ginkgo biloba; Humans; Indans; Male; Middle Aged; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Plant Extracts

Topics: Alzheimer Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Psychomotor Performance; Sex Characteristics

To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship.. The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD.. Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants.. Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Brain; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder; Disease Progression; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebos; Severity of Illness Index; Time Factors; Tocopherols; Treatment Outcome

To observe clinical therapeutic effect of acupuncture combined with Yizhi Jiannao Granules for treatment of Alzheimer's disease and its effects on intelligence, daily life and social activity ability.. Eighty-four cases were randomly divided into 3 groups, 28 cases in each group. The combined acupuncture and medication group was treated with acupuncture at Baihui (GV 20), Sishencong (EX-HN 1), Dazhui (GV 14), Guanyuan (CV 4), etc. and oral administration of Yizhi Jiannao Granules; the Chinese herb group was treated with Yizhi Jiannao Granules, and the western medicine group with oral administration of Aricept. The scores for the Mini-Mental State Examination (MMSE), Ability of Daily Life (ADL) and the therapeutic effects were assessed and compared before treatment and after treatment for 12 weeks among the groups.. After treatment, the scores for MMSE and ADL were improved in the combined acupuncture and medication group, the Chinese herb group and the western medicine group, which were better in the combined acupuncture and medication group (P < 0.05). The total effective rate of 85.7% in the combined acupuncture and medication group was better than 71.4% in the Chinese herb group and 67.9% in the western medicine group.. Acupuncture combined with Yizhi Jiannao Granules has a significant therapeutic effect on Alzheimer's disease, which is better than that of Yizhi Jiannao Granules or Aricept.

Topics: Acupuncture Points; Acupuncture Therapy; Administration, Oral; Aged; Alpinia; Alzheimer Disease; Combined Modality Therapy; Donepezil; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Plant Extracts; Quality of Life; Treatment Outcome

Olfactory dysfunction, impaired odor identification in particular, is known to occur in Alzheimer disease (AD). The entorhinal cortex and the olfactory bulb, critical areas for olfactory function, are rich in acetylcholine, the neurotransmitter implicated in AD pathology and treatment. In view of the common anatomical substrate, we aimed to determine whether performance on an olfaction test can be used as a clinical marker for monitoring the efficacy of donepezil in elderly people with AD.. Twenty-five participants with mild to moderate AD, planned for donepezil treatment, were recruited from mental health services for older adults in this open-labeled study. Assessments before commencing donepezil included Mini-Mental State Examination, Neuropsychiatric Inventory, Bristol Activities of Daily Living, and the University of Pennsylvania Smell Identification Test. After 3 months of treatment, the primary outcome measure, the Clinician Interview Based Impression of Change plus caregiver input (CIBIC-plus), was completed, and the baseline assessments were repeated.. Eighteen patients continued to receive donepezil at follow-up. The CIBIC-plus outcome correlated with changes in University of Pennsylvania Smell Identification Test and Bristol Activities of Daily Living scores from the baseline (r = 0.7, P < 0.01). In addition, it was the change in smell identification function after treatment that best predicted CIBIC-plus outcome (P < 0.05) on ordinal regression analysis.. Smell identification function could be useful as a clinical measure to assess treatment response with donepezil in AD. This is a nonblind uncontrolled study, and the outcome indicates the need for a controlled study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Monitoring; Female; Humans; Indans; Male; Odorants; Olfaction Disorders; Piperidines; Predictive Value of Tests; Severity of Illness Index; Smell; Treatment Outcome

Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease.. We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated.. The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials.. The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.

Topics: Aged; Alzheimer Disease; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genetic Predisposition to Disease; Humans; Indans; Japan; Male; Nootropic Agents; Piperidines

Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.. DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.. There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.. Current controlled trials ISRCTN49545035.

Topics: Alzheimer Disease; Donepezil; Dopamine Agents; Evidence-Based Medicine; Humans; Indans; Memantine; Nootropic Agents; Piperidines; Research Design; Severity of Illness Index

Good practice guidelines state that a psychological intervention should usually precede pharmacotherapy, but there are no data evaluating the feasibility of psychological interventions used in this way.. At the first stage of a randomized blinded placebo-controlled trial, 318 patients with Alzheimer disease (AD) with clinically significant agitated behavior were treated in an open design with a psychological intervention (brief psychosocial therapy [BPST]) for 4 weeks, preceding randomization to pharmacotherapy. The therapy involved social interaction, personalized music, or removal of environmental triggers.. Overall, 318 patients with AD completed BPST with an improvement of 5.6 points on the total Cohen-Mansfield Agitation Inventory (CMAI; mean [SD], 63.3 [16.0] to 57.7 [18.4], t = 4.8, df = 317, p < 0.0001). Therapy worksheets were completed in six of the eight centers, with the key elements of the intervention delivered according to the manual for >95% of patients. More detailed evaluation of outcome was completed for the 198 patients with AD from these centers, who experienced a mean improvement of 6.6 points on the total CMAI (mean [SD], 62.2 [14.3] to 55.6 [15.8], t = 6.5, df = 197, p < 0.0001). Overall, 43% of participants achieved a 30% improvement in their level of agitation.. The specific attributable benefits of BPST cannot be determined from an open trial. However, the BPST therapy was feasible and was successfully delivered according to an operationalized manual. The encouraging outcome indicates the need for a randomized controlled trial of BPST.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Homes for the Aged; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nursing Homes; Piperidines; Psychomotor Agitation; Psychotherapy; Treatment Outcome

Does psychosocial intervention for caregivers whose spouses with Alzheimer disease (AD) are taking donepezil delay nursing home (NH) placement or death of patients?. Randomized controlled trial with 2 years of active treatment and up to 8.5 years of follow-up (mean: 5.4 years, SD: 2.4).. Outpatients of research clinics in Australia, the United Kingdom, and the United States.. One hundred and fifty-five persons with AD and their spouses.. Five sessions of individual and family counseling (+ prn ad hoc counseling) or usual care.. Time to institutionalization and death using Cox proportional hazards methods.. Over a mean of 5.4 years (SD: 2.4), there were no differences in NH placement or mortality by intervention group, but there were by country, with Australian patients admitted to NHs earlier than U.S. than U.K. patients.. Earlier NH admission of Australian compared to U.K. and U.S. subjects may be due to differences in health care, NH systems, availability, and affordability.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Australia; Caregivers; Cholinesterase Inhibitors; Counseling; Donepezil; Female; Homes for the Aged; Humans; Indans; Institutionalization; Male; Nursing Homes; Piperidines; Social Support; Spouses; Surveys and Questionnaires; United Kingdom; United States

Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD).. Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10-27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures).. At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients.. In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Odds Ratio; Piperidines; Treatment Outcome

Topics: Aged; Alzheimer Disease; Art; Cognition Disorders; Combined Modality Therapy; Donepezil; Humans; Indans; Nootropic Agents; Nursing Homes; Occupational Therapy; Piperidines; Quality of Life; Social Support; Treatment Outcome

To learn if acetylcholinesterase inhibitors alter verbal recall by improving semantic encoding in a double-blind randomized placebo-controlled trial.. Cholinergic supplementation has been shown to improve delayed recall in adults with Alzheimer disease. With functional magnetic resonance imaging, elderly adults, when compared with younger participants, have reduced cortical activation with semantic processing. There have been no studies investigating the effects of cholinergic supplementation on semantic encoding in healthy elderly adults.. Twenty elderly participants (mean age 71.5, SD+/-5.2) were recruited. All underwent memory testing before and after receiving donepezil (5 mg, n=11 or 10 mg, n=1) or placebo (n=8) for 6 weeks. Memory was tested using a Levels of Processing task, where a series of words are presented serially. Subjects were either asked to count consonants in a word (superficially process) or decide if the word was "pleasant" or "unpleasant" (semantically process).. After 6 weeks of donepezil or placebo treatment, immediate and delayed recall of superficially and semantically processed words was compared with baseline performance. Immediate and delayed recall of superficially processed words did not show significant changes in either treatment group. With semantic processing, both immediate and delayed recall performance improved in the donepezil group.. Our results suggest that when using semantic encoding, older normal subjects may be aided by anticholinesterase treatment. However, this treatment does not improve recall of superficially encoded words.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Attention; Cholinesterase Inhibitors; Comprehension; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Memory, Short-Term; Mental Recall; Neuropsychological Tests; Nootropic Agents; Pattern Recognition, Visual; Piperidines; Retention, Psychology; Semantics; Serial Learning; Verbal Learning

Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily).. This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy.. Enrollment of 641 subjects is complete. The baseline mean data are age 74 +/- 8 years, 53% women, MMSE 22 +/- 3, ADAS-cog 23 +/- 10, AD Functional Assessment and Change Scale (ADFACS) 13 +/- 9, Neuropsychiatric Inventory (NPI) 10 +/- 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 +/- 3. Mean prior donepezil treatment was 409 +/- 407 days. Mean baseline lipid levels are total cholesterol 5.8 +/- 0.8 mmol/L (224 +/- 33 mg/dL), LDL-C 3.7 +/- 0.7 mmol/L (143 +/- 26 mg/dL), triglycerides 1.5 +/- 0.7 mmol/L (132 +/- 64 mg/dL), and high-density lipoprotein cholesterol 1.6 +/- 0.5 mmol/L (64 +/- 18 mg/dL).. LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Anticholesteremic Agents; Atorvastatin; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Female; Heptanoic Acids; Humans; Indans; Lipids; Male; Middle Aged; Piperidines; Pyrroles

To build and analyze regression models predicting (1) the long-term cognitive outcome in donepezil-treated patients with Alzheimer's disease, and (2) the short-term (6 months) cognitive impact of treatment depending on cognitive severity at baseline.. The Swedish Alzheimer Treatment Study (SATS) is an open-label, non-randomized, 3-year, multicentre study in a routine clinical setting. A total of 435 patients, mostly in the mild and moderate stages of Alzheimer's disease, received the cholinesterase inhibitor donepezil. They were assessed with the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at baseline and every 6 months for a total period of 3 years. Regression models were fitted from the actual scores at different intervals for the prediction of the cognitive outcome.. The ADAS-cog and MMSE scores during the 3-year treatment period could be predicted with a high degree of explanation using regression models (p < 0.001). Moreover, there was a significant relation between the mean cognitive change after 6 months of treatment and the baseline scores on MMSE (p < 0.01) and ADAS-cog (p < 0.001), respectively.. Statistical models can be used to predict cognitive outcome in donepezil-treated cohorts of AD patients. These models can be clinically valuable, for example when assessing the efficacy of new therapies when added to cholinesterase inhibitor treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Models, Statistical; Nootropic Agents; Patient Dropouts; Piperidines; Predictive Value of Tests; Psychiatric Status Rating Scales; Regression Analysis; Severity of Illness Index

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear.. Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.. 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.. PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Atrophy; Brain; Cerebral Ventricles; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Piperidines; Prospective Studies; Temporal Lobe; Time Factors; Treatment Outcome; Vitamin E

To evaluate the effectiveness of a combination of cholinesterase inhibitor therapy for patients with Alzheimer disease (AD) and psychosocial intervention, for their spouse caregivers compared with drug treatment alone in three countries simultaneously.. Randomized controlled trial. Structured questionnaires were administered at baseline and at regular follow-up intervals for 24 months by independent raters blind to group assignment.. Outpatient research clinics in New York City, U.S., Manchester, U.K. and Sydney, Australia.. Volunteer sample of 158 spouse caregivers of community dwelling patients with AD.. Five sessions of individual and family counseling within 3 months of enrollment and continuous availability of ad hoc telephone counseling were provided for half the caregivers. Donepezil was prescribed for all patients.. Depressive symptoms of spouse caregivers measured at intake and follow-up assessments for 24 months using Beck Depression Inventory (revised).. Depression scores of caregivers who received counseling decreased over time, whereas the depression scores for caregivers who did not receive counseling increased. The benefit of the psychosocial intervention was significant after controlling for site, gender and country was not accounted for by antidepressant use and increased over 2 years even though the individual and family counseling sessions occurred in the first 3 months.. Effective counseling and support interventions can reduce symptoms of depression in caregivers when patients are taking donepezil. Harmonized multinational psychosocial interventions are feasible. Combined drug and supportive care approaches to the management of people with AD should be a priority.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Australia; Caregivers; Cholinesterase Inhibitors; Counseling; Depression; Donepezil; Family Therapy; Female; Humans; Indans; Linear Models; Longitudinal Studies; Male; Middle Aged; Piperidines; Social Support; Spouses; Surveys and Questionnaires; United Kingdom; United States

The most successful therapeutic approaches to Alzheimer's disease (AD) have involved acetylcholinesterase inhibitors (ChEIs). In view of the different response rates to ChEIs therapy, it is important to identify the pharmacokinetic and pharmacodynamic mechanisms which may interfere with this effect. The aim of the study is to evaluate the efficacy on cognition of donepezil, a cholinesterase inhibitor, in a sample of mild to moderate AD patients with various serum albumin levels, a condition modifying drug distribution.. Ninety-eight Alzheimer patients treated with donepezil were analyzed in an outpatient clinic between January 2003 and January 2005. At study entry, participants underwent multidimensional assessment evaluating cognitive, functional and psychobehavioral domains. All concomitant illnesses and treatments were recorded. Patients were grouped in three categories (with low, medium and high albumin levels).. The total sample of patients showed cognitive improvement from baseline of the ADAS Cog score at three months (ADAS Cog mean change -1.4+5.4; p=0.01), cognitive stabilization at nine (ADAS Cog mean change 0.03+6.7; p=ns), and not statistically significant worsening at fifteen months (ADAS Cog mean change 0.9+7.3; p=ns). The low serum albumin level group was associated with a greater response to donepezil. In fact, cognition, evaluated by the ADAS Cog mean change from baseline, improved during the first 15 months of treatment in the low serum albumin level group, but worsened in the two higher groups.. Our preliminary data suggest that serum albumin level should be monitored to evaluate the clinical efficacy of ChEIs therapy.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Monitoring; Female; Humans; Indans; Male; Piperidines; Serum Albumin; Treatment Outcome

Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (omega3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEomega4 carriers and neuropsychiatric symptoms in AD has also been suggested.. To determine effects of dietary omega3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype.. Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74+/-9 years) with acetylcholine esterase inhibitor treatment and a MMSE>15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (omega3 group) or placebo for 6 months. Then, all received the omega3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Asberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed.. One hundred and seventy-four patients fulfilled the trial. 72% were APOEomega4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEomega4 carriers (p=0.006) and in MADRS scores in non-APOEomega4 carriers (p=0.005) were found.. Supplementation with omega3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEomega4 carriers and agitation symptoms (assessed by NPI) in APOEomega4 carriers. ClinicalTrials.gov identifier: NCT00211159

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Analysis of Variance; Apolipoproteins E; Cholinesterase Inhibitors; Depression; Dietary Supplements; Donepezil; Double-Blind Method; Fatty Acids, Omega-3; Female; Galantamine; Genotype; Humans; Indans; Male; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Rivastigmine; Statistics, Nonparametric; Treatment Outcome

This paper reviews the key lessons learned from the first published short-term, placebo-controlled trial of a cholinesterase inhibitor for treatment of mild cognitive impairment (MCI).. The study was a 24-week placebo-controlled trial designed to evaluate the efficacy and safety of donepezil HCl (donepezil) in the treatment of cognitive impairment in subjects with MCI. Primary outcome measures were the NYU Paragraphs Test and the ADCS Clinicians Global-Impression of Change in the intent-to-treat last-observation-carried-forward group.. There was no benefit of donepezil treatment on primary outcome measures (NYU Paragraphs and ADCS CGI-C) in the ITT-LOCF group but positive findings were seen on NYU Paragraphs in the fully evaluable group and in certain secondary outcome measures across both groups.. The results highlight the need for the use of primary cognitive and functional measures that are reliable and sensitive to change in patients with MCI. Measures of episodic memory, psychomotor speed and complex attention were most sensitive in this study. Functional rating scales are needed that measure change in individual subjects' key areas of functional deficit, which typically involve executive aspects of instrumental ADLs. Tolerability can be increased by use of flexible dosing and efficacy is likely to be enhanced by increasing the length of the trial from six to 12 months and by enriching the sample with subjects more likely to decline during the trial.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; History, 20th Century; Humans; Indans; Memory Disorders; Neuropsychological Tests; Outcome Assessment, Health Care; Piperidines; Placebos; Psychiatric Status Rating Scales; Psychomotor Performance; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Treatment Outcome; United States

(1) to assess the effect of 1 mg folic acid supplementation of cholinesterase inhibitors (ChI) in a 6 month double-blind placebo-controlled study of patients with Alzheimer's Disease (AD) and (2) to assess whether outcome measures were affected by changes in homocysteine levels.. Fifty-seven consecutive outpatients with probable AD were treated concurrently with a ChI and either folic acid or placebo. None had conditions or medication known to interfere with folate metabolism. Fasting folate and homocysteine levels were measured prior to commencing ChI and 6 months later. Response was categorised using criteria of the National Institute of Clinical Excellence (NICE).. Twelve males and 29 females completed treatment (mean age 76.27 SD 6.23 years, Mini-Mental State Examination (MMSE) 23.49 SD 3.53, baseline homocysteine 18.39 SD 4.62 micromoles per litre). 23 received folic acid and 18 placebo. There were no significant baseline differences or use of individual ChI between the two arms. After 6 months a significant difference was seen in the change from baseline in combined Instrumental Activities of Daily Living and Social Behaviour scores between arms (folate+1.50 (SD 5.32) vs placebo -2.29 (SD 6.16) (p=0.03) but not change in MMSE scores. Sixteen of 23 subjects receiving folic acid and 7/18 placebo subjects were classified as NICE responders (p=0.05).. This pilot double blind study suggests that response to ChI in patients with AD may be improved by the use of folic acid. The relationship between any change in homocysteine levels and response to treatment is discussed.

Topics: Aged; Alzheimer Disease; Analysis of Variance; Chi-Square Distribution; Cholinesterase Inhibitors; Dietary Supplements; Donepezil; Double-Blind Method; Female; Folic Acid; Folic Acid Deficiency; Galantamine; Homocysteine; Humans; Indans; Male; Mental Status Schedule; Phenylcarbamates; Piperidines; Placebos; Rivastigmine; Treatment Outcome; Vitamin B Complex; Vitamins

Alzheimer's disease (AD) can be treated with inhibitors of the enzyme acetylcholinesterase (AChE). Recent pre-clinical and clinical studies gave evidence that AChE-inhibitors have neuroprotective effects and thereby a disease-modifying potential. The mechanism of this action is still discussed. In an animal model oral administration of an AChE-inhibitor lead to an increase of brain derived neurotrophic factor (BDNF) in hippocampus and cortex. Recent studies have found a decrease of BDNF in the serum and brain of AD patients with potentially consecutive lack of neurotrophic support and contribution to progressive neurodegeneration. BDNF serum concentrations were assessed by ELISA in 19 AD patients and 20 age-matched healthy controls at baseline and in the AD patients after 15 months of treatment with donepezil 10 mg per day (one patient received just 5 mg). Before treatment with donepezil we found in AD significantly decreased BDNF serum concentrations (19.2 +/- 3.7 ng/ml) as compared to healthy controls (23.2 +/- 6.0 ng/ml, P = 0.015). After 15 months of treatment the BDNF serum concentration increased significantly in the AD patients (23.6 +/- 7.0 ng/ml, P = 0.001) showing no more difference to the healthy controls (P = 0.882). The results of the present study confirm data of prior investigations that a down-regulation of BDNF in serum and brain of AD patients seems to begin with the first clinical symptoms and to be persistent. A treatment with the AChE-inhibitor donepezil is accompanied with an increase of BDNF serum concentration in AD patients reaching the level of healthy controls. Thus, up-regulation of BDNF might be part of a neuroprotective effect of AChE-inhibitors. The molecular mechanism of this potentially disease-modifying mechanism of action of donepezil should be clarified.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain-Derived Neurotrophic Factor; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Matched-Pair Analysis; Middle Aged; Piperidines; Up-Regulation

There is an association between Alzheimer disease and sleep-disordered breathing. Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease. This study evaluates the effects of donepezil on obstructive sleep apnea in patients with Alzheimer disease.. Randomized, double-blind, placebo-controlled design. Twenty-three patients with mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12). Polysomnography and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using analysis of variance.. AHI and oxygen saturation improved significantly after donepezil treatment compared to baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01).. Donepezil treatment improved AHI and oxygen saturation in patients with Alzheimer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores.. ClinicalTrials.gov Identifier: NCT00480870.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Polysomnography; Psychometrics; Sleep Apnea, Obstructive; Sleep, REM; Treatment Outcome

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Double-Blind Method; Female; Humans; Indans; Male; Memantine; Piperidines; Severity of Illness Index

In the UK it is recommended that acetylcholinesterase inhibitors be restricted to patients with moderate Alzheimer's disease, and progress monitored within specialist clinics.. To describe a cohort of patients with Alzheimer's disease from a whole city population treated with donepezil, and to analyse outcomes over 4 years.. Historical cohort design: 88 patients recruited 1997-1998, assessed at baseline with 4-year follow-up, using an agreed protocol and validated measures: survival, retention in treatment, cognition, non-cognitive symptoms, weight change, carer stress.. 64.7% remained on treatment beyond 6 months, 57.9% beyond 1 year and 12.5% beyond 4 years. 56% remained alive at 4 years - almost twice the number predicted. Mean MMSE score amongst patients in treatment did not deteriorate over 4 years. Survival, retention in treatment, maintenance/improvement of cognition was greater with high baseline MMSE. Non-cognitive symptoms, carer stress and weight change remained low throughout.. A minority of people with dementia from the population (88 of potential 2,000 at outset, 11 by 4 years) received treatment. Benefits for individuals were confirmed, especially for those with mild impairment. Expenditure on medication was modest in a population context. These findings question recent guidance from the National Institute for Clinical Excellence, which would restrict therapy to patients with moderate cognitive impairment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index

The purpose of this study was to measure metabolite level changes in patients with newly diagnosed Alzheimer Disease (AD) following four months of donepezil treatment. A small number of cognitively normal elderly subjects were also scanned longitudinally (twice within one year) to assess the reproducibility. Short echo-time (1)H magnetic resonance spectra were acquired at 4.0 T in the right hippocampus. Subjects were scanned at the time of first diagnosis (prior to receiving donepezil) and then following four months of donepezil treatment (5 mg/day for the first month, 10 mg/day thereafter). Changes in absolute metabolite levels and metabolite ratios were quantified and compared. There was no change in measured cognitive function following four months of donepezil treatment in the AD patients. Decreased levels of N-acetylaspartate, choline, N-acetylaspartate/creatine, choline/creatine, and myo-inositol/creatine were observed in AD patients after four months of treatment. Cognitively normal elderly subjects showed an increase in myo-inositol/choline ratio following one year. The reduced levels of N-acetylaspartate in AD patients indicates continued decline in neuronal function and/or integrity. However decreased levels of choline and myo-inositol/creatine ratio may indicate a positive treatment effect.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aspartic Acid; Brain Chemistry; Choline; Cholinesterase Inhibitors; Creatine; Donepezil; Female; Hippocampus; Humans; Indans; Inositol; Magnetic Resonance Spectroscopy; Male; Piperidines; Protons

Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD.. To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day.. A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes.. No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline.. In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Humans; Indans; Male; Middle Aged; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Severity of Illness Index; Treatment Outcome

A 24-week, randomized, parallel-group, double-blind placebo-controlled study was conducted to evaluate the efficacy and tolerability of donepezil in severe Alzheimer's disease (AD).. Patients with severe AD (Mini-Mental State Examination score 1-12; modified Hachinski Ischemic Score < or =6; Functional Assessment Staging > or =6) were enrolled in this study in Japan. A total of 325 patients were randomized to donepezil 5 mg/day (n = 110), donepezil 10 mg/day (n = 103) or placebo (n = 112). Primary outcome measures were change from baseline to endpoint in the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIC-plus) at the endpoint visit.. Donepezil 5 mg/day and 10 mg/day were significantly superior to placebo on the SIB, with a least-squares mean treatment difference of 6.7 and 9.0, respectively (p < 0.001 compared with placebo). CIBIC-plus analyses showed significant differences in favor of donepezil 10 mg/day over placebo at endpoint (p = 0.003). A statistically significant dose-response relationship was demonstrated with the SIB and CIBIC-plus. Donepezil was well tolerated.. This study confirmed the effectiveness of donepezil 10 mg/day in patients with severe AD and demonstrated a significant dose-response relationship. Donepezil at dosages of both 5 mg/day and 10 mg/day is safe and well tolerated in Japanese patients with severe AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Japan; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

The possible influence of apolipoprotein E (ApoE) genotype on the response to acetylcholinesterase inhibitor therapy in patients with Alzheimer's disease (AD) remains a matter of controversy. In order to address this issue, we investigated the effects of ApoE genotype on the clinical response to donepezil in patients with mild to moderate AD.. An open study was carried out in 51 patients with probable AD who were treated with 5-10 mg of donepezil per day for 48 weeks.. Eighteen (35.3%) of the 51 patients had 1 or 2 ApoE epsilon4 alleles. ApoE epsilon4 carriers with AD showed a mean 1.1-point increase from the baseline score of 23.9 on the 70-point Alzheimer's Disease Assessment Scale-Cognitive Component at 48 weeks, while the ApoE epsilon4 noncarrier group showed a 3.1-point increase from the baseline score of 22.5 (p = 0.03). The ApoE epsilon4 carrier group exhibited a mean 0.13-point worsening from the baseline score of 0.97 on the Korean Instrumental Activities of Daily Living at 48 weeks, while the ApoE epsilon4 noncarrier group exhibited a 0.17-point worsening from the baseline score of 0.64 (p = 0.05).. AD patients who carry the ApoE epsilon4 allele may respond more favorably to donepezil than epsilon4 noncarriers.

Topics: Aged; Alzheimer Disease; Apolipoprotein E4; Donepezil; Drug Resistance; Female; Follow-Up Studies; Genotype; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Treatment Outcome

We performed combined studies of magnetic resonance imaging (MRI) analysis of the substantia innominata and single photon emission CT (SPECT) measurement of cerebral perfusion with the goal of predicting which patients with Alzheimer's disease are most likely to respond to donepezil treatment.. Ninety-one patients treated with donepezil were divided into responders and non-responders on the basis of changes in their MMSE scores from baseline to study endpoint. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. SPECT data were analysed using three-dimensional stereotactic surface projections.. Responders had significantly greater atrophy of the substantia innominata, but less prominent frontal hypoperfusion than non-responders. Receiver operating characteristic analysis revealed that combined MRI and SPECT examination showed an overall discrimination rate of 70% between responders and non-responders.. Our results suggest that responder patients have more severe damage in the cholinergic system and/or less prominent frontal cortical dysfunction. Combined MRI analysis of the substantia innominata and SPECT measurement of frontal perfusion at baseline may help to predict response to donepezil treatment in patients with Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Brain; Cerebrovascular Circulation; Donepezil; Female; Humans; Indans; Male; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Substantia Innominata; Subtraction Technique; Tomography, Emission-Computed, Single-Photon

Donepezil, an acetylcholinesterase inhibitor, has been reported to have an effect that improves cerebral blood flow (CBF) alongside its primary effect on memory function. The aim of this study was to investigate the effects of long-term, low-dose donepezil therapy on blood perfusion in Alzheimer's disease (AD) by using a fully automated regional CBF quantification program named 3DSRT.. Fifteen subjects with mild to moderate AD according to NINCDS/ADRDA criteria underwent 99mTc-ethylcysteinate dimer (ECD) brain perfusion single photon emission computed tomography (SPECT) twice with an interval of 55.1 +/- 11.0 weeks. The dose of donepezil was fixed at 5 mg/day following the induction period (3 mg/day) of 2 weeks. Clinical efficacy of donepezil was assessed by using the Mini-Mental State Examination (MMSE). The results of SPECT imaging under exactly identical conditions were analyzed by 3DSRT, which enables us to perform a very objective assessment.. Despite a decrease of the MMSE score from 20.9 +/- 4.7 to 18.7 +/- 5.7, CBF was increased in almost all cerebral areas except the left temporal segment. The increase was statistically significant in the left callosomarginal, right central, and bilateral pericallosal and lenticular nucleus segments.. Thus far, no direct cerebrovascular effects have been reported for donepezil. We hypothesize that these CBF-promoting effects of donepezil might be related to increased neuronal activity and enhanced connection of neurons.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Indans; Male; Piperidines; Tomography, Emission-Computed, Single-Photon

Standard measurement scales used in anti-dementia trials may not capture symptomatic changes recognized by clinicians and caregivers. We studied a symptom checklist, completed separately by caregivers and by clinicians, to identify patterns of change associated with donepezil treatment.. In a multi-centre, 6-month, open-label study of 101 primary care patients, changes in a 19-symptom checklist were assessed in relation to changes in standardized scales of cognition, activities of daily living, behavior, and caregiver burden.. Three symptoms were reported in more than 80% of patients by both clinicians and caregivers: problems in remembering, (97%), temporal orientation (89%), and repetitiveness (85%). Five others overlapped on each of the clinician and caregiver 'top ten', including cognitive activation, spatial orientation, leisure, attention, and apathy. Clinicians reported that symptoms did not improve in 38 patients, whereas there was some improvement in 43, and improvement in most symptoms in 20. Caregivers reported that symptoms did not improve in 55 patients, whereas 27 and 19 patients showed some and most symptoms improving respectively. Patients with the greatest symptomatic improvement also improved most on the ADAS-Cog and the other standardized measures, whereas no improvement (or decline) in each standardized measure was observed in people whose symptoms worsened or did not improve.. A symptom checklist allowed clinically meaningful profiles to be identified, but revealed different estimates of response between clinicians and caregivers. Both agreed that improved executive function was the most common response. A symptom checklist can help translate between standard measures and everyday practice.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Caregivers; Cost of Illness; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Mental Recall; Mental Status Schedule; Motivation; Nootropic Agents; Orientation; Piperidines; Primary Health Care; Stereotyped Behavior; Treatment Outcome

This 132-week, open-label extension study assessed the long-term efficacy and safety of donepezil in 579 patients with mild to moderate Alzheimer's disease (AD) who had previously participated in a 24-week double-blind study of 5 or 10 mg/day donepezil vs placebo.. Patients enrolled in the present study had a 6-week single-blind placebo washout period followed by treatment with donepezil 5 mg/day for 6 weeks with an optional increase in dosage to 10 mg/day between weeks 6 and 32.. After 6 weeks of open-label treatment with donepezil 5 mg/day, mean Alzheimer's Disease Assessment Scale -- cognitive subscale scores (ADAS-cog) improved by approximately two points, while after 12 weeks of open-label treatment (with a majority of patients receiving 10 mg/day), the mean ADAS-cog score was 1 point better than the score at the end of the placebo washout period. Scores then declined gradually over the remainder of the study. Mean changes in Clinical Dementia Rating-Sum of Boxes scores showed slight improvement over the first 12 weeks of open-label treatment and then slowly declined for the remainder of the study period. Donepezil was well tolerated over the entire 162-week study period. Overall, 85% of patients experienced at least one adverse event (AE). The most common included diarrhoea (12%), nausea (11%), infection (11%) and accidental injury (10%). Some patients discontinued the study due to AEs (15%).. These results support the conclusion that donepezil is safe and effective for the long-term treatment of patients with mild to moderate AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Indans; Long-Term Care; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Single-Blind Method; Treatment Outcome

To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD).. We evaluated 539 participants with aMCI from the Alzheimer's Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimer's Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog).. The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%.. Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.

Topics: Age Distribution; Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Genotype; Humans; Indans; Linear Models; Male; Neuropsychological Tests; Piperidines; Placebo Effect; Predictive Value of Tests; Prognosis; Sex Distribution; Vitamin E

Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer's disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated.. The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer's disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years.. The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0-4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4-10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points; 95% CI, 14.5-16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment.. Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Disease Progression; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Statistics, Nonparametric; Sweden; Treatment Outcome

To study the efficacy and safety of Reinhartdt and sea cucumber capsule (RSC) combined with donepezil in treating Alzheimer's disease (AD), and its effect on thyroid function axis.. Sixty-eight patients were randomly assigned to the RSC group, the Donepezil group and the combined treatment group, who were treated for 3 and 6 months with RSC, Donepezil and RSC combined with Donepezil, respectively. The curative effect was evaluated by scoring according to Mini-Mental State Examination (MMSE), ADAS-Cog and ADL chart, and the level of thyroid hormones, including TSH, FT3, FT4, TT3 and TT4, were measured with radioimmunoassay before treatment, 3 and 6 months after treatment respectively.. As compared with the baseline, MMSE score increased, ADAS-Cog score and ADL score decreased significantly in all the three groups after 3 months and 6 months of treatment (P < 0.05 and P < 0.01), but the improvement in the combined treatment group was more significant than that in the other two groups (P < 0.01). After 6 months of treatment, the levels of FT3 and FT4 in the combined treatment group were significantly changed (P < 0.01), but no significant change in all the thyroid hormones was found in the other two groups. No obvious adverse reaction occurred in all the three groups.. RSC combined with Donepezil in treating AD is effective and safe with no evident adverse reaction, better than single drug treatment, which may be through influencing the metabolism of thyroid hormones to improve the cognition function of AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Capsules; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Medicine, Chinese Traditional; Middle Aged; Nootropic Agents; Piperidines; Radioimmunoassay; Sea Cucumbers; Thyroid Hormones

To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism.. Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment.. No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.. Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antiparkinson Agents; Antipsychotic Agents; Cholinesterase Inhibitors; Confounding Factors, Epidemiologic; Dementia; Dibenzothiazepines; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Patient Selection; Piperidines; Placebo Effect; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Research Design; Severity of Illness Index; Treatment Failure

To examine whether the presence of domain-specific cognitive impairments would predict a response to donepezil medication in patients with mild-to-moderate Alzheimer disease (AD).. The protocol was an open-label study of 30 AD subjects (mean age 74 years; education 11 years; Mini-Mental State Exam (MMSE) 23 of 30) beginning a 6-month course of treatment with donepezil. Global response to treatment was determined using a combination algorithm based on changes over 6 months in the ADAS-cog, MMSE and CIBIC. In addition, a set of neuropsychological and experimental cognitive tests designed to test five domains of cognition were administered before beginning therapy in order to determine which domain of testing would be predictive to response to treatment. The tests examined attention, short-term and working memory, learning and memory, visuo-spatial motor skills, and lexical-semantic knowledge.. Eighteen of the thirty subjects were rated as having responded (stable or improved scores on the combination algorithm) to the therapy. Responders were significantly less impaired prior to treatment on the following tests: the Clock Drawing Test, a Visual-Spatial Motor Tracking Test, and the Boston Picture Naming Test. No significant initial group differences were noted on the other neuropsychological or experimental cognitive measures.. The tests that most reliably predicted response to donepezil in AD subjects were in the domains of visual-spatial motor abilities and lexical-semantic functioning.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Predictive Value of Tests; Prospective Studies; Severity of Illness Index

Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.

Topics: Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Learning; Male; Neuropsychological Tests; Pilot Projects; Piperidines; Psychomotor Performance; Reaction Time

To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD).. Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores > or =6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving > or =1 dose of donepezil or placebo.. Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD.. Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebos; Recovery of Function; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear.. We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks.. There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change.. In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Psychomotor Agitation; Psychotherapy; Social Support; Treatment Failure

Oxidative stress and neuronal energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD). It is therefore conceivable that pro-energetic and antioxidant drugs such as alpha-lipoic acid might delay the onset or slow down the progression of the disease. In a previous study, 600mg alpha-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of 12 months. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer's disease assessment score cognitive subscale, ADAScog). In this report, we have extended the analysis to 43 patients over an observation period of up to 48 months. In patients with mild dementia (ADAScog < 15), the disease progressed extremely slowly (ADAScog: +1.2 points/year, MMSE: -0.6 points/year), in patients with moderate dementia at approximately twice the rate. However, the progression appears dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with alpha-lipoic acid might be a successful 'neuroprotective' therapy option for AD. However, a state-of-the-art phase II trial is needed urgently.

Topics: Aged; Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Long-Term Care; Male; Mental Status Schedule; Middle Aged; Oxidative Stress; Piperidines; Thioctic Acid

To evaluate the efficacy and safety of donepezil in patients with Alzheimer's disease (AD) who discontinue memantine due to a lack of efficacy or not being well tolerated.. This study enrolled patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] score 5-17) who had a history of treatment with memantine monotherapy (10 mg/BID) for > or = 3 months prior to screening and maintained until study baseline. For inclusion in this study, the patient's memantine treatment had to have been judged as lacking efficacy or not well tolerated at the screening visit. Information on previous memantine use was also obtained with regard to dose and duration of treatment. At the baseline visit, patients were switched to open-label donepezil 5 mg/day for 4 weeks, and 10 mg/day thereafter. The primary efficacy measure was a change in MMSE at week 12 using a last observation carried forward (LOCF) analysis. Secondary measures included Physician and Caregiver Satisfaction Questionnaires (PSQ, CSQ), the Clinical Global Impression-Improvement (CGI-I), Neuropsychiatric Inventory (NPI), and a Caregiver Diary (CD).. At week 12-LOCF, MMSE scores increased by a mean of 1.55 points from baseline (p < 0.0001). At end point, the PSQ and CSQ indicated consistent improvements in satisfaction/ease of use with donepezil; 60.2% of patients improved on the CGI-I; and 44.4-55.6% improved on each of three components of the CD. Improvements on the MMSE, CSQ, and CGI-I were apparent, irrespective of previous cholinesterase (ChE) inhibitor use. No significant effects were seen for the total score on the NPI. Withdrawal rates (8.7% due to adverse events [AEs]) and AEs were consistent with the known donepezil safety profile.. Donepezil was effective and well tolerated in moderate-to-severe AD patients who discontinued memantine monotherapy, including those with previous exposure to ChE inhibitors.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Treatment Outcome

Elevated serum homocysteine levels have been associated with the development of Alzheimer's dementia (AD). The combined use of a mecobalamin capsule preparation, which contains vitamin B12 0.5 mg with an active methyl base, and an over-the-counter nutritional supplement that contains folic acid 1 mg and pyridoxine hyperchloride 5 mg may be effective as a homocysteine-lowering vitamin regimen.. The aim of this study was to determine whether oral multivitamin supplementation containing vitamins B6 and B12 and folic acid would improve cognitive function and reduce serum homocysteine levels in patients with mild to moderate AD.. This randomized, double-blind, placebocontrolled trial was conducted at En Chu Kong Hospital, Taipei, Taiwan. Male and female patients aged >50 years with mild to moderate AD and normal folic acid and vitamin B12 concentrations were enrolled. All patients received treatment with an acetylcholinesterase inhibitor and were randomized to receive add-on mecobalamin (B12) 500 mg + multivitamin supplement, or placebos, PO QD for 26 weeks. The multivitamin contained pyridoxine (B6) 5 mg, folic acid 1 mg, and other vitamins and iron. Serum homocysteine level was measured and cognitive tests were conducted at baseline and after 26 weeks. The primary efficacy outcome was change in cognition, measured as the change in score from baseline to week 26 on the Alzheimer's Disease Assessment Scale 11-item Cognition subscale. Secondary efficacy outcomes included changes in function in performance of activities of daily living (ADLs) and concentrations of homocysteine, B12, and folic acid. Tolerability was assessed by comparing the 2 study groups with respect to physical examination findings, including changes in vital signs, laboratory test abnormalities, concomitant medication use, and compliance of study medication was assessed using an interview with the patient's caregiver, as well as the monitoring of adverse events (AEs) throughout the study.. Eighty-nine patients (45 men, 44 women; all Taiwanese; mean [SD] age, 75 [7.3] years) were enrolled and randomized. Overall, there were no significant differences in cognition or ADL function scores between the 2 groups. At week 26, the mean (SD) between-group difference in serum homocysteine concentration versus placebo was -2.25 (2.85) micromol/L (P = 0.008), and the mean serum concentrations of vitamin B12 and folic acid were significantly higher (but within normal range) in the multivitamin group compared with placebo (., +536.9 [694.4] pg/mL [P < 0.001] and +13.84 ng/mL [11.17] [P = 0.012] at 26 weeks, respectively). The 2 most common AEs were muscle pain (11.1% and 6.8%) and insomnia (8.9% and 9.1%) in the multivitamin and placebo groups, respectively.. In this population of patients with mild to moderate AD in Taiwan, a multivitamin supplement containing vitamins B(6) and B(12) and folic acid for 26 weeks decreased homocysteine concentrations. No statistically significant beneficial effects on cognition or ADL function were found between multivitamin and placebo at 26 weeks.

Topics: Aged; Alzheimer Disease; Asian People; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Folic Acid; Homocysteine; Humans; Indans; Male; Piperidines; Taiwan; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Alzheimer's disease (AD) leads to a degeneration of the nucleus basalis of Meynert and thus to decreased cholinergic tonus in the brain. The transcription of endothelial nitric oxide synthase depends on an adequate cholinergic innervation of microvessels and vasoregulative abnormalities have been reported in AD. We investigated activation-flow coupling to study the role of acetylcholine esterase inhibition (AChEI) on vasoregulative function.. A functional transcranial Doppler approach was used to measure the visually evoked flow velocity response in the posterior cerebral artery in AD patients who had no vascular risk factors. The diagnosis of AD was made according to the ICD10/DSMIIIR-criteria. After baseline recording the effect of four weeks 5mg donepezil and then four weeks 10 mg was investigated. Doppler data were evaluated with a control system approach to obtain dynamic properties of vasoregulation and were compared with a healthy control group.. AD patients showed an increased damping (0.64 +/- 0.2; p = 0.007 vs. control) in evoked responses and lower resting flow velocity levels (40 +/- 13 cm/s; p = 0.06 vs. control), which were restored in a dose-dependent manner under AChEI (0.4 +/- 0.2; 44 +/- 11 cm/s).. AD is associated with a functional vasoregulative deficit possibly due to decreased levels of the endothelial nitric oxide synthase. Augmenting levels with AChEI normalized flow regulation possibly leading to a better blood supply to active neurons.

Topics: Aged; Alzheimer Disease; Analysis of Variance; Blood Flow Velocity; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Echocardiography, Doppler; Female; Humans; Indans; Male; Mental Status Schedule; Piperidines

The increased pro-inflammatory cytokine production was previously observed in Alzheimer's disease (AD). We sought to explore whether acetylcholinesterase inhibitor (AChEI) therapy ameliorates clinical symptoms in AD through down-regulation of inflammation. Expression and release of monocyte chemotactic protein-1 (MCP-1), a positive regulator of Th2 differentiation, and interleukin (IL)-4, an anti-inflammatory cytokine from peripheral blood mononuclear cells (PBMC) in AD patients, were investigated. PBMC were purified from AD patients at time of enrollment (T0) and after 1 month of treatment with AChEI (T1) and from healthy controls (HC). Supernatants were analyzed for cytokine levels by ELISA methods. mRNA expression were determined by RT-PCR. Expression and production of MCP-1 and IL-4 were significantly increased in AD subjects under therapy with the AChEI Donepezil, compared to the same AD patients at time of enrollment (P < 0.001). Our data suggest another possible explanation for the ability of Donepezil [diethyl(3,5-di-ter-butyl-4-hydroxybenzyl)phosphonate] to delay the progression of AD; in fact, Donepezil may modulate MCP-1 and IL-4 production, which may reflect a general shift towards type Th0/Th2 cytokines which could be protective in AD disease. The different amounts of MCP-1 and IL-4 observed might reflect the different states of activation and/or responsiveness of PBMC, that in AD patients could be kept in an activated state by pro-inflammatory cytokines.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cell Differentiation; Chemokine CCL2; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Female; Humans; Indans; Interleukin-4; Leukocytes, Mononuclear; Male; Phytohemagglutinins; Piperidines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Th2 Cells

Cholinesterase inhibitor (ChEI) medications (ie, donepezil, rivastigmine, and galantamine) have been useful in slowing the progression of the mild to moderate stages of Alzheimer's disease (AD). Findings supporting this have largely relied on a global error score from the Alzheimer's Disease Assessment Scale and have not described the nature of the memory problems. We examined this issue by comparing learning, recall, and recognition scores among 2 groups of mild to moderately demented AD patients. Participants were patients from a memory clinic who either were on ChEI treatment (AD+ChEI, n = 14) or had never taken a ChEI (AD-ChEI, n = 14). Participants underwent a comprehensive neuropsychological evaluation, including administration of the CERAD Word List Memory test. Results indicated no significant group difference for learning and delayed free recall, but the AD+ChEI group had significantly fewer errors than the AD-ChEI group on the CERAD Recognition test. Our findings provide preliminary evidence that the aspect of memory that is most affected by ChEIs appears to be facilitation of retention of new information in memory. The implications of this on clinical care and functional abilities as well as future directions are discussed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Mental Recall; Mental Status Schedule; Neuropsychological Tests; Phenylcarbamates; Piperidines; Retention, Psychology; Rivastigmine; Verbal Learning

Cognitive impairment and negative signs are common in patients with schizophrenia. Up to 35% of elderly patients with schizophrenia fulfill the diagnostic criteria of dementia. Donepezil inhibits cholinesterase, thus enhancing cholinergic neurotransmission. We tested the efficacy of donepezil in elderly patients with chronic schizophrenia and severe cognitive impairment.. Following baseline assessment, patients were randomly assigned to receive either donepezil or placebo. The dose was 5 mg daily for the first week and 10 mg for an additional 11 weeks. The procedure was repeated using the crossover compound. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI) and Alzheimer Disease Assessment Scale - Cognitive subscale (ADAS-Cog) were used to assess the severity of symptoms, cognitive status and intervention effects.. Twenty subjects were enrolled (15 females, five males), mean age 70.2 years (SD 6.5) and mean duration of disease 38.5 years (SD 9.3). A modest treatment effect was found for both placebo and donepezil treatment periods. No crossover effect was found. No statistical differences were demonstrated between the two treatment groups (CGI p = 0.37, PANSS p = 0.71, ADAS-Cog p = 0.86). Two patients died during the study period due to unrelated causes and one patient discontinued participation due to increased agitation.. Donepezil does not seem to improve negative signs and cognitive impairment in elderly patients with chronic schizophrenia.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Comorbidity; Cross-Over Studies; Dementia; Depressive Disorder; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Examine the effects of donepezil on sleep and rapid eye movement (REM) sleep electroencephalogram (EEG) in patients with Alzheimer disease, using polysomnography, and the correlation between REM sleep EEG parameters and cognitive scores.. Randomized, double-blind, placebo-controlled design.. Two sleep research centers, University Hospital.. Thirty-five patients with mild to moderate Alzheimer disease, allocated to 2 groups: donepezil treated (n=17) and placebo treated (n=18).. Patients were administered donepezil or placebo.. Polysomnography with REM sleep EEG spectral analysis and cognitive evaluation using the Alzheimer Disease Assessment Scale, cognitive subscale, were performed at baseline and after 3 and 6 months. Slowing ratio was the ratio between slow and fast EEG frequency bands. Cognitive and sleep data were analyzed using analysis of variance. Correlations between cognitive improvement and REM sleep EEG were also calculated.. REM sleep increased significantly after 3 and 6 months of donepezil treatment compared with baseline and placebo (p < .01). Overall theta (p = .04), frontal theta (p < .01) and frontal delta (p = .03) absolute power during REM sleep decreased after 6 months of donepezil treatment. The occipital slowing ratio decreased during treatment (p = .04). REM sleep overall and frontal and centroparietal alpha absolute power significantly correlated with the cognitive improvement rate on the Alzheimer Disease Assessment Scale, cognitive subscale (r = 0.75, r = 0.71, r = 0.78); p < .01).. Donepezil treatment enhanced REM sleep and reduced slow frequencies of REM sleep EEG, suggesting a possible action upon REM sleep-related cholinergic neurons in patients with Alzheimer disease. Furthermore, REM sleep alpha power may predict the cognitive response to donepezil.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Electroencephalography; Female; Humans; Indans; Male; Piperidines; Polysomnography; Psychometrics; Sleep, REM

Delays in the diagnosis of Alzheimer's disease, and, therefore, delays in treatment, may have a detrimental effect on a patient's long-term well-being. This study assessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer's disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer's disease. These data support the long-term efficacy and safety of donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Topics: Alzheimer Disease; Cognition Disorders; Donepezil; Humans; Indans; Long-Term Care; Piperidines; Treatment Outcome; Vitamin E

Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment.. For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged >or= 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS-ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) epsilon4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population.. Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI-10, NPI-12, NPI-D, GDS and ADCS-ADL (all p < 0.05, ITT-LOCF). With the exception of the NPI-D in favour of donepezil (p < 0.05, ITT-LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS-ADL (p < 0.01, ITT-LOCF) and SIB (p < 0.05, ITT-LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients.. In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine; Severity of Illness Index; Treatment Outcome

The cholinesterase inhibitor donepezil is used to treat mild-to-moderate Alzheimer's disease. Its efficacy in severe dementia has not been assessed and is controversial. Our aim was to ascertain the effectiveness of donepezil in patients with severe Alzheimer's disease, by focusing primarily on cognition and activities of daily living.. We did a 6-month, double-blind, parallel-group, placebo-controlled study in 248 patients with severe Alzheimer's disease (mini mental state examination score 1-10) who were living in assisted care nursing homes ran by trained staff in Sweden. We assigned patients oral donepezil (5 mg per day for 30 days then up to 10 mg per day thereafter, n=128) or matched placebo (n=120). Our primary endpoints were change from baseline to month 6 in the severe impairment battery (SIB) and modified Alzheimer's Disease Cooperative Study activities of daily living inventory for severe Alzheimer's disease (ADCS-ADL-severe). We analysed outcomes for patients with data at baseline and at one or more other timepoints (modified intent-to-treat population) with last observation carried forward used to replace missing data.. 95 patients assigned donepezil and 99 patients assigned placebo completed the study. Patients treated with donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores at 6 months after initiation of treatment compared with baseline than did controls (least squares [LS] mean difference, 5.7, 95% CI 1.5-9.8; p=0.008, and 1.7, 0.2-3.2; p=0.03, respectively). The incidence of adverse events was comparable between groups (donepezil 82% [n=105] vs placebo 76% [n=91]), with most being transient and mild or moderate in severity. More patients discontinued treatment because of adverse events in the donepezil group (n=20) than in the placebo group (n=8).. Donepezil improves cognition and preserves function in individuals with severe Alzheimer's disease who live in nursing homes.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Humans; Indans; Middle Aged; Nursing Homes; Piperidines; Severity of Illness Index

To determine the value of continued donepezil treatment in patients with Alzheimer's disease for whom clinical benefit was initially judged to be uncertain.. The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer's disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12-24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase.. Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer's Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, -3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)].. Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer's disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cognition; Disease Progression; Donepezil; Double-Blind Method; Drug Evaluation; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Single-Blind Method; Time Factors; Treatment Outcome

Acetylcholinesterase inhibitors (AChEI) such as donepezil act in mild Alzheimer's disease (AD) by increasing cholinergic tone. Differences in the clinical response in patients who do or do not benefit from therapy may be due to different functional features of the central neural systems. We tested this hypothesis using cortical electroencephalographic (EEG) rhythmicity. Resting eyes-closed EEG data were recorded in 58 mild AD patients (Mini Mental State Examination [MMSE] range 17-24) before and approximately 1 year after standard donepezil treatment. Based on changes of MMSE scores between baseline and follow-up, 28 patients were classified as "Responders" (MMSEvar >or=0) and 30 patients as "Non-Responders" (MMSEvar <0). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were studied with low-resolution brain electromagnetic tomography (LORETA). Before treatment, posterior sources of delta, alpha 1 and alpha 2 frequencies were greater in amplitude in Non-Responders. After treatment, a lesser magnitude reduction of occipital and temporal alpha 1 sources characterized Responders. These results suggest that Responders and Non-Responders had different EEG cortical rhythms. Donepezil could act by reactivating existing yet functionally silent cortical synapses in Responders, restoring temporal and occipital alpha rhythms.

Topics: Aged; Alzheimer Disease; Brain Mapping; Cerebral Cortex; Data Interpretation, Statistical; Donepezil; Electroencephalography; Female; Humans; Indans; Magnetoencephalography; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales

The objective of this study was to examine the clinical utility of memantine for moderate-to-severe Alzheimer disease (AD) using responder analyses.. Data from a previously published 24-week, randomized, double-blind, placebo-controlled trial of 10 mg memantine twice a day in patients with moderate-to-severe AD (N = 404) on stable donepezil therapy were evaluated using three sets of responder criteria. Response rates were calculated and analyzed for the intention-to-treat population using a generalized estimating equations model. The following outcomes were examined separately and in combination: the Alzheimer's Disease Cooperative Study-Activities of Daily Living 19-Item Inventory (ADCS-ADL19), Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), and Neuropsychiatric Inventory (NPI).. When treatment response required cognitive improvement relative to baseline, memantine yielded higher response rates than placebo. When treatment response was defined as stabilization of individual outcomes, memantine resulted in significantly higher response rates than placebo for all outcomes, with number needed to treat (NNT) ranging from 8-10. More conservative definitions of response that required simultaneous stabilization on multiple outcome measures again favored memantine treatment for six of 10 combinatorial definitions.. These responder analyses may assist clinicians in evaluating the impact of memantine in a relevant clinical scenario, i.e., in patients with AD previously stabilized on a cholinesterase inhibitor. The current results indicate that in this setting, memantine produces both improvement and stabilization of symptoms, across multiple outcomes, and thus provides a clinically important treatment benefit for patients with moderate-to-severe AD.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Female; Geriatric Assessment; Humans; Indans; Male; Memantine; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Current outcome measures for Alzheimer's disease (AD) drugs have been criticized as insufficiently patient-centred. One commonly unmeasured goal of patients and caregivers is verbal repetition.. We examined how often reducing repetition (of questions, statements or stories) was set as treatment goal, whether and when it responded, and how change in repetition correlated with change in other domains.. This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure.. Reducing repetition was a treatment goal in 46%, who were not systematically different from others. Of 18 patients in whom repetition improved for 9 months, 83% (15) showed a response at 3 months. Early (3-month) response correlated best with the overall level of goal attainment (r = 0.74) and changes in leisure activities (r = 0.69) and social interactions (r = 0.68) compared with changes in cognition (r = 0.44) or behaviour (r = 0.11). Correlations with the ADAS-Cog and MMSE change scores remained only modest (at 12 months = -0.25 and 0.19, respectively). Correlations with the CIBIC-Plus were higher (-0.47 at 3 months and -0.43 at 12 months).. Diminution of repetition is common, and appears to mark response to cholinesterase inhibition in some patients. Responders generally also show improved cognition and function, perhaps as an aspect of improved executive function.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Memory, Short-Term; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome; Verbal Behavior

When otherwise unexplained, syncope in patients with Alzheimer's disease may be attributed to bradycardia caused by cholinesterase inhibitors. We studied prospectively the clinical events and cardiovascular changes occurring during treatment with donepezil in patients with Alzheimer's disease.. Consecutive patients presenting with mild-to-moderate Alzheimer's disease were included in the study. Their clinical characteristics, blood pressure, heart rate and electrocardiogram were recorded before (baseline) and during treatment with donepezil. The drug was administered at a dosage of 5 mg/day for 1 month and 10 mg/day for the following 7 months, as tolerated. We compared the baseline observations with those made at 1, 2 and 8 months of donepezil treatment. We also examined the effects of negatively chronotropic or dromotropic drugs concomitantly administered with donepezil.. Thirty patients were included in the study, of whom 43% were taking negatively chronotropic or dromotropic drugs. The first month of therapy (donepezil 5 mg/day) was completed by 26 patients. During the 7-month high-dosage phase (10 mg/day), four patients dropped out of the study; thus, 22 patients completed the full 8 months of the study. The mean heart rate was 66 +/- 8 beats/min at baseline in the overall study population. This decreased significantly to 62 +/- 9, 61 +/- 7 and 62 +/- 8 beats/min at the 1, 2 and 8 month timepoints, respectively (all p = 0.002 vs baseline). Among patients not receiving negatively chronotropic or dromotropic drugs, heart rate decreased significantly over the course of the study (from 67 +/- 8 beats/min at baseline to 62 +/- 8 beats/min at 1 month, 62 +/- 7 beats/min at 2 months and 62 +/- 8 beats/min at 8 months [all p = 0.005 vs baseline]). There was no significant change in heart rate in patients who were receiving negatively chronotropic or dromotropic drugs. The PR interval increased over the course of the study in all patient groups, but these changes were only statistically significant in the group of patients who were not taking negatively chronotropic or dromotropic drugs (155 +/- 23ms at baseline vs 158 +/- 21, 160 +/- 22 and 163 +/- 24ms at the 1, 2 and 8 month timepoints; all p = 0.02 vs baseline). One patient developed syncope due to orthostatic hypotension; there were no cases of bradycardia-induced syncope. Gastrointestinal manifestations were reported in ten of the study patients. Abdominal pain and vomiting were the reasons for study termination in five of the eight patients who did not complete the trial.. A donepezil-induced decrease in heart rate and increase in PR interval were observed only in patients with Alzheimer's disease who were not treated with negatively chronotropic or dromotropic drugs. These changes were not associated with bradycardia-induced syncope.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Blood Pressure; Cardiovascular System; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Indans; Male; Piperidines; Prospective Studies; Risk; Syncope

Topics: Aged; Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Piperidines; Single-Blind Method

Cholinergic enhancement is among the best established treatments of Alzheimer's disease (AD). The cognitive effects of treatment are thought to be mediated by improvement of neuronal transmission. Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) by measuring cortical metabolic response to activation assesses integrity of neuronal transmission in vivo.. To determine the effects of treatment with donepezil, a centrally selective acetylcholinesterase inhibitor, on cortical metabolism in AD using 18FDG-PET.. We enrolled 23 patients, 18 of which completed the study, with mild to moderate probable AD (mini-mental status exam scores of 15-28, inclusive) in a double-blind cross over trial of 8 weeks donepezil compared to 8 weeks placebo with repeated double 18FDG-PET examinations during passive audio-visual stimulation. Effects of treatment on cortical metabolic response to stimulation were determined with a linear model on a voxel level using Statistical Parametric Mapping (SPM 99, Wellcome Department of Imaging Neuroscience, London).. Effects of treatment on cognitive measures were not different between donepezil and placebo. During passive audio-visual stimulation, patients showed activation in posterior visual and auditory areas and decreased activation in frontal cortex and basal ganglia. Resting state metabolism was increased with donepezil in left prefrontal cortex and decreased in right hippocampus. Cortical response to activation was increased in right hippocampus with donepezil compared to placebo.. Donepezil treatment shows a spatially limited functional effect on right hippocampus and left prefrontal cortical metabolism, independently of clinical response to treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebral Cortex; Cholinesterase Inhibitors; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Fluorodeoxyglucose F18; Humans; Indans; Learning; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Piperidines; Positron-Emission Tomography

To evaluate the clinical efficacy and safety of akatinol memantine in the treatment of patients with mild to moderate Alzheimer disease (AD).. One hundred patients with diagnosis of possible or probable AD and Mini Mental State Examination total scores between 10 and 26 from 6 centers in two cities of China were randomly divided into two groups: akatinol memantine group (n = 50, given akatinol memantine 5 mg/d in first week, 10 mg/d in second week, 15 mg/d in third week and 20 mg/d from fourth to sixteenth week); donepezil group (n = 50, donepezil 5 mg/d). Different scales were used to evaluated cognitive function (MMSE), activity of daily life and behavior and mood (Blessed-Roth scale) as well as the severity of dementia (GDS). Safety evaluation was conducted every 4 weeks.. In comparison with the baseline data, there were significant improvements in cognition assessed with MMSE on 16th week in akatinol memantine group (P = 0.000) and donepezil group (P = 0.000) respectively; There also were significant improvements in activity of daily life, behavior and mood assessed by Blessed-Roth scale in akatinol memantine group (P = 0.000) and donepezil group (P = 0.000) on 8th week and 16th week. However there was no improvements in the change of the basic habit of life assessed with the Part II of Blessed-Roth scale (P > 0.05), and nor an improvements in the serious level of dementia assessed with GDS (P > 0.05). In comparison with the data in donepezil group, there were no improvement in the change of MMSE score, Blessed-Roth scale score and GDS score in akatinol memantine group on 16th week (P > 0.05). Mild and transient adverse events were observed in 6% of akatinol memantine group.. As a safe and effective medicine, akatinol memantine, which has a similar effect as donepezil for AD, can remarkably improve the cognition, behavior, and mood of AD patients.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Excitatory Amino Acid Antagonists; Female; Follow-Up Studies; Humans; Indans; Male; Memantine; Middle Aged; Piperidines

To investigate the behavioral effects of memantine in moderate to severe Alzheimer disease (AD).. The authors conducted a hypothesis-generating, exploratory analysis of a 24-week, double-blind, placebo-controlled trial comparing memantine (20 mg/day) with placebo in subjects with moderate to severe AD on stable donepezil treatment. They employed the Neuropsychiatric Inventory (NPI; 12-item), administered at baseline, week 12, and week 24, to assess the effects of memantine on behavior. Global, cognitive, and functional measures were collected and relationships between these assessments and changes in behavior were determined. The intent-to-treat population was examined using last-observation-carried-forward and observed-cases approaches.. Patients treated with memantine had significantly lower NPI total scores than patients treated with placebo. Analyses of the 12 NPI domains revealed significant effects in favor of memantine on agitation/aggression, eating/appetite, and irritability/lability. Of patients who exhibited agitation/aggression at baseline, those treated with memantine showed significant reduction of symptoms compared with placebo-treated patients. Memantine-treated patients without agitation/aggression at baseline evidenced significantly less emergence of this symptom compared with similar patients receiving placebo. Caregivers of patients receiving memantine registered significantly less agitation-related distress. There were significant relationships between the NPI and the global rating scale and performance of activities of daily living, but not between changes in the NPI and cognition.. Treatment with memantine reduced agitation/aggression, irritability, and appetite/eating disturbances. Memantine reduced agitation/aggression in patients who were agitated at baseline and delayed its emergence in those who were free of agitation at baseline.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antiparkinson Agents; Behavioral Symptoms; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memantine; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Prospective Studies; Psychomotor Agitation; Severity of Illness Index; Time Factors

To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients.. CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 +/- 0.4; age 75 +/- 1 years (mean +/- SEM); n=53 for CSF and n=51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman's direct colorimetric assay. Protein levels of two variants of AChE ("read-through" AChE-R and synaptic AChE-S) were determined by an ELISA-like method.. The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19-29%). CSF AChE-S inhibition was estimated to 30-40% in the 5-mg and 45-55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (>or=45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Cognition; Donepezil; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Indans; Male; Piperidines; Time Factors

Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs.. 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed.. AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters.. Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Polysomnography; Rivastigmine; Sleep Stages; Sleep Wake Disorders

Treatment with donepezil improves cognitive function of patients with Alzheimer's disease (AD) when compared to a placebo-controlled group. The purpose of this study was to investigate changes in regional cerebral blood flow (rCBF) of AD patients in short-term and long-term treatment with donepezil.. rCBF was measured by N-isopropyl-p-123I-iodoamphetamine (IMP) autoradiography method. CBF measurements were performed in 17 AD patients before treatment and after 3 months (short-term therapy) and 1 year (long-term therapy). Regions of interest were set at cerebral cortex and cerebellar hemisphere. We used absolute CBF and relative CBF expressed as ratio to cerebellar CBF.. Significant increases in relative rCBF were noted in the frontal, parietal and temporal lobes at the end of short-term therapy. rCBF was decreased after the long-term therapy, whereas rCBF was still increased to a slight extent, as compared with the pre-treatment levels. Absolute rCBF showed minimal change and a tendency to decline.. Relative rCBF significantly increased in the short-term donepezil therapy, while following the long-term therapy, rCBF decreased to the pre-treatment level.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Circulation; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Radionuclide Imaging; Treatment Outcome

Topics: Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cholinesterase Inhibitors; Confidence Intervals; Donepezil; Double-Blind Method; Humans; Indans; Mental Status Schedule; Neuropsychological Tests; Piperidines; Treatment Outcome

The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective effects in neurodegenerative diseases of multifactorial origin. There is still debate about the efficacy of Ginkgo biloba special extract EGb 761 compared with second-generation cholinesterase inhibitors in the treatment of mild to moderate Alzheimer's dementia. Our aim is to assess the efficacy of the Ginkgo biloba special extract E.S. in patients with dementia of the Alzheimer type in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with donepezil and placebo. The trial was designed as a 24-week randomized, placebo-controlled, double-blind study. Patients aged 50-80 years, suffering from mild to moderate dementia, were allocated into one of the three treatments: Ginkgo biloba (160 mg daily dose), donepezil (5 mg daily dose), or placebo group. The degree of severity of dementia was assessed by the Syndrom Kurz test and the Mini-Mental State Examination. Clinical Global Impression score was recorded to assess the change in the patients' conditions and the therapeutic efficacy of tested medications. Our results confirm the clinical efficacy of Ginkgo biloba E.S. (Flavogin) in the dementia of the Alzheimer type, comparable with donepezil clinical efficacy. There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia. This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type and could be a valid contribution in this debate. Our study suggests that there is no evidence of relevant differences in the efficacy of EGb 761 and donepezil in the treatment of mild to moderate Alzheimer's dementia, so the use of both substances can be justified. In addition, this study contributes to establish the efficacy and tolerability of the Ginkgo biloba special extract E.S. in the dementia of the Alzheimer type with special respect to moderately severe stages.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinesterase Inhibitors; Dementia; Donepezil; Double-Blind Method; Female; Ginkgo biloba; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Piperidines; Plant Extracts

Sensory gating is defined as the brain's ability to inhibit repetitive and irrelevant incoming sensory stimuli and is supposed to be related to cholinergic transmission. Indeed, Alzheimer's disease (AD) is characterized by a cholinergic deficit that is believed to be involved in cerebral cortex hyperexcitability and short latency afferent inhibition deficit. Therefore, a sensory gating deficit may be supposed present in AD within the frame of cortex hyperexcitability and loss of cortex modulation of sensory inputs. The authors investigated whether a sensory gating deficit may be present in AD and whether this deficit may be related to the presence of neuropsychiatric symptoms (NPS) and reversed by donepezil treatment. Sensory gating was evaluated using a paired-stimulus auditory P50 event-related potential paradigm. Eighteen drug-naïve probable AD patients (mean age 76.1 years; SD 5.6 years; 13 females and 5 males) and 15 healthy elderly controls (mean age 74.2 years; SD 5.4 years; 10 females and 5 males) were recruited. Sensory gating was evaluated in AD patients before starting therapy and after 1 and 3 months of donepezil treatment. Auditory P50 sensory gating was impaired in AD patients but no correlation was found between gating deficit and NPS. Moreover, AD patients displayed increased P50 amplitude when compared with healthy elderly subjects. Donepezil treatment did not improve P50 sensory gating in AD patients but decreased P50 amplitude. Patients with AD displayed an augmented P50 amplitude, in accordance with previous studies, suggesting increased cortex excitability. Donepezil does not affect P50 sensory gating but reduces P50 amplitude. Donepezil may induce P50 amplitude reduction by means of enhanced dopamine release. Indeed, it has been demonstrated that donepezil induces dopamine release "in vitro." The findings suggest that AD patients have a sensory gating impairment but the link with both NPS and the cholinergic deficit is doubtful.

Topics: Acoustic Stimulation; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cerebral Cortex; Chi-Square Distribution; Cholinesterase Inhibitors; Donepezil; Evoked Potentials; Female; Gait Disorders, Neurologic; Humans; Indans; Male; Piperidines; Reaction Time; Statistics, Nonparametric; Time Factors

A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.

Topics: Aged; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Female; Genetic Variation; Genotype; Heterozygote; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine; Treatment Outcome

African Americans have a higher incidence and prevalence of Alzheimer's disease (AD) than whites but have been underrepresented in clinical trials, including studies of cholinesterase inhibitors.. The purpose of this 12-week, open-label study was to evaluate the efficacy and safety of donepezil in African Americans with mild-to-moderate AD.. Efficacy was assessed via the Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change-Plus interview with the patient and caregiver (CIBIC-Plus) and Fuld Object Memory Evaluation (FOME), a measure that has been validated for use with elderly African Americans.. Significant improvements were observed in cognition (MMSE), global function (CIBIC-Plus) and memory (all four subscales of the FOME). Donepezil was well tolerated; 51% of patients experienced adverse events, most commonly diarrhea (5.6%), hypertension (5.6%) and urinary tract infection (4.8%).. These results suggest that donepezil is effective and safe in treating African Americans with mild-to-moderate AD, and support the value of FOME in assessing efficacy in AD trials in diverse populations.

Topics: Aged; Alzheimer Disease; Black or African American; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Piperidines; Severity of Illness Index; Treatment Outcome

Donepezil hydrochloride, a central cholinergic drug, is widely used for improving cognitive decline in Alzheimer's disease (AD). We investigated whether donepezil might affect the lower urinary tract (LUT) function in AD.. Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) (0-70, increase as impairment), urinary questionnaire, and electromyography (EMG)-cystometry were performed in eight patients with AD before and after treatment with 5 mg/day of donepezil.. The first assessment (before donepezil) showed moderate cognitive decline in the patients as a mean ADAS-cog score of 27.0 (range: 17-35) (normal < 15). Seven patients had urinary symptoms including urinary urgency incontinence in five. EMG-cystometry revealed neurogenic detrusor overactivity in seven with a mean detrusor pressure of 44.9 cm H(2)O (20-101), mean bladder capacity of 202 ml (20-412), and post-void residuals in none. The second assessment (3 months after donepezil) showed a decrease in the ADAS-cog score to 23.3 (11-35) though without statistical significance. Urinary incontinence disappeared in one and none had a new onset of incontinence. EMG-cystometry revealed an increase in the detrusor pressure on overactivity to 54.1 cm H(2)O (20-122), but also an increase in the bladder capacity to 234 ml (80-400), and post-void residuals in one (40 ml).. Although the number of our patients was small, it seems possibly that donepezil could ameliorate cognitive function without serious adverse effects on the LUT function in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Electromyography; Female; Humans; Indans; Male; Muscle Hypertonia; Nootropic Agents; Pilot Projects; Piperidines; Treatment Outcome; Urinary Incontinence; Urodynamics

There are various anticholinesterase inhibitors (AChEIs) for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). All AChEIs have shown greater efficacy than placebo in randomized, double-blind, parallel-group clinical trials. No differential studies have yet been made of the efficacy between all AChEIs. The study aims to determine the differential efficacy of the AChEIs with respect to a historical sample of patients with AD that were not treated with AChEIs. An open-label, prospective, observational study with a retrospective control group was undertaken to examine the evolution of the cognitive function over a 6-month period. The patients were assessed with the Mini-Mental State Examination (MMSE) at study entry and at 6 months. A general linear model was applied for repeated measurements with the MMSE score as the dependent variable, treatment type as an independent variable and the severity of the deterioration, age and the MMSE baseline score as covariables. Of the sample of 147 patients, 40 initiated treatment with donepezil, 32 with galantamine, 30 with rivastigmine and 45 were part of a historical sample of the memory clinic patients between 1991 and 1996 that had not been treated with AChEIs. The average age was 73.7 years (SD = 6.9; range = 52-86), 67.3% were women, 78.2% of the cases were mild and the MMSE baseline score was 18.1 points (range = 11-27). No significant intergroup differences were observed in these variables. The average doses of donepezil, galantamine and rivastigmine were 5.87 mg/day (SD = 1.92), 14.81 mg/day (SD = 6.25) and 6.41 mg/day (SD = 1.82), respectively. At 6 months, the difference in the MMSE score with respect to the untreated group was 1.6 points for donepezil (95% CI 0.79-2.37; p < 0.001), 0.99 points for galantamine (95% CI 0.14-1.85; p = 0.01) and 0.90 points for rivastigmine (95% CI 0.05-1.74; p = 0.03). No significant differences were observed in the efficacy among the groups treated with AChEIs (p > 0.05). Treatment with AChEIs significantly delays the global cognitive impairment associated with AD for at least 6 months. Our study found no significant differences in efficacy between donepezil, galantamine and rivastigmine. Further studies in the context of daily clinical practice will determine the clinical significance of the changes observed. An important variability of the response to the treatment was observed in treated patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Female; Galantamine; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Phenylcarbamates; Piperidines; Prospective Studies; Retrospective Studies; Rivastigmine; Severity of Illness Index; Time Factors

To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy.. Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy.. Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05).. Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Cerebral Cortex; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Piperidines; Positron-Emission Tomography

GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period. Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007). This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.

Topics: Aged; Aging; Alzheimer Disease; Analysis of Variance; Area Under Curve; Cholinesterase Inhibitors; Donepezil; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Indans; Insulin-Like Growth Factor I; Male; Piperidines; Single-Blind Method

The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression.. In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups.. The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.. Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Apolipoproteins E; Atrophy; Cholinesterase Inhibitors; Cohort Studies; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genotype; Geriatric Assessment; Hippocampus; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Time Factors; Treatment Outcome

Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.. In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.. A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.. Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Humans; Indans; Nootropic Agents; Piperidines; Proportional Hazards Models; Treatment Failure; Vitamin E

The purpose was to identify vascular influences on the responsiveness to donepezil chloride. The study included 50 untreated probable Alzheimer's disease patients with the Modified Hachinski Ischemic Score <4. We assessed baseline cognitive status using the Revised Hasegawa Dementia Scale (HDS-R), Clinical Dementia Rating (CDR) and the clock drawing test (CDT). The response to 5 mg of donepezil was monitored by the CDT for 12 months. Patients were classified as true responders (TR), unchanged (UC) and non-responders according to changes on the CDT in response to treatment. High HDS-R scores, low CDT scores, low CDR and presence of hypertension (HBP) and periventricular hyperintensities (PVH) predicted a TR- or UC-type outcome. Aggravation of executive function by HBP and/or PVH and its improvement by donepezil may have been detected by the CDT.

Topics: Aged; Alzheimer Disease; Brain; Brain Ischemia; Cholinesterase Inhibitors; Cognition Disorders; Demography; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Piperidines; Risk Factors; Severity of Illness Index

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Galantamine; Humans; Indans; Male; Piperidines

Attentional function is impaired in Alzheimer's disease (AD). Moreover, attention is mediated by acetylcholine. But, despite the widespread use of acetylcholinesterase inhibitors (AChE-I) to augment available acetylcholine in AD, measures of attentional function have not been used to assess the drug response.. We hypothesized that as cholinergic augmentation impacts directly on the attentional system, higher-order measures of visual selective attention would be sensitive to effects of treatment using an AChE-I (donepezil hydrochloride). We also sought to determine whether these attentional measures were more sensitive to treatment than other measures of cognitive function.. Seventeen patients with AD (8 untreated, 9 treated with donepezil) were contrasted on performance of a selective cancellation task. Two signal detection parameters were used as outcome measures: decision strategy (beta, beta) and discriminability (d-prime, d'). Standard screening and cognitive domain measures of vigilance, language, memory, and executive function were also contrasted.. Treated patients judged stimuli more conservatively (p = 0.29) by correctly endorsing targets and rejecting false alarms. They also discriminated targets from distractors more easily (p = 0.58). The screening and neuropsychological measures failed to differentiate the groups.. Higher-order attentional measures captured the effects of donepezil treatment in small groups of patients with AD. The results suggest that cholinergic availability may directly affect the attentional system, and that these selective attention measures are sensitive markers to detect treatment response.

Topics: Aged; Alzheimer Disease; Attention; Cholinesterase Inhibitors; Cognition; Decision Making; Discrimination, Psychological; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Pattern Recognition, Visual; Photic Stimulation; Piperidines; Signal Detection, Psychological

To characterise the population of Alzheimer's disease patients treated with acetylcholinesterase inhibitors, to analyse effectiveness and drug safety in the clinical practice, and to identify variables that may predict the response to therapy.. From September 2000 to December 2001, a total of 5,462 patients diagnosed with mild to moderate Alzheimer's disease were enrolled at the time of their first prescription of the study drugs and followed up for an average of 10.5 months. Responders were defined as patients with a mini-mental state examination (MMSE) score improvement of 2 or more points from baseline after 9 months of therapy.. At 9 months, 2,853 patients (52.2%) completed the study. The mean change from baseline in MMSE scores was an improvement of 0.5 points (+/-3.0). The proportion of responders to the therapy was 15.7% at 9 months. A greater probability of response at 9 months was observed among patients without concomitant diseases at baseline [odds ratio (OR)=2.1, 95% confidence interval (CI) 1.5-2.9] and among those with a response at 3 months (OR=20.6, 95% CI 17.2-24.6). During the study period, 285 patients (5.2%) discontinued the treatment because of an adverse drug reaction.. Effectiveness of acetylcholinesterase inhibitors on cognitive symptoms of patients with mild to moderate Alzheimer's disease is modest. At 9 months, improvement was evident only in a subgroup of patients without concomitant diseases and who had demonstrated a response at 3 months.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Italy; Male; Middle Aged; Phenylcarbamates; Piperidines; Rivastigmine; Time Factors; Treatment Outcome

There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini-Mental State Examination [sMMSE] score 5-12) within a randomized, placebo-controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5-17).. Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview-Based Impression of Change (CIBIC-plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment x disease severity interaction in the full MSAD study sample.. CIBIC-plus scores for donepezil patients were significantly improved compared with placebo for each time-point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment x severity interactions for any of the efficacy measures.. In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Disability Evaluation; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.. Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.. In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.. Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Rivastigmine; Time Factors; Treatment Outcome

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Patient Compliance; Phenylcarbamates; Piperidines; Research Design; Rivastigmine

Reality orientation therapy combined with cholinesterase inhibitors has not been evaluated in patients with Alzheimer's disease.. To perform such an evaluation.. We randomly assigned 79 of 156 patients treated with donepezil to receive a reality orientation programme. Caregivers of the treatment group were trained to offer the programme at home 3 days a week, 30 min/day, for 25 consecutive weeks, and were invited to stimulate and involve patients in reality-based communication.. The treatment group showed a slight improvement in Mini-Mental State Examination (MMSE) scores (mean change +0.2, s.e.=0.4) compared with a decline in the control group (mean change -1.1, s.e.=0.4; P=0.02). Similarly for the Alzheimer's Disease Assessment Scale--Cognition (treatment group mean change +0.4, s.e.=0.8; control group -2.5, s.e.=0.8; P=0.01). The intervention had an equal effect on cognition in those with mild (MMSE score > or = 20) and moderate (score <20) dementia. No significant effect was observed for behavioural and functional outcomes.. Reality orientation enhances the effects of donepezil on cognition in Alzheimer's disease.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition; Combined Modality Therapy; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Quality of Life; Reality Therapy; Treatment Outcome

Patients with dementia of the Alzheimer type (DAT) respond variably to treatment with acetylcholinesterase inhibitors.. To determine whether measures of hippocampal volume and shape predict the response to donepezil in patients with DAT.. T1-weighted, magnetic resonance images were obtained from patients with DAT, who subsequently underwent treatment with donepezil. Brain-mapping algorithms were used to quantify hippocampal volume and shape, and growth curves were used to estimate clinical outcome.. A referral outpatient center specializing in treatment of dementia.. Thirty-seven patients with very mild or mild DAT received donepezil therapy for up to 4 weeks before magnetic resonance imaging and for 24 to 96 weeks after magnetic resonance imaging.. Donepezil, 10 mg/d.. Rate of change in the cognitive portion of the Alzheimer's Disease Assessment Scale total scores.. Smaller hippocampal volume and inward variation of the lateral and inferomedial portions of the hippocampal surface were correlated with a poorer response to donepezil therapy.. Measures of hippocampal volume and surface variation can be used to predict the response of patients with DAT to the acetylcholinesterase inhibitor donepezil.

Topics: Alzheimer Disease; Brain Mapping; Cholinesterase Inhibitors; Donepezil; Hippocampus; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Piperidines; Time Factors

There is an increasing interest in the effects of the acetylcholinesterase inhibitors (AChEIs) in Alzheimer's disease (AD), as investigated by means of objective, neurophysiological tools. In an open-label study, we evaluated the neurophysiological effects of chronic administration of donepezil to AD patients, by means of a correlative approach between quantitative EEG (qEEG) and perfusional brain single photon emission computed tomography (SPECT).. Sixteen patients (mean age: 74.8+/-7.9 years) with mild to moderate AD (MMSE score >13, mean: 20.7+/-4.6) underwent qEEG and SPECT examinations at the time of diagnosis (t0) and after approximately 1 year of donepezil therapy (t1). The brain SPECT (99mTc-hexamethylpropyleneamine oxime) was performed by means of a high-resolution SPECT camera; the qEEG was recorded from 19 scalp electrodes by average reference and digitized at 512 Hz. The mean frequency (MF) value of the mean power spectrum (fast Fourier transform) from 4 brain regions (one frontal and one temporal-parietal in each hemisphere) was chosen for statistical analysis. Changes in MMSE score and qEEG-MF values between t0 and t1 were assessed by analysis of variance. SPECT differences between t0 and t1, as well as the relationships between SPECT and qEEG changes, were assessed by statistical parametric mapping (SPM 99; height threshold: P=0.001 at cluster level).. Between t0 and t1, the MMSE score significantly (P<0.05) decreased (from 20.7+/-4.64 to 19.1+/-5.09; 95% confidence interval: 1.14) and qEEG was unchanged. There was no regional perfusion decrease; a small area of relative perfusion increase was observed, including the right occipital cuneus and the left lingual gyrus. A positive correlation was found between the right frontal MF and brain perfusion in the left superior parietal lobule. A post hoc SPM analysis (height threshold: P=0.01) showed a positive correlation between brain perfusion and each of the 4 qEEG MF values in the left parietal lobe, including the precuneus, the superior parietal lobule, and the post-central gyrus.. The posterior parietal region, which is involved in memory and attention, is often affected by hypoperfusion in AD, as a likely consequence of disconnection from the atrophic mesial temporal cortex. Metabolic activation induced by AChEIs may especially influence this disconnected but still not grossly impaired area, which could be one of the pathophysiological substrates of the cognitive effects of AChEIs. The modest topographical sensitivity of qEEG, reflecting the rather diffuse changes in AD, is further confirmed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Donepezil; Electroencephalography; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Radiopharmaceuticals; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil.. Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales.. 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group.. Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.

Topics: Aged; Alzheimer Disease; Ambulatory Care; Antidepressive Agents; Behavioral Symptoms; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome

To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL).. Patients with mild to moderate AD from 14 European centres were randomised to receive open-label donepezil (up to 10 mg once daily) or galantamine (up to 12 mg twice daily) for 12 weeks, according to the approved product labelling. Physicians and caregivers completed questionnaires rating satisfaction with treatment/ease of use in daily practice. Secondary assessments were the ADAS-cog, the MMSE, and the DAD scale to assess ADL. Tolerability was evaluated by reporting adverse events (AEs).. Both physicians and caregivers reported significantly greater overall satisfaction/ease of use for donepezil (n = 64) compared with galantamine (n = 56) at weeks 4, 12, and endpoint (week 12 LOCF; all p-values <0.05). Significantly greater improvements in cognition were also observed for donepezil versus galantamine on the ADAS-cog at Week 12 and endpoint (p-values <0.05). ADL improved significantly in the donepezil group compared with the galantamine group at weeks 4, 12, and endpoint (p-values <0.05). Most AEs were mild to moderate, however, 46% galantamine-treated patients reported gastrointestinal AEs vs 25% donepezil patients.. Physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Attitude of Health Personnel; Attitude to Health; Caregivers; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Galantamine; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Treatment Outcome

Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed.. To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil.. A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial.. Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.. Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).. The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively.. In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index

This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Electrocardiography; Female; Germany; Hemodynamics; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

A study was performed on patients with Alzheimer's disease (AD) in order to evaluate the efficacy of a combined treatment (donepezil plus cognitive training) in both cognitive processes and affective states. Eighty-six subjects, 25 men and 61 women, with an average age of 75.58 years, were studied. Almost all the subjects had a basic educational level. Donezepil was administered at a dose of 10 mg daily along with cognitive treatment involving images of everyday life and reminiscent music; the sessions took place on Monday to Friday and lasted three quarters of an hour. The study lasted 12 months. Subjects underwent test-retest with the following tests: Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog); the Geriatric Depression Scale (GDS) and the overall deterioration scale (FAST). The results showed that subjects receiving the combined treatment had a better response than those who did not receive any cognitive training. These subjects' MMSE score decreased by 3.24 on average. The affective symptomatology of those receiving only drug treatment improved whereas the cognitive processes did not.

Topics: Aged; Aging; Alzheimer Disease; Cholinergic Agents; Cognition; Cognitive Behavioral Therapy; Combined Modality Therapy; Dementia; Donepezil; Female; Humans; Indans; Long-Term Care; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Sex Characteristics

The study evaluates the expression and production of cytokines in peripheral blood mononuclear cells of patients with Alzheimer disease treated or not treated with acetylcholinesterase inhibitor, which enhances neuronal transmission. Cytokines associated with brain inflammation such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha have been implicated in the regulation of amyloid peptide protein synthesis. The anti-inflammatory cytokine, IL-4, may suppress the activity of IL-1beta. Patients were assessed for clinical and immunologic features at baseline and after 1 month of treatment with Donepezil, an acetylcholinesterase inhibitor. Peripheral blood mononuclear cells were cultured with and without phytohemagglutinin stimulation. IL-1beta and IL-4 levels were measured by enzyme-linked immunosorbent assay. Reverse transcriptase-polymerase chain reaction was used to determine the expression of cytokines in peripheral mononuclear cells. Compared with untreated patients and healthy control subjects, IL-1beta levels and expression decreased in Alzheimer disease patients treated with Donepezil (P < 0.001). In contrast, IL-4 levels and expression were significantly higher in Alzheimer patients treated with the acetylcholinesterase inhibitor. This increment was observed in both unstimulated and phytohemagglutinin-stimulated peripheral blood mononuclear cells.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cells, Cultured; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Interleukin-1; Interleukin-4; Leukocytes, Mononuclear; Male; Piperidines

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerat

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Galantamine; Humans; Indans; Male; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index

Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long?. 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models.. Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil.. Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cost-Benefit Analysis; Disease Progression; Donepezil; Double-Blind Method; Female; Health Care Costs; Health Resources; Humans; Indans; Institutionalization; Male; Middle Aged; Piperidines; Treatment Outcome; United Kingdom

We have developed a radiolabeled lipophilic acetylcholine analogue, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) to measure brain acetylcholinesterase (AChE) activity by positron emission tomography (PET) in vivo. Aiming to develop a new SPECT tracer similar to MP4A, we first proposed a simple method for diagnosing Alzheimer's disease (AD) using [11C]MP4A PET. We performed [11C]MP4A PET and N-isopropyl [123I]iodoamphetamine ([123I]IMP) SPECT in 13 patients with AD and in 17 normal controls (NC). We calculated the ratio of radioactivity of the cortical region of interest (ROI) to that of the cerebellum measured with [11C]MP4A PET (MP4A ratio) and the ratio of regional cerebral blood flow (rCBF) to that of the cerebellum measured with [123I]IMP SPECT (IMP ratio). Eleven cortical ROIs were placed in the frontal, sensorimotor, temporal, parietal, and occipital cortices in both hemispheres and in the posterior cingulate cortex, and z-score was calculated in each ROI in patients with AD compared with NC. When the z-score was 2 or more in a ROI, it was defined as a positive ROI. When a patient had 3 or more positive ROIs, the patient was diagnosed as having AD. The reduction in the MP4A ratio was greater than that in the IMP ratio in all cortical ROIs except for in the right parietal cortex and cingulate cortex in patients with AD. MP4A ratio method showed 92% sensitivity and the IMP ratio method 69% sensitivity for the diagnosis of AD. These results encourage us to develop a new SPECT tracer similar to MP4A for the diagnosis of AD.

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Carbon Radioisotopes; Cerebral Cortex; Female; Humans; Image Interpretation, Computer-Assisted; Iofetamine; Male; Middle Aged; Piperidines; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

To determine the efficacy of donepezil in the treatment of neuropsychiatric symptoms in patients with Alzheimer disease (AD) in a randomized withdrawal study.. Patients with mild to moderate AD with marked neuropsychiatric symptoms at baseline (Neuropsychiatric Inventory [NPI] > 11 points) were treated openly with donepezil 5 mg daily for 6 weeks followed by 10 mg daily for a further 6 weeks. Patients were then randomized (60:40) to either placebo or 10 mg donepezil daily. All patients were assessed at 6 weeks and provided there was no marked cognitive deterioration their blinded treatment was continued for a further 6 weeks. NPI and carer distress were assessed at 6 weekly intervals throughout the study.. A total of 134 patients participated. Following randomization patients who continued on donepezil 10 mg for 12 weeks had improvements in NPI compared with the placebo group (mean change -2.9 vs 3.3 points; ITT-LOCF p = 0.02) and in NPI-Distress scores (median change -2.0 vs 1.0 points; ITT-LOCF p = 0.01). During the open-label phase the total NPI and NPI-Distress scores were lower after 12 weeks treatment with open label donepezil compared with baseline (total NPI 22 points vs13 points; ITT-LOCF p < 0.0001; NPI-Distress 13.5 vs 7.9 points; ITT-LOCF p < 0.0001). In the open-label phase all domains of the NPI (with the exception of elation) were improved (all p < 0.05 after Bonferroni correction).. Donepezil has significant efficacy in the treatment of neuropsychiatric symptoms in patients with mild to moderate AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Nootropic Agents; Patient Dropouts; Piperidines; Severity of Illness Index; Treatment Outcome; Withholding Treatment

To assess the impact of donepezil treatment compared with placebo on caregiver time spent assisting patients with Alzheimer's disease (AD).. Patient and caregiver data were collected as part of a 1-year, prospective, double-blind, randomized, placebo-controlled trial. The Resource Utilization in Dementia (RUD) questionnaire was used to record caregiver time at study baseline and at Weeks 12, 24, 36, and 52. This analysis focuses solely on those caregivers who were actively (> 0 h/day reported on the RUD) providing care at study baseline.. The change in time relative to baseline that caregivers spent assisting patients over the course of the study.. The active caregiver population was composed of 96 caregivers of donepezil-treated patients and 94 caregivers of patients receiving placebo. Over the course of the 1-year study, and as the condition of the AD patients deteriorated, it was expected that caregiver time would increase. As expected, after 52 weeks, caregivers of placebo patients were providing almost 2 h each day (106.8 min) more care than they had done at study baseline. For those caregivers of donepezil-treated patients, although they were spending more time caring than they had done at study baseline, their time burden had only increased by 42.6 min more each day. This difference in caring time between the 2 groups, relative to baseline at Week 52, was 1.1 h (64.2 min) each day, and was significant (p = 0.03).. Caregiver time devoted to helping an AD patient typically increases with the severity of the disease. By helping the patient maintain his/her ability to perform activities of daily living for longer, treatment with donepezil is not only beneficial to the patient, but also has positive time-burden implications for the caregiver.

Topics: Activities of Daily Living; Alzheimer Disease; Caregivers; Donepezil; Home Nursing; Humans; Indans; Nootropic Agents; Piperidines; Time Factors

To investigate the costs to society of Alzheimer disease (AD) care in a multinational, randomized, placebo-controlled trial of donepezil in patients with moderate to severe AD.. A total of 290 patients with AD (screening standardized Mini-Mental State Examination score 5 to 17) were randomized to receive either donepezil (n = 144; 5 mg/day for 28 days, followed by 10 mg/day as per clinician's judgment) or placebo (n = 146) for 24 weeks. The authors collected data on patient and caregiver health resource utilization prospectively using the Canadian Utilization of Services Tracking questionnaire. Costs were calculated for patients and caregivers in each group based on resource utilization multiplied by the unit prices for each resource. A cost (the average Ontario minimum wage for 1998 [Can 6.85 dollars per hour]) was assigned to unpaid time that caregivers spent assisting the patient with activities of daily living (ADL).. Patient and caregiver demographics at baseline were similar across the two groups. After adjusting for baseline total cost per patient, the mean total societal cost per patient for the 24-week period was donepezil, Can 9,904 dollars (US 6,686 dollars) and placebo, Can 10,236 dollars (US 6,910 dollars). This net cost saving of Can 332 dollars (US 224 dollars) included the average 24-week cost of donepezil treatment. Most of the cost-saving with donepezil treatment was due to less use of residential care by patients, and caregivers spending less time assisting patients with ADL.. This cost-consequence analysis reveals economic benefits of treatment of moderate to severe AD with donepezil.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Ambulatory Care; Australia; Canada; Caregivers; Cholinesterase Inhibitors; Cost of Illness; Cost-Benefit Analysis; Counseling; Donepezil; Drug Costs; Female; France; Health Resources; Home Care Services; Home Nursing; Hospitalization; Humans; Indans; Institutionalization; Male; Middle Aged; Nootropic Agents; Nursing Homes; Piperidines; Prospective Studies; Surveys and Questionnaires

Donepezil is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). Since behavioral symptoms severely affect quality of life for AD patients and their caregivers, predicting behavioral responses to donepezil will be useful in managing patients with AD. In this study, we analyzed 70 consecutive cases with mild to moderate AD. Caregivers were interviewed with the Neuropsychiatric Inventory for behavioral assessment and 4-point improvement at week 12 was accepted as a treatment response. Twenty-one (30.0%) patients showed a behavioral response, while 42 (60.0%) showed no behavioral change and 7 (10.0%) worsened. Dysphoria, anxiety and apathy significantly improved after treatment among the responder group. The baseline profile including age, sex, Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Geriatric Depression Scale did not differ significantly among the three groups. Statistical Parametric Mapping analysis of single photon emission computed tomography (SPECT) images at baseline showed that cerebral blood flow in the premotor and parietotemporal cortices was significantly higher in the responder group than in the worse group. The present study suggested usefulness of SPECT imaging in the prediction of behavioral response to donepezil among AD patients even with similar psychiatric symptoms and cognitive functions.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Mapping; Caregivers; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Mental Status Schedule; Neuropsychological Tests; Piperidines; Predictive Value of Tests; Regional Blood Flow; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

We analysed the effects of donepezil, rivastigmine and galantamine, prescribed for the treatment of Alzheimer disease in a real-world setting in Italy.. Outcome measures included the MiniMental State Examination (MMSE), the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog), Instrumental Activity of Daily Living (IADL) and ADL scales.. Seventy patients were treated with donepezil, 121 with rivastigmine and 51 with galantamine. At 6 months, rivastigmine-treated patients improved by 1.29 points from baseline on the ADAS-cog, while donepezil- and galantamine-treated patients showed 'no change' (changes of < 0.2 points). On the IADL, patients treated with rivastigmine, donepezil and galantamine showed decreases of 0.42, 0.58 and 0.75 points, respectively. On the ADL, donepezil- and galantamine-treated patients showed decreases of 0.44 and 0.86 points, respectively, while there was 'no change' with rivastigmine. On the MMSE, donepezil- and rivastigmine-treated patients showed 'no change' and galantamine-treated patients showed a mean decrease of 1.19 points. A subgroup analysis of 'pseudo-randomised' patients (rivastigmine, n = 63; donepezil, n = 55; galantamine, n = 51) supported the main findings. Side effects were similar (in type and frequency) in the three treatment groups.. This is the first study to compare the effects of the three most commonly-used cholinesterase inhibitors on the MMSE, ADAS-cog, IADL and ADL. Limitations included its small population size, its open-label design, and the fact that patients were randomised only after the introduction of galantamine. There were no statistically significant differences between the three drugs at 3 months. While numerical trends were observed suggesting the effect of rivastigmine > donepezil > galantamine, larger, longer-term prospective studies are needed to confirm whether there are important differences in the long-term efficacy of the three drugs.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Humans; Indans; Male; Mental Status Schedule; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

To evaluate the efficacy of donepezil in patients with early-stage Alzheimer disease.. Multicenter, randomized, double-blind, 24-week, placebo-controlled study that enrolled patients with early-stage Alzheimer disease. Patients were randomized in an approximately 2:1 ratio to donepezil, 5 mg/d, for the first 6 weeks, with a forced escalation to 10 mg/d thereafter (n = 96), or placebo (n = 57). The primary efficacy measure was the modified Alzheimer Disease Assessment Scale-cognitive subscale. Secondary efficacy measures included the Mini-Mental State Examination, the Computerized Memory Battery Test, the Clinical Dementia Rating Scale-Sum of the Boxes, the Patient Global Assessment Scale, and the Apathy Scale.. Improvements favoring donepezil on the Alzheimer Disease Assessment Scale-cognitive subscale were found at weeks 12 and 24 and at the end point (last observation carried forward); treatment differences were 1.9 (P = .03), 2.3 (P = .008), and 2.3 (P = .001) points, respectively. Improvements favoring donepezil on the Mini-Mental State Examination were found at weeks 6, 12, and 24 and at the end point (last observation carried forward); treatment differences were 1.4 (P = .02), 1.2 (P = .04), 1.4 (P = .03), and 1.8 (P = .002) points, respectively. Donepezil-treated patients showed greater mean improvement compared with placebo-treated patients on the following Computerized Memory Battery Test subscales: facial recognition (P = .007 in the intent-to-treat population and P = .04 in the fully evaluable population), first and last name total acquisition (P = .02), and name-face association delayed recall (P = .04). Donepezil was safe and well tolerated in this population; serious adverse events occurred in similar numbers of donepezil- and placebo-treated patients.. These data suggest significant treatment benefits of donepezil in early-stage Alzheimer disease, supporting the initiation of therapy early in the disease course to improve daily cognitive functioning.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Chi-Square Distribution; Donepezil; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Indans; Male; Middle Aged; Piperidines

The aim of this study was to observe the effects of donepezil on both the cognitive function and sleep patterns in patients of Alzheimer's Type Dementia (ATD), especially to determine the relationship between the improvement of cognitive function and the amount of rapid eye movement (REM) sleep. A total of 12 patients (7 females, 5 males; age, 73.0 +/- 6.8) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria of probable AD were studied. These patients presented with mild to moderate dementia, which was confirmed by a Clinical Dementia Rating score of 1 or 2. Following baseline examinations consisting of the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and polysomnography (PSG), 5 mg of donepezil was administered to the patients at breakfast every day. All patients were reassessed 6 weeks later using the same examinations. With sleep patterns, the percentage of REM sleep to total sleep time increased after the administration of donepezil. In addition, it was also found that sleep efficiency was increased and sleep latency was shortened by this administration. Although the ADAS-Jcog score did not decrease significantly, there was significant positive correlation between the decrease of the ADAS-Jcog score and the increase in the percentage of REM sleep. These results indicate the increase action of REM sleep due to activate central cholinergic systems and the possibility to improve sleep conditions due to one-time administration after breakfast of donepezil in mild to moderate ATD. It is concluded that the increase in REM sleep may reflect the improvement of cognitive function in ATD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Polysomnography; Psychiatric Status Rating Scales; Sleep; Sleep Wake Disorders; Sleep, REM

This randomized study evaluated the combined effect of a cognitive-communication program plus an acetylcholinesterase inhibitor (donepezil; donepezil-plus-stimulation group; n = 26), as compared with donepezil alone (donepezil-only group; n = 28) in 54 patients with mild to moderate Alzheimer's disease (AD; Mini-Mental Status Examination score of 12- 28) ranging in age from 54 to 91 years. It was hypothesized that cognitive-communication stimulation in combination with donepezil would positively affect the following: (a) relevance of discourse, (b) performance of functional abilities, (c) emotional symptoms, (d) quality of life, and (e) overall global function, as measured by caregiver and participant report and standardized measures. Cognitive-communication, neuropsychiatric, functional performance, and quality of life evaluations were conducted at baseline and Month 4, the month after the 2-month active stimulation period. Follow-up evaluations were performed at Months 8 and 12. The stimulation program consisted of 12 hr of intervention over an 8-week period and involved participant-led discussions requiring homework, interactive sessions about AD, and discussions using salient life stories. Additive effects of active stimulation with donepezil were examined in 2 ways: (1) comparing mean group performance over time and (2) evaluating change scores from baseline. A Group x Time interaction was found for the donepezil-plus-stimulation group in the emotional symptoms of apathy and irritability as compared with the donepezil-only group. Evaluation of change scores from baseline to 12 months revealed a positive effect for the donepezil-plus-stimulation group on discourse and functional abilities with a trend on apathy, irritability, and patient-reported quality of life. In sum, the research revealed benefits to the donepezil-plus-stimulation group in the areas of discourse abilities, functional abilities, emotional symptoms, and overall global performance. This study adds to growing evidence that active cognitive stimulation may slow the rate of verbal and functional decline and decrease negative emotional symptoms in AD when combined with acetylcholinesterase inhibitors, indicating a need to advance research in the area of cognitive treatments. The fact that AD is a progressive brain disease should not preclude ameliorative treatment.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Behavior; Cholinesterase Inhibitors; Cognition; Cognitive Behavioral Therapy; Combined Modality Therapy; Communication; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Quality of Life; Treatment Outcome

To investigate whether variations within normal ranges of thyroid functioning are related to cognitive and neuropsychiatric functioning in Alzheimer disease (AD).. Mild alterations of thyroid hormone levels, even in the normal range, are associated with changes in mood and cognitive functioning in older, nondemented adults, and lower concentrations of thyroid hormones have been shown to be associated with an increased risk for cognitive decline. Less is known about the relationship between thyroid hormone levels and cognitive and neuropsychiatric dysfunction in AD.. Twenty-eight euthyroid patients with AD on donepezil underwent evaluation of thyroid status, including measures of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and cognitive and neuropsychiatric assessment with the Alzheimer's Disease Assessment Scale, Neuropsychiatric Inventory, and Visual Analog Mood Scales.. Correlational analyses indicated statistically significant associations between FT4 concentrations and self-reported feelings of fear and fatigue. Fear and fatigue were negatively correlated with FT4. There were no significant relationships between thyroid hormones and cognition and other depressive and anxiety symptoms.. Results of this preliminary study support a relationship between thyroid status and neuropsychiatric symptoms in euthyroid individuals with AD, with lower concentrations of FT4 associated with fear and fatigue.

Topics: Affective Symptoms; Aged; Alzheimer Disease; Cognition Disorders; Cross-Sectional Studies; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Statistics, Nonparametric; Thyroid Function Tests; Thyrotropin; Thyroxine

To evaluate the efficacy of a cognitive-motor program in patients with early Alzheimer disease (AD) who are treated with a cholinesterase inhibitor (ChEI).. Patients with mild cognitive impairment (MCI) (12), mild AD (48), and moderate AD (24) (Global Deterioration Scale stages 3, 4, and 5) were randomized to receive psychosocial support plus cognitive-motor intervention (experimental group) or psychosocial support alone (control group). Cognitive-motor intervention (CMI) consisted of a 1-year structured program of 103 sessions of cognitive exercises, plus social and psychomotor activities. The primary efficacy measure was the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary efficacy measures were the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Geriatric Depression Scale. Evaluations were conducted at 1, 3, 6, and 12 months by blinded evaluators.. Patients in the CMI group maintained cognitive status at month 6, whereas patients in the control group had significantly declined at that time. Cognitive response was higher in the patients with fewer years of formal education. In addition, more patients in the experimental group maintained or improved their affective status at month 12 (experimental group, 75%; control group, 47%; p = 0.017).. A long-term CMI in ChEI-treated early Alzheimer disease patients produced additional mood and cognitive benefits.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Patient Satisfaction; Patients; Phenylcarbamates; Physical Therapy Modalities; Piperidines; Psychomotor Disorders; Rivastigmine; Single-Blind Method; Treatment Outcome

The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer's disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician's judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK -43,959 (USD -5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Topics: Aged; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cost of Illness; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Severity of Illness Index; Treatment Outcome

Brain acetylcholinesterase activity was determined in healthy controls and in patients with mild cognitive impairment and early Alzheimer's disease.. A specific acetylcholinesterase tracer, [methyl-(11)C]N-methyl-piperidyl-4-acetate ([(11)C]MP4A), and a three dimensional PET system with magnetic resonance coregistration were used for imaging.. There was a significant difference in the acetylcholinesterase activity in the hippocampus between the groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k(3) values, min(-1)) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment, and 0.085 (0.022) in Alzheimer's disease. The mini-mental state examination score showed no significant relation with acetylcholinesterase activity in any brain area in the combined mild cognitive impairment/Alzheimer group.. Hippocampal acetylcholinesterase activity is only slightly reduced in mild cognitive impairment and early Alzheimer's disease and so the value of in vivo acetylcholinesterase measurements in detecting the early Alzheimer process is limited.

Topics: Acetates; Acetylcholinesterase; Aged; Alzheimer Disease; Analysis of Variance; Brain; Carbon Radioisotopes; Cognition Disorders; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Male; Middle Aged; Neuropsychological Tests; Piperidines; Predictive Value of Tests; Reference Values; Tomography, Emission-Computed

An acetylcholine deficit remains the most consistent neurotransmitter abnormality found in Alzheimer's disease and various therapeutic agents have been targeted at this. In this study we investigated the action of Donepezil, a cholinesterase inhibitor that has few side-effects. In particular we set out to investigate whether muscarinic acetylcholine receptor (mAChR) availability influences the response to this therapy. We used the novel single-photon emission tomography (SPET) tracer (R, R)[(123)I]I-quinuclidinyl benzilate (R, R[(123)I]I-QNB), which has high affinity for the M1 subtype of mAChR. Regional cerebral perfusion was also assessed using technetium-99m hexamethylpropylene amine oxime. We investigated 20 patients on Donepezil treatment and ten age-matched controls. The results showed a reduction in (R, R)[(123)I]I-QNB binding in the caudal anterior cingulate in patients compared with controls and relatively high binding in the putamen and rostral anterior cingulate, suggesting a relative sparing of mAChR in these regions. The main finding of the study was that mAChR availability as assessed by (R, R)[(123)I]I-QNB binding did not distinguish responders from non-responders. Interestingly, we found that the extent of cognitive improvement showed no positive correlation with (R, R)[(123)I]I-QNB binding in any brain region but was inversely related to binding in the insular cortex. This suggests that, within the advised cognitive performance band for use of Donepezil, response is greater in those patients with evidence of a more marked cholinergic deficit. A larger study should investigate this.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Quinuclidinyl Benzilate; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Muscarinic M1; Receptors, Muscarinic; Reproducibility of Results; Sensitivity and Specificity; Statistics as Topic; Technetium Tc 99m Exametazime; Tissue Distribution; Treatment Outcome

We attempted to identify the characteristic patterns in regional cerebral blood flow (rCBF) of patients with Alzheimer's disease who responded to donepezil therapy. Sixty-one patients treated with donepezil were divided into two groups (responders and nonresponders) on the basis of changes in their Mini Mental State Examination (MMSE) scores from baseline to study endpoint. We analyzed single-photon emission computed tomography data (SPECT) at baseline using three-dimensional stereotactic surface projections and compared differences in rCBF between the two groups. Statistical maps showed a significantly lower rCBF of the lateral and medial frontal lobes in the nonresponders than in the responders. There was a significant inverse correlation between the relative rCBF reduction in the frontal lobe and the MMSE change. These results suggest that frontal function, as assessed by SPECT, affects the patient's response to treatment with donepezil. Measuring rCBF may aid in the selection of possible treatment responders.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Topics: Alzheimer Disease; Biomechanical Phenomena; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Hand; Handwriting; Humans; Indans; Male; Motor Activity; Piperidines

This phase III trial was conducted to evaluate the safety and efficacy of donepezil in Alzheimer's disease (AD) patients with a greater range of comorbid conditions and concomitant medication use than those previously evaluated in placebo-controlled studies. Patients (n = 1,035) with mild to moderate probable or possible AD were enrolled from 255 sites in the USA; 894 (86%) completed the trial. Mean age was 74.9 years (+/- 7.8); baseline standardized Mini-Mental State Examination (sMMSE) score was 19.77 (+/- 5.4). Nearly all patients had at least 1 prior or comorbid medical condition (97%) or were taking at least 1 concomitant medication (93%). Safety assessments included recording treatment-emergent adverse events (AEs). To confirm comparability with past studies, efficacy was measured using the sMMSE. Over the 12-week study period, the mean sMMSE score increased by 1.54 points over baseline (p < 0.0001) in donepezil-treated patients. Most AEs (64%) were mild, and the occurrence of cholinergic-induced AEs was significantly lower after a dose increase at 4 weeks than that seen with a dose increase after 1 week in previous trials. Risk ratios for gastrointestinal side effects were not significantly increased by the use of aspirin or nonsteroidal anti-inflammatory drugs. Risk ratios for bradycardia were not significantly increased by the use of beta-blockers, nondihydropyridine calcium channel blockers or digoxin. Therefore, donepezil improved cognition, as measured by the sMMSE, and was well tolerated despite high concomitant medication use and extensive comorbidity. These results highlight donepezil as a safe and effective treatment for AD patients typically seen by community-based physicians.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Aspirin; Cholinesterase Inhibitors; Comorbidity; Donepezil; Female; Gastrointestinal Diseases; Humans; Indans; Male; Middle Aged; Piperidines; Risk Assessment; Vitamins

This study investigated the efficacy of donepezil treatment on activities of daily living (ADLs) and social functioning in patients with moderate to severe Alzheimer's disease (AD) and the possible benefits of this treatment on caregiving time and stress levels.. Randomized, double-blind, placebo-controlled, multinational study.. Patients resided in the community or in assisted living facilities who did not require skilled 24-hour nursing care.. Two hundred ninety patients with moderate to severe AD (baseline standardized Mini-Mental State Examination score of 5-17).. Donepezil (5 mg/d for 4 weeks and 10 mg/d per clinician's judgment thereafter) or placebo for 24 weeks.. ADLs were assessed using the Disability Assessment for Dementia (DAD), the modified instrumental activities of daily living (IADL) scale (IADL+), and the modified Physical Self Maintenance Scale (PSMS+). Caregiver time spent assisting patients with basic and instrumental ADLs was recorded as part of the IADL+ and PSMS+ scales. Patients' social behavior was evaluated through the use of a caregiver diary that captured observations of patients' motivation, interactions, and engagement. Caregivers were evaluated for their levels of caregiver stress with a modified, multiple-item Caregiver Stress Scale (CSS). For each outcome measure, the mean change from baseline at Week 24 using a last observation carried forward (LOCF) analysis was calculated.. IADL+ and PSMS+ mean change from baseline scores for donepezil-treated patients showed a slower decline during the study than placebo-treated patients (Week 24 LOCF mean treatment differences: IADL+ = 6.83, P <.0001; PSMS+ = 1.32, P =.0015). Significant differences between the groups in favor of donepezil were observed on the DAD for instrumental and basic ADLs and on the three components required for the completion of each ADL: initiation, planning and organization, and effective performance. At baseline, caregivers of patients treated with donepezil (n = 141) did not differ significantly from caregivers of patients treated with placebo (n = 146) with respect to demographics or mean total scores on the CSS. At Week 24 LOCF, the overall distribution of caregiver ratings on each of the three caregiver diary items favored donepezil-treated patients over placebo-treated patients (P <.005). At Week 24 LOCF, mean change from baseline scores for CSS total and individual domain scores (all domains except caregiving competence, personal gain, and management of distress) were better for caregivers of donepezil-treated patients than for those of placebo-treated patients (CSS total, mean treatment difference = 1.82). Caregivers of donepezil-treated patients reported spending less time assisting with ADLs than caregivers of placebo-treated patients (mean difference = 52.4 min/d).. Donepezil demonstrated a significantly slower decline than placebo in instrumental and basic ADLs in these patients with moderate to severe AD. The ADL benefits in AD patients treated with donepezil were associated with less caregiving time and lower levels of caregiver stress.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cost of Illness; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Social Behavior; Stress, Physiological; Time Factors; Treatment Outcome

The clinical, genetic or biological variables which regulate long-term efficacy of cholinesterase inhibitors (ChEIs) in Alzheimer disease (AD) are still unknown and it is not possible to predict who will benefit from the treatment. In this study we showed that high cholesterol levels correlated with faster decline at 1-year follow-up in AD patients on ChEIs. These findings suggest that serum cholesterol is a modulating factor of treatment response and additional therapies aimed at reducing treatable high cholesterol levels may represent an alternative strategy to improve ChEIs efficacy and slow down disease progression over time.

Topics: Aged; Alzheimer Disease; Apolipoproteins E; Carbamates; Cholesterol; Cholinesterase Inhibitors; Disease Progression; Donepezil; Female; Genotype; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Down Syndrome; Humans; Indans; Long-Term Care; Middle Aged; Neuropsychological Tests; Piperidines

To assess the relationship between donepezil treatment and time to nursing home placement (NHP) for patients with Alzheimer's disease (AD).. Observational follow-up of patient NHP and vital status.. Community.. Patients previously enrolled in one of three randomized, double-blind, placebo-controlled clinical trials of donepezil and two subsequent open-label studies (total N = 1,115); 671 patients provided complete data for analysis.. Data were obtained through follow-up interviews with caregivers and chart reviews of patients with AD. Comparison groups were defined by whether patients received an effective dose of donepezil (>/=5 mg/d; >/=80% compliance) for specific numbers of weeks during the double-blind or open-label trial phase, in both phases, or in neither. Cox proportional hazards models were used to estimate risk ratios for NHP and survival curves from which median times to NHP were estimated for first dementia-related placement of longer than 2 weeks and permanent placement. The models were adjusted for age, sex, baseline Mini-Mental State Examination score, whether the caregiver was a spouse, caregiver continuity, and use of other cholinesterase inhibitors after the clinical trials.. Use of donepezil of 5 mg/d or more was associated with significant delays in NHP. A cumulative dose-response relationship was observed between longer-term sustained donepezil use and delay of NHP. When donepezil was taken at an effective dose for at least 9 to 12 months, conservative estimates of the time gained before NHP were 21.4 months for first dementia-related NHP and 17.5 months for permanent NHP.. Use of donepezil by AD patients resulted in significant delays in NHP. Long-term use of donepezil may help AD patients live longer in community settings, with consequent personal, social, and economic benefits.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Indans; Institutionalization; Male; Nursing Homes; Piperidines; Severity of Illness Index; Time Factors

Acetyl-L-carnitine (ALC) is a compound acting as an intracellular carrier of acetyl groups across inner mitochondrial membranes. It also appears to have neuroprotective properties and it has recently been shown to reduce attention deficits in patients with Alzheimer's disease (AD) after long-term treatment. We performed an open study to evaluate the effect of ALC (2 g/day orally for 3 months) in association with donepezil or rivastigmine in 23 patients with mild AD who had not responded to treatment with acetylcholinesterase inhibitors (AChE-I). Clinical effects were evaluated by assessing cognitive functions, functional status and behavioural symptoms. The response rate, which was 38% after AChE-I treatment, increased to 50% after the addition of ALC, indicating that the combination of these two drugs may be a useful therapeutic option in AD patients. These data do not permit a conclusion as to the possible mechanism of action of the association of the two treatments.

Topics: Acetylcarnitine; Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Nootropic Agents; Phenylcarbamates; Pilot Projects; Piperidines; Rivastigmine

To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease.. This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks.. The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed.. BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments. Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.. Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

Topics: Aged; Alzheimer Disease; Cognition; Donepezil; Drug Administration Schedule; Female; Galantamine; Humans; Indans; Male; Mental Status Schedule; Piperidines; Time; Treatment Outcome

The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease.. In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale.. At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24.. These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Topics: Aged; Alzheimer Disease; Aspartic Acid; Biomarkers; Brain Chemistry; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Hippocampus; Humans; Indans; Inositol; Magnetic Resonance Spectroscopy; Male; Neurons; Piperidines; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

To determine the effects of cholinergic treatment on the muscarinic receptor in patients with Alzheimer's disease.. 12 patients with mild to moderate Alzheimer's disease and six controls were studied. The patients underwent ADAS-COG psychometric assessment and SPECT brain imaging with (123)I quinuclidinyl benzilate (QNB), to demonstrate the postsynaptic muscarinic M1 receptor, before being randomised in a double blind study to receive either an acetylcholinesterase inhibitor (donepezil) or placebo for four months. Following this, the ADAS-COG and the (123)I-QNB receptor scan were repeated. The controls were imaged on one occasion only. All image analyses were undertaken using SPM99.. (123)I-QNB imaging showed a significant relation between baseline psychometric impairment and deficits on scanning. Both placebo and actively treated groups had reductions in (123)I-QNB uptake. Greater reductions in receptor binding were demonstrated in the placebo group than in those receiving active treatment. Intraindividual reproducibility of the (123)I-QNB imaging technique appeared highly robust.. The results suggest that (123)I-QNB uptake is better preserved in Alzheimer's disease patients on cholinergic treatment than on placebo. Cholinergic treatment may play a neuroprotective role. Sequential (123)I-QNB imaging seems to be a powerful tool in monitoring the response of these receptors to disease modifying treatments.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Iodine Radioisotopes; Male; Middle Aged; Muscarinic Antagonists; Piperidines; Placebos; Psychometrics; Quinuclidinyl Benzilate; Sensitivity and Specificity; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Acetylcholinesterase inhibitor treatment enhances cholinergic neurotransmission and may thus partially reverse EEG slowing and memory impairment in Alzheimer patients within short time.. We studied the short-term effects of treatment with either rivastigmine or donepezil on EEG and memory performance in a group of 35 Alzheimer patients in an open, controlled design.. Under a 1- or 2-week acetylcholinesterase inhibitor treatment, a decrease of global theta power and an improvement in the ADAS memory score were observed. However, compared to the control condition, only the theta power decrease remained significant and can be definitely considered a medication effect.. EEG spectral analysis could be shown to rapidly reflect the cerebral cholinergic action of short-term acetylcholinesterase inhibitor treatment. Whether this action is related to the therapeutic efficacy of this type of drug must be determined in further longitudinal studies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Female; Humans; Indans; Male; Memory; Memory Disorders; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Theta Rhythm; Time Factors; Treatment Outcome

There are difficulties in accurately defining patients with vascular dementia (VaD) and, therefore, little is known about the characteristics of this population.. To examine the population characteristics in patients with VaD enrolled in two randomized, double-blind, placebo-controlled, 24-week clinical trials of the efficacy and tolerability of the acetylcholinesterase inhibitor donepezil.. Enrolled patients had probable or possible VaD, classified according to NINDS-AIREN criteria. Patients were excluded if they had a diagnosis of Alzheimer's disease or dementia caused by other conditions not associated with the cardiovascular system.. A total of 1,219 patients, 73% with probable VaD and 27% with possible VaD, were enrolled. Patients had a mean Hachinski score of 9.7, with memory impairment the most prominent feature of their dementia. Sixty-eight percent of patients had a history of at least one stroke and 28% of patients had a history of transient ischemic attack before dementia. In the 99% of patients who had abnormal computer-assisted tomography or magnetic resonance imaging scans, cortical and subcortical infarcts were among the lesions observed, with significant white-matter lesions also present in some patients. Seventy-three percent of patients had experienced an abrupt onset of cognitive symptoms. Vascular risk factors were prominent and included hypertension (70%), smoking (62%), and hypercholesterolemia (39%).. The patients enrolled in these trials had probable or possible VaD; these patients exhibited a history of cerebrovascular disease and a broad range of comorbid cardiovascular conditions. The large number of patients enrolled will permit a thorough examination of the efficacy and tolerability of donepezil in VaD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Humans; Indans; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Population Surveillance; Psychometrics; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Individuals with Down syndrome who develop Alzheimer disease may show an improvement in cognitive functioning after treatment with acetylcholinesterase inhibitors.. To determine whether individuals with Down syndrome and Alzheimer disease will show improvement after institution of donepezil treatment.. A nonrandomized controlled trial using donepezil in a pilot study format.. Academic medical center.. Convenience sample of 6 treated patients with Down syndrome and 9 closely matched historical control subjects.. Oral administration of donepezil for a 5-month period.. The Down Syndrome Dementia Scale.. Significant improvement in dementia scores for the treated group during a 3- to 5-month period (P =.03).. Acetylcholinesterase inhibitors may be helpful in reversing the symptoms of dementia during early and middle stages of cognitive decline. These findings support the rationale for a more extensive study of the efficacy of acetylcholinesterase inhibitors in Down syndrome dementia.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

The recent introduction of acetylcholinesterase inhibitors (AChEIs) therapy for Alzheimer's Disease (AD) has led to the need to assess the brain's response to the therapy on an objective, neurophysiological basis. Brain perfusion single photon emission computed tomography (SPECT) was used in an open-label study to evaluate the effect of chronic Donepezil administration to a group of patients affected by mild to moderate AD, compared to a group of AD patients not receiving AChEIs and kept under observation for a similar period.. Twenty-five consecutive patients with probable AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria) (19 women, 6 men; mean age: 74.2+/-7.2; mean Mini-Mental State Examination score, MMSE: 19.8+/-3.5) underwent (t0) brain SPECT with 99mTc-hexamethylpropylene-amine-oxime by a brain-dedicated, high-resolution camera and were re-evaluated (t1) after 11+/-2.6 months of chronic Donepezil administration (5mg/day) (treated group). Thirteen AD patients (9 women, 4 men, mean age: 71.4+/-5.7, MMSE score: 20.6+/-3.5) were not treated with AChEIs and served as controls (untreated group). They were subjected to the same evaluation after 13+/-1.4 months as the treated group. Statistical parametric mapping (SPM) was employed to analyse SPECT findings.. The MMSE score declined significantly (P<0.01) from t0 to t1 both in untreated (from 20.6+/-3.5 to 17.8+/-4.4) and in treated (from 19.8+/-3.5 to 17.8+/-4.1) group. At t(0), the untreated group showed higher regional cerebral blood flow (rCBF) than the treated group in a frontal and a frontal-parietal region of the left hemisphere. Between t0 and t1, significant rCBF reduction was observed in the temporal lobe and occipital-temporal cortex of the left hemisphere in the untreated group, whereas no significant change was observed in the treated group. The rCBF of the two groups did not significantly differ at t1. By covariate SPM analysis between t0 and t1 in treated patients, MMSE score changes correlated significantly with rCBF changes in a large left frontal-temporal region.. Brain perfusion is preserved in AD patients undergoing chronic Donepezil therapy while it is reduced in untreated patients. SPECT is a promising tool with which to assess the impact of AChEI therapy on brain functioning of AD patients.

Topics: Aged; Alzheimer Disease; Brain; Brain Mapping; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Regional Blood Flow; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

The objective was to evaluate the effects of the apolipoprotein E (ApoE) genotype and gender on the response to donepezil treatment in Alzheimer's disease. ApoE genotyping was performed on 117 patients with mild to moderate Alzheimer's disease who were included in a 36-week open label trial of donepezil therapy. Of these 117 patients, who constituted the intent-to-treat population (ITT), 80 completed the trial, and constituted the evaluable population. Patients were treated blindly in relation to ApoE genotype. Outcome measures were Alzheimer's disease Assessment Scale-Cognitive Component (ADAS-Cog), the Mini Mental State Examination, Instrumental Activities of Daily Living, and the Caregiver-rated Clinical Global Impression of Change. ITT analysis did not reveal significant differences between the responses of epsilon 4- and epsilon 4+ carriers according to the ADAS-Cog (P = 0.28). No differences were found either between the responses of men and women (P = 0.81), and there was no significant interaction between genotype and gender (P = 0.09). Other outcome measures all exhibited similar patterns of change to those seen using the ADAS-Cog. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to donepezil in Alzheimer's disease patients.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Donepezil; Educational Status; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Predictive Value of Tests; Sex Characteristics

The correlates of dropout, efficacy, and adverse events in the treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (ChEI) are unclear. To investigate these issues, a 26-week prospective, randomized, open-labeled trial with donepezil or rivastigmine was undertaken. Sixty-four Korean patients with AD were recruited, and data on sociodemographic and clinical characteristics and several assessment scales were collected. Characteristics of available caregivers were also gathered. Information on adverse events and dropout was recorded. Thirty-five (55%) patients dropped out during treatment with ChEI, for reasons mainly related to financial burden of caregivers. Of the 29 patients who completed the 26-week trial, 16 (55%) were responsive to ChEI. Lower scores on the Clinical Dementia Rating and Blessed Dementia Scale at baseline were associated with the efficacy of ChEI. Of the total participants, 26 (41%) experienced adverse events, although these seemed to be mild and appeared to be associated with the psychological state of patients or coadministration of psychotropic drugs. In conclusion, ChEI seemed to be effective and well tolerated in the treatment of Korean patients with AD, but the use of this drug was limited mainly by the financial burden of caregivers.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Patient Dropouts; Phenylcarbamates; Piperidines; Prospective Studies; Rivastigmine

To understand the treatment goals of Alzheimer's disease (AD) patients, carers, and physicians; to estimate whether clinically important goals are met during treatment with donepezil; and to compare a measure of goal attainment with standard measures used to evaluate AD treatment.. In a 12 month phase IV trial, 108 patients with mild to moderate AD, their primary carers, and treating physicians set goals assigned to five domains, using Goal Attainment Scaling (GAS) as the primary outcome. Goal attainment was assessed quarterly. GAS scores were correlated with standard outcomes, including the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), and the Clinician's Interview-Based Impression of Change-Plus (CIBIC-plus).. Physicians set fewer goals (342, mean (SD) per patient=3 (1)) than patients/carers (855, mean=9 (3)), particularly in leisure (20% by physicians compared with 76% by patients/carers), and social interaction (24% versus 49%). Physicians observed statistically significant improvement in global goal attainment for six months, and patients/carers for nine months. Patients/carers described consistent goal attainment, whereas physicians observed variable effects, such as decline in cognition but improved social interaction and behaviour. Physician global GAS scores correlated highly with the CIBIC-plus at weeks 12 (r= -0.82) and 52 (r=-0.80), but not with the ADAS-cog (r=0.12 and r=-0.45, respectively). Patient/carer global GAS scores correlated moderately with the physician's CIBIC-plus (week 12 r=-0.51; week 52 r=-0.56), and nominally with the ADAS-cog.. Patients/carers and physicians differ in their expectations and impressions of treatment effects. Clinically important changes correlated only modestly with psychometric tests. Attainment of treatment goals does not accord with a simplistic model in which successful AD treatment means that all declines uniformly improve.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Goals; Humans; Indans; Interpersonal Relations; Male; Neuropsychological Tests; Piperidines; Professional-Patient Relations; Prospective Studies; Psychometrics; Severity of Illness Index

Donepezil, a selective acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). In a post-marketing surveillance (PMS) study in Germany, patients under routine treatment conditions were observed while treatment was switched from other antidementia drugs (i.e., nootropics) to donepezil. A total of 913 patients were enrolled (60.1% female, mean+/-S.D. age 73.4+/-8.6 years, mean Mini-Mental Status Examination [MMSE] 18.0+/-5.3), and were treated with donepezil (5 or 10 mg/day according to recommended dosing). 709/913 (77.1%) of patients had been pretreated with other antidementive drugs (piracetam, memantine, ginkgo, and others). In 29.6% of patients, investigators documented concomitant cerebrovascular disease (CVD+) according to their clinical judgment. Observation period was 3 months for the individual patient. Efficacy parameters were changes in MMSE, global clinical (investigators) judgment of efficacy, and a clinical judgment about the patients' quality of life (QoL). Adverse events were also analyzed. The objective of the present investigation was to compare-in a "real-life" setting-the differential efficacy and tolerability of donepezil in AD patients with and without concomitant cerebrovascular disease. After 3 months, patients had improved by a mean MMSE change from baseline of 2.2 points (CVD+: 2.4 pts, CVD-: 2.1 pts). QoL was judged "improved" in 70.0% of patients (CVD+: 72.5%, CVD-: 69.6%). Adverse events were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD-: 7.9%). Reported adverse events were substantially less than reported previously in controlled clinical trials. This suggests that donepezil therapy is effective and well tolerated in AD patients, both with and without concomitant cerebrovascular disease.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Disorders; Donepezil; Female; Germany; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quality of Life

To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial.. Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patents received either donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter according to the clinician's judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis.. Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48-92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = -4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = -9.25, p < 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly different from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups.. The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared wih placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Behavior; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Carbamates; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Frontal Lobe; Humans; Indans; Magnetic Resonance Imaging; Male; Parietal Lobe; Phenylcarbamates; Piperidines; Reproducibility of Results; Rivastigmine; Temporal Lobe; Tomography, Emission-Computed

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Donepezil; Enzyme-Linked Immunosorbent Assay; Galantamine; Humans; Indans; Peptide Fragments; Phenylcarbamates; Phosphorylation; Piperidines; Rivastigmine; tau Proteins

This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimer's disease (AD), and the effect of treatment with donepezil.. Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinician's judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI).. Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05).. Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.

Topics: Aged; Alzheimer Disease; Anxiety; Arousal; Depression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Nootropic Agents; Piperidines; Social Behavior Disorders; Treatment Outcome

Atrophy of the substantia innominata on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, may be an in vivo marker of cholinergic damage. We attempted to investigate whether the MRI features of the substantia innominata predict response to donepezil treatment in Alzheimer's patients. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. Seventy-two patients treated with donepezil were divided into the two groups (responders and non-responders) based on changes in Mini-Mental State Examination (MMSE) scores from baseline to study endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. There was a significant inverse correlation between thickness of the substantia innominata and MMSE changes. MRI analysis of the substantia innominata may be a simple and practical method for the selection of possible treatment responders.

Topics: Acetylcholine; Aged; Alzheimer Disease; Atrophy; Cholinergic Fibers; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neurons; Patient Selection; Piperidines; Predictive Value of Tests; Substantia Innominata; Treatment Outcome

Donepezil Hydrochloride (Aricept) is a selective anticholinesterase inhibitor developed for the treatment of Alzheimer's disease (AD). This study investigated the safety and efficacy of the drug to treat Down syndrome (DS) adults with mild to moderate AD.. This was a 24-week, double blind, placebo controlled, parallel-group trial. Patients were randomized to receive placebo or donepezil (5 mg per day during the first four weeks, and then 10 mg per day thereafter). Primary efficacy was measured using the Dementia Scale for Mentally Retarded Persons (DMR), and secondary efficacy was measured using the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI) and by the Adaptive Behavior Scale (ABS).. A total of 30 DS patients with AD entered the study of which 27 were included in the subsequent data analysis. The donepezil group had non-statistically significant reduction in deterioration in DMR, SIB, and ABS mean scores relative to the placebo group. However NPI scores showed less improvement in the donepezil group when compared to the placebo group. Fifty percent of subjects in the donepezil group showed improvement in mean DMR scores at the end point compared to baseline, when compared to 31% on placebo. There were no life threatening adverse effects associated with treating adults with DS with donepezil. A number of side-effects did occur including diarrhoea, insomnia, fatigue, and nausea.. Donepezil Hydrochloride administered once a day appears to be generally well tolerated and safe in DS adults who have AD. There is some possible efficacy in the treatment of symptoms of mild to moderate Alzheimer's disease in this population, although the sample size of this study was too small for statistical significance. It is recommended that donepezil, with the appropriate precautions, should be considered for the treatment of AD in adults with DS as deemed by a specialist.

Topics: Adult; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Comorbidity; Donepezil; Double-Blind Method; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Pilot Projects; Piperidines; Treatment Outcome

Donepezil is a cholinesterase inhibitor which has been previously shown to affect the cognitive evoked potentials (EPs) of patients with Alzheimer's Disease (AD) during treatment with the drug. The purpose of this study was to determine the effect of treatment with donepezil 5 mg daily for 1 month on quantitative EEG (QEEG) in patients with AD. Treatment was associated with no significant differences between the pre- and post-treatment QEEGs for (1) absolute power (all four frequency bands), (2) percent relative power (all four frequency bands), (3) total mean frequency, (4) mean frequency for theta and beta, (5) absolute power asymmetry across homologous electrode pairs (all four frequency bands), and (6) interhemispheric coherence across homologous electrode pairs (all four frequency bands). There were significant decreases in mean alpha and delta frequencies that were consistent across broad electrode arrays except for an increase in the delta frequency at T3. The implications of these changes are not yet clear. Studies of QEEG changes with higher doses of donepezil over longer periods of time may yield a better understanding of the neurophysiological effects of the medication.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Female; Humans; Indans; Male; Piperidines; Reproducibility of Results; Sensitivity and Specificity

Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is a specific, reversible inhibitor of AChE, while rivastigmine is a slowly reversible (pseudoirreversible) dual cholinesterase (ChE) inhibitor, with brain-regional specificity for the cerebral cortex and hippocampus. According to the European Marketing Authorisations, the clinical benefit of ChE inhibitors should be reassessed on a regular basis and discontinuation should be considered when evidence of a therapeutic effect is no longer present. However, substantial differences in the pharmacological and pharmacokinetic profiles of the available ChE inhibitors suggest that it may be desirable to switch between ChE inhibitors if patients fail to show efficacy, deteriorate or are unable to tolerate their initially prescribed medication.. This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons).. At the end of the study, 56.2% of patients were responders to rivastigmine, as assessed using a global function scale (the Clinicians' Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of patients, respectively. Rivastigmine was generally well tolerated, the most common adverse events being nausea and vomiting, consistent with reports from previous clinical studies. The occurrence of side-effects or lack of efficacy with donepezil treatment was not a predictor of similar problems when treated with rivastigmine.. Rivastigmine treatment appears to be beneficial in AD patients who have previously failed to benefit from, or were unable to tolerate treatment with, donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Prospective Studies; Rivastigmine; Severity of Illness Index; Treatment Failure; Treatment Outcome

The clinical significance and the effects of pharmacological treatment of patients with Alzheimer's disease (AD) were evaluated by measurement of acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF). CSF-AChE of AD patients was lower, not significantly, compared with controls. However, CSF-AChE was significantly increased after treatment of AD patients with AChE inhibitors (donepezil and galantamine). The increase was higher in patients treated with donezepil than in those treated with galantamine, which might be related to different mechanisms for the substances. The increase was also dose-dependent, and was especially marked in patients showing a clinical response. These data suggest that CSF biomarkers are capable not only of identifying a biochemical effect of drugs, but also of differentiating between different compounds in a dose-dependent manner.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Biomarkers; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Galantamine; Humans; Indans; Male; Middle Aged; Piperidines

Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function.. To investigate the long-term benefits of donepezil treatment in patients with AD.. Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout).. All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged.. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes.. After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events.. Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Treatment Outcome

Amyloid precursor protein (APP) forms with apparent molecular weights of 130, 110, and 106 kd are present in human platelets. It has been demonstrated that Alzheimer disease (AD) is specifically associated with a decreased APP forms ratio in platelets.. To investigate whether acetylcholinesterase (AChE) inhibitor treatment modifies the ratio of platelet APP forms in patients with AD.. From a large sample of patients with probable AD, 30 with mild to moderate AD were selected. Each patient underwent a clinical evaluation including the Mini-Mental State Examination (MMSE) and platelet APP forms analysis at baseline and after 30 days. During this interval, 20 of 30 patients with AD were treated with donepezil hydrochloride (5 mg/d), a piperidine phosphate-based cholinesterase inhibitor. Platelets were subjected to Western blot analysis using monoclonal antibody (22C11). The ratio between the immunoreactivity of the higher-molecular-weight APP form (130 kd) and the lower forms (106 and 110 kd) was measured.. All patients taking donepezil completed the 30 days of treatment without adverse effects. The platelet APP forms ratio at baseline did not differ between the 2 AD groups (mean +/- SD optical density ratio: untreated AD, 0.47 +/- 0.12; treated AD, 0.38 +/- 0.18), whereas a significant difference was found at follow-up (mean +/- SD optical density ratio: untreated AD, 0.45 +/- 0.17; treated AD, 0.77 +/- 0.29; P<.001). A significant improvement in MMSE scores in treated AD patients was observed from baseline (16.9 +/- 3.8) to 30 days (18.9 +/- 4.42) (P<.009, 30 days vs baseline), but no significant correlation was found in treated AD patients between MMSE score improvement and APP forms/ratio increase (P =.09).. Administration of AChE inhibitors increases the ratio of APP forms in platelets of patients with AD, suggesting a potential effect of AChE inhibitors on APP trafficking or processing in a peripheral cell.

Topics: Aged; Alzheimer Disease; Amyloid beta-Protein Precursor; Blood Platelets; Blotting, Western; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimer's disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 x [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis (P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.

Topics: Acetates; Acetylcholinesterase; Aged; Alzheimer Disease; Arteries; Blood Specimen Collection; Brain; Carbon Radioisotopes; Humans; Middle Aged; Monte Carlo Method; Piperidines; Tomography, Emission-Computed

To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period.. This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol.. Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test).. Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Time Factors

To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD.. Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year.. The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population.. As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Piperidines; Time Factors

To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score < or =6 at baseline).. Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician's judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+).. Patients' mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean +/- SE sMMSE scores at baseline were 11.7 +/- 0.35 for the donepezil group and 12.0 +/- 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups.. These data suggest that donepezil's benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Least-Squares Analysis; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

The aim of this SPECT study was to investigate the effects of donepezil on regional cerebral blood flow (rCBF) in patients with mild to moderate Alzheimer's disease (AD) using statistical parametric mapping.. rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer in 35 AD patients with a Mini-Mental State Examination score > 16 on initial evaluation. Baseline and follow-up SPECT studies with a mean interval of 12 mo were performed on these patients. We used the adjusted rCBF images in the relative flow distribution (normalization of global cerebral blood flow for each patient to 50 mL/100 g/min with proportional scaling) to compare these groups through statistical parametric mapping.. In the follow-up study, the adjusted rCBF was significantly preserved in the right and left anterior cingulate gyri, right middle temporal gyrus, right inferior parietal lobules, and prefrontal cortex of donepezil-treated AD patients, compared with placebo-treated AD patients.. Treatment with donepezil for 1 y appears to reduce the decline in rCBF, suggesting preservation of functional brain activity.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Humans; Image Processing, Computer-Assisted; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Tomography, Emission-Computed, Single-Photon

N -[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [(11)C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [(11)C]MP4A through AChE (k(3); an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k(3) with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k(3) values. The authors then applied these methods to [(11) C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k(3) estimates between RLS and NLS analyses (456 cerebral regions, [RLS k(3) ] = 0.98 x [NLS k(3) ], r = 0.92, P < 0.001). Significant reductions were observed in k(3) estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices (P < 0.001, single-tailed t-test), and hippocampus (P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) in these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k 3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [(11)C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [(11)C]MP4A studies.

Topics: Acetates; Acetylcholinesterase; Adult; Aged; Alzheimer Disease; Blood Specimen Collection; Brain; Carbon Radioisotopes; Computer Simulation; Humans; Kinetics; Least-Squares Analysis; Middle Aged; Models, Biological; Piperidines; Tomography, Emission-Computed

To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities.. Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial.. Twenty-seven nursing homes across the United States.. Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7.. The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs).. Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed.. Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nursing Homes; Outcome Assessment, Health Care; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index

To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice.. Two-center, randomized, placebo-controlled, double-masked crossover study.. Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston.. Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale.. Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks.. Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods.. Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each).. This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

Alzheimer's disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimer's disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimer's disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from -1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Donepezil; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Nootropic Agents; Piperidines; Radiopharmaceuticals; Retrospective Studies; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

This multicentre, open-label study evaluated the long-term efficacy and safety of donepezil in the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The 133 patients who entered the study had previously completed a 14-week randomized, double-blind, placebo-controlled study with donepezil. In this open-label study, patients were treated initially with 3 mg per day donepezil, which could be increased to 5, 7 and 10 mg per day in a step-wise fashion. Patients attended the clinic for assessments at 3-week intervals for the first 12 weeks, then subsequently at 12-week intervals for up to 240 weeks (254 cumulative weeks). Efficacy was assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), and data were compared with those predicted for historical untreated AD patients. During the first 6-9 months of the study, mean ADAS-cog and CDR-SB scores showed evidence of clinical improvement from baseline. After this time scores gradually deteriorated. Overall the decline was less than that estimated if this cohort of patients had not been treated. The most common adverse events were related to the nervous and digestive systems, and were generally mild and transient, resolving without the need for dose modifications. There was no evidence of hepatotoxicity. In conclusion, these data demonstrate that donepezil is a well-tolerated, realistic symptomatic treatment for AD over a period of up to 4.9 years. An interim report of the first 98 weeks of the study has been published previously.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; United States

This open-label study examined the effects of the reversible cholinesterase inhibitor donepezil on emotional/behavioral symptoms in Alzheimer's disease (AD) patients.. Patients were diagnosed as having probable/possible AD by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria. This study used the CERAD Behavior Rating Scale for Dementia (CBRSD) and its subscales to evaluate a group of 25 AD patients treated with donepezil. Dosage was increased at 4 months for most patients from 5 to 10 mg q.h.s. Analysis of variance was used to compare scores over a period of 12 months. These patients were also compared, using t tests, to a reference group that had received no donepezil or other anticholinesterase.. Donepezil administration was associated with improvement in Mini-Mental State Examination (MMSE) and CBRSD total scores at 3-month evaluation (p< or =.05). CBRSD depression and behavioral dysregulation scores improved transiently at 4 months (p< or =.05). MMSE, CBRSD total, CBRSD depression, and CBRSD behavioral dysregulation scores returned to baseline levels at 12 months, in contrast to the reference group, whose MMSE and CBRSD total scores worsened minimally over the 12 months.. Donepezil has a mildly positive effect on emotional/behavioral symptoms in AD in addition to its effect on cognitive function.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

The objective of this study was to assess the efficacy of donepezil in patients with mild to moderate Alzheimer's disease (AD) in clinical practice. This was an open-label study in which patients were referred to an elderly mental health clinic in Southampton, UK. Eighty patients with mild to moderate AD received 5 mg/day donepezil for the first 4 weeks, after which, if tolerated, the dose was increased to 10 mg/day. Efficacy and safety assessments were carried out every 3 months. Efficacy was assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-carer Distress Scale (NPI-D). Mean improvements from baseline were observed at the 3-month assessment on all four efficacy measures. At 3 months, 39% of patients showed an improvement of at least 4 points on the ADAS-cog, and 37% of patients had improved by 4 points or more on the NPI. In those patients who showed improvement and were maintained on donepezil, improvements were sustained for 18 months on the MMSE and NPI, 15 months on the NPI-D, and for 6 months on the ADAS-cog. Six per cent of patients discontinued medication due to adverse events. In a typical clinical practice setting, patients with mild to moderate AD tolerated donepezil well. Clinically meaningful improvements in cognitive function and a reduction in neuropsychiatric symptoms were demonstrated in nearly 40% of patients with associated reduction in carer distress. Continued benefit was seen for up to 18 months in the selected group of patients who initially responded in treatment.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Donepezil; Dose-Response Relationship, Drug; England; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electromyography; Female; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Motor Skills Disorders; Piperidines; Prospective Studies; Treatment Outcome

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Piperidines; Quality of Life; Treatment Outcome

Regulatory guidelines in the US and Europe generally require that a drug specifically indicated for treating Alzheimer's disease (AD) must demonstrate an effect upon the core manifestations of dementia. Progressive cognitive and functional losses are the cardinal features of AD. In the US, current guidelines require that new AD treatments show effectiveness on performance-based measures of cognition and on clinician-rated global assessments. Improvement in function is also emphasized in the European guidelines. The primary instruments that have been used to evaluate changes in cognition and global function in most recent AD trials are the cognitive subscale of the Alzheimer's Disease Assessment Scale and a version of the Clinician's Interview Based Impression of Change, respectively. The results from three pivotal trials investigating the acetylcholinesterase inhibitor, donepezil, are used to demonstrate the way in which these tools are used, how to interpret the data they provide, and to determine their overall value in ascertaining efficacy in clinical practice.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Guidelines as Topic; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Donepezil is a cholinesterase inhibitor used for the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The purpose of this study was to determine the effect of treatment with donepezil 5 mg qd on cognitive evoked potentials (EPs) of patients with AD. Although treatment with donepezil did not normalize EP latencies, treatment was associated with a significant decrease in the auditory P300 latency (mean latency pretreatment=401. 5 msec; posttreatment=392.7 msec.; P=0.04), and the visual P300 latency (mean latency pretreatment=605.7 msec; posttreatment=580.3 msec; P=0.04). Treatment with donepezil had no discernible effect on auditory or visual P300 EP amplitudes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Event-Related Potentials, P300; Evoked Potentials, Auditory; Evoked Potentials, Visual; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Refractory Period, Electrophysiological

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory; Mental Status Schedule; Piperidines

The long-term efficacy and safety of donepezil (up to 10 mg/day) was evaluated in a multicentre, non-randomised, open-label extension study of 133 patients with mild to moderate Alzheimer's disease (AD) who had completed a previous 14-week double-blind, placebo-controlled trial of donepezil. Assessments were conducted at three-weekly intervals for 12 weeks, then 12-weekly for up to 192 weeks. Efficacy, assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum of the Boxes (CDR-SB), was examined in comparison with published data of untreated AD patients. Safety was monitored by physical examinations, laboratory tests and vital sign measurements. Results of this interim analysis (at 98 weeks) show that donepezil produced improvements in cognition which remained superior to baseline for 38 weeks. CDR-SB likewise showed improvement, with scores maintained near baseline values for 26 weeks. Scores for both instruments then increased as expected in a progressive disease. However, the slope of score progression was less than has been historically reported for untreated patients. While the lack of a concurrent placebo group does not allow conclusions about the ability of donepezil to attenuate disease progression, the data, nonetheless, demonstrate that there is no loss of treatment benefit over 98 weeks. Donepezil was well tolerated, with no evidence of hepatotoxicity.

Topics: Adult; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Psychiatric Status Rating Scales; United States

Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease.. To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response.. This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus).. A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors.. Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Piperidines; Treatment Outcome; United States

Experience of the use of Donepezil (Aricept) in the UK since licensing is discussed. The results of a 30 week double blind parallel group study in the US of Donepezil 5 or 10 mg versus placebo show statistically significant improvements in cognitive and clinical global assessments. Beneficial effects were demonstrated in the absence of significant adverse effects on physical or laboratory values. The guidelines for use adopted in the UK are discussed with the emphasis on identifying non-cognitive behaviours, as significant improvements in these have been found and often have more impact on quality of life than cognitive improvements alone.

Topics: Alzheimer Disease; Clinical Protocols; Donepezil; Double-Blind Method; Humans; Indans; Licensure, Pharmacy; Nootropic Agents; Patient Selection; Piperidines; United Kingdom

The First International Pharmacoeconomic Conference on Alzheimer's Disease (AD) was held in Amsterdam in July 1998. The meeting was held under the auspices of the International Working Group for Harmonization of Dementia Drug Guidelines (http://dementia.ion.ucl.ac.uk/harmon), bringing together academics, clinicians, purchasers, and representatives from industry. Presentations were given on the methodology of pharmacoeconomic studies in AD, particularly focusing on caregiver burden, quality of life (QOL), and resource utilization. Three economic models of AD were presented based on data from the United States, Canada, and the United Kingdom. In two studies, these data were then used to model the cost-effectiveness and effect on cost of treatment with donepezil. Both studies suggested a possible cost advantage for the use of donepezil, when compared with no placebo or treatment, particularly when donepezil is used appropriately in mild-to-moderate AD. These data need to be interpreted with care, as none of the cost or utility information were collected during the clinical trials. Additional data from a 2-year clinical trial of selegiline and vitamin E suggest that cognitive measures may be poor predictors of economic outcome, which is better measured directly. Both economic models of donepezil rely on short-term cognitive data to predict long-term outcome, a methodf that may not be useful in predicting economic savings. The issues facing pharmacoeconomists, researchers, clinicians, and families in the future were addressed in a series of workshops using a method of strategic futuring. The workshops attempted to see 7 years into the future for a range of areas, including consumer and caregiver use of pharmacoeconomic data; early detection and prevention; Japanese perspectives; activities of daily life and what will be daily life activities; caregiver burden; QOL at the end of life; new uses for new information and communication technology in clinical research; and physicians' use of pharmacoeconomic data. A range of exciting futures were predicted, although common themes that arose when considering barriers to achieving these futures included cost, education, political will, confidentiality, privacy, and ethics. The first conference was deemed to have been a success, having attracted more than 160 delegates and many distinguished speaker. A second conference is planned for the year 2000. Over the next 2 years, research needs to be broadened particularly in t

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Humans; Indans; Middle Aged; Models, Economic; Neuroprotective Agents; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Selegiline

Sabeluzole, a new benzothiazole derivative, has been shown to be neurobiologically active preclinically and clinically appears to exert beneficial effects on memory. In this study, sabeluzole (5 or 10 mg twice daily vs. placebo) was investigated in patients with probable Alzheimer's disease over 1 year, with assessments of cognitive performance and structural changes. Cognitive performance was measured using the Alzheimer's Disease Assessment Scale periodically during treatment. Potential structural correlates in the frontal horn, caudate, third ventricle and hippocampal regions were examined by obtaining computerized tomographic (CT) images before and after treatment. Patients receiving sabeluzole evidenced greater stability than did placebo-treated patients in some cognitive measures. CT measures showed no significant changes from baseline, but some weak associations were found between relative preservation of cognitive function and smaller structural declines in the third ventricle and hippocampus. Cognitive outcome measures suggest that sabeluzole may have potential in slowing the cognitive deterioration of Alzheimer's disease. Furthermore, the method used to explore potential benefits on a morphologic level, although negative in this study, could yet have potential.

Topics: Aged; Alzheimer Disease; Brain; Cognition; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Thiazoles; Tomography, X-Ray Computed

To compare the reliability of instruments used in clinical trials involving cognitively impaired older adults when the instruments are administered in-home rather than in-clinic and to compare withdrawal rates is these two groups.. This study was part of a larger n-of-1 clinical trial to investigate the efficacy and safety of a MAO/A inhibitor (Brofaromine) in patients with Alzheimer's disease. Participants were initially assessed at the clinic (baseline) and then randomly allocated to in-home or in-clinic assessments for the remainder of the trial. The baseline and second assessment (performed before initiation of the treatment) were used for the reliability analysis. Withdrawal rates were examined over the course of the 6-month trial.. Assessments took place at a geriatric clinic in an urban university teaching hospital and at residences of some of the patients.. Forty-six Alzheimer's disease patients participated in the study, of which, 22 were randomized to in-home assessments and 24 to in-clinic assessments.. Test-retest reliability was measured for all five instruments used in the study and was based on the first two assessments. Sample size requirements, based on within-group variance, were calculated. Withdrawal rates were obtained for the total duration of the trial.. Test-retest reliability of the instruments, as determined by intraclass correlations, was good in both groups but favored in-clinic for all but one instrument (range: 0.47-0.90 for in-home vs 0.57-0.92 for in-clinic). Sample size requirements based on reliability assessment data were found to be larger for some instruments when administered in-home. Only four in-home patients withdrew before completion of the study, compared with eight in-clinic patients.. The results suggest the in-home assessments in cognitively impaired older adults may result in lower withdrawal rates but may necessitate larger sample sizes to offset larger test-retest variability.

Topics: Aged; Alzheimer Disease; Clinical Trials as Topic; Female; Geriatric Assessment; Home Care Services; Humans; Male; Monoamine Oxidase Inhibitors; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Reproducibility of Results; Selection Bias; Survival Analysis

E2020, a central-acting cholinesterase inhibitor, is now under clinical development as a potential therapeutic agent for senile dementia of Alzheimer type. In the current study, the authors compared the pharmacokinetics of this drug after single oral administration in 12 healthy young volunteers (20-27 years of age) and 6 elderly volunteers (65-82 years of age). The subjects received a single 2-mg oral dose of E2020 after a meal. Blood samples for determination of the drug level were collected over 168 hours after drug administration and were measured by specific high-pressure liquid chromatography methods with ultraviolet detection. E2020 was generally well tolerated by all subjects of both groups. The plasma elimination half-life of the beta-phase (t 1/2 beta) and time to maximum peak plasma concentration (tmax) were significantly longer in the elderly than in the young: t 1/2 beta, 103.8 +/- 40.6 versus 59.7 +/- 16.1 hours; and tmax, 5.2 +/- 2.8 versus 3.4 +/- 1.5 hours, respectively. There were no statistically significant differences in maximum peak plasma concentration and area under the curve between the two groups. The mean (+/- standard deviation) oral clearance (Cl/F) in the elderly (9.1 +/- 2.4 L/h) was similar to that in the young (10.6 +/- 2.7 L/h). The volume of distribution in the steady state (Vdss/F) was significantly larger in the elderly than that in the young: 1217.2 +/- 223.2 versus 852.5 +/- 147.7 L, respectively. These results suggested that the drug was absorbed more slowly and distributed more widely and thoroughly, but that its clearance from the body is essentially unaffected by age.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Aging; Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Female; Half-Life; Humans; Indans; Male; Metabolic Clearance Rate; Piperidines; Protein Binding

E2020 is a new cholinesterase inhibitor with a novel chemical structure, which is under clinical investigation for use in Alzheimer's disease in Japan and the USA. Three separate studies were conducted to evaluate the safety and to establish the pharmacokinetic profile of E2020 after oral administration to healthy male subjects. E2020 was administered as: (1) single oral doses (0.3 mg, 1 mg, 2 mg, 5 mg, 8 mg and 10 mg) in a fasting condition, (2) a single oral dose (2 mg) after a meal and (3) repeated oral doses (2 mg once daily for 21 days). The concentrations of E2020 and its metabolites in plasma, serum, urine and feces were determined by HPLC methods with UV detection. E2020 was generally well tolerated by all subjects. In the single-dose study, there was a linear relationship between dose and mean AUC. The mean plasma half-life was about 50 hours and was dose-independent. The total clearance and renal clearance of E2020 were also dose-independent and the mean values after 10 mg dosing were 9.7 l/hour and 0.86 l/hour, respectively. The cumulative total urinary and fecal excretion of the sum of unchanged E2020 and its metabolites at 264 hours after the administration of the single 10-mg-dose was 36.1% and 8.6% of the dose, respectively. The mean serum protein binding was 92.6%. No effect of food intake on the pharmacokinetics was observed. Evaluation of the mean trough levels and AUC0-24 of E2020 indicated that a steady-state was achieved after approximately 2 weeks of daily dosing.

Topics: Adult; Alzheimer Disease; Blood Proteins; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Food; Humans; Indans; Male; Piperidines; Protein Binding; Single-Blind Method; Spectrophotometry, Ultraviolet

Alzheimer's Disease (AD), the most common and major disability issue in our society, has a substantial economic impact. Despite substantial advances in aetiology, diagnosis, and therapy, the fundamental causes of the disease remain unknown, accurate biomarkers are not well characterized, and current pharmaceutical medications are not cost-effective. Effective care for Alzheimer's disease and other types of dementia is crucial for patients' long-term health. Pathogenesis advances have aroused the scientific community's interest in the creation of new pharmacological treatments that target recognized disease targets throughout the previous two decades. Pharmacological therapy has recently been assigned 10 - 20% of the direct costs of AD. Less than 20% of Alzheimer's patients respond somewhat to standard medicines with questionable cost-effectiveness (donepezil, galantamine, memantine and rivastigmine). Therefore, currently known treatment approaches address the condition indirectly, as acetyl cholinesterase related inhibitors and the Nmethyl d-aspartate as receptor and antagonists have little effect on the sickness. Novel targets and specific small molecules must also be found in order to be useful in the therapy of AD. This chapter examines a wide spectrum of Alzheimer's disease targets as well as contemporary progress in the discovery of disease inhibitors. In addition, brief in-silico investigations were highlighted and provided to understand how the theoretical lead in AD treatment development is attainable.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Drug Discovery; Humans; Indans; Phenylcarbamates; Piperidines

Curcumin (CUR) and piperine (PIP) are very well-known phytochemicals that claimed to have many health benefits and have been widely used in foods and traditional medicines. This study investigated the therapeutic efficacy of these compounds to treat Alzheimer's disease (AD). However, poor oral bioavailability and permeability of curcumin are a major challenge for formulation scientists. In this research study, the researcher tried to enhance the bioavailability and permeability of curcumin by a nanotechnological approach. In this research study, we developed a CUR-PIP-loaded SNEDDS in various oils. Optimised formulation NF3 was subjected to evaluate its therapeutic effectiveness on AD animal model in comparison with untreated AD model and treated group (by market formulation donepezil). On the basis of characterisation results, it is confirmed that NF3 formulation is the best formulation. The optimised formulation shows a significant dose-dependent manner therapeutic effect on AD-induced model. Novel formulation CUR-PIP solid-SNEDDS was successfully developed and optimised. It is expected that the developed S-SNEDDS can be a potential, safe and effective carrier for the oral delivery of curcumin to the brain. To date, this article is the only study of CUR-PIP-loaded S-SNEDDS for the treatment of AD.

Topics: Alzheimer Disease; Animals; Biological Availability; Curcumin; Drug Delivery Systems; Emulsions; Nanoparticles; Particle Size; Piperidines

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDAC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Drug Design; Histone Deacetylase Inhibitors; Humans; Piperidines; Structure-Activity Relationship

Patient 1, an 80-year-old woman with Alzheimer's disease, had been taking donepezil 5 mg for 2 years. Donepezil was increased to 10 mg, and 2 months later, the patient developed dropped head syndrome. MRI and needle EMG abnormality of the neck extensor muscles suggested focal myopathy, but the symptom disappeared within 2 months by discontinuing donepezil. Patient 2, a 78-year-old man with Lewy body dementia, had been taking levodopa and pramipexole (PPX). One month after tapering levodopa, donepezil 3 mg was introduced, and Pisa syndrome (bending of the trunk to the right anterior direction) developed 10 days later. Donepezil and PPX were discontinued and levodopa was increased. Within 5 months, his posture had almost recovered. Cholinesterase inhibitors can induce abnormal posture of the trunk, and clinicians should be aware of this uncommon but important side effect.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Levodopa; Male; Movement Disorders; Piperidines; Posture

Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Disease Models, Animal; Humans; Male; Maze Learning; Memory Disorders; Neurodegenerative Diseases; Piperidines; Rats; Rats, Wistar; Streptozocin

Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin-4-one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1-(4-methoxyphenethyl)piperidin-4-yl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one (VII

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Pyridines; Structure-Activity Relationship

To investigate the clinical effect of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with Alzheimer disease (AD), a total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. The control group was treated with donepezil tablets, while the observation group was treated with donepezil tablets combined with hydrogen-oxygen mixture inhalation. The scores of mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognition, activity of daily living scale (ADL) and the P300 event-related potential were compared between the 2 groups. After treatment, MMSE score, MoCA score, and ADL score in both groups increased after treatment (P < .01), while the improvement in the observation group was more significant than that in the control group (P < .001 for MMSE, P = .003 for MoCA, and P = .013 for ADL). The scores of Alzheimer's Disease Assessment Scale-Cognition in the observation group decreased after treatment (P < .05), while the improvement in the observation group was more significant than that in the control group (P = .005). After treatment, the latency of P300 in both groups was shortened (P < .01), and the improvement in the observation group was more significant than that in the control group (P < .001). The amplitude of the observation group increased after treatment (P < .01), and the improvement of the observation group was significant than that of the control group (P = .007). The clinical efficacy of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of AD is better than that of donepezil alone, which is worthy of further study.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Humans; Indans; Piperidines; Retrospective Studies; Treatment Outcome

There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population.. To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic.. Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019.. Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020.. The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; COVID-19; Donepezil; Female; Galantamine; Humans; Indans; Male; Memantine; Pandemics; Phenylcarbamates; Piperidines; Prevalence; Retrospective Studies; Rivastigmine

Oral formulations are not suitable for demented patients with dysphagia, those refuse to take tablets, or those with drug compliance problem. However, only oral formulations of donepezil hydrochloride are approved for the treatment of severe Alzheimer's disease in Japan.. To evaluate the safety, tolerability, and efficacy of long-term application of a 55.0 mg transdermal donepezil patch switched from a 10 mg oral donepezil hydrochloride tablet, for the treatment of patients with severe Alzheimer's disease.. A 52-week, multicenter, open-label, uncontrolled (phase III) study (jRCT2080224612) was conducted in Japan between April 2019 and August 2021. A 10 mg donepezil hydrochloride tablet was administered once a day for four weeks; a 55.0 mg donepezil patch was then applied once a day for 52 weeks in patients with severe Alzheimer's disease.. Of 64 patients received the patch, 45 completed the 52-week period. The overall discontinuation rate was 29.7% (19/64). Among the 19 patients discontinued, six patients 9.4% (6/64) discontinued due to adverse events. The incidence of adverse events at application sites was 67.2% (43/64), including application site erythema 29.7% (19/64), application site pruritus 25.0% (16/64), and contact dermatitis 20.3% (13/64). Adverse events were mild and did not increase with time, demonstrating a favorable safety profile. Cognitive function, measured using the Mini-Mental State Examination, was maintained for up to 24 weeks.. Adverse events were considered manageable in a clinical setting. The long-term application of a 55.0 mg donepezil patch once a day was feasible treatment in patients with severe Alzheimer's disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines; Tablets; Treatment Outcome

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship

Symptomatic treatment for Alzheimer's disease (AD) dementia could temporarily slow symptom worsening and improve the quality of life for both AD dementia patients and their caregivers. A comprehensive evaluation of symptomatic treatment patterns using recent data for newly diagnosed AD dementia has not been performed and compared across different countries.. The drug name, time to the first therapy, duration, discontinuation or switches were described in newly diagnosed AD dementia patients in two databases (a major U.S. health plan [US] and UK-Clinical Practice Research Datalink [CPRD GOLD]). This analysis included patients with newly diagnosed AD dementia in 2018-2019, who initiated symptomatic AD drug therapy, with ≥ 1 year baseline period and ≥ 1 year of follow-up.. Over median follow-ups of 698 and 645 days, 63% and 65% of AD dementia patients used symptomatic treatments, with 34% and 77% newly initiating therapy, constituting analytic samples of 7637 patients in the US database and 4470 patients in the CPRD, respectively. The median time to the first therapy was 14 days for US and 49 days for CPRD; donepezil ranked the as most frequently used (69% vs 61%), followed by memantine (19% vs 28%) in the US database and CPRD, respectively. Median time on first therapy was 213 and 334 days, and 30% and 12% of patients proceeded to a second treatment in the US and CPRD databases, respectively.. Approximately two thirds of newly diagnosed AD dementia patients utilized approved symptomatic treatment. Time on first therapy was relatively short (< 1 year) and the majority did not move to a second therapy, highlighting the need for better adherence and persistence to existing AD symptomatic therapies and the need for additional therapies to alleviate the significant burden of AD dementia.

Topics: Alzheimer Disease; Donepezil; Humans; Indans; Piperidines; Quality of Life

To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020.. National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels.. Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020.. The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

Topics: Alzheimer Disease; Brazil; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Memantine; Phenylcarbamates; Piperidines

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-β (Aβ) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Animals; Brain; Cognitive Dysfunction; Gliosis; Male; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Neuroprotective Agents; Piperidines

The Dementia Management Act (DMA) came into effect on August 4, 2011, in South Korea. Diagnosis and medication were rapidly performed for dementia in a short time. We investigated the cardiac effects of increased drug prescription following DMA. We observed a correlation between Alzheimer's disease (AD) and anti-AD drug (AAD) groups from 2010 to 2019 on the National Health Insurance System (NHIS) of South Korea. This study investigated the increase and decrease in deaths of AD patients with AAD. We analysed the mortality per 100,000 population with the R

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Rivastigmine

Anti-dementia medications are widely prescribed to patients with Alzheimer's dementia (AD) in South Korea. This study investigated the pattern of medical management in newly diagnosed patients with AD using a standardized data format-the Observational Medical Outcome Partnership Common Data Model from five hospitals. We examined the anti-dementia treatment patterns from datasets that comprise > 5 million patients during 2009-2019. The medication utility information was analyzed with respect to treatment trends and persistence across 11 years. Among the 8653 patients with newly diagnosed AD, donepezil was the most commonly prescribed anti-dementia medication (4218; 48.75%), followed by memantine (1565; 18.09%), rivastigmine (1777; 8.98%), and galantamine (494; 5.71%). The rising prescription trend during observation period was found only with donepezil. The treatment pathways for the three cholinesterase inhibitors combined with N-methyl-D-aspartate receptor antagonist were different according to the drugs (19.6%; donepezil; 28.1%; rivastigmine, and 17.2%; galantamine). A 12-month persistence analysis showed values of approximately 50% for donepezil and memantine and approximately 40% for rivastigmine and galantamine. There were differences in the prescribing pattern and persistence among anti-dementia medications from database using the Observational Medical Outcome Partnership Common Data Model on the Federated E-health Big Data for Evidence Renovation Network platform in Korea.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Rivastigmine

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [

Topics: Alzheimer Disease; Amyloid beta-Peptides; Basal Forebrain; Cholinergic Agents; Cognitive Dysfunction; Dementia; Humans; Magnetic Resonance Imaging; Piperidines; Positron-Emission Tomography

Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK).. To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model.. LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain. The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain

Topics: Acetylcholinesterase; Aged; Aging; Alzheimer Disease; Amyloid Precursor Protein Secretases; Brain; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Indans; Piperidines; Rivastigmine

Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk.. This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs.. The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses.. The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Donepezil; Female; Galantamine; Humans; Indans; Male; Medicare; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine; United States

The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cholinesterase Inhibitors; Drug Design; Humans; Hydrazones; Ligands; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Piperidines; Structure-Activity Relationship

To search for multi-target directed ligands for the treatment of Alzheimer's disease (AD), eight hybrid compounds from the combination of non-steroidal anti-inflammatory drugs with donepezil were designed and synthesized. The enzyme test revealed that the synthesized compounds had remarkable inhibitory activity towards both AChE and BChE. The IC

Topics: Acetylcholinesterase; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Cyclooxygenase 2; Donepezil; Humans; Ligands; Lipopolysaccharides; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans.. In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model.. We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity.. Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cognitive Dysfunction; Donepezil; Humans; Indans; Mice; Piperidines; RNA-Binding Protein FUS; Scopolamine

Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan.. To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data.. Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation.. We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94-1.07) for patients with support needs, 1.12 (1.06-1.18) for patients with low long-term care needs, and 1.31 (1.21-1.40) for patients with moderate-to-high long-term care needs relative to independent patients.. Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Japan; Piperidines

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D

Topics: Alzheimer Disease; Animals; Dopamine; Ligands; Pain; Piperidines; Receptors, sigma

Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Cholinesterase Inhibitors; Coumaric Acids; GABA Uptake Inhibitors; Nipecotic Acids; Piperidines; Rats; Reducing Agents

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Humans; Indans; Memantine; MicroRNAs; Piperidines

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ± standard deviation (SD) of 80.33 ± 7.98 years (78.97 ± 8.26 for males and 81.04 ± 7.98 for females), as compared to 79.95 ± 7.67 (78.87 ± 7.61 for males and 80.61 ± 7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment.

Topics: Alzheimer Disease; Donepezil; Female; Galantamine; Humans; Indans; Male; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cattle; Cholinesterase Inhibitors; Factor Xa; Factor Xa Inhibitors; Humans; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship; Thrombin

Acetylcholine esterase (AChE) is a key biological target responsible for the management of cholinergic transmission, and its inhibitors are used for the therapy of Alzheimer's disease. In the present study, a small library of molecules with 1,3-di-4-piperidylpropane nucleus were docked on AChE. The selected compounds were synthesized and evaluated for their enzyme inhibition. P25 and P17 expressed significantly higher AChE inhibition than standards with IC50 values of 0.591μM and 0.625μM, respectively. Binding mode of derivatives in the active site of AChE revealed dual binding of molecules in peripheral anionic site (PAS) and catalytic anionic site (CAS) of enzyme cavity.

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Humans; In Vitro Techniques; Molecular Docking Simulation; Piperidines

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN

Topics: Administration, Oral; Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Piperidines

Real-world studies to describe the use of first, second and third line therapies for the management and symptomatic treatment of dementia are lacking. This retrospective cohort study describes the first-, second- and third-line therapies used for the management and symptomatic treatment of dementia, and in particular Alzheimer's Disease.. Medical records of patients with newly diagnosed dementia between 1997 and 2017 were collected using four databases from the UK, Denmark, Italy and the Netherlands.. We identified 191,933 newly diagnosed dementia patients in the four databases between 1997 and 2017 with 39,836 (IPCI (NL): 3281, HSD (IT): 1601, AUH (DK): 4474, THIN (UK): 30,480) fulfilling the inclusion criteria, and of these, 21,131 had received a specific diagnosis of Alzheimer's disease. The most common first line therapy initiated within a year (± 365 days) of diagnosis were Acetylcholinesterase inhibitors, namely rivastigmine in IPCI, donepezil in HSD and the THIN and the N-methyl-D-aspartate blocker memantine in AUH.. We provide a real-world insight into the heterogeneous management and treatment pathways of newly diagnosed dementia patients and a subset of Alzheimer's Disease patients from across Europe.

Topics: Alzheimer Disease; Electronic Health Records; Europe; Galantamine; Humans; Indans; Italy; Netherlands; Phenylcarbamates; Piperidines; Retrospective Studies

Topics: Alzheimer Disease; Animals; Apoptosis; Biphenyl Compounds; Brain; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Male; Mice; Mitochondria; Mitochondrial Dynamics; Morris Water Maze Test; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Nootropic Agents; Open Field Test; Piperidines; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spatial Memory

Dysfunction of cholinergic system plays an important role in disease associated with cognitive blockage, such as Alzheimer's disease (AD). Central administration of scopolamine, an antagonist of acetylcholine receptor, could induce memory impairment in mice. Endocannabinoid system was also implicated in AD, as two peptides agonists of cannabinoid 1 receptor (CB1R), (m)RVD-hemopressin (α) (RVD) and (m)VD-hemopressin (α) (VD) have been reported to inhibit the AD-relating impairment in animal and cell models. More than one-third of the cholinergic cells expressed CB1R, so we speculated that RVD and VD might have ability to inhibit the memory-impairing effect of scopolamine. Our results showed RVD and VD ameliorated the memory toxicity of scopolamine, and the effects of the two peptides could be blocked by CB1R antagonists hemopressin (Hp) and AM251 in novel object and object location recognition tasks in mice. This study suggested that RVD and VD might be potential compounds for the treatment of the disease associated with impairment of cholinergic system.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Endocannabinoids; Hemoglobins; Humans; Memory Disorders; Mice; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Scopolamine

The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Isoxazoles; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; PC12 Cells; Piperidines; Rats; Structure-Activity Relationship

Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and I

Topics: Alzheimer Disease; Animals; Arrhythmias, Cardiac; Atrioventricular Block; Cholinesterase Inhibitors; Dogs; Donepezil; Halothane; Indans; Piperidines

The modulatory effects of piperine on drug metabolizing enzymes play an important role in the control of pharmacokinetic and the bioavailability properties of the administered drugs. The present study investigated the effect of piperine and piperine-donepezil co-administration on cognitive functions and synaptic plasticity at hippocampal perforant pathway (PP) to dentate gyrus (DG) synapses in an experimental model of Alzheimer's disease (AD).. Intracerebroventricularly (ICV) streptozotocin (STZ) injected rats were treated once daily with piperine, donepezil and piperine combined with donepezil for 4 weeks. Cognitive performance was evaluated using passive avoidance and Morris water maze performance tasks. Analysis of evoked field potentials was done to explore possible effects on input/output response, paired-pulse facilitation and long-term synaptic plasticity (LTP) at PP to DG synapses of hippocampus.. Rats subjected to ICV injection of STZ exhibited cognitive deficit associated with a hippocampal oxidative stress, effects that were reversed by chronic treatment with piperine or donepezil and or piperine combined with donepezil. Chronic treatment with piperine or donepezil restored the disruptive effects of STZ on LTP without altering basal synaptic transmission.. We found that optimal hippocampal function is dependent on tissue redox homeostasis. Piperine might reduce the synaptotoxic effects of STZ on hippocampal synaptic neurotransmission and correspondently is a good potential for neuroprotection against oxidative damage from ICV injection of STZ. These results suggest that piperine or donepezil significantly ameliorate cognitive deficit and LTP induction by attenuating oxidative status.

Topics: Alkaloids; Alzheimer Disease; Animals; Avoidance Learning; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Hippocampus; Male; Neuronal Plasticity; Nootropic Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Streptozocin; Treatment Outcome

Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC

Topics: Alzheimer Disease; Aminoacyltransferases; Amyloid beta-Peptides; Brain; Cell Line, Tumor; Humans; Molecular Docking Simulation; Piperidines; Pyrrolidonecarboxylic Acid

Indirect agonism has been invoked as part of the mechanism of antipsychotic action at dopamine D

Topics: Alzheimer Disease; Animals; Brain; Depression; Disease Models, Animal; Mice; Mice, Transgenic; Pharmaceutical Preparations; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Agonists; Urea

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Crystallography, X-Ray; Dogs; Drug Design; Female; Humans; Indans; Kinetics; Male; Mice, Inbred ICR; Molecular Structure; Nootropic Agents; Piperidines; Protein Binding; Rats, Sprague-Dawley; Scopolamine; Structure-Activity Relationship

Alzheimer's disease (AD) is an age-related neurodegenerative disease, and the imbalance between production and clearance of β-amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up-regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up-regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ-induced injury. The neuroprotection by thioperamide against AD was reversed by 3-MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic-related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic-lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB-dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy; Cell Death; Cell Survival; Cells, Cultured; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Hippocampus; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neurons; Neuroprotective Agents; Piperidines; Presenilin-1; Up-Regulation

We previously demonstrated that ibrutinib modulates LPS-induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aβ plaque levels by promoting the non-amyloidogenic pathway of APP cleavage, decreased Aβ-induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin-dependent kinase-5 (p-CDK5). Importantly, tau-mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long-term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short- and long-term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3-kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD-associated pathology and cognitive function and may be a potential therapy for AD.

Topics: Adenine; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition; Cyclin-Dependent Kinase 5; Cytokines; Dendritic Spines; Disease Models, Animal; Down-Regulation; Gliosis; Inflammation; Inflammation Mediators; Memory, Long-Term; Mice, Transgenic; Neurogenesis; Neuroglia; Phosphorylation; Piperidines; Plaque, Amyloid; tau Proteins

Evidence regarding the initiation of antipsychotic medications across individual cholinesterase inhibitors (ChEIs) to manage the behavioral symptoms of dementia is lacking.. This study compared the risk of initiation of antipsychotic medications among older adults with dementia treated with the ChEIs donepezil, rivastigmine, or galantamine.. This retrospective cohort study used multiyear (2013-2015) Medicare claims data involving Parts A, B, and D. The study sample included community-dwelling older adults (aged ≥ 65 years) with a diagnosis of dementia. The study identified new users of ChEIs and followed them for up to 180 days for antipsychotic initiation. The ChEIs included donepezil, rivastigmine, and galantamine, whereas antipsychotics included typical and atypical agents. Donepezil was used as the reference category as it is the most commonly used ChEI and only acts on acetylcholinesterase, whereas both rivastigmine and galantamine have dual mechanisms of action. Multivariable Cox proportional hazards regression compared the risk of and time to antipsychotic initiation among the three ChEIs, adjusting for other risk factors.. The study cohort consisted of 178,441 older adults with dementia who were new users of ChEIs. A total of 23,433 (15.14%) donepezil users, 4114 (19.04%) rivastigmine users, and 324 (15.77%) galantamine users initiated antipsychotics. The mean time to antipsychotic initiation among patients who received antipsychotics was 109.29 ± 69.72 days for donepezil users, 96.70 ± 71.60 days for rivastigmine users, and 104.15 ± 72.53 days for galantamine users. The Cox regression analysis showed that rivastigmine (adjusted hazard ratio [aHR] = 1.27; 95% confidence interval [CI], 1.20-1.34) was significantly associated with antipsychotic initiation compared with donepezil, whereas no significant difference was observed between galantamine and donepezil (aHR = 0.98; 95% CI, 0.81-1.20).. The study found a 27% increased risk of antipsychotic initiation among users of rivastigmine compared with donepezil users. There was no difference between galantamine and donepezil for antipsychotic initiation. Although the limitations of the study should be considered, the results suggest that donepezil or galantamine may be more appropriate treatments for older patients with dementia, to minimize antipsychotic use.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Cohort Studies; Humans; Indans; Medicare; Phenylcarbamates; Piperidines; Retrospective Studies; United States

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cholinesterase Inhibitors; Donepezil; Humans; Ligands; Piperazines; Piperidines; Structure-Activity Relationship; Sulfonamides

Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates β-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3β and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.

Topics: Alzheimer Disease; Animals; Arachidonic Acids; Benzodioxoles; Cognition; Endocannabinoids; Female; Glycerides; Inflammation Mediators; Male; Maze Learning; Mice; Mice, Transgenic; Monoacylglycerol Lipases; Piperidines; tau Proteins; Tauopathies

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship

The aim was to determine trends and patterns of symptomatic medication used against dementia in 66 countries and regions.. This was a cross-sectional study that used the wholesale data from the IQVIA Multinational Integrated Data Analysis System database. Sale data for symptomatic medication against dementia from 66 countries and regions from 2008 to 2018 were analysed and stratified by income level (low/middle-income countries [LMICs], n = 27; high-income countries [HICs], n = 37; regions, n = 2). The medication use volume was estimated by defined daily dose (DDD) per 1000 inhabitants per day (World Health Organization DDD harmonized the size, strength and form of each pack and reflects average dosing). Changes in medication use over time were quantified as percentage changes in compound annual growth rates (CAGRs).. Total symptomatic medication against dementia sales increased from 0.85 to 1.33 DDD per 1000 inhabitants per day between 2008 and 2018 (LMICs 0.094-0.396; HICs 3.88-5.04), which is an increase of CAGR of 4.53% per year. The increase was mainly driven by the LMICs (CAGR = 15.42%) in comparison to the HICs (CAGR = 2.65%). The overall medication use from 2008 to 2018 increased for all four agents: memantine (CAGR = 8.51%), rivastigmine (CAGR = 6.91%), donepezil (CAGR = 2.72%) and galantamine (CAGR = 0.695%). In 2018, the most commonly used medication globally was donepezil, contributing to 49.8% of total use volume, followed by memantine (32.7%), rivastigmine (11.24%) and galantamine (6.36%).. There was an increasing trend in the use of symptomatic medications against dementia globally, but the use remained low in LMICs. Interventions may be needed to support the medication use in some countries.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cross-Sectional Studies; Humans; Indans; Memantine; Phenylcarbamates; Piperidines

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Eicosanoids; Epoxide Hydrolases; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Memory Disorders; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Piperidines; Signal Transduction; Spatial Learning

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Benzopyrans; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Histamine H3 Antagonists; Horses; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Piperidines; Receptors, Histamine H3; Structure-Activity Relationship

The only recommended pharmacological treatments for specific dementias are donepezil, galantamine, rivastigmine, and memantine (recommended drugs, RD). However, other drugs without recommendations (not recommended drugs, NRD) are often used to treat patients with cognitive impairment (CI) in Argentina. The INSSJyP is the largest health insurance in Argentina. The objective of this study is to analyze the prescription pattern, cost, and implications of NRD used for the treatment of CI in the INSSJyP.. This is a retrospective, population-based study of the INSSJyP outpatients' prescriptions database for drugs usually prescribed for CI during 2015. These data were compared with the same database in 2009. The number of "prescriptions" always refers to dispensed packages.. A total of 3 255 438 packages of drugs usually indicated for CI were prescribed during 2015: 1 912 476 packages of RD (59%) and 1 342 962 packages of NRD (41%).Comparing the results with those obtained in 2009, there is a 148% gross increase in the prescription of both RD and NRD for CI, although the rates/1000 affiliates/year show a lesser rise for NRD (70.1%) compared to RD (103.9 %).The expenditure on CI drugs prescribed during 2015 was 77 million USD. NRD cost represented approximately 20 million USD.. Inappropriate drug use increases health costs in developing countries. We found a high number of patients with a probable diagnosis of CI treated with NRD. It is extremely relevant that all the healthcare professionals can update their knowledge and modify behavioral insights about appropriate prescription for specific dementias.

Topics: Alzheimer Disease; Argentina; Cholinesterase Inhibitors; Humans; Indans; Piperidines; Retrospective Studies

Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.. Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework.. An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia.. In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.

Topics: Aged; Aged, 80 and over; Alkaloids; Alzheimer Disease; Benzodioxoles; Biomarkers; Chromatography, Liquid; Cognitive Dysfunction; Female; Glutamine; Humans; Male; Mass Spectrometry; Metabolome; Metabolomics; Middle Aged; Piperidines; Polyunsaturated Alkamides

We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT. We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.. In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.. Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Brain; Disease Models, Animal; Maze Learning; Mice; Mice, Transgenic; Piperidines; Rats

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Animals; Cell Proliferation; Cognition; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Mice; Mice, Transgenic; Neural Stem Cells; Piperidines; Receptors, Adiponectin; Signal Transduction

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Humans; Indazoles; Ligands; Molecular Docking Simulation; Molecular Structure; Piperazine; Piperidines; Structure-Activity Relationship

We investigated the associations of the single-nucleotide polymorphism rs1080985 of cytochrome P4502D6 (CYP2D6) and the apolipoprotein E (APOE) genotypes with cognitive and functional changes in patients treated with donepezil.. Sixty-five outpatients with Alzheimer's disease or mixed dementia being treated with donepezil were assessed at baseline and over 27 months. Changes in cognitive status, assessed with the Mini-Mental State Examination, and in functional status, assessed by the Activities of Daily Living Scale and the Instrumental Activities of Daily Living Scale, were evaluated as a function of CYP2D6 and APOE genotypes by using linear mixed models. Multiplicative interactions between the CYP2D6 and APOE genotypes and time were investigated.. Individuals with the mutated CYP2D6 exhibited a slower decline in total Mini-Mental State Examination scores, orientation, registration, and functional status than those with the wild type. A significant interaction between CYP2D6, APOE, and time was found for changes in the Activities of Daily Living Scale; among the ε4 carriers, those with the mutated CYP2D6 exhibited a slower decline on the Activities of Daily Living Scale than those with the wild type.. The CYP2D6 and APOE genotypes may modulate the effectiveness of donepezil on cognitive and functional status.

Topics: Activities of Daily Living; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cognition; Cytochrome P-450 CYP2D6; Donepezil; Genotype; Humans; Indans; Nootropic Agents; Piperidines

Alzheimer's disease is type of dementia in which cognitive functions get declined. More than 50 million people are affected by this disease across the world. Many clinical and preclinical studies have been conducted on the treatment of AD but very limited number of drugs have found a clinical application. Because regeneration of neuron is a complicated process due to the involvement of multiple pathways, a combination of drugs that can work through multiple pathways could prove to be effective in treating AD. Based on prior studies and different mechanisms involved in the treatment, a new hypothesis has been proposed that a combination of galantamine, memantine and lycopene is anticipated to produce better activity as compared to the current therapies available in market for the treatment of this disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Lycopene; Memantine; Piperidines

Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease.. We aimed to shed light on the mode of action of masitinib in Alzheimer's disease.. We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments.. These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzamides; Cognition; Disease Models, Animal; Male; Mice, Transgenic; Piperidines; Presenilin-1; Pyridines; Synapses; Thiazoles

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-β (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aβ and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aβ (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aβ (1-42) level, GSK-3β activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hippocampus; Insulin Resistance; Male; Maze Learning; Peptide Fragments; Piperidines; Random Allocation; Rats; Rats, Wistar; Uracil

Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer's disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD β amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.

Topics: Alzheimer Disease; Animals; Epoxide Hydrolases; Epoxy Compounds; Humans; Mice; Phenylurea Compounds; Piperidines

Elucidating the relationship between neuronal metabolism and the integrity of the cholinergic system is prerequisite for a profound understanding of cholinergic dysfunction in Alzheimer's disease. The cholinergic system can be investigated specifically using positron emission tomography (PET) with [

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals

Multitargeted hybrids of

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Drug Design; Molecular Docking Simulation; Oxadiazoles; Piperidines; Rats; Structure-Activity Relationship

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system that is characterized by progressive cognitive dysfunction and which ultimately leads to dementia. Studies have shown that energy dysmetabolism contributes significantly to the pathogenesis of a variety of aging‑associated diseases and degenerative diseases of the nervous system, including AD. One focus of research thus has been how to regulate the expression of nicotinamide phosphoribosyltransferase (NAMPT) to prevent against neurodegenerative diseases. Therefore, the present study used 6‑month‑old APPswe/PS1ΔE9 (APP/PS1) transgenic mice as early AD mouse models and sought to evaluate nicotinamide adenine dinucleotide (NAD+) and FK866 (a NAMPT inhibitor) treatment in APP/PS1 mice to study NAMPT dysmetabolism in the process of AD and elucidate the underlying mechanisms. As a result of this treatment, the expression of NAMPT decreased, the synthesis of ATP and NAD+ became insufficient and the NAD+/NADH ratio was reduced. The administration of NAD+ alleviated the spatial learning and memory of APP/PS1 mice and reduced senile plaques. Administration of NAD+ may also increase the expression of the key protein NAMPT and its related protein sirtuin 1 as well as the synthesis of NAD+. Therefore, increasing NAMPT expression levels may promote NAD+ production. Their regulation could form the basis for a new therapeutic strategy.

Topics: Acrylamides; Alzheimer Disease; Amyloid; Animals; Behavior, Animal; Cytokines; Disease Models, Animal; Hippocampus; Learning; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Signal Transduction; Sirtuin 1

Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT

Topics: Acetylcholinesterase; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Humans; Indoles; Ligands; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Torpedo

A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Horses; Humans; Hydrazones; Models, Molecular; Molecular Structure; Neuroprotective Agents; Picrates; Piperidines; Structure-Activity Relationship; Sulfonic Acids

Topics: Alzheimer Disease; Animals; Dendritic Spines; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hippocampus; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor; Synapses

Bruton's tyrosine kinase (BTK), a critical component of B cell receptor signaling, has recently been implicated in regulation of the peripheral innate immune response. However, the role of BTK in microglia, the resident innate immune cells of the central nervous system, and its involvement in the pathobiology of neurodegenerative disease has not been explored. Here we found that BTK is a key regulator of microglial phagocytosis. Using potent BTK inhibitors and small interfering RNA (siRNA) against BTK, we observed that blockade of BTK activity decreased activation of phospholipase gamma 2, a recently identified genetic risk factor in Alzheimer's disease (AD), and reduced phagocytosis in rodent microglia and human monocyte-derived macrophages. Inhibition of BTK signaling also decreased microglial uptake of synaptosomes but did not have major impacts on other key microglial functions such as migration and cytokine release. Similarly, blocking BTK function ex vivo in acute brain slices reduced microglial phagocytosis and maintained numbers of resting microglia. In brain tissues from the 5xFAD mouse model of AD, levels of microglial BTK were elevated while in two gene expression datasets of post-mortem AD patient brain tissues, upregulation of BTK transcript was observed. Our study provides novel insights into the role of BTK in regulating microglial phagocytosis and uptake of synaptic structures and suggests that inhibiting microglial BTK may improve cognition in AD by preventing microglial activation and synaptic loss. Graphical Abstract Microglial-mediated synapse loss has been implicated in AD pathogenesis. Inhibition of BTK decreases activation of PLCγ2, a genetic risk factor in AD, and reduces microglial phagocytosis and uptake of synaptic structures. As such BTK inhibition may represent a therapeutic route to prevent microglial activation and synapse loss in AD.

Topics: Acrylamides; Adenine; Agammaglobulinaemia Tyrosine Kinase; Alzheimer Disease; Animals; Brain; Cell Line; Cell Movement; Cytokines; Datasets as Topic; Enzyme Induction; Gene Expression Profiling; Humans; Mice; Mice, Inbred C57BL; Microglia; Nerve Tissue Proteins; Phagocytosis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Small Interfering

Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.

Topics: Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Click Chemistry; Drug Design; Drug Discovery; Humans; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship

The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Blood-Brain Barrier; Cell Line, Tumor; Cholinesterase Inhibitors; Cognitive Dysfunction; Drug Design; Humans; Mice; Piperidines; Protein Aggregation, Pathological; Structure-Activity Relationship

DL0410, a dual‑action cholinesterase inhibitor and histamine‑3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography‑mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid‑liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment.

Topics: Alzheimer Disease; Animals; Bile; Biphenyl Compounds; Body Fluids; Brain; Cholinesterase Inhibitors; Cytochrome P-450 CYP2D6; Feces; Female; Histamine H3 Antagonists; Humans; Male; Piperidines; Rats; Rats, Sprague-Dawley

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

Alzheimer's disease is a devastating neurodegenerative disease that requires pharmacological intervention. We conducted a descriptive study using pharmacy prescription data of antidementia drugs. Prescription information of 99 541 patients was obtained from 55 hospitals. Overall the number of Alzheimer's disease outpatients of sampling days increased from 10 239 in 2012 to 20 546 in 2017. The main age range of patients suffering Alzheimer's disease was 75-84, while the patients aged above 85 was increasing. Nonusers of antidementia drugs, cholinesterase inhibitors (ChEIs) and memantine slowly decreased over the study period. The percentage of patients taking ChEIs and ChEIs-combined memantine increased. The most frequently prescribed ChEI was donepezil. These results are mostly in line with the guideline recommendations and clinical evidence during the study period. Efforts should be made to reduce the number of nonusers and optimize the use of antidementia drugs.

Topics: Aged; Alzheimer Disease; China; Cholinesterase Inhibitors; Donepezil; Female; Humans; Male; Memantine; Nootropic Agents; Piperidines

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Eels; Horses; Humans; Models, Molecular; Molecular Structure; Piperidines; Structure-Activity Relationship

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Macaca fascicularis; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Neurons; Peptide Fragments; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley; Swine; Swine, Miniature

Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholesterol; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Oxysterols; Piperidines

The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid; Animals; Biomarkers; Caspase 12; Cerebral Cortex; Connexin 43; Disease Models, Animal; Donepezil; Endoplasmic Reticulum Stress; Gene Expression Regulation; Glucose; Glucose Transport Proteins, Facilitative; GPI-Linked Proteins; Heat-Shock Proteins; Hippocampus; Indans; Injections, Intraventricular; Male; Neurons; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Streptozocin; tau Proteins

The present study describes a generic strategy using capillary electrophoretic (CE) method for chiral enantioseparation of anti-Alzheimer drugs, namely, donepezil (DON), rivastigmine (RIV), and antifungal drugs, namely, ketoconazole (KET), Itraconazole (ITR), fluconazole (FLU), and sertaconazole (SRT) in which these drugs have different basic and acidic properties. Several modified cyclodextrins (CDs) were applied for enantioseparation of racemates such as highly sulfated α, γ CDs, hydroxyl propyl-β-CD, and Sulfobutyl ether-β-CD. The starting screening conditions consist of 50-mM phosphate-triethanolamine buffer at pH 2.5, an applied voltage of 15 kV, and a temperature of 25°C. The CE strategy implemented in the separation starts by screening prior to the optimization stage in which an experimental design is applied. The design of experiment (DOE) was based on a full factorial design of the crucial two factors (pH and %CD) at three levels, to make a total of nine (3

Topics: Alzheimer Disease; Antifungal Agents; Cyclodextrins; Donepezil; Electrophoresis, Capillary; Indans; Injections; Piperidines; Rivastigmine; Stereoisomerism

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an indepe

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cerebral Cortex; Cholinergic Agents; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Oxygen; Piperidines; Positron-Emission Tomography; Rivastigmine

To provide pilot data for the safety and efficacy of EGb 761 in the oldest-old patients (aged 80 or older).. In a retrospective analysis, we compared treatment outcomes with EGb 761 or donepezil over 12 months in 189 patients aged 80 years or older suffering from Alzheimer's disease (AD).. Over 12 months, there was no significant difference in cognitive decline, measured with the mini-mental state examination (MMSE) score, between donepezil and EGb 761 (p = 0.31). We found more adverse events in the donepezil group.. Results suggest similar effects on cognitive symptoms from the use of EGb 761 in the treatment of dementia in AD together with favorable safety compared to donepezil.
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Topics: Aged, 80 and over; Alzheimer Disease; Cognition; Donepezil; Female; Ginkgo biloba; Humans; Indans; Male; Mental Status and Dementia Tests; Nootropic Agents; Piperidines; Plant Extracts; Retrospective Studies; Treatment Outcome

Clinical and preclinical studies firmly support the involvement of the inflammation in the pathogenesis of Alzheimer's disease (AD). Despite acetylcholinesterase inhibitors (AChEI) being widely used in AD patients, there is no conclusive evidence about their impact on the inflammatory response.. This study investigates peripheral proinflammatory cytokines (interferon gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukins 1β [IL-1β] and 6 [IL-6]) by firstly comparing peripheral blood mononuclear cell (PBMC)-derived secretion in drug-naïve and AChEI-treated AD patients versus healthy controls. A subset of those drug-naïve AD patients, who were prescribed the AChEI donepezil, was followed-up for 6 months to investigate if donepezil suppresses proinflammatory cell-derived cytokine secretion.. Patients with AD showed higher levels of PBMC-derived proinflammatory cytokines (IFN-γ, TNF-α, IL-1β, and IL-6) in comparison with healthy controls. On reexamination, previously drug-naïve AD patients who received donepezil treatment for 6 months displayed a decrease in cell-derived IFN-γ, TNF-α, IL-1β, and IL-6.. Proinflammatory PBMC-derived cytokines were increased in patients with AD in comparison with healthy controls and donepezil-reduced proinflammatory cytokines when examining drug-naïve AD patients before and after AChEI treatment.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cytokines; Donepezil; Female; Follow-Up Studies; Humans; Indans; Inflammation; Male; Middle Aged; Piperidines

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Discovery; Hep G2 Cells; Humans; Hydrazones; Indans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Structure-Activity Relationship

Topics: Alzheimer Disease; Double-Blind Method; Humans; Piperidines; Psychotic Disorders; Urea

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cognition; Cysteine; Disease Progression; Donepezil; Female; Humans; Indans; Language; Male; Memory; Mental Status and Dementia Tests; Middle Aged; Nootropic Agents; Organotechnetium Compounds; Piperidines; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset.. The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age.. 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels.. Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart.. Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

Topics: Acetates; Acetylcholinesterase; Age of Onset; Aged; Aging; Alzheimer Disease; Brain; Brain Mapping; Carbon Radioisotopes; Female; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals

With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with K

Topics: Acetylcholinesterase; Alzheimer Disease; Benzoxazines; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Molecular Docking Simulation; Piperazines; Piperidines; Protein Binding; Structure-Activity Relationship

Following the premises of the multitarget-directed ligands approach for the drug R&D against neurodegenerative diseases, where Alzheimer's disease (AD) outstands, we have synthesized and evaluated analogues of the gramine derivative ITH12657 (1-benzyl-5-methyl-3-(piperidin-1-ylmethyl-1H-indole, 2), which had shown important neuroprotective properties, such as blocking effect of voltage-gated Ca

Topics: Alkaloids; Alzheimer Disease; Calcium; Calcium Channel Blockers; Cell Line, Tumor; Humans; Indole Alkaloids; Indoles; Molecular Docking Simulation; Molecular Structure; Neurons; Neuroprotective Agents; Okadaic Acid; Piperidines; Protein Phosphatase 2; Structure-Activity Relationship

There are debates on representation and generalizability of previous randomized controlled trials about anti-dementia agents in the oldest old population. In this context, we aimed to investigate the efficacy and safety of anti-dementia agents in the very elderly patients with dementia.. We conducted a retrospective study of patients with dementia 1) who were 85 years or older, 2) got started anti-dementia agents, and 3) went through follow-up evaluation about one year thereafter. As a control, patients with dementia who were less than 85 years old with similar inclusion criteria were randomly selected during the same period. The adverse drug effects and discontinuation rates were investigated with self-reported complaint after starting or increasing anti-dementia drugs. For efficacy outcome, we also analyzed the change in neuropsychological results during follow-up period.. A total of 77 dementia patients who were at least 85 years were enrolled. As a control group, 78 patients with dementia who were younger than 85 was analyzed. The adverse drug effects were observed in 26 (33.3%) patients in the younger old and in 26 (33.8%) in the oldest old (. The use of anti-dementia agents in the oldest old dementia patients may be safe and effective as the younger old dementia patients.

Topics: Activities of Daily Living; Aged, 80 and over; Alzheimer Disease; Donepezil; Exanthema; Female; Humans; Indans; Male; Medication Adherence; Nausea; Neuropsychological Tests; Nootropic Agents; Piperidines; Retrospective Studies; Rivastigmine; Treatment Outcome

Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, contilisant significantly restores the cognitive deficit induced by Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterases; Histamine Antagonists; Indoles; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Piperidines; Protein Multimerization; Protein Structure, Quaternary; Receptors, Histamine; Receptors, sigma; Sigma-1 Receptor; Spatial Memory

This study explored the possible mechanism of flavones from Vitis vinifera L. (VTF) on neurotransmitters, synaptic transmission and related learning and memory in rats with Alzheimer disease (AD).. The researchers injected amyloid-β. VTF may enhance the protein expression of p-CREB, BDNF and SYT1 in rat hippocampi, depending on dose. The messenger RNA (mRNA) level of CREB was significantly higher in the VTF high-dose group than in the model group, which was consistent with the results of Western blotting. VTF may reduce the activity of AChE and increase that of ChAT in rat hippocampi. Finally, VTF effectively improved the learning and memory abilities of AD rats.. VTF can promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters, which may be one mechanism of VTF protection in AD rats.

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Choline O-Acetyltransferase; Cyclic AMP Response Element Modulator; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Flavones; Gene Expression Regulation; Hippocampus; Indans; Male; Maze Learning; Memory; Neurotransmitter Agents; Nootropic Agents; Peptide Fragments; Piperidines; Protein Aggregates; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Synaptotagmin I; Vitis

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cell Line; Cholinesterase Inhibitors; Donepezil; Enzyme Inhibitors; Flavonoids; Humans; Indans; Lipoxygenase Inhibitors; Male; Mice, Inbred BALB C; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurogenesis; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor

The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Butyrylcholinesterase; Caco-2 Cells; Cell Line, Tumor; Cholinesterase Inhibitors; Drug Design; Humans; Ligands; Models, Molecular; Neuroprotective Agents; Piperidines

Acetylcholinesterase enzyme (AChE) is the main target in Alzheimer's disease therapy and designing of novel AChE inhibitors is a great deal of attention.. In this study, 2D-QSAR and 3D-QSAR models were generated using stepwise multiple linear regressions (SW-MLR) and comparative molecular field analysis (CoMFA) respectively.. It was found that CoMFA model with r2 of 0.947 for the training set and r2 of 0.816 for the test set is more favorable than model which is established by SW-MLR method with r2 =0.825 and r2pred =0.778 in 2D-QSAR.. In addition, obtaining models were validated by cross validation with cut off values of q2 > 0.5 and r2pred > 0.6.

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Humans; Models, Molecular; Molecular Targeted Therapy; Piperazine; Piperidines; Quantitative Structure-Activity Relationship

There is clear evidence that neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease. Consequently, modulating the inflammatory environment in brain has become a powerful and attractive strategy to deal with Alzheimer's disease physiopathology. In spite of the neuroprotective capacity shown by ASS234, a multitarget propargylamine targeted for Alzheimer's disease, its regulation of inflammation in the brain still remains unexplored. Therefore, we aimed to characterize possible anti-inflammatory effects of ASS234, counteracting induced inflammatory effects in RAW 264.7 cells and evaluating seven neuroinflammation related genes expression profiling (IL-6, IL-10, IL1β, NF-κB, TNF-α, TNFR1, and TGF-β), after ASS234 (5 μM) treatment in SH-SY5Y cells. The analysis of the obtained fold changes lead us to conclude that ASS234 may play an important role facing the neuroinflammatory environment in Alzheimer's disease pathology.

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cytokines; Gene Expression; Humans; Indoles; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mice; Neurons; NF-kappa B; Piperidines; RAW 264.7 Cells; Receptors, Tumor Necrosis Factor, Type I; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butylated Hydroxytoluene; Cell Line; Cholinergic Agents; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Indans; Mice; Molecular Structure; Neuroprotective Agents; PC12 Cells; Piperidines; Protein Aggregates; Rats; Structure-Activity Relationship

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Caco-2 Cells; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Models, Molecular; Molecular Structure; Piperidines; Protein Aggregates; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Carbazoles; Cholinesterase Inhibitors; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Neuroprotective Agents; PC12 Cells; Piperidines; Rats

Topics: Alzheimer Disease; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Glutathione; Glutathione Peroxidase; MAP Kinase Signaling System; Mice; Mitochondria; Models, Biological; Neuroprotective Agents; Oxidative Stress; Piperidines; Quinolizidines

Alzheimer's disease (AD) is a neurodegenerative disorder that has no cure till now. Piperine (PIP) is an alkaloid characterized by memory-enhancing properties but challenging oral delivery obstacles. The objectives of this study are as follows: preparation of microemulsion (ME) as a proposed oral PIP nanocarrier for treatment of Alzheimer's disease and testing its safety on the brain and other internal organs. This study employs bioactive surfactants in the common safe doses to improve PIP targeting to the brain. Selected ME systems encompassed Caproyl 90 (oil)/Tween 80/Cremophor RH 40 (surfactant) and Transcutol HP (co-surfactant). The particle size of the prepared formulations was less than 150 nm with negative zeta potential. The in vivo results showed a superior effect of ME over free PIP. Colchicine-induced brain toxicity results showed the safety of ME on brain cells. Nevertheless, toxicological results showed a potential ME nephrotoxicity. Oral microemulsion increased PIP efficacy and enhanced its delivery to the brain resulting in better therapeutic outcome compared to the free drug. However, the toxicity of this nanosystem should be carefully taken into consideration on chronic use.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Brain; Drug Delivery Systems; Emulsions; Humans; Piperidines; Polyunsaturated Alkamides; Rats, Wistar

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Indans; Inhibitory Concentration 50; Kinetics; Metformin; Molecular Structure; Piperidines; Protein Binding; Structure-Activity Relationship; Sulfonamides

Alzheimer's disease (AD) is believed to develop due to deposition of β-amyloid (Aβ) peptide. Hence, efforts are being made to develop potent drug that target amyloid hypothesis.. The present study explores the effect of the seaweed Gelidiella acerosa (Forsskål) Feldmann & Hamel (Gelidiellaceae) against Aβ 25-35 peptide in Swiss albino mice.. The animals were administered through intracerebroventricular (ICV) injection with the Aβ 25-35 peptide (10 μg/10 μL/ICV site) on 21st day of the pretreatment of G. acerosa (whole plant) benzene extract (200 and 400 mg/kg bw). On day 30, animals were sacrificed and brain tissue homogenate was prepared. The activities of AChE, BuChE, b-secretase, MAO-B, and caspase-3 were determined, and Bax expression was assessed by Western blotting.. Gelidiella acerosa benzene extract restored the level of antioxidant enzymes and prevented lipid and protein oxidation significantly (p < 0.05). The extract protected the mice from cholinergic deficit significantly (p < 0.05) by inhibiting the activities of AChE and BuChE, which was about 0.116 ± 0.0088 U/mg of protein and 0.011 ± 0.0014 U/mg of protein respectively, which was otherwise increased in peptide-treated group (0.155 ± 0.007 U/mg of protein and 0.015 ± 0.0012 U/mg of protein respectively). Interestingly, G. acerosa benzene extract inhibited β-secretase and MAO-B activity. Reduction (p < 0.05) in level of caspase-3 activity and Bax expression suggests that G. acerosa protects the cells from apoptosis.. The results suggest that G. acerosa possesses excellent neuroprotective potential against peptide mediated toxicity under in vivo conditions.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Apoptosis; bcl-2-Associated X Protein; Behavior, Animal; Brain; Butyrylcholinesterase; Caspase 3; Disease Models, Animal; Donepezil; Escape Reaction; GPI-Linked Proteins; Indans; Lipid Peroxidation; Male; Maze Learning; Memory; Memory Disorders; Mice; Monoamine Oxidase; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Peptide Fragments; Piperidines; Protein Carbonylation; Seaweed

The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses.. This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement.. Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64).. ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement.. ISRCTN26167328.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Canada; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Double-Blind Method; Female; Galantamine; Goals; Humans; Indans; Male; Multicenter Studies as Topic; Outcome Assessment, Health Care; Piperidines; Severity of Illness Index

Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M

Topics: Acetylcholine; Allosteric Site; Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Cholinesterase Inhibitors; Donepezil; Drug Delivery Systems; Gene Expression Regulation; Humans; Indans; Ligands; Lipids; Mice; Models, Theoretical; Nanoconjugates; Nanomedicine; Particle Size; Phosphorylation; Piperidines; Plaque, Amyloid; Receptor, Muscarinic M1; Surface Properties

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Donepezil; Drug Design; Electrophorus; Humans; Indans; Mice; Molecular Docking Simulation; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Piperidines; Protein Aggregates; Pyridinium Compounds; Rats; Structure-Activity Relationship

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.

Topics: Activities of Daily Living; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Clinical Trials, Phase III as Topic; Donepezil; Drug Discovery; Humans; Indans; Piperidines; Treatment Outcome

Alzheimer's disease (AD) is a serious multifactorial disorder with progressive neurodegenerative outcomes related with impaired redox homeostasis. Inhibition of the enzyme acetylcholinesterase (AChE), as one of the major therapeutic strategies, is considered to be offering only symptomatic relief and moderate disease modifying effect. We intended to investigate the effects of acetylcholinesterase inhibition via donepezil on protein carbonyl (PCO), advanced protein oxidation products (AOPP) and ischemia modified albumin (IMA) as protein oxidation markers and ferric reducing antioxidant power (FRAP), prooxidant-antioxidant balance (PAB), total thiol (T-SH), protein thiol (P-SH) as antioxidant status markers and also kynurenine (KYN), N-formyl kynurenine (N-FKYN) and protein bound dityrosine (DT) levels all in one demonstrating the redox homeostasis in Alzheimer patients also correlated with AChE activity. The AChE activity and PCO, KYN, N-FKYN and DT levels were found to be significantly higher in the AD group than the control group. The FRAP, T-SH and P-SH levels were significantly lower in the AD group than in the control group. The AChE activity was significantly higher both in donepezil treated and untreated groups when compared with the control group. PCO levels were significantly higher in Alzheimer's untreated group than the healthy control and donepezil treated groups. AChE activity was positively correlated with PCO, IMA, PAB, KYN and N-FKYN levels and negatively correlated with FRAP, T-SH and P-SH levels in all participants. Our data showed that treatment with donepezil had ameliorating effects on redox homeostasis in Alzheimer patients. AChE inhibition seems to be exhibiting a potent antioxidant role and may inhibit protein oxidation by decreasing AChE activity in AD, thus medicinal natural substances exhibiting the similar mechanism of action with their antioxidant behaviours can be recommended for the emphasis on new drug new drug development. Further clinical and experimental studies are needed to support our current findings and conclusions.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Antioxidants; Biomarkers; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Female; Homeostasis; Humans; Indans; Male; Oxidation-Reduction; Oxidative Stress; Piperidines; Serum Albumin, Human

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Donepezil; Indans; Levetiracetam; Male; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Piperidines; Piracetam; Recognition, Psychology

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid; Animals; Cholinesterase Inhibitors; Donepezil; Drug Design; Female; Humans; Indans; Mice; Molecular Docking Simulation; Piperidines; Prodrugs

It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task.. For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm.. Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade.

Topics: Allosteric Regulation; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Galantamine; Male; Memory Disorders; Mice; Nicotinic Antagonists; Piperidines; Receptors, Nicotinic; Receptors, Serotonin, 5-HT4; Scopolamine; Serotonin 5-HT4 Receptor Agonists

Donepezil is the most commonly prescribed acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, an ailment that affects millions of older adult patients. By inhibiting the breakdown of acetylcholine in the central nervous system, donepezil has been shown to slow cognitive decline and improve patients' functional status. While donepezil is well-tolerated and generally considered safe at therapeutic doses, taking more than the prescribed dose could result in adverse cholinergic effects that range from mild gastrointestinal distress to serious cardiac dysrhythmias. We present a case of an 84-year-old man who developed gastrointestinal and cardiac disturbances after ingesting seven-times his daily dose of donepezil. As no specific antidote is available for donepezil overdose, this case highlights the importance of supportive care with particular attention to the management of cardiac dysrhythmias in patients displaying signs of toxicity.

Topics: Aged, 80 and over; Alzheimer Disease; Arrhythmias, Cardiac; Cholinesterase Inhibitors; Donepezil; Drug Overdose; Electrocardiography; Humans; Indans; Male; Piperidines

Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Chromones; Donepezil; Electrophorus; Erythrocytes; Hemolysis; Humans; Indans; Inhibitory Concentration 50; Neuroblastoma; Piperidines

In this report we assessed by docking and molecular dynamics the binding mechanisms of three FDA-approved Alzheimer drugs, inhibitors of the enzyme acetylcholinesterase (AChE): donepezil, galantamine and rivastigmine. Dockings by the softwares Autodock-Vina, PatchDock and Plant reproduced the docked conformations of the inhibitor-enzyme complexes within 2Å of RMSD of the X-ray structure. Free-energy scores show strong affinity of the inhibitors for the enzyme binding pocket. Three independent Molecular Dynamics simulation runs indicated general stability of donepezil, galantamine and rivastigmine in their respective enzyme binding pocket (also referred to as gorge) as well as the tendency to form hydrogen bonds with the water molecules. The binding of rivastigmine in the Torpedo California AChE binding pocket is interesting as it eventually undergoes carbamylation and breaks apart according to the X-ray structure of the complex. Similarity search in the ZINC database and targeted docking on the gorge region of the AChE enzyme gave new putative inhibitor molecules with high predicted binding affinity, suitable for potential biophysical and biological assessments.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Hydrogen Bonding; Indans; Molecular Conformation; Molecular Dynamics Simulation; Piperidines; Rivastigmine; Torpedo

Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin, a flavonoid derived from milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Aβ-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Aβ1-42-treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Aβ1-42-injected rats. Silibinin-treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anxiety; Autophagy; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Hippocampus; Indans; Male; Neurons; Neuroprotective Agents; Peptide Fragments; Piperidines; Psychotropic Drugs; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction; Silybin; Silymarin; Up-Regulation

Large-scale studies of utilization of medical services among patients with Alzheimer's disease (AD) are lacking. We aimed to investigate the usage of Western medicine and traditional Chinese medicine (TCM) among these patients in Taiwan.. We analyzed one million samples from the National Health Insurance Research Database in Taiwan. Patients (n = 1814) newly diagnosed with AD in 2001-2010 were divided into TCM users (n = 528) and non-TCM users (n = 1286).. Compared with non-TCM users, TCM users were younger, had a higher female:male ratio and higher utilization rate of Western medicine. The median interval between diagnosis and the first TCM consultation was 7.92 months. Donepezil and rivastigmine were commonly prescribed medications. Chinese herbal medicine was the most popular treatment among TCM users.. This study revealed the specific usage patterns of TCM and non-TCM medical services among patients with AD. The information could be used for improving the healthcare of patients with AD.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Medicine, Chinese Traditional; Middle Aged; Piperidines; Rivastigmine; Sex Factors; Taiwan; Time-to-Treatment; Urbanization

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B; Caco-2 Cells; Dogs; Humans; Madin Darby Canine Kidney Cells; Molecular Docking Simulation; Piperidines

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Cell Line; Central Nervous System Agents; Chelating Agents; Cholinesterase Inhibitors; Chromans; Copper; Donepezil; Drug Design; Drug Evaluation, Preclinical; Humans; Indans; Male; Mice, Inbred ICR; Microglia; Molecular Docking Simulation; Monoamine Oxidase Inhibitors; Neurotoxins; Oxidants; PC12 Cells; Peptide Fragments; Piperidines; Protein Aggregation, Pathological; Rats; Structure-Activity Relationship

The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation.. D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo.. The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model.. Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule. Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats.

Topics: 3T3 Cells; Acetylcholinesterase; Alzheimer Disease; Animals; Cell Survival; Chemistry, Pharmaceutical; Donepezil; Drug Liberation; Female; Humans; Hydrophobic and Hydrophilic Interactions; Indans; Mice; Nanoparticles; Naphthols; Particle Size; Piperidines; Polyethylene Glycols; Proof of Concept Study; Rats, Sprague-Dawley; Solubility; Streptozocin; Surface Properties

Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Behavior, Animal; Disease Models, Animal; Encephalitis; Entorhinal Cortex; Learning; Male; Memory; Mice, Transgenic; Neuroglia; Piperidines; Plaque, Amyloid; Serotonin 5-HT4 Receptor Agonists

Aim of the present study is to investigate the effects of medication with donepezil (acetylcholinesterase inhibitor) on the liver and kidney function in Alzheimer's disease (AD) and to compare the effects of donepezil medication during short (one month) and long term (six years) follow-ups. We evaluated female and male patients from Cukurova [42 AD patients; short term (5 mg/day)] and Dokuz Eylul [68 AD patients; long term (10 mg/day)] University Hospital. The results compared with the geriatric population without dementia in other words who are not in medication with donepezil. For short term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; firstly, before starting treatment and then repeated one month later. For long term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; three times at the end of each two consecutive years of treatment with donepezil. AD patients' results were also compared with 79 neurologically healthy geriatric patients without dementia who were over 65 years of age and were not receiving medication with donepezil. For this task, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are used to predict possible liver damage, while the blood urea nitrogen (BUN) and creatinine (CRE) levels for kidney damage. No significant difference between the groups regarding the routine control of biochemical parameters was observed in short term drug medication. In long term patients' group; the effects of two years use of donepezil on renal and hepatic function were also evaluated and levels of AST, ALT, BUN and CRE were found to be increased significantly compared to pretreatment levels. But, they remained in the reference intervals. However, levels of AST and ALT at the end of the fourth year of therapy were similar to those measured at the end of the second year, levels of BUN and CRE continuing to increase with staying below the reference limits. Functional markers obtained at the end of the sixth year of therapy were not differing from those of the fourth year. No significant difference was found during comparisons within the results of the neurologically healthy geriatric patient group. During comparisons between the two groups, measurements obtained at all-time points were significantly high in donepezil treated AD patients. We concluded that customized dosage according to hepatic and renal functions is

Topics: Aged; Alanine Transaminase; Alzheimer Disease; Aspartate Aminotransferases; Biomarkers; Blood Urea Nitrogen; Cholinesterase Inhibitors; Creatinine; Donepezil; Female; Follow-Up Studies; Humans; Indans; Kidney; Liver; Male; Piperidines; Time Factors

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Case-Control Studies; Cholinergic Agents; Cholinergic Neurons; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Presynaptic Terminals; Radioactive Tracers; Vesicular Acetylcholine Transport Proteins

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

Topics: Aging; Alzheimer Disease; Animals; Cheirogaleidae; Disease Models, Animal; Donepezil; Indans; Male; Memantine; Memory Disorders; Piperidines; Sleep Deprivation; Spatial Memory

Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC

Topics: Acetylcholinesterase; Alzheimer Disease; Binding Sites; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Hydrazones; Indans; Inhibitory Concentration 50; Models, Molecular; Piperidines; Structure-Activity Relationship

Background Donepezil hydrochloride commonly used in the management of Alzheimer's disease (AD), exhibiting its inhibitory effects on acetylcholinesterase and butyrylcholinesterase activity thereby enhance cognitive function. Caffeic acid member of hydroxycinnamic acid is widely present in human diet. This study aims to investigate influence of caffeic acid on acetylcholinesterase and butyrylcholinesterase inhibitory properties of donepezil (in vitro). Methods 5 mg of donepezil was dissolved in 50 mL distilled water while 10 mg of caffeic acid was dissolved in 100 mL distilled water. Therefore, mixtures of samples were prepared as follows: A2=donepezil 0.075 mg/mL+caffeic acid 0.025 mg/mL; A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL; A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL. All samples were kept in the refrigerator at 4 °C for subsequent analysis. Results The result showed that all the combinations show an inhibitory effect on acetylcholinesterase and butyrylcholinesterase activity in vitro, with the combination A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL had significant (p<0.05) highest inhibitory effect on acetylcholinesterase and butyrylcholinesterase activity in vitro. More so, all the samples were able to prevent pro-oxidants (FeSO4 and sodium nitroprusside [SNP] ) induced lipid peroxidation in rat brain homogenate, with the combination A4=donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL and A3=donepezil 0.050 mg/mL+caffeic acid 0.050 mg/mL had highest inhibitory effect against FeSO4 and SNP induced lipid peroxidation in rat brain homogenate in vitro respectively. Moreover, all the samples exhibit antioxidant properties as typified by their ability to chelate iron (II) ion (Fe2+), hydroxyl radical (OH٭) radical scavenging ability and ferric reducing property (FRAP). Conclusions Therefore, the combination of caffeic acid with donepezil enhances the antioxidant properties of donepezil. The combination of caffeic acid with donepezil could be a therapeutic aid in the management of AD, possibly with fewer side effects of donepezil. Nevertheless, the combination donepezil 0.025 mg/mL+caffeic acid 0.075 mg/mL acid look promising.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Caffeic Acids; Cholinesterase Inhibitors; Donepezil; Drug Synergism; Drug Therapy, Combination; Humans; Indans; Male; Nootropic Agents; Piperidines; Rats; Rats, Wistar

Surgery and anesthesia have been linked to postoperative cognitive disturbance and increased risk of Alzheimer's disease. It is not clear by which mechanisms this increased risk for cognitive disease is mediated. Further, amyloid β production has been suggested to depend on the sleep-wake cycle and neuronal activity. The aim of the present study was to examine if cerebrospinal fluid (CSF) concentrations of a number of biomarkers for Alzheimer's disease-related processes, including amyloid β, neuronal injury, and inflammation, changed over time during intravenous anesthesia in surgical patients.. We included patients scheduled for hysterectomy via laparotomy during general anesthesia with intravenous propofol and remifentanil. CSF samples were obtained before, during, and after surgery (5 h after induction) and tested for 27 biomarkers. Changes over time were tested with linear mixed effects models.. A total of 22 patients, all females, were included. The mean age was 50 years (± 9 SD). The mean duration of the anesthesia was 145 min (± 40 SD). Interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and vascular endothelial growth factor A increased over time. IL-15 and IL-7 decreased slightly over time. Macrophage inflammatory protein 1β and placental growth factor also changed significantly. There were no significant effects on amyloid β (Aβ) or tau biomarkers.. Surgery and general anesthesia with intravenous propofol and remifentanil induce, during and in the short term after the procedure, a neuroinflammatory response which is dominated by monocyte attractants, without biomarker signs of the effects on Alzheimer's disease pathology or neuronal injury.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Anesthesia, Intravenous; Biomarkers; Cohort Studies; Cytokines; Female; Humans; Inflammation; Middle Aged; Peptide Fragments; Piperidines; Propofol; Remifentanil; tau Proteins; Vascular Endothelial Growth Factor A

Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM).. First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed.. Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different.. BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Avoidance Learning; Behavior, Animal; Benzothiazoles; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Indans; Locomotion; Maze Learning; Molecular Docking Simulation; Piperazines; Piperidines; Rats; Rats, Wistar; Streptozocin

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The cerebral metabolic rate of glucose oxidation has been shown to be reduced in AD. The present study evaluated efficacy of dietary Amalaki Rasayana (AR), an Ayurvedic formulation used in Indian traditional system, in AbPP-PS1 mouse model of AD in ameliorating memory and neurometabolism, and compared with donepezil, a standard FDA approved drug for AD. The memory of mice was measured using Morris Water Maze analysis. The cerebral metabolism was followed by 13C labelling of brain amino acids in tissue extracts ex vivo using 1H-[13C]-NMR spectroscopy together with a short time infusion of [1,6-13C2]glucose to mice. The intervention with Amalaki Rasayana showed improved learning and memory in AbPP-PS1 mice. The 13C labelings of GluC4, GABAC2 and GlnC4 were reduced in AbPP-PS1 mice when compared with wild-type controls. Intervention of AR increased the 13C labelling of amino acids suggesting a significant enhancement in glutamatergic and GABAergic metabolic activity in AbPP-PS1 mice similar to that observed with donepezil treatment. These data suggest that AR has potential to improve memory and cognitive function in AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Carbon Isotopes; Cognition; Donepezil; gamma-Aminobutyric Acid; Gene Expression; Glucose; Glutamic Acid; Glutamine; Humans; Indans; Male; Maze Learning; Medicine, Ayurvedic; Memory; Mice; Mice, Transgenic; Neurons; Neuroprotective Agents; Piperidines; Plant Extracts; Presenilin-1

The brain region that shows reductions in regional cerebral blood flow (rCBF) earliest is the posterior cingulate cortex (PCC), which is thought to have a relationship with cognitive function. We made a hypothesis that the PCC hypoperfusion is a result of cholinergic dysfunction and can be restored by cholinergic enhancement. This present longitudinal study aimed to detect the restoration of PCC rCBF in response to donepezil, an acetylcholine esterase inhibitor.. We evaluated rCBF changes in the PCC, precuneus and anterior cingulate cortex using perfusion single-photon emission computed tomography (SPECT), statistical analysis and region of interest analysis, prospectively. We allocated 36 patients with mild AD to either the responder or non-responder groups based on changes in Mini-Mental State Examination scores. The patients were followed up for 18 months.. The PCC rCBF significantly increased in responders after 6 months of donepezil therapy. Statistical maps at baseline showed a typical decreased pattern of mild AD and obvious rCBF restoration in the bilateral PCC at 6 months in responders. Changes in Mini-Mental State Examination scores and the AD assessment scale cognitive scores significantly correlated with rCBF changes in the PCC of responders.. Cholinergic enhancement restored PCC rCBF under the three conditions of mild AD, responders and short follow-up interval, and that increase correlated with improved cognitive function. These findings support our hypothesis that PCC rCBF reflects cholinergic function in AD patients. Geriatr Gerontol Int 2017; 17: 951-958.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Gyrus Cinguli; Humans; Indans; Male; Piperidines; Prospective Studies; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Topics: Aged, 80 and over; Alzheimer Disease; Canes; Cholinesterase Inhibitors; Donepezil; Executive Function; Female; Femoral Neck Fractures; Gait; Humans; Indans; Learning; Piperidines; Stair Climbing; Treatment Outcome

The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-β aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data.. We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells.. In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine.. The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration.. ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.

Topics: Alzheimer Disease; Animals; Cell Survival; Cerebral Cortex; Disease Models, Animal; Donepezil; Gliosis; Hep G2 Cells; Hippocampus; Humans; Indans; Indoles; Learning; Male; Mice, Inbred C57BL; Nootropic Agents; Piperidines; Plaque, Amyloid; Proof of Concept Study; Recognition, Psychology; Scopolamine; Tacrine

Topics: Alzheimer Disease; Animals; Benzylamines; Brain Stem; Cholinesterase Inhibitors; Donepezil; Electric Stimulation; Electroencephalography; Frontal Lobe; Gamma Rhythm; Indans; Indoles; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Sleep Stages; Wakefulness

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

Topics: Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Indans; Memantine; Mitochondria; Monoamine Oxidase; Nootropic Agents; Oxygen Consumption; Piperidines; Rivastigmine; Swine

A novel series of donepezil based multi-functional agents "(E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-ones" have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9, IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9, IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds (IP-9, IP-13 and IP-15) successfully diminished H

Topics: Acetylcholine; Alzheimer Disease; Cell Line; Donepezil; Drug Delivery Systems; Drug Design; Humans; Indans; Ligands; Microscopy, Electron, Transmission; Molecular Dynamics Simulation; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregation, Pathological; Protein Binding

A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N-benzylpiperidine- or p-bromo-N-benzylpiperizine moiety, resembling the N-benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds (1-25) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series (1-8, 10-13) showing nano-molar hMAO-B inhibition (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzyl Compounds; Binding Sites; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Piperidines; Protein Aggregation, Pathological; Protein Binding; Structure-Activity Relationship

Persons with Alzheimer's disease are at an increased risk of pneumonia, but the comparative risks during specific antidementia treatments are not known. We compared the risk of pneumonia in the use of donepezil, rivastigmine (oral, transdermal), galantamine and memantine.. We used data from a nationwide cohort of community-dwelling individuals diagnosed with Alzheimer's disease during 2005-2011 in Finland, who initiated monotherapy with acetylcholinesterase inhibitor or memantine (n = 65,481). The risk of hospitalization or death due to pneumonia was investigated with Cox proportional hazard models.. The risk of pneumonia was higher in persons using rivastigmine patch (n = 9709) (adjusted hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04-1.27) and memantine (n = 11,024) (HR 1.59, 95% CI 1.48-1.71) compared with donepezil users (n = 26,416) whereas oral rivastigmine (n = 7384) (HR 1.08, 95% CI 0.98-1.19) and galantamine (n = 10,948) (HR 0.91, 95% CI 0.83-1.00) were not associated with an increased risk. These results did not change when adjusting for comorbid conditions, use of psychotropic drugs or with inverse probability of treatment weighting.. The increased risk of pneumonia in this fragile group of aged persons should be taken into account. Memantine is associated with the highest risk in the comparison of antidementia drugs. KEY Message Pneumonia risk is increased in persons with Alzheimer's disease who use memantine or rivastigmine patches.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Finland; Galantamine; Hospitalization; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Pneumonia; Risk; Rivastigmine

Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest.. In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives.. We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation.. Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Antioxidants; Azepines; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Oxidative Stress; Peptide Fragments; Piperidines; Rats

A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cell Line, Tumor; Cholinesterase Inhibitors; Donepezil; Esters; Humans; Indans; Inhibitory Concentration 50; Molecular Docking Simulation; Molecular Targeted Therapy; Piperidines; Protein Conformation; Structure-Activity Relationship

Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD.. We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil.. Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting.. AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months.. Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

Topics: ADAM10 Protein; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Blood Platelets; Cholinesterase Inhibitors; Donepezil; Down-Regulation; Female; Humans; Indans; Male; Middle Aged; Piperidines; Presenilin-1; Time Factors

In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cell Death; Cell Line; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Naphthalenes; Peptide Fragments; Piperidines; Structure-Activity Relationship; Sulfonamides

Drug fluorination has the potential to reproduce useful drugs with decreasing the side effect of them. Identifying the effect of this improvement on the chemical properties and biological interactions of drug symbolizes a meaningful progress in drug design. Here the fluorination of Donepezil as an anti-Alzheimer drug, including 7 fluorinated derivatives of it, was investigated computationally. In the first part of our calculations, the most important chemical properties of drug that affects the drug efficiency were investigated by applying the M06/6-31g (d, p) and M062X/6-31g (d, p) levels of theories. Findings showed that the fluorine substitution changed the drug stability as altered the solubility and molecular polarity. Furthermore, the intramolecular hydrogen bonding, charge distribution and electron delocalization of the drug were affected by this replacement. In the second section, the effect of fluorination on the drug⋯enzyme interactions was evaluated by using two effective methods Based on the molecular docking and density functional theory (DFT) calculations fluorine substitution influenced the Donepezil⋯Acetylcholinesterase interactions. Calculated binding energies by two computational methods displayed that the fluorine replacement changed the binding affinity of drug. Finally, the most significant non-bonded interactions between drugs and involved residues were investigated by bond length data analysis.

Topics: Alzheimer Disease; Donepezil; Electrons; Fluorine; Humans; Hydrogen Bonding; Indans; Models, Molecular; Molecular Docking Simulation; Piperidines; Quantum Theory; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Static Electricity

We previously reported that the frontal lobe was stimulated by psychosocial intervention for dementia patients, and that the parietal lobe was associated with logical judgment. We hypothesized that the combined therapeutic approach with symptomatic drug treatment can directly stimulate not only attention function but also judgment function indirectly to observing other participants' behaviors. Fifty-two patients with Alzheimer disease underwent the group reminiscence approach with reality orientation, as well as the donepezil treatment. The cerebral blood flow (CBF) was assessed with

Topics: Aged; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuroimaging; Piperidines; Social Behavior; Tomography, Emission-Computed, Single-Photon

Neurodegenerative diseases including Alzheimer's disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer's disease and one for amyotrophic lateral sclerosis.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Computational Biology; Computer Simulation; Cyclosporine; Donepezil; Drug Repositioning; Humans; Indans; Molecular Probes; Neuroprotective Agents; Piperidines; Riluzole; Structure-Activity Relationship

Different solid state forms of the research chemical fasoracetam, which counters the effects of Alzheimer's disease, have been subjected to a thermal and structural analysis. Single crystals were obtained from solution evaporation and from the melt. Single-crystal X-ray analyses of the crystals show the existence of 2 hydrated and 1 non-hydrated crystalline form of fasoracetam. Under ambient conditions, the hydrate form I is found to be the most stable form, showing a melting point of 57C. This low melting point, combined with possible water losses could cause problems when formulating the hydrated form and impact the storage conditions of the compound.

Topics: Alzheimer Disease; Crystallization; Nootropic Agents; Pharmaceutical Preparations; Piperidines; Proline; X-Ray Diffraction

Alzheimer's disease (AD) is a most serious age-related neurodegenerative disorder accompanied with significant memory impairments in this world. Recently, microRNAs (miRNAs) have been reported to be invlolved in the pathophysiology of AD. Previous studies have shown that miRNA-206 (miR-206) is implicated in the pathogenesis of AD via suppressing the expression of brain-derived neurotrophic factor (BDNF) in the brain. Here, we examined the miR-206-3p and miR-206-5p expression in the hippocampus and cortex of Abeta precursor protein (APP)/presenilin-1 (PS1) transgenic mice treated with donepezil, a drug approved for treating AD in clinic. We found that the expression of miR-206-3p was significantly up-regulated in the hippocampus and cortex of APP/PS1 mice, while donepezil administration significantly reversed this dysfunction. In addition, enhancing the miR-206-3p level by the usage of AgomiR-206-3p significantly attenuated the anti-dementia effects of donepezil in APP/PS1 mice. Together, these results suggested that miR-206-3p is involved in the anti-dementia effects of donepezil, and could be a novel pharmacological target for treating AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Donepezil; Hippocampus; Humans; Indans; Maze Learning; Memory; Mice; Mice, Transgenic; MicroRNAs; Piperidines; Presenilin-1; Reverse Transcriptase Polymerase Chain Reaction

To evaluate the in-vitro and in-vivo effects on monoaminergic neurotransmission of ASS234, a promising multitarget-directed ligand (MTDL), for Alzheimer's disease (AD) therapy.. In vitro was explored the effect of ASS234 on the monoaminergic metabolism in SH-SY5Y and PC12 cell lines, and remaining activity of both monoamine oxidase (MAO) isoforms was assessed. The corresponding dopamine (DA), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) levels were determined by HPLC-ED. In-vivo experiments were carried out Wistar rats and intracerebral guide cannulas were implanted in the hippocampus and in the prefrontal cortex by sterotaxic coordinates. The day after microdialysis samples were collected and levels of 5-HT, DA and NA were determined by (UHPLC) with electrochemical detector.. ASS234 induced a significant increase in serotonin (5-HT) levels in SH-SY5Y cells. In PC12 cells, ASS234 increased significantly the ratio of dopamine (DA)/(HVA + DOPAC), although no apparent differences in (NA) were observed. By in-vivo microdialysis, ASS234 showed a significant increase in the extracellular levels of 5-HT and NA in hippocampus whereas in the prefrontal cortex, DA and NA also increased significantly.. This study reveals the ability of ASS234 a MTDL compound, to enhance the monoaminergic neurotransmission supporting its potential use in AD therapy.

Topics: 3,4-Dihydroxyphenylacetic Acid; Alzheimer Disease; Animals; Biogenic Monoamines; Cell Line, Tumor; Dopamine; Hippocampus; Homovanillic Acid; Indoles; Ligands; Male; Monoamine Oxidase; Norepinephrine; PC12 Cells; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Serotonin

Cholinesterase inhibitors (ChEIs) are prescribed to dementia patients despite their poor tolerance. Low tolerability potentially reduces persistence and adherence, while inducing switching between medications. Comparisons of these utilization measures contribute to knowledge of the relative tolerability of these medications.. The aim was to compare persistence, adherence, and switching between donepezil, galantamine, oral rivastigmine, and rivastigmine patch.. A population-based cohort study, using British Columbia claims data (2009-2013), assessed ChEI new users aged 40 and older. We conducted survival analysis to compare persistence and Poisson regression to estimate switching rates. Good adherence, defined as a medication possession ratio of ≥80%, was modeled using log-binomial regression. Analyses were adjusted using propensity scores.. Patients on galantamine had longer mean persistence and better adherence compared with patients on donepezil, with a hazard ratio for discontinuation of 0.91 [95% confidence interval (CI) 0.87-0.96] and a relative risk for good adherence of 1.01 (95% CI 1.002-1.03). Rivastigmine was associated with the shortest mean persistence [3.6 months (95% CI 3.0-4.2) and 5.0 (95% CI 4.7-5.3) for oral and patch, respectively] and the highest mean switching rates. Comparing the two rivastigmine preparations, the patch was associated with decreased discontinuation compared with oral [hazard ratio 0.79 (95% CI 0.71-0.89)] and decreased switching [relative risk 0.63 (95% CI 0.46-0.87) during the first 6 months of treatment]. Paradoxically, the patch was also associated with poorer adherence [relative risk for good adherence 0.94 (95% CI 0.91-0.98)] than the oral formulation.. Based on estimates of persistence, adherence, and switching, galantamine was the best tolerated ChEI and rivastigmine the least.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Tolerance; Female; Galantamine; Humans; Indans; Male; Medication Adherence; Piperidines; Rivastigmine

The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.

Topics: Acetylcholinesterase; Aging; Alzheimer Disease; Animals; Antioxidants; Brain; Cholinesterase Inhibitors; Donepezil; Female; Indans; Inflammation; Learning; Male; Maze Learning; Memory Disorders; Mice; Neutrophil Infiltration; Oxidative Stress; Phosphodiesterase 4 Inhibitors; Piperidines; Plaque, Amyloid; Rolipram; Streptozocin

The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Cell Line, Tumor; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Humans; Indans; Interleukin-1beta; Male; Memory Disorders; Nootropic Agents; Peptide Fragments; Piperidines; Protein Aggregation, Pathological; Random Allocation; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

In Alzheimer's disease (AD), white matter lesions (WMLs) are associated with an increased risk of progression from mild cognitive impairment (MCI) to dementia, while memory deficits have, at least in part, been linked to a cholinergic deficit. We investigated the relationship between WML load assessed with the Scheltens scale, cerebral acetylcholinesterase (AChE) activity measured with [

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Piperidines; Positron-Emission Tomography; White Matter

Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.

Topics: Alzheimer Disease; Animals; Brain Ischemia; Calcium Channel Blockers; Cholinesterase Inhibitors; Donepezil; Glutamates; Hippocampus; Humans; Indans; Neuroprotective Agents; Piperidines; Rats; Solid-Phase Synthesis Techniques

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC

Topics: Acrylates; Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Cells, Cultured; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Male; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Neurons; Neuroprotective Agents; Piperidines; Structure-Activity Relationship

In this work, the graft copolymer, poly(vinyl alcohol)-grafted polyacrylamide (PVA-g-PAAm), was synthesized and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and elemental analysis. Microspheres of PVA-g-PAAm/sodium alginate (NaAlg)/sodium carboxymethyl cellulose (NaCMC) were prepared by the emulsion-crosslinking method and used for the delivery of an Alzheimer's drug, donepezil hydrochloride (DP). The release of DP increased with the increase in drug/polymer ratio (d/p) and PVA-g-PAAm/NaAlg/NaCMC ratio, while it decreased with the increase in the extent of crosslinking. The optimum DP release was obtained as 92.9% for a PVA-g-PAAm/NaAlg/NaCMC ratio of 1/2/1, d/p ratio of 1/8, and FeCl3 concentration of 7% (w/v).

Topics: Acrylamide; Alginates; Alzheimer Disease; Carboxymethylcellulose Sodium; Chlorides; Donepezil; Drug Carriers; Drug Compounding; Drug Liberation; Ferric Compounds; Glucuronic Acid; Hexuronic Acids; Hydrogen-Ion Concentration; Indans; Kinetics; Microspheres; Piperidines; Polyvinyl Alcohol

Vascular endothelial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). Patients with AD have displayed decreased circulating endothelial progenitor cells (EPCs) which repair and maintain the endothelial function. Transplantation of EPCs has emerged as a promising approach for the management of cerebrovascular diseases including ischemic stroke, however, its impact on AD has been poorly described. Thus, the current study aimed at investigating the effects of bone marrow-derived (BM) EPCs transplantation in repeated scopolamine-induced cognitive impairment, an experimental model that replicates biomarkers of AD. Intravenously transplanted BM-EPCs migrated into the brain of rats and improved the learning and memory deficits. Meanwhile, they mitigated the deposition of amyloid plaques and associated histopathological alterations. At the molecular levels, BM-EPCs blunted the increase of hippocampal amyloid beta protein (Aβ), amyloid precursor protein (APP) and reinstated the Aβ-degrading neprilysin together with downregulation of p-tau and its upstream glycogen synthase kinase-3β (GSK-3β). They also corrected the perturbations of neurotransmitter levels including restoration of acetylcholine and associated esterase along with dopamine, GABA, and the neuroexitatory glutamate. Furthermore, BM-EPCs induced behavioral recovery via boosting of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its upstream cAMP response element binding (CREB), suppression of the proinflammatory tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and upregulation of interleukin-10 (IL-10). BM-EPCs also augmented Nrf2 and seladin-1. Generally, these actions were analogous to those exerted by adipose tissue-derived mesenchymal stem cells (AT-MSCs) and the reference anti-Alzheimer donepezil. For the first time, these findings highlight the beneficial actions of BM-EPCs against the memory deficits and AD-like pathological dysfunction.

Topics: Adipose Tissue; Alzheimer Disease; Animals; Cell Movement; Cells, Cultured; Cognition Disorders; Cytokines; Disease Models, Animal; Donepezil; Endothelial Progenitor Cells; Gene Expression Profiling; Hippocampus; Indans; Intercellular Signaling Peptides and Proteins; Learning Disabilities; Male; Maze Learning; Mesenchymal Stem Cell Transplantation; Nerve Tissue Proteins; Neurotransmitter Agents; Piperidines; Random Allocation; Rats; Rats, Wistar; Scopolamine

Alzheimer's disease (AD) is one of the most important diseases in aging society, and non-drug therapy might be an alternative therapeutic approach. Thus, we evaluated the add-on effect of cognitive rehabilitation on AD patients under donepezil treatment.. We retrospectively analyzed 55 AD patients with a Mini-Mental State Examination score of 15-25, dividing them into two groups depending on whether they were receiving ambulatory cognitive rehabilitation (group D + R, n = 32) or not (group D, n = 23) in Kurashiki Heisei Hospital over 1 year. The present cognitive rehabilitation included physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week.. Between group D and group D + R, there was no significant difference in baseline data, such as age, Mini-Mental State Examination score, periventricular hyperintensity on magnetic resonance imaging, deep white matter hyperintensity on magnetic resonance imaging or donepezil dose (4.1 mg/day). At 1 year later, however, the Mini-Mental State Examination score improved only in group D + R from 21.7 to 24.0 (**P < 0.001), whereas that of group D remained at 21.5 with both groups of donepezil 5.0 mg/day.. The combination of cognitive rehabilitation plus a choline esterase inhibitor donepezil showed a better effect for the cognitive function of AD patients than drug only therapy at 1 year.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Combined Modality Therapy; Donepezil; Humans; Indans; Piperidines; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79-year-old woman with dementia of the Alzheimer's type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6-year follow-up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor-induced increased libido and the current literature on hypersexuality as a side-effect of donepezil treatment are discussed.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Libido; Piperidines; Sleep Initiation and Maintenance Disorders; Thiazepines; Treatment Outcome

Depression is a frequent comorbid condition in patients with Alzheimer's disease (AD). In the present study, we reported the effect of additional donepezil treatment for patients with geriatric depression who exhibited cognitive deficit and were diagnosed with AD during treatment for depression.. The present retrospective study investigated 14 AD outpatients who were diagnosed with geriatric depression at first and received antidepressant treatment. When apparent cognitive decline was observed, all of them were diagnosed with AD and received donepezil (5 mg/day) for at least 1 year. All patients underwent periodic examination of cognitive function (Mini-Mental State Examination, Rorschach Cognitive Index) and clinical evaluation (Clinical Dementia Rating). The 14 patients were classified into three groups according to their treatment course: (i) 'A' group, patients who showed cognitive impairment during a long course of treatment for depression; (ii) 'B' group, patients who showed cognitive impairment at an early stage of treatment for depression and started to take additional donepezil at least 20 months after the first examination; and (iii) 'C' group, patients who showed cognitive impairment at an early stage of treatment for depression and began taking additional donepezil within 10 months of the first examination. The clinical feature and treatment effects were examined for each group.. At 1 and 2 years after the start of treatment, the proportion of patients who had improved or maintained their Clinical Dementia Rating score was higher in 'A' and 'C' groups than in 'B' group. In 'B' group, additional donepezil treatment commenced later than in the other groups. Therefore, donepezil had an insufficient curative effect.. The results of this study suggested that early induction of donepezil treatment was necessary when apparent cognitive decline was identified during the treatment of geriatric depression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depression; Donepezil; Female; Geriatric Assessment; Humans; Indans; Male; Nootropic Agents; Piperidines; Retrospective Studies; Severity of Illness Index; Treatment Outcome

There have been very few long-term studies involving a large study population; existing studies usually have no more than a few hundred patients with Alzheimer's disease. For these reasons, there are no detailed investigations regarding changes in activities of daily living evaluated by the Functional Assessment Staging Test (FAST).. A long-term, large-scale observational study of donepezil hydrochloride (Aricept(®); Eisai Co., Ltd, Tokyo, Japan) is currently in progress. Its objective is to investigate disease state changes associated with the long-term administration of this drug and its safety in patients with Alzheimer's disease. In this report, data collected over a maximum of 24 months were compiled. Efficacy was assessed using FAST and a cognitive function test (Mini-Mental State Examination or the Hasegawa's Dementia Scale-Revised).. The percentages of patients whose FAST stage improved or remained the same compared to at the start of donepezil hydrochloride administration (baseline) were 91.1% at 6 months, 83.0% at 12 months, 79.5% at 18 months, and 74.8% at 24 months. Multivariate logistic regression analysis was conducted to investigate factors that affect the improvement and maintenance or exacerbation of FAST at 24 months. 'Independence level in the daily life of elderly with dementia' and 'duration of illness' were identified as variables that affected the improvement and maintenance or exacerbation of FAST. Cognitive function improved significantly at 12 weeks and at 6 months compared to baseline, maintained baseline levels at 12 months and at 18 months, and decreased significantly at 24 months compared to baseline.. This is the largest prospective study involving Alzheimer's disease patients in Japan, and we believe it is an important study that shows the reality of daily clinical practice.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Japan; Long-Term Care; Male; Mental Status Schedule; Middle Aged; Piperidines; Prospective Studies; Treatment Outcome

A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single-photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy.. We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini-Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy).. After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy.. Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase acetylcholine and the nicotinic receptor-modulation effect within the frontal lobe, both of which are associated with apathy and executive dysfunction in AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Apathy; Cholinesterase Inhibitors; Donepezil; Executive Function; Female; Galantamine; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Piperidines; Prospective Studies; Tomography, Emission-Computed, Single-Photon

In humans, donepezil (D) is metabolized to 5-O-desmethyl-donepezil (5DD), 6-O-desmethyl-donepezil (6DD), and donepezil-N-oxide (DNox). Although 6DD and DNox are pharmacologically active, the activity of 5DD is unknown. At present, no routine methods are available to detect D and its 3 metabolites simultaneously. In this study, a novel high-performance liquid chromatography method was developed and applied to a population of patients with Alzheimer disease on stable treatment with the drug.. Liquid-liquid extraction from plasma was accomplished by means of a solvent mixture of n-hexane/dichloromethane/ethylacetate (45:40:15) after sample alkalinization. Disopyramide was the internal standard. After evaporation, the residue was reconstituted in 200 μL of mobile phase (acetonitrile 85%:1% acetic acid 15%) and 50 μL was injected into the high-performance liquid chromatography column (X-Terra, RP8; flow: 1 mL/min). Photometric and fluorimetric detectors were used in tandem, to maximize the sensitivity of fluorescent compounds (D, 5DD, and DNox) and also to reveal nonfluorescent compounds (6DD and internal standard).. The method was linear in the 10-100 ng/mL concentration range. Imprecision (coefficient of variation) varied between 3.2% and 12.6% and inaccuracy (% mean absolute error) between 1.3% and 13.3%, depending on the compound, concentration, and detection mode. The quantitation limits were 0.1-0.3 ng/mL for fluorescent compounds and 1.2-4.3 ng/mL for photometric compounds. D, 5DD, 6DD, and DNox through concentrations were measured in 54 patients with Alzheimer disease on treatment with D (10 mg q.d.). No interfering peaks by endogenous compounds or coadministered drugs were noted. Plasma concentrations were quite variable among patients (D: 10-106 ng/mL; 5DD: 0.07-2.8 ng/mL; 6DD: 1.2-36 ng/mL; DNox: 0.5-45.4 ng/mL). Of note, in 6 patients, the plasma concentrations of the 2 active metabolites (6DD and DNox) were higher than those of the parent drug.. The above method proved to be suitable for therapeutic drug monitoring and may be useful in ascertaining the real contribution of metabolites to the therapeutic effects of donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Chromatography, High Pressure Liquid; Cyclic N-Oxides; Donepezil; Drug Monitoring; Female; Humans; Indans; Liquid-Liquid Extraction; Male; Nootropic Agents; Piperidines

Determine if donepezil will raise the insulin-like growth factor-1 levels of patients with amnestic mild cognitive impairment and Alzheimer's disease.. In an outpatient setting, recruit amnestic mild cognitive impairment and Alzheimer's disease patients who were to start treatment with donepezil. Measure total serum insulin-like growth factor-1 levels before and after 3-6 months of treatment.. Twenty-four patients were recruited. After a mean duration of 129 ± 37 days, 14 patients returned taking 5 mg (n=4) or 10 mg (n=10) donepezil per day. Twelve patients experienced decreases in their insulin-like growth factor-1 levels, one had no change, and one experienced an increase. Their mean insulin-like growth factor-1 level dropped by 13%, from 113 ± 31 ng/ml to 98 ± 28 ng/ml (p<0.001).. Contrary to the expected increase in insulin-like growth factor-1 levels in response to donepezil that has been reported for normal elderly adults, our patients experienced decreases. This finding suggests that the somatotropic axis is altered in amnestic mild cognitive impairment and Alzheimer's disease relative to normal older adults.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Insulin-Like Growth Factor I; Male; Piperidines

Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.

Topics: Alzheimer Disease; Animals; Avoidance Learning; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Indans; Male; Maze Learning; Muscarinic Antagonists; Piperidines; Quinuclidinyl Benzilate; Rats, Wistar; Tacrine

The recent DOMINO-AD trial suggests that continued treatment with donepezil delays nursing home placement for patients with severe Alzheimer disease, but more work is needed to support strong conclusions about whether the benefits outweigh the costs.

Topics: Alzheimer Disease; Female; Homes for the Aged; Humans; Indans; Male; Memantine; Nootropic Agents; Nursing Homes; Piperidines

Polymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease.. A total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5-10mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined.. We found that ApoE E3 non-carriers responded better to DNP treatment than E3 carriers (p=0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29±3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients (p=0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy.. The ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E3; Asian People; Cytochrome P-450 CYP2D6; Donepezil; Female; Genotype; Humans; Indans; Male; Piperidines; Polymorphism, Genetic; Precision Medicine

Donepezil is a drug usually administered by oral route for Alzheimer disease treatment, but several gastric side effects have been reported as diarrhea, nausea, and anorexia. We explored the phase behavior of lyotropic liquid crystalline (LLC) mesophases composed by monoolein/oleic acid/water for enhanced administration of donepezil. Polarized light microscopy suggested that these systems ranged from isotropic inverse micellar solutions (L2) to viscous and birefringent reverse hexagonal (HII) mesophases according to the amount of water in the ternary systems. Phase transition was observed from a L2 phase to HII mesophase after swelling studies, an interesting property to be explored as a precursor of LLC mesophases for mucosal administration that increases its viscosity in situ. Mucoadhesive properties of LLC mesophases were characterized using a texture analyzer indicating that these systems can have an increased residence time in the site of absorption. Donepezil-free base was incorporated in the evaluated formulations, and their in vitro release was controlled up to 24 h. The phase behavior of the systems demonstrated a great potential for enhanced donepezil administration once these mucoadhesive-controlled release formulations can incorporate the drug and prolong its release, possibly reducing its side effects.

Topics: Adhesiveness; Alzheimer Disease; Animals; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Delayed-Action Preparations; Donepezil; Drug Carriers; Drug Liberation; Glycerides; Humans; In Vitro Techniques; Indans; Intestinal Mucosa; Models, Theoretical; Nanostructures; Oleic Acid; Phase Transition; Piperidines; Solubility; Swine; Water

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents; Cognition Disorders; Cyclin-Dependent Kinases; Disease Models, Animal; Flavonoids; Frontal Lobe; Hippocampus; Male; Memory; Memory Disorders; Mice; Neurons; Peptide Fragments; Piperidines

We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and β-amyloid (Aβ)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aβ self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cell Line, Tumor; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Clioquinol; Copper; Donepezil; Drug Design; Human Umbilical Vein Endothelial Cells; Humans; Indans; Oxyquinoline; Piperidines; Structure-Activity Relationship; Zinc

There is an increasing interest in cognitive and functional outcomes in the respective stages of Alzheimer's disease (AD) and in novel therapies particularly for the milder phases of AD. Our aim was to describe and compare various aspects of disease progression in patients with mild versus moderate AD in routine clinical practice of cholinesterase inhibitor (ChEI) therapy.. This 3-year, prospective, observational, multicentre study included 1021 participants. Of these, 734 had mild AD (Mini-Mental State Examination (MMSE) score, 20-26) and 287 had moderate AD (MMSE score, 10-19) at the start of ChEI treatment. At baseline and every 6 months, patients were assessed using cognitive, global, instrumental and basic activities of daily living (ADL) scales. Potential predictors of deterioration in moderate AD were analysed using mixed-effects models.. The change from baseline between participants with mild and moderate stages of AD after 3 years of ChEI therapy differed significantly on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and basic ADL, but not using the MMSE and instrumental ADL scales. Protective independent factors for better cognitive long-term outcome in the group with moderate AD were older age, higher instrumental ADL ability, no antipsychotics, usage of non-steroidal anti-inflammatory drugs/acetylsalicylic acid, living with family member, lower education and a higher mean dose of ChEI. Apolipoprotein E genotype did not influence the rates of disease progression or the longitudinal outcomes. Prediction models were provided for moderate AD.. More sensitive cognitive measures, such as the ADAS-cog scale, are required to detect a possibly faster deterioration among the participants with moderate AD. This study highlighted the clinical importance of instrumental ADL evaluations in patients at a mild stage of AD, and the importance of optimizing the ChEI dose even for individuals with moderate AD. Solitary living was a risk factor for faster cognitive decline, and probably expanded the need for formal care in the group with moderate AD. The patients with more advanced AD and presumably more pronounced neuroinflammation might have additional cognitive benefits from longer-term treatment with anti-inflammatory drugs.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Galantamine; Humans; Indans; Male; Mental Status Schedule; Piperidines; Prospective Studies; Rivastigmine; Severity of Illness Index; Treatment Outcome

Combining N-benzylpiperidine moiety of donepezil and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activity were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for AChE and BuChE, and clearly selective inhibition to MAO-B. Of these compounds, 5m was the most potent inhibitor for eeAChE and eqBuChE (0.87 μM and 0.93 μM, respectively), and it was also a good and balanced inhibitor to hChEs and hMAO-B (1.37 μM for hAChE; 1.98 μM for hBuChE; 2.62 μM for hMAO-B). Molecular modeling and kinetic studies revealed that 5m was a mixed-type inhibitor, which bond simultaneously to CAS, PAS and mid-gorge site of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, 5m showed good ability to cross the BBB and had no toxicity on SH-SY5Y neuroblastoma cells. Collectively, all these results suggested that 5m might be a promising multi-target lead candidate worthy of further pursuit.

Topics: Alzheimer Disease; Animals; Butyrylcholinesterase; Cell Line, Tumor; Cholinesterase Inhibitors; Cholinesterases; Coumarins; Donepezil; Dose-Response Relationship, Drug; Drug Design; Eels; Humans; Indans; Models, Molecular; Molecular Structure; Molecular Targeted Therapy; Piperidines; Structure-Activity Relationship

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; ATP-Binding Cassette Transporters; Benzamides; Brain; Dogs; Hep G2 Cells; Humans; Lipids; Liver; Liver X Receptors; Locomotion; Macaca mulatta; Madin Darby Canine Kidney Cells; Mice; Mice, Transgenic; Orphan Nuclear Receptors; Piperidines

Transdermal drug delivery is an attractive route of drug administration; however, there are relatively few marketed transdermal products. To increase delivery across the skin, strategies to enhance skin permeability are widely investigated, with microneedles demonstrating particular promise. Hydrogel-forming microneedles are inserted into the skin, and following dissolution of a drug loaded reservoir and movement of the drug through the created channels, the microneedle array is removed intact, and can then be readily and safely discarded. This study presents the formulation and evaluation of an integrated microneedle patch containing the Alzheimer's drug, donepezil hydrochloride. The integrated patch consisted of hydrogel-forming microneedles in combination with a donepezil hydrochloride containing film. Formulation and characterisation of plasticised films, prepared from poly(vinylpyrrolidone) or poly (methyl vinyl ether co-maleic anhydride/acid) (Gantrez®) polymers, is presented. Furthermore, in vitro permeation of donepezil hydrochloride across neonatal porcine skin from the patches was investigated, with 854.71μg±122.71μg donepezil hydrochloride delivered after 24h, using the optimum patch formulation. Following administration of the patch to an animal model, plasma concentrations of 51.8±17.6ng/mL were obtained, demonstrating the success of this delivery platform for donepezil hydrochloride.

Topics: Alzheimer Disease; Animals; Area Under Curve; Cholinesterase Inhibitors; Donepezil; Indans; Male; Microinjections; Needles; Piperidines; Rats; Rats, Sprague-Dawley

A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Indans; Linear Models; Male; Piperidines; Rats; Rats, Wistar; Reproducibility of Results; Sensitivity and Specificity; Tacrine; Tandem Mass Spectrometry

Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

Topics: Alzheimer Disease; Animals; Blood Glucose; Body Weight; Brain; Cytokines; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Nerve Tissue Proteins; Nitric Oxide Synthase Type II; Oxidative Stress; Piperidines; Rats; Rats, Zucker; Signal Transduction; Transcriptome; Uracil

Alzheime's disease (AD) is an overwhelming neurodegenerative disorder, characterized by synaptic dysfunction, memory loss, neuro-inflammation and neural cell death. Very few treatments are in hand for the management of AD and they are only concentrating on peculiar aspects. Hence, an immense thrust is required to find utmost therapeutic targets to conquer this condition. This study investigates a potential role of vanillin, a selective agonist of transient receptor potential vanilloid subtype 1 (TRPV1) in the experimental models of AD viz. intracerebroventricular (i.c.v.) streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose induced AD in mice. The i.c.v. administration of STZ and intraperitoneally administration of AlCl3+d-galactose have significantly impaired learning-memory (Morris water maze and attentional set-shifting test), brain structure (hematoxylin, eosin and Congo red staining), enhanced brain oxidative stress (thiobarbituric acid reactive substance - TBARS and glutathione - GSH), nitrosative stress (nitrite/nitrate), acetylcholinesterase activity (AChE), inflammation (MPO), and calcium levels (Ca(++)). Treatment with vanillin in different doses and donepezil have significantly ameliorated i.c.v. STZ and AlCl3+d-galactose induced reduction in executive function, impaired reversal learning, cognition, memory and brain damage. Treatment with these drugs has also reduced the brain oxidative stress (TBARS and GSH), nitrosative stress (nitrite/nitrate), and AChE, MPO, and Ca(++) levels. These results indicate that vanillin, a selective agonist of TRPV1 and donepezil, a potent acetylcholine esterase inhibitor have attenuated i.c.v. STZ and AlCl3+d-galactose induced experimental AD. Hence, pharmacological positive modulation of TRPV1 channels may be a potential research target for mitigation of AD.

Topics: Aluminum Chloride; Aluminum Compounds; Alzheimer Disease; Animals; Benzaldehydes; Brain; Chlorides; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Galactose; Indans; Mice; Neuroprotective Agents; Nootropic Agents; Piperidines; Streptozocin; TRPV Cation Channels

A few studies have performed on the brain morphometric changes over the whole brain structure following donepezil treatment in patients with Alzheimer's disease (AD). We evaluated the gray matter (GM) and white matter (WM) volume alterations and cellular metabolic changes in patients with AD before and after donepezil treatment, and further to reveal the correlations of the scores of various neuropsychological scales with the volumetric and metabolic changes. Twenty-one subjects comprising of 11 patients with AD and 10 age-matched healthy controls participated in this study. All of the patients participated in the follow-up study 24weeks following donepezil treatment. In this study, a combination of voxel-based morphometry (VBM) and proton magnetic resonance spectroscopy ((1)H-MRS) was used to assess the brain morphometric and metabolic alterations in AD. In the GM volumetric analysis, both of the untreated and treated patients with donepezil showed significantly reduced volumes in the hippocampus (Hip), parahippocampal gyrus (PHG), precuneus (PCu) and middle frontal gyrus compared with healthy controls. However, donepezil-treated patients showed significantly increased volumes in the Hip, PCu, fusiform gyrus and caudate nucleus compared to untreated patients. In the WM volumetric analysis, untreated and treated patients showed significant volume reductions in the posterior limb of internal capsule (PLIC), cerebral peduncle of the midbrain and PHG compared to healthy controls. However, there was no significant WM morphological change after donepezil treatment in patients with AD. In MRS study, untreated patients with AD showed decreased N-acetylaspartate/creatine (NAA/Cr) and increased myo-inositol (mI)/Cr compared to healthy controls, while treated patients showed only decreased NAA/Cr in the same comparison. However, the treated patients showed simultaneously increased NAA/Cr and decreased mI/Cr and choline (Cho)/Cr ratios compared to untreated patients. This study shows the regional GM and WM volume changes in combination with metabolic changes following donepezil treatment in AD. These findings would be helpful to aid our understanding of the neuroanatomical mechanisms associated with effects of donepezil on the cognitive function in AD.

Topics: Aged; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Organ Size; Piperidines; Proton Magnetic Resonance Spectroscopy; Severity of Illness Index

Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood.

Topics: Alzheimer Disease; Animals; Autopsy; Blood Chemical Analysis; Cholinesterase Inhibitors; Donepezil; Hydrogen-Ion Concentration; Indans; Piperidines; Postmortem Changes; Rats; Time Factors; Tissue Distribution

PET imaging studies using 5-HT1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT1A receptor impairment during AD. Quantitative autoradiography using [(18)F]F13640 and [(18)F]MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of patients with AD (n = 25, at different Braak stages) and control subjects (n = 9). The neuronal density was measured in the same tissues by NeuN immunohistochemistry. The specific binding of both radiotracers was determined by addition of WAY-100635, a selective 5-HT1A receptor antagonist. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was in the pyramidal layer of CA1. Incubation with Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [(18)F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [(18)F]MPPF binding. In the CA1 subfield, [(18)F]F13640 binding was significantly decreased at Braak stages I/II (-19%), Braak stages III/IV (-23%), and Braak stages V/VI (-36%) versus control. In contrast, [(18)F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (-33%). Since [(18)F]F13640 and [(18)F]MPPF can be used in vivo in humans, this neuropharmacological paradigm supports testing the concept of functional imaging using agonist radiopharmaceuticals in future clinical studies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Autopsy; Female; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Protein Binding; Pyridines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists

Topics: Aged, 80 and over; Alzheimer Disease; Antidepressive Agents, Second-Generation; Chemical and Drug Induced Liver Injury; Citalopram; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Nootropic Agents; Piperidines

Natural and plant-based polymers could be used for control release of drugs and also helps in targeting drug to the site of action. The main objective of present work was to check the feasibility of plant-based, namely, mango gum polymeric nanoparticles (NPs) as a carrier for central nervous system (CNS) delivery using model drug donepezil (DZP). The NPs were prepared by modified ionic gelation method and emulsion cross-linking method. Zeta sizer results showed that the diameter of NPs was about 90-130 nm. The polymeric DZP-loaded NPs were almost spherical in shape, as revealed by transmission electron microscopy (TEM). On increasing concentration of NPs suspension from 50 μg/ml to 5000 μg/ml there was no significant increase in % hemolysis. In vivo studies showed that brain targeting was achieved. So on the basis of above results, the extracted water soluble fraction of mango gum is a suitable candidate for brain delivery in the form of nanoformulations.

Topics: Alzheimer Disease; Animals; Anions; Cell Line, Tumor; Central Nervous System; Central Nervous System Agents; Donepezil; Drug Carriers; Drug Delivery Systems; Emulsions; Gels; Humans; Indans; Nanoparticles; Particle Size; Piperidines; Polymers; Rats; Rats, Wistar

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Mice; Molecular Structure; Piperidines; Rats; Rats, Wistar; Reactive Oxygen Species; Structure-Activity Relationship; Thiazoles; Tumor Cells, Cultured

5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Chemistry Techniques, Synthetic; Drug Design; Guinea Pigs; HEK293 Cells; Humans; Ligands; Male; Mice; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

Here we describe new families of multi-target directed ligands obtained by linking antioxidant cinnamic-related structures with N-benzylpiperidine (NBP) or N,N-dibenzyl(N-methyl)amine (DBMA) fragments. Resulting hybrids, in addition to their antioxidant and neuroprotective properties against mitochondrial oxidative stress, are active at relevant molecular targets in Alzheimer's disease, such as cholinesterases (hAChE and hBuChE) and monoamine oxidases (hMAO-A and hMAO-B). Hybrids derived from umbellic - NBP (8), caffeic - NBP (9), and ferulic - DBMA (12) displayed balanced biological profiles, with IC50s in the low-micromolar and submicromolar range for hChEs and hMAOs, and an antioxidant potency comparable to vitamin E. Moreover, the caffeic - NBP hybrid 9 is able to improve the differentiation of adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.

Topics: Alzheimer Disease; Amines; Animals; Antioxidants; Cell Line, Tumor; Cholinesterases; Drug Design; Humans; Male; Mice; Molecular Targeted Therapy; Monoamine Oxidase; Neuroprotective Agents; Piperidines

Topics: Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Donepezil; Female; Hemianopsia; Humans; Indans; Magnetic Resonance Imaging; Middle Aged; Neuropsychological Tests; Occipital Lobe; Parietal Lobe; Piperidines; Visual Field Tests; Visual Fields

Donepezil hydrochloride (DPH) is often used in the treatment of Alzheimer's disease. A new treatment method was developed by encapsulating high DPH content in the tips of dissolving microneedles for rapid, transdermal delivery of a predetermined dose of DPH. The microneedles were prepared by a micromolding method using a hydroxy-propyl-methyl-cellulose (HPMC)-ethanol/water mixture (80:20, v/v) for the tips and carboxy-methyl cellulose (CMC)-water for the base of the needles. The micromolding method involved centrifuging a DPH-HPMC-ethanol/water mixture at 10°C to obtain tips with sufficient mechanical strength. To test their mechanical strength, microneedles with different DPH content were inserted into porcine skin. Then the amount of DPH encapsulated in the microneedles was measured using high-performance liquid chromatography. The efficiency of administering DPH tip-loaded microneedles was investigated using four administrations of a pharmacokinetic test: (1) two oral administration groups (283μg/kg and 692μg/kg) and (2) two microneedle administration groups (283μg/kg and 692μg/kg). High DPH content (up to 78%, w/w) was encapsulated in the microneedle tips without serious loss of mechanical strength by using a mixture of hydroxy-propyl-methyl-cellulose (HPMC) and ethanol/water mixture (80:20, v/v). Because of the distribution of DPH in the tips, 95% of the DPH was delivered into porcine skin after 5min of insertion. As measured by Cmax and AUC, transdermal delivery of DPH tip-loaded microneedles was more effective compared to oral administration of the same dose of DPH. Transdermal delivery could replace oral administration of DPH.

Topics: Administration, Cutaneous; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Needles; Piperidines; Solubility

Differential diagnosis between Lewy body disease and Alzheimer´s disease might be difficult because of similarities of clinical symptoms in both neurodegenerative diseases. DatSCAN is a modern functional neuroimmaging method which differentiates between this similar diseases and helps in correct treatment strategy. We report our positive experience with DatSCAN in differentiating Lewy body disease from Alzheimer´s disease. This is a case report of a woman with Lewy body disease, initially diagnosed as Alzheimer´s disease. DatSCAN neuroimmaging method was used in differential diagnosis of dementia. Memory impairment, impaired activities of daily living, sleep and behavioral disturbances were present in our case. Donepezil was well tolerated, but haloperidol administration was followed by development of severe dystonia. DatSCAN showed deficient dopaminergic presynaptic transport in substantia nigra and striatum. This finding is typical for Lewy body disease not for Alzheimer´s disease. DatSCAN neuroimmaging is a suitable method for differentiating Lewy body disease from Alzheimer´s disease. Deficient dopaminergic presynaptic transport in substantia nigra and striatum is typical for Lewy body disease.

Topics: Aged, 80 and over; Alzheimer Disease; Czech Republic; Diagnosis, Differential; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines; Synaptic Transmission; Tomography, X-Ray Computed

Donepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Aβ). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC).. Fifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n = 25) or not (DNPZ-, n = 25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for Aβ and NAb determination.. Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-Aβ NAb with respect to DNPZ- patients and Aβ 1-42 with respect to normal controls.. Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aβ may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Aged; Aged, 80 and over; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Cells, Cultured; Donepezil; Female; GATA3 Transcription Factor; Humans; Immunity, Cellular; Indans; Leukocytes, Mononuclear; Male; Middle Aged; Nootropic Agents; Piperidines

Topics: Alzheimer Disease; Animals; Catalase; Cholinesterase Inhibitors; Humans; Indoles; Pargyline; Piperidines; Propylamines; Signal Transduction; Superoxide Dismutase-1; Up-Regulation

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Electrophorus; Horses; Humans; Indans; Kinetics; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Piperidines; Rats; Structure-Activity Relationship

A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Catalytic Domain; Cell Line, Tumor; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Electrophorus; Horses; Humans; Indans; Indoles; Iron; Kinetics; Melatonin; Molecular Docking Simulation; Peptide Fragments; Piperidines; Protein Multimerization; Rats; Zinc

The cannabinoid system plays an important role in memory processes, many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents. A nonapeptide hemopressin (Hp) derived from rat brain, acts as a peptide antagonist or selective inverse peptide agonist of cannabinoid 1 (CB1) receptor. N-terminally extended forms of Hp isolated from mouse brain, (m)RVD-hemopressin(α) (RVD) and (m)VD-hemopressin(α) (VD) also bind CB1 receptor, however, as peptide agonists. Here, we investigated the roles of Hp, RVD, and VD on memory in mice using novel object recognition (NOR) and object location recognition (OLR) tasks. In normal young mice, intracerebroventricular (i.c.v.) infusion of Hp before training not only improved memory formation, but also prolonged memory retention in the tasks, these effects could be inhibited by RVD or VD at the same dose and intraperitoneal (i.p.) injection of a small molecule agonist of CB1 receptor WIN55, 212-2 15min before administration of Hp inhibited the memory-improving effect of Hp. In addition, under the same experimental conditions, i.c.v. RVD or VD displayed memory-impairing effects, which could be prevented by Hp (i.c.v.) or AM251 (i.p.), a small molecule antagonist of CB1 receptor. Infusion of amyloid-β (1-42) (Aβ1-42) 14days before training resulted in impairment of memory in mice which could be used as animal model of Alzheimer's disease (AD). In these mice, RVD or VD (i.c.v.) reversed the memory impairment induced by Aβ1-42, and the effects of RVD and VD could be suppressed by Hp (i.c.v.) or AM251 (2mg/kg, i.p.). Separate administration of Hp had no effect in Aβ1-42-treated mice. The above results suggested that Hp, RVD and VD, as CB1 receptor peptide ligands, may be potential drugs to treatment of the memory deficit-involving disease, just as AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Hemoglobins; Infusions, Intraventricular; Male; Memory Disorders; Mice; Morpholines; Naphthalenes; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Copper; Donepezil; Drug Design; Humans; Indans; Kinetics; Liver; Mice; Models, Molecular; Peptide Fragments; Piperidines; Protein Aggregates; Protein Conformation

Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both β amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Female; Indans; Male; Memantine; Memory; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neuroimmunomodulation; Neuroprotective Agents; Peptide Fragments; Phenotype; Piperazines; Piperidines; Pyridazines; Random Allocation; Rats, Sprague-Dawley

Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.

Topics: Aldehydes; Alzheimer Disease; Amyloid Precursor Protein Secretases; Chemistry Techniques, Synthetic; Drug Discovery; Humans; Ketones; Piperidines; Stereoisomerism

Hydrazones and the piperidine ring containing compounds were considered as beneficial substrates in drug design. Therefore, this study was aimed at the synthesis of new benzoyl hydrazones derived from ethyl 4-oxopiperidine-1-carboxylate and 2,6-diphenylpiperidin-4-one. The synthesized compounds (1-19) were screened for their antioxidant, anticholinesterase and anticancer activities. The antioxidant capacity of the compounds was evaluated by using four complementary tests. The results showed that compound 7 and 17 have the higher lipid peroxidation inhibitory activity than the other compounds. In DPPH˙ scavenging assay, compounds 5, 6, 10, 14, 17 demonstrated better activity than that of standard BHT, while in ABTS

Topics: Acetylcholinesterase; Alzheimer Disease; Antineoplastic Agents; Butyrylcholinesterase; Catalytic Domain; Cell Line, Tumor; Cell Survival; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Drug Design; Humans; Hydrazones; Molecular Docking Simulation; Piperidines

Accumulation of amyloid-β (Aβ) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3β (GSK3β) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aβ and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3β. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3β signaling and contributes to subsequent down-regulation of Aβ and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aβ production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3β activity by increasing phosphorylation of GSK3β at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3β signaling which may contribute to down-regulation of Aβ and tau hyperphosphorylation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Disease Models, Animal; Donepezil; Drugs, Chinese Herbal; Glycogen Synthase Kinase 3; Hippocampus; Indans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperidines; Signal Transduction; tau Proteins

Alzheimer's disease (AD) is a neurodegenerative disease characterized by sequential progression of pathological events, such as aggregation of amyloid-β proteins, followed by outward symptoms of cognitive impairments. Given that a combination of different therapeutic strategies often provides more rapid and effective outcomes in diverse areas of clinical treatment, we hypothesized that administration of anti-amyloid drugs with cognitive enhancers would result in synergistic effects in AD treatment. Here, we co-administered 4-(2-hydroxyethyl)-1-piperazinepropane-sulphonic acid (EPPS), an amyloid-clearing chemical, and donepezil, an acetylcholinesterase inhibitor, to determine whether they could serve complementary roles for each other in regards to AD treatment. We found that oral administration of these two molecules led to a rapid and consistent cognitive improvement in APP/PS1 transgenic mice. Although there was no evidence for synergistic effects, our results indicated that EPPS and donepezil function complementary to each other without altering their individual effects. Thus, the combined use of disease-modifying and symptomatic relief drugs may be a promising approach in the treatment of AD.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cognition; Donepezil; Humans; Indans; Mice; Mice, Transgenic; Piperazines; Piperidines; Recovery of Function

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities.

Topics: Acetylcholinesterase; Alzheimer Disease; Binding Sites; Cholinesterase Inhibitors; Donepezil; GPI-Linked Proteins; Indans; Ligands; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; Piperidines; Protein Binding; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Reproducibility of Results; Thermodynamics

Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM. In AβPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-β peptide 1-42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Berberine; Brain; Cell Survival; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Enzyme Inhibitors; Humans; Indans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Male; Mice, Transgenic; Nootropic Agents; PC12 Cells; Piperidines; Plaque, Amyloid; Presenilin-1; Rats

Matrix type transdermal films of donepezil (DNP) as an alternative delivery approach was designed to improve patient compliance to Alzheimer disease treatment. Sodium alginate, a natural polysaccharide, was used as matrix-forming agent in the optimization of transdermal films. Propylene glycol and dl-limonene was added into films as a plasticizer and permeation enhancer, respectively. As well as mechanical strength and bioadhesiveness of optimized transdermal films of DNP, the impact of dl-limonene concentration in films on DNP in vitro permeation across pig skin was assessed. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) measurements were carried out to examine the effects of enhancer on in vitro conformational order of the stratum corneum intercellular lipids following permeation study. Results showed that transdermal formulations of DNP were suitable due to both mechanical and bioadhesive features of the films. In vitro skin permeation study indicated that dl-limonene at a concentration of 3% was optimum with high drug flux. ATR-FTIR results confirmed a more fluidized stratum corneum lipid state in the presence of dl-limonene, indicating its permeation enhancement effect. Regarding to achieve therapeutic levels of DNP, it seems to be feasible deliver DNP with transdermal films for the management of Alzheimer disease.

Topics: Adhesiveness; Administration, Cutaneous; Alzheimer Disease; Animals; Biopolymers; Chemistry, Pharmaceutical; Cyclohexenes; Donepezil; Dosage Forms; Indans; Limonene; Lipids; Permeability; Piperidines; Plasticizers; Propylene Glycol; Skin; Skin Absorption; Swine; Terpenes

Adherence to cholinesterase inhibitor (ChEI) is associated with treatment effectiveness in the treatment of Alzheimer's disease (AD). We investigated the clinical adherence to donepezil in Taiwan.. This was a retrospective study. Patients treated with donepezil were recruited from Kaohsiung Medical University Hospital and Kaohsiung Municipal Ta-Tung Hospital from February 2004 to April 2013. We analyzed their treatment duration in months.. A total of 273 patients were included in our analysis. Sixty-seven patients withdrew from donepezil treatment with mean treatment duration of 28.0 ± 25.9 months. Better initial scores on the Mini-Mental Status Examination (P = .007), Cognitive Abilities Screening Instrument (P = .003), and the Clinical Dementia Rating Scale (CDR) Sum of Boxes (P = .011) were positively associated with clinical adherence. The clinical adherent rate was higher in the CDR-0.5 group than in the CDR-2.0 group with significant difference.. Although there are some limitations in our study, these findings indicate that early intervention with ChEI in patients with AD should be emphasized and may lead to a better clinical adherence.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Medication Adherence; Piperidines; Taiwan

Aiming to verify that therapeutic drug monitoring has the potential to optimize treatment with acetylcholine esterase inhibitors of patients with Alzheimer dementia, this study investigated whether serum concentrations of donepezil are associated with clinical improvement.. Clinical improvement was measured using the clinical global impression (CGI) scale, and donepezil concentrations were measured in serum by a high-performance liquid chromatographic method with spectrophotometric detection.. In total, 206 serum samples from 106 patients (49.5% female) were retrospectively available for analysis. Patients included were treated under everyday conditions. Their mean ± SD age was 72 ± 9 years, daily doses of donepezil were 5 and 10 mg, and their mean ± SD serum concentrations were 23 ± 9 and 47 ± 18 ng/mL, respectively. Serum concentrations correlated significantly (P < 0.001) with CGI scores (Pearson's correlation coefficient r = 0.511, P < 0.01). In patients who were "very much improved," according to their CGI score, the mean serum concentration was 66 ± 20 ng/mL and thus significantly higher (P < 0.01) than in patients with "minimal improvement" (29 ± 12 ng/mL). Receiver operating characteristics analysis suggests that donepezil serum concentrations of at least 50 ng/mL may be recommended for maximal clinical benefit.. Because donepezil serum concentrations were highly variable between individual patients and the majority of patients exhibited concentrations that were below 50 ng/mL at therapeutic doses of 5 and 10 mg/d, it can be concluded that therapeutic drug monitoring may be used to enhance the effectiveness of donepezil treatment.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Indans; Male; Piperidines; Retrospective Studies; Treatment Outcome

Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aβ) peptide. Aβ interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aβ-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aβ, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aβ + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aβ or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aβ or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Aβ. Aβ-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aβ + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Aβ + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aβ-mediated GluN2B-composed NMDARs activation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Beclomethasone; Calcium; Cerebral Cortex; Cognition; Cytosol; Endoplasmic Reticulum; Inositol 1,4,5-Trisphosphate Receptors; Membrane Potential, Mitochondrial; Mice, Transgenic; Mitochondria; Neurons; Piperidines; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Rotenone

GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied amyloid beta (Aβ), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual Aβ accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice. Although LTP induced by theta burst stimulation (TBS) was normal in PS2APP mice, it was significantly reduced by the selective GluN2B-NMDAR antagonist Ro25-6981 (Ro25) in PS2APP mice, but not wild type (wt) mice. While NMDARs activated by single synaptic stimuli were not blocked by Ro25, NMDARs recruited during burst stimulation showed larger blockade by Ro25 in PS2APP mice. Thus, the unusual dependence of LTP on GluN2B-NMDARs in PS2APP mice suggests that non-synaptic GluN2B-NMDARs are activated by glutamate that spills out of synaptic cleft during the burst stimulation used to induce LTP. While long-term depression (LTD) was normal in PS2APP mice, and Ro25 had no impact on LTD in wt mice, Ro25 impaired LTD in PS2APP mice, again demonstrating aberrant GluN2B-NMDAR function during plasticity. Together these results demonstrate altered GluN2B-NMDAR function in a model of early AD pathology that has implications for the therapeutic targeting of NMDARs in AD.

Topics: Alzheimer Disease; Animals; Blotting, Western; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Microscopy, Electron, Transmission; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Tissue Culture Techniques

The standards of care for Alzheimer's disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated.. We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window.. All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range.. These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer's disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.

Topics: Aged; Alzheimer Disease; Animals; Appetitive Behavior; Attention; Cognition; Defecation; Donepezil; Female; Humans; Indans; Macaca mulatta; Male; Muscarinic Agonists; Neuropsychological Tests; Orientation; Piperidines; Problem Solving; Pyridines; Quinolizines; Receptor, Muscarinic M1; Salivation; Thiadiazoles

The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00μM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01μM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63μM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23μM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500μM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).

Topics: Alzheimer Disease; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Donepezil; Drug Interactions; Humans; Indans; Microsomes, Liver; Models, Molecular; Molecular Structure; Nootropic Agents; Piperidines; Structure-Activity Relationship

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Binding Sites; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Donepezil; Free Radical Scavengers; Humans; Indans; Molecular Dynamics Simulation; Piperidines; Protein Binding; Sulfonamides

Due to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget drugs.. Donepezil-ferulic acid hybrids (DFAHs) were prepared by the one-pot Ugi-4CR in low-to-moderate yields. DFAHs are potent antioxidant agents, showing oxygen radical absorbance capacity values in the range 4.80-8.71 trolox equivalents, quite higher compared with those recorded for ferulic acid and melatonin. From the ChEs inhibition studies, we conclude that DFAH 8, bearing an ethylene linker, and DFAH 12, bearing a propylene linker, both substituted with a melatonin motif, are the most potent inhibitors, in the nanomolar range.. We have identified DFAH 8 as a very potent antioxidant, and totally selective equineButyrylCholinEsterase (eqBuChE) inhibitor.

Topics: Alzheimer Disease; Antioxidants; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Donepezil; Humans; Indans; Piperidines

The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780;OR= 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer’s disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer’s disease and human leukocyte antigen.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Apolipoproteins E; Apoptosis; Cholinesterase Inhibitors; Cytochrome P-450 CYP2D6; Donepezil; Fas Ligand Protein; Female; Humans; Indans; Longitudinal Studies; Male; Mental Status Schedule; Meta-Analysis as Topic; Pharmacogenetics; Piperidines; Polymorphism, Genetic; Predictive Value of Tests; Treatment Outcome; Tumor Necrosis Factor-alpha

Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer's disease (AD). Following this approach, a new series of N'-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aβ) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors 5h and 5k, strongly inhibited AChE, with IC50 value of 6.83nM and 2.13nM, respectively, and particularly, compound 5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that 5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aβ1-42 aggregation at 25μM with percentage inhibition from ∼54% to 89% and specially compound 5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that 5k might be a promising lead compound for further AD drug development.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Humans; Kinetics; Molecular Docking Simulation; Oxidative Stress; Piperazines; Piperidines

To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years).. The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total).. The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions.. The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Donepezil; Dopamine Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Galantamine; Humans; Indans; Japan; Male; Memantine; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales

Alzheimer's disease (AD) is a common neurodegenerative disease affecting cognitive function in the elderly, which is characterized by the presence of extracellular deposits of insoluble amyloid-β plaques and neuronal loss. Modern pharmacology and drug development usually follow a single-target principle, which might contribute to the failure of most compounds in clinical trials against AD. Considering AD is a multifactorial disease, a combination therapeutic strategy that applies drugs with different mechanisms would be an alternative way. Smart Soup (SS), a Traditional Chinese Medicine formula, is composed of three herbaceous plants and has been applied in the treatment of amnesia in China for hundreds of years. In this work, we studied the clinical potency of the combination of SS and Aricept in AD therapy. In the in vivo model, both longevity and locomotive activity of AD transgenic Drosophila were improved remarkably in the combined medicine treated group. We also observed less amyloid-β deposition and retarded neuronal loss following the combined drug treatment. In the retrospective cohort study, we found the combination therapy exerted better therapeutic effect on AD patients. Our study revealed that combination therapy with multiple drug targets did have a better therapeutic outcome. It provides a new strategy to develop an optimum pharmaceutical approach against AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Brain; Disease Models, Animal; Donepezil; Drosophila; Drug Therapy, Combination; Drugs, Chinese Herbal; Humans; Indans; Medicine, Chinese Traditional; Neurons; Nootropic Agents; Piperidines; Retrospective Studies; Treatment Outcome

The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-β (Aβ)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of mitochondrial permeability transition (MPT) by calcium ions. Moreover, the level of mitochondrial Aβ in the brain of donepezil-treated APP/PS1 transgenic mice is significantly lower than that of vehicle-treated APP/PS1 mice. Our in vitro study using isolated mitochondria from rat brains, which is expected as an AChE-free subcellular system, further confirms the ameliorative effects of donepezil on oligomeric Aβ1-42 induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the Aβ accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Aβ-associated mitochondrial dysfunction are closely associated with the reduction of Aβ accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Male; Mice, Transgenic; Mitochondria; Neuroprotective Agents; Piperidines; Presenilin-1; Random Allocation; Rats, Sprague-Dawley

To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil.. Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity.. The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data.. Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Topics: Aged; Alzheimer Disease; Donepezil; Ethnicity; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Prospective Studies; Treatment Outcome

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

Topics: Alzheimer Disease; Aminoquinolines; Amyloid beta-Protein Precursor; Animals; Animals, Genetically Modified; Brain; Caenorhabditis elegans; Disease Models, Animal; Donepezil; Hep G2 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Indans; Mice; Molecular Structure; Piperidines

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Computer Simulation; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Ligands; Male; Memory, Short-Term; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship; Toxicity Tests, Acute

We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aβ were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.

Topics: Aging; Alzheimer Disease; Animals; Cholinergic Agents; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Indans; Memory Disorders; Mice, Transgenic; Nootropic Agents; Piperidines; Quinolizines; Receptor, Muscarinic M1; Recognition, Psychology

Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3-3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3-3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD.

Topics: Alzheimer Disease; Animals; Antipsychotic Agents; Basal Ganglia Diseases; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Galantamine; Haloperidol; Hypokinesia; Indans; Male; Mice, Inbred Strains; Nootropic Agents; Piperidines; Receptor, Serotonin, 5-HT1A; Receptors, Muscarinic; Serotonin Agents

Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and β-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and β-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of β-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50=0.72 μM) that has β-amyloid anti-aggregation activity (72.5% inhibition at 10 μM) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Humans; Indans; Indoles; Male; Memory; Mice; Models, Molecular; Neuroprotective Agents; Phthalimides; Piperidines; Protein Aggregates; Scopolamine; Structure-Activity Relationship

Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Blood Platelets; Cholinesterase Inhibitors; Donepezil; Female; Glycogen Synthase Kinase 3; Group VI Phospholipases A2; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Phosphorylation; Piperidines; Time Factors

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Benzodioxoles; Brain; Calcium-Binding Proteins; Disease Models, Animal; Encephalitis; Enzyme Inhibitors; Interferon-gamma; Mice; Mice, Transgenic; Microfilament Proteins; Monoacylglycerol Lipases; Neuroglia; Nitrites; Piperidines

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment that ultimately leads to death. Endothelin (ET) and its receptors have been considered as therapeutic targets for AD. Recent studies in our lab have shown that stimulation of ETB receptors provide significant neuroprotection following Aβ1-40 administration. It is possible that IRL-1620 may be neuroprotective due to angiogenesis. However, the effect of IRL-1620 on neurovascular remodeling following Aβ1-40 administration has not been established. The purpose of this study was to determine the effect of stimulation of ETB receptors by IRL-1620 on vascular and neuronal growth factors after Aβ1-40 administration. Rats were treated with Aβ1-40 (day 1, 7 and 14) in the lateral cerebral ventricles using stereotaxically implanted cannula and received three intravenous injections of IRL-1620 (an ETB agonist), and/or BQ788 (an ETB antagonist) at 2-h interval on day 8; experiments were performed on day 15. Rats were sacrificed for estimation of brain ETB receptors, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression using immunofluorescence and Western blot. In the Morris swim task, amyloid-β (Aβ)-treated rats showed a significant (p<0.0001) impairment in spatial memory. Rats treated with IRL-1620 significantly (p<0.001) reduced the cognitive impairment induced by Aβ. BQ788 treatment completely blocked IRL-1620-induced improvement in cognitive impairment. IRL-1620 treatment enhanced the number of blood vessels labeled with VEGF compared to vehicle treatment. Additionally, cells showed increased (p<0.001) positive staining for NGF in IRL-1620-treated animals. ETB, VEGF and NGF protein expression significantly (p<0.001) increased in the brain of IRL-1620-treated rats as compared to vehicle. Pretreatment with BQ788 blocked the effects of IRL-1620, thus confirming the role of ETB receptors in the neurovascular remodeling actions of IRL-1620. Results of the present study demonstrate that IRL-1620 improves both acquisition (learning) and retention (memory) on the water maze task and enhances angiogenic and neurogenic remodeling. These findings indicate that the ETB receptor may be a novel therapeutic target for AD and other neurovascular degenerative disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Progression; Endothelin B Receptor Antagonists; Endothelins; Male; Maze Learning; Memory; Neovascularization, Pathologic; Nerve Growth Factor; Oligopeptides; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Vascular Endothelial Growth Factor A

The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans.. Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment.. A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not.. These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Atrophy; Cognition Disorders; Donepezil; Entorhinal Cortex; Female; Hippocampus; Humans; Indans; Language; Lewy Body Disease; Magnetic Resonance Imaging; Male; Mental Recall; Neuropsychological Tests; Nootropic Agents; Piperidines; Software; Temporal Lobe; Verbal Behavior

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5mg/kg, 5mg/kg, 10mg/kg and Donepezil (DON) 1mg/kg intraperitoneally (i.p) for 14days. The last 7days of treatment regimen included daily injection of SCP 1.5mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P<0.001) and significantly decreased the acetylcholinesterase activity (P<0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P<0.001) and decreased malonaldehyde levels (P<0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P<0.001) in the SCP group. Additionally, PHL (10mg/kg) significantly enhanced the spatial memory formation (P<0.05) and neurotrophicity (P<0.001) compared to DON (1mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Animals; Antioxidants; Brain-Derived Neurotrophic Factor; Cognition Disorders; Donepezil; Glial Fibrillary Acidic Protein; Indans; Male; Maze Learning; Mice; Motor Activity; Muscarinic Agonists; Neuroprotective Agents; Nootropic Agents; Phloretin; Piperidines; Scopolamine

Latency of P300 subcomponent of event-related potentials (ERPs) increases in Alzheimer disease (AD) patients, which correlate well with cognitive impairment. Cholinesterase inhibitors (ChEIs) reduce P300 latency in AD patients with parallel improvement in cognition. It is not known whether N200 response to ChEIs is similar to that of P300. The aim of this study was to evaluate and compare characteristics of P300 and N200 in AD patients, treatment-naïve and on stable donepezil treatment, matched by age, education, sex, and cognitive function.. We recruited 22 consecutive treatment-naïve AD patients (AD-N group), 22 AD patients treated with a stable donepezil dose of 10 mg/day for at least 3 months (AD-T group), and 50 healthy controls were recruited. Neuropsychological testing (MMSE, ADAS-Cog, and additional tests) and ERP recording was performed and analyzed.. All groups did not differ according to age, duration of education, or sex (p>0.05). AD-N and AD-T groups did not differ according to cognitive function. The AD-T group had longer duration of disease than the AD-N group (p<0.001). The AD-T and AD-N groups did not differ in P300 latencies (p=0.49). N200 latency was longer in the AD-T group (p<0.001). The general linear model showed that significant predictors of P300 latency were age (p=0.019) and AD treatment status (p<0.001). Duration of AD was a significant predictor of N200 latency (p=0.004).. The response of N200 latency to donepezil treatment differs from the response of P300. P300 is a better marker of ChEI treatment-dependent cognitive functions. N200 is more dependent on the duration of AD.

Topics: Aged; Alzheimer Disease; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Event-Related Potentials, P300; Evoked Potentials; Female; Humans; Indans; Male; Piperidines

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.

Topics: Administration, Intranasal; Alkaloids; Alzheimer Disease; Animals; Antioxidants; Apoptosis; Benzodioxoles; Brain Diseases; Caspase 3; Chitosan; Cholinesterase Inhibitors; Cognition; Drug Delivery Systems; Male; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) patients have a poor response to the voices of caregivers. After administration of donepezil, caregivers often find that patients respond more frequently, whereas they had previously pretended to be "deaf." We investigated whether auditory selective attention is associated with response to donepezil.. The subjects were40 AD patients, 20 elderly healthy controls (HCs), and 15 young HCs. Pure tone audiometry was conducted and an original Auditory Selective Attention (ASA) test was performed with a MoCA vigilance test. Reassessment of the AD group was performed after donepezil treatment for 3 months.. Hearing level of the AD group was the same as that of the elderly HC group. However, ASA test scores decreased in the AD group and were correlated with the vigilance test scores. Donepezil responders (MMSE 3+) also showed improvement on the ASA test. At baseline, the responders had higher vigilance and lower ASA test scores.. Contrary to the common view, AD patients had a similar level of hearing ability to healthy elderly. Auditory attention was impaired in AD patients, which suggests that unnecessary sounds should be avoided in nursing homes. Auditory selective attention is associated with response to donepezil in AD.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Cholinesterase Inhibitors; Donepezil; Female; Hearing; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines

To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).. Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed.. Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000).. Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Case-Control Studies; Cerebral Cortex; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Positron-Emission Tomography; ROC Curve

No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market.. To describe ChEI related ADRs in Alzheimer's disease (donepezil, rivastigmine, and galantamine) and characterize their seriousness as reported by national pharmacovigilance systems to VigiBase, a World Health Organization International Drug Monitoring Program database, between 1998 and 2013.. All ChEI RELATED REPORTS: , submitted to VigiBase between 1998 and 2013 from THE FIVE CONTINENTS: were extracted. Analyses were carried out for general, serious, and nonserious ADRs.. A total of 18 955 reports (43 753 ADRs) FROM 58 COUNTRIES: were reported: 60.1% in women; mean age 77.4 ± 9.1 years. Most reports originated from Europe (47.6%) and North America (40.4%). Rivastigmine and donepezil were involved in MOST: reports (41.4% each). The most frequently reported ADRs were neuropsychiatric (31.4%), gastrointestinal (15.9%), general (11.9%), and cardiovascular (11.7%) disorders. During the 2006-2013 period, serious ADRs remained more often reported than nonserious ones; the most serious were neuropsychiatric (34.0%), general (14.0%), cardiovascular (12.1%), and gastrointestinal (11.6%) disorders. Medication errors were reported in 2.0% of serious cases. Death occurred in 2.3% of the reports.. This international pharmacovigilance study highlights the ADR pattern induced by ChEIs. Neuropsychiatric events were the most frequently reported ADRs. Serious cardiovascular events were frequently reported, suggesting that their significance has probably been previously underestimated. Given the frailty of the patients and the frequent comedications, caution is advised before introducing a ChEI.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Galantamine; Humans; Indans; Male; Medication Errors; North America; Pharmacovigilance; Piperidines; Rivastigmine; World Health Organization

Alzheimer's disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood-brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer's type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Blood-Brain Barrier; Brain; Caspase 3; Disease Models, Animal; Drug Delivery Systems; Glycerides; Humans; Inflammation; Kidney; Liquid Crystals; Liver; Male; Nanomedicine; Nanoparticles; Oxidative Stress; Particle Size; Piperidines; Poloxamer; Polyethylene Glycols; Polysorbates; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics.. We performed the "Okayama Rivastigmine Study (ORS)" to retrospectively analyze the clinical effects of rivastigmine (n = 75) or donepezil (n = 71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe's BPSD score (ABS) <6) and the severe BPSD group (6≤ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months.. Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (*p <  0.05 versus baseline) and at 6 months (*p <  0.05), the Frontal Assessment Battery (FAB) at 6 months (*p <  0.05), and ABS at 3 months (**p <  0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (*p <  0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (**p <  0.01) in the rivastigmine group.. Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics.

Topics: Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Mental Status Schedule; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Retrospective Studies; Rivastigmine; Severity of Illness Index; Time Factors; Treatment Outcome

There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting.. "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy.. All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months, *p <  0.05) and rivastigmine (3 months, **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05).. OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Japan; Male; Memantine; Piperidines; Retrospective Studies; Rivastigmine; Treatment Outcome

In this issue, an article by Waring et al. provides a meta-analysis of the effects of apo-lipo-protein E (APOE) genotype on the beneficial effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD). There was no significant effect found. As of 2015, AChEI medications are the mainstay of AD treatment, and APOE genotype is the most significant factor associated with AD causation. This lack of a significant effect of APOE is analyzed with respect to the "Cholinergic Hypothesis" of AD, dating from 1976, through the recognition that cholinergic neurons are not the sole target of AD, but rather that AD attacks all levels of neuroplasticity in the brain, an idea originated by Ashford and Jarvik in 1985 and which still provides the clearest explanation for AD dementia. The "Amyloid Hypothesis" is dissected back to the alpha/beta pathway switching mechanism affecting the nexin-amyloid pre-protein (NAPP switch). The NAPP switch may be the critical neuroplasticity component of all learning involving synapse remodeling and subserve all learning mechanisms. The gamma-secretase cleavage is discussed, and its normal complementary products, beta-amyloid and the NAPP intracellular domain (NAICD), appear to be involved in natural synapse removal, but the link to AD dementia may involve the NAICD rather than beta-amyloid. Understanding neuroplasticity and the critical pathways to AD dementia are needed to determine therapies and preventive strategies for AD. In particular, the effect of APOE on AD predisposition needs to be established and a means found to adjust its effect to prevent AD.

Topics: Alzheimer Disease; Apolipoprotein E4; Cholinesterase Inhibitors; Female; Humans; Indans; Male; Piperidines

Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive dysfunction. The pathology of AD is mainly related to amyloid ß (Aß)-peptides, but glutamate-mediated toxicity is also one of the main processes of memory impairment in AD. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is particularly involved in synaptic plasticity, memory, and learning. Memantine is a low-affinity voltage-dependent noncompetitive antagonist at glutamatergic NMDA receptors. Here,we investigated whether memantine protects against glutamate-induced senescence. In PC12 cells, treatment with glutamate induced senescent phenotypes as judged by the cell appearance and senescence-associated ß-galactosidase (SA-ßgal) in parallel with decreased SIRT1 and increased p53 expression. However, treatment with memantine decreased glutamate-induced senescent PC12 cells and reversed the changes in SIRT1 and p53 expression. Glutamate is known to stimulate the production of NO and O2(-) and has the capacity to generate ONOO(-) in the CNS. Therefore, we investigated whether glutamate activates nNOS and memantine reverses it. Treatment with glutamate increased nNOS expression, activity, and production of NO,whereas memantine blocked them. Next, the in vivo effects of memantine on cognitive function in senescence-accelerated mouse prone 8 (SAMP8), as a model of AD, were investigated. In the Morris water maze test, SAMP8 showed a marked decline in performance, but memantine administration improved it. Moreover, neuronal senescence and the level of oxidative stress in the hippocampus were decreased by memantine. Finally, the effects of combination treatment with memantine and donepezil, a cholinesterase inhibitor, were investigated. We observed additive effects of memantine and donepezil on the senescent phenotype of PC12 cells and the hippocampus of SAMP8. These results indicate that inhibition of the NMDA receptor by memantine leads to a decrease innNOS activity and results in a reduction of glutamate-induced senescence. Thus, our present study suggests a critical role of memantine in the prevention of neuronal aging, and supports that donepezil has a combined effect with memantine.

Topics: Aging; Alzheimer Disease; Animals; beta-Galactosidase; Cholinesterase Inhibitors; Cognition; Disease Models, Animal; Donepezil; Glutamic Acid; Hippocampus; Indans; Male; Maze Learning; Memantine; Memory; Mice; Neuronal Plasticity; Nitric Oxide Synthase Type I; PC12 Cells; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate

The possibility that drug-induced lupus erythematosus (DILE) can be induced by donepezil is presented in this clinical case. Donepezil is an inhibitor of acetylcholinesterase used for the treatment of Alzheimer's disease. It is the first time that donepezil causes DILE.

Topics: Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Hydrolases; Indans; Lupus Erythematosus, Systemic; Nootropic Agents; Piperidines; Skin

An 80-year-old woman with Alzheimer's dementia presented with diarrhoea, vomiting and worsening confusion following an increase in donepezil dose from 5 to 10 mg. The ECG revealed prolongation of QTc interval. Soon after admission, she became unresponsive with polymorphic ventricular tachycardia (VT). Cardiopulmonary resuscitation with a 200 J shock was successful in establishing cardiac output. Following the discontinuation of donepezil, the QTc interval normalised and no further arrhythmias were recorded. Treatment with anticholinesterase inhibitors may result in life-threatening VT. Vigilance is required for the identification of this condition in patients presenting with presyncope, syncope or seizures.

Topics: Aged, 80 and over; Alzheimer Disease; Cardiopulmonary Resuscitation; Donepezil; Electrocardiography; Female; Humans; Indans; Long QT Syndrome; Nootropic Agents; Piperidines; Seizures; Syncope; Torsades de Pointes

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Nursing Homes; Patient Admission; Piperidines; Randomized Controlled Trials as Topic; Withholding Treatment

Amyloid beta (Aβ) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimer's disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Aβ with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and β1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti-Alzheimer's agents.

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Catalytic Domain; Cholinesterase Inhibitors; Donepezil; Drug Design; Indans; Inhibitory Concentration 50; Models, Molecular; Piperidines; Structure-Activity Relationship

Topics: Alzheimer Disease; Female; Homes for the Aged; Humans; Indans; Male; Memantine; Nootropic Agents; Nursing Homes; Piperidines

Inhibition of β-amyloid (Aβ) aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer's disease (AD). Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Aβ 25-35 by acetone extracts of P. gymnospora (ACTPG) was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM) analysis and Fourier transform infrared (FTIR) spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Aβ and the co-treatment of ACTPG (250 μg/ml) with Aβ 25-35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 μg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 μg/ml) and support its use for the treatment of neurological disorders.

Topics: Acetone; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Humans; Indans; Microscopy, Confocal; Peptide Fragments; Piperidines; Plant Extracts; Protein Binding; Protein Structure, Secondary; Seaweed; Spectroscopy, Fourier Transform Infrared; Tandem Mass Spectrometry

We previously demonstrated a positive correlation with nursing home (NH) replacement and donepezil (DNP) administration on lifetime expectancy after the onset of Alzheimer's disease (AD). However, the correlation with quality-adjusted life-year (QALY) remains to be elucidated, along with the additional impact of concomitant cerebrovascular disease (CVD). Based upon our recently reported health state utility values, we retrospectively analyzed the correlation with NH replacement and/or DNP administration on QALY and life expectancy in 'pure' AD (without CVD) and AD with CVD patients.. All outpatients at the Tajiri Clinic from 1999-2012 with available medical records and death certificates were included. The entry criteria were a dementia diagnosis (DSM-IV) and diagnoses of pure AD or AD with CVD (NINCDS-ADRDA), medical treatment for more than 3 months, and follow up to less than 1 year before death. The main outcomes were lifetime expectancy (months between the onset of dementia and death) and QALY.. We identified 390 subjects, of whom 275 had the diagnosis of dementia that met the entry criteria, including 67 pure AD, 33 AD with CVD, and 110 VaD patients. For the AD patients, 52 had taken DNP and 48 had not received the drug due to treatment prior to the introduction of DNP in 1999 in Japan. For the pure AD group, there were positive correlation between NH and DNP and QALY, as well as lifetime expectancy. As for the AD with CVD group, only a correlation between DNP and lifetime expectancy was noted, with no correlation with QALY.. We found positive correlations between DNP administration and NH replacement and lifetime expectancy and QALY after the onset of AD. However, concomitant CVD negated such a positive correlation with QALY. The findings suggest that QALY in AD is affected by CVD; thus, indicating the importance of CVD prevention.

Topics: Alzheimer Disease; Cerebrovascular Disorders; Cholinesterase Inhibitors; Comorbidity; Donepezil; Humans; Indans; Japan; Life Expectancy; Nursing Homes; Piperidines; Quality-Adjusted Life Years; Retrospective Studies

The therapeutic response rates of patients to donepezil vary from 20% to 60%, one of the reasons is their genetic differences in donepezil-metabolizing enzymes, which directly influence liver metabolism. However, the mechanism of donepezil metabolism and that of its enantiomers is unknown. This study evaluated CYP2D6 polymorphisms to elucidate the stereoselective metabolism of donepezil and to confirm the association between the steady-state plasma concentrations of the pharmaco-effective S-donepezil and the therapeutic responses of Han Chinese patients with Alzheimer's disease. The in vitro study of the stereoselective metabolism demonstrated that CYP2D6 is the predominant P450 enzyme that metabolizes donepezil and that different CYP2D6 alleles differentially affect donepezil enantiomers metabolism. A total of 77 Han Chinese patients with Alzheimer's disease were recruited to confirm these results, by measuring their steady-state plasma concentrations of S-donepezil. The related CYP2D6 genes were genotyped. Plasma concentrations of S-donepezil (based on CYP2D6 polymorphisms) were significantly associated with therapeutic responses. This finding suggests that plasma concentrations of S-donepezil influence therapeutic outcomes following treatment with donepezil in Han Chinese patients with Alzheimer's disease. Therefore, determining a patient's steady-state plasma concentration of S-donepezil in combination with their CYP2D6 genotype might be useful for clinically monitoring the therapeutic efficacy of donepezil.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Asian People; Cholinesterase Inhibitors; Cytochrome P-450 CYP2D6; Donepezil; Female; Humans; Indans; Liver; Male; Microsomes, Liver; Nootropic Agents; Piperidines; Polymorphism, Genetic; Stereoisomerism; Treatment Outcome

Rivastigmine transdermal patch has shown higher caregiver satisfaction and greater preference than oral formulation in patients with Alzheimer's disease. However, there is limited literature available related to caregiver preference or treatment compliance in real-world clinical settings. To date, no such data are available from Asia and the Middle East, which account for a sizeable proportion of patients with Alzheimer's disease. The objective of this study was to evaluate treatment preference and compliance with oral and transdermal medications in daily clinical practice in an ethnically diverse patient population from Asia and the Middle East with mild-to-moderate Alzheimer's disease.. RECAP (Real-world Evaluation of Compliance And Preference in the treatment of Alzheimer's disease) was a 24-week, multicenter, prospective, noninterventional study. Two treatment cohorts were observed during the study: oral (cholinesterase inhibitors or memantine) and transdermal (rivastigmine patch). Caregiver preference, physician preference, and patient compliance were evaluated at week 24.. A total of 978 of 1,931 enrolled patients (mean age: 72.8 years; 50.5% female) were in the transdermal cohort. For patients with exposure to both oral and transdermal monotherapy (n=330), a significant caregivers' preference for the transdermal monotherapy was observed (82.7%; P<0.0001). Of the 89 participating physicians, 71 indicated preference for transdermal monotherapy. Patient compliance was also significantly higher for transdermal than oral monotherapy (P<0.0001).. Our study showed higher caregiver and physician preference and greater patient compliance with transdermal monotherapy in daily practice.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Aged, 80 and over; Alzheimer Disease; Asia; Attitude of Health Personnel; Caregivers; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Humans; Indans; Male; Medication Adherence; Memantine; Middle East; Patient Preference; Physicians; Piperidines; Prospective Studies; Rivastigmine

This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

Topics: Adverse Drug Reaction Reporting Systems; Alzheimer Disease; Canada; Cholinesterase Inhibitors; Databases, Factual; Dementia; Donepezil; Galantamine; Humans; Indans; Pharmacovigilance; Piperidines; Rivastigmine; United States; United States Food and Drug Administration

To conduct a psychometric analysis to determine the adequacy of instruments that measure cognition in Alzheimer's disease trials.. Both the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and the Neuropsychological Test Battery (NTB) are validated outcome measures for clinical trials in Alzheimer's disease and are approved also for regulatory purposes. However, it is not clear how comparable they are in measuring cognitive function. In fact, many recent trials in Alzheimer's disease patients have failed and it has been questioned if ADAS-Cog still is a sensitive measure.. The present paper examines the psychometric properties of ADAS-Cog and NTB, based on a post hoc analysis of data from a clinical trial (NCT01024660), which was conducted by AstraZeneca, in mild-to-moderate Alzheimer's disease (AD) patients, with a Mini Mental State Examination (MMSE) Total score 16-24. Acceptability, reliability, different types of validity and ability to detect change were assessed using relevant statistical methods. Total scores of both tests, as well as separate domains of both tests, including the Wechsler Memory Scale (WMS), Rey Auditory Verbal Learning Test (RAVLT) and Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Condition, were analyzed.. Overall, NTB performed well, with acceptable reliability and ability to detect change, while ADAS-Cog had insufficient psychometric properties, including ceiling effects in 8 out of a total of 11 ADAS-Cog items in mild AD patients, as well as low test-retest reliability in some of the items.. Based on a direct comparison on the same patient sample, we see advantages of the NTB compared with the ADAS-Cog for the evaluation of cognitive function in the population of mild-to-moderate AD patients. The results suggest that not all of ADAS-Cog items are relevant for both mild and moderate AD population.. This validation study demonstrates satisfactory psychometric properties of the NTB, while ADAS-Cog was found to be psychometrically inadequate.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychometrics; Randomized Controlled Trials as Topic

Neurotransmitter enhancement therapy with acetylcholinesterase inhibitors (AChEIs) is a clinically proven approach for patients with Alzheimer's disease (AD). Donepezil is one of the three currently approved AChEIs for treating AD symptoms delaying the decline in cognitive function. In addition to cholinergic hypofunction, there are several factors in AD pathogenesis. For example, adipocytokines released from adipose tissue are also thought to play a role in the progress of dementia. Adipokines, i.e., leptin and adiponectin, are involved in the modulation of certain cognitive functions in the brain. The goal of our study was to elucidate effects of donepezil therapy on the serum levels of certain adipokines, such as leptin and adiponectin in AD patients. Clinically diagnosed mild-to-moderate AD patients (n = 26) were involved in this open-labeled, single-center, prospective self-control study. ApoE polymorphism, serum adiponectin, leptin, LDL, HDL, triglyceride levels, and BMI were determined before and at 12 and 24 weeks intervals of donepezil treatment, respectively. Twenty-four weeks of donepezil treatment induced a linear decrease of serum leptin levels (p = 0.013) and a linear elevation of serum adiponectin levels (p = 0.007). BMI (p < 0.001) and abdominal circumference (p = 0.017) were significantly lower at 24 weeks as compared to control values. None of the other examined metabolic parameters were changed during the treatment period. This previously unrecognized serum adipokine regulating potential of donepezil may be relevant in its therapeutic, disease modifying effect in AD by transferring protective (by increasing serum adiponectin levels) and detrimental (by decreasing serum leptin levels) effects onto the neurodegenerative process at the same time.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Prospective Studies; Time Factors

The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients.. A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥ 55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine.. Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy.. CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.

Topics: Aged; Alleles; Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Cognitive Dysfunction; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Diagnostic and Statistical Manual of Mental Disorders; DNA; Donepezil; Dopamine Agents; Drug Therapy, Combination; Female; Genotype; Humans; Indans; India; Male; Memantine; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Polymorphism, Genetic; Tandem Mass Spectrometry; Treatment Outcome

Many factors could be responsible for the different response to treatment with the cholinesterase inhibitors (ChEIs) donepezil and rivastigmine in Alzheimer's disease (AD) patients. Sex and the variants of the estrogen receptor α (ESR1) gene are reported to modulate AD susceptibility or the course of the disease. The aim of the present study was to verify whether patient's sex and ESR1 genotype could influence the response to ChEI treatment, as there is evidence that estrogens affect cholinergic system functioning.. Two ESR1 intronic polymorphisms (PvuII, rs2234693; XbaI, rs9340799) were examined in 184 AD patients: 157 were receiving treatment with donepezil or rivastigmine and 27 were receiving no treatment. Cognitive status was assessed using the mini mental state examination at four time points (1, 3, 9, and 15 months into therapy).. Among the patients under treatment with either ChEI, the women responded more markedly than the men. As compared with the untreated patients, the effects of treatment were statistically significant for both donepezil and rivastigmine. A significant effect of ESR1 genotypes was observed for the donepezil-treated patients, among which those carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than the noncarriers.. The present data seem to confirm a sex-related influence on treatment, as the women seemed to be more sensitive to therapy and to have experienced less cognitive decline. ESR1 may be another gene contributing to interindividual variability in response to treatment with ChEIs.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Brief Psychiatric Rating Scale; Cholinesterase Inhibitors; Donepezil; Estrogen Receptor alpha; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Polymorphism, Single Nucleotide; Rivastigmine; Sex Factors

p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Biomarkers; Calcium-Binding Proteins; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Endophenotypes; Female; Humans; Indans; Male; Nootropic Agents; Peptide Fragments; Piperidines

Alzheimer's disease is an advanced dementia. In this disease, little by little the brain loses most of its functions. Pain is a prevalent complaint. It seems easing the pain had the better recovery to antipsychotic drug in controlling agitation in dementia patients. Donepezil is a drug that is used to treat Alzheimer's disease. This brief report describes an 83-year-old woman with Alzheimer's disease who experienced boredom and changes in attitude for about 1 year and complained about general pain in her extremity. Starting donepezil controlled the patient's symptoms. As soon as the treatment started, all pain was dramatically eliminated and her behavior improved. Donepezil may be effective in controlling the pain and improve the outcome of these patients.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Pain; Piperidines

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Piperidines; Sick Sinus Syndrome

The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Drug Design; Electrophorus; Horses; Humans; Indans; Indoles; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Quantitative Structure-Activity Relationship

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006-2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer's disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295-1458) days and 1103 (interquartile range 489-1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22-1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15-1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer's disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cohort Studies; Diagnostic and Statistical Manual of Mental Disorders; Donepezil; Drug Monitoring; Drug Prescriptions; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Finland; Follow-Up Studies; Galantamine; Guideline Adherence; Humans; Indans; Male; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Practice Guidelines as Topic; Proportional Hazards Models; Registries; Rivastigmine

Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Binding Sites; Catalytic Domain; Cholinesterase Inhibitors; Humans; Molecular Docking Simulation; Piperidines; Quinolones; Structure-Activity Relationship

The present study was to develop donepezil loaded nanosuspension for direct olfactory administration which reaches the brain and determining safety profile in Sprague-Dawley rats. Nanosuspension was prepared by ionic-crosslinking method. The developed nanosuspension was intranasally instilled into the nostrils of rats with the help of cannula (size 18/20) so that drug reached into the brain directly via nose to brain pathway. The nanosuspension had an average size of 150-200nm with a polydispersity index of 0.341. The donepezil concentration was estimated in the brain homogenate using HPLC method. The Cmax showed concentration of donepezil in brain and plasma as 7.2±0.86 and 82.8±5.42ng/ml, respectively, for drug suspension and concentration of donepezil in brain and plasma as 147.54±25.08 and 183.451±13.45ng/ml, respectively, for nanosuspension at same dose of 0.5mg/ml when administered intranasally (p<0.05). The in vivo safety evaluation studies showed that no mortality, hematological changes, body weight variations and toxicity in animals was observed, when nanosuspension was administered in different doses as compared to control group (normal saline). Donepezil loaded chitosan nanosuspension is a potential new delivery system for treatment of Alzheimer's disease, when transported via olfactory nasal pathway to the brain.

Topics: Administration, Intranasal; Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Donepezil; Drug Delivery Systems; In Vitro Techniques; Indans; Nanostructures; Piperidines; Rats; Rats, Sprague-Dawley; Suspensions

PSEN1 gene mutations represent the first cause of familiar early-onset Alzheimer's disease (EOAD). More than 190 mutations in PSEN1 have been reported to date. The clinical phenotype is mainly characterized by cognitive decline but movement disorders have been rarely described. We report a novel PSEN1 mutation (p.Thr147Pro) responsible for a sporadic early-onset dementia with prominent cerebellar symptoms, resembling a spinocerebellar syndrome. Neuroradiological and cerebrospinal fluid biomarkers examinations were performed on the patient, showing typical findings of EOAD and suggesting the pathogenicity of the novel mutation. Our study widens the number of unusual phenotypes related to PSEN1 mutations.

Topics: Adult; Alzheimer Disease; Cerebellar Ataxia; Cholinesterase Inhibitors; DNA Mutational Analysis; Donepezil; Female; Fluorodeoxyglucose F18; Humans; Indans; Magnetic Resonance Imaging; Male; Mutation; Piperidines; Positron-Emission Tomography; Presenilin-1; Young Adult

Cholinesterase inhibitors (ChEIs) such as donepezil have the effect of delaying progression of Alzheimer's disease (AD), but their effect on life expectancy is unclear. We analyzed the influence of donepezil on life expectancy after onset of AD, together with the effects of antipsychotic drugs and residency in a nursing home.. All outpatients at the Tajiri Clinic from 1999-2012 with available medical records and death certificates were included in a retrospective analysis. The entry criteria were a dementia diagnosis based on DSM-IV criteria and diagnosis of AD using NINCDS-ADRDA criteria; medical treatment for more than 3 months; and follow up until less than 1 year before death.. We identified 390 subjects with medical records and death certificates, of whom 275 had a diagnosis of dementia that met the entry criteria. Of 100 patients diagnosed with AD, 52 had taken donepezil and 48 patients had not received the drug due to treatment prior to the introduction of donepezil in 1999 in Japan. The lifetime expectancies after onset were 7.9 years in the donepezil group and 5.3 years in the non-donepezil group. There was a significant drug effect with a significant covariate effect of nursing home residency. Other covariates did not reach a significant level.. Although this report has the limitation of all retrospective analyses: the lack of randomization, we found a positive effect of donepezil on lifetime expectancy after onset of AD. This may be due to a decreased mortality rate caused by reduction of concomitant diseases such as pneumonia. The similar life expectancies in patients taking donepezil at home and those not taking donepezil in a nursing home indicated a positive health economic effect of the drug.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Japan; Life Expectancy; Male; Nursing Homes; Piperidines; Retrospective Studies

Donepezil is an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD). In this study, we used a voxel-based specific regional analysis system for AD (VSRAD) to analyze the hippocampal volume and to assess the pharmacologic effects of donepezil as a disease modifier.. A total of 185 AD patients underwent MRI, 120 (43 men and 77 women, 77.8 ± 7.1 years) without and 65 (29 men and 36 women, 78.4 ± 6.0 years) with donepezil treatment. VSRAD was compared in both groups and against a database of 80 normal subjects. The Z-score was used to assess the degree of hippocampal atrophy.. No significant difference between the groups was found for age, sex, or Z-scores, but a significant difference was found for mean Mini-Mental State Examination (MMSE) scores (p = 0.02, Student's t test). Single regression analysis showed no significant association between Z-scores and MMSE scores in the treated group (p = 0.494), but a significant association in the untreated group (p = 0.001) was observed. This implies that the MMSE score becomes lower when the Z-score is higher in the untreated group, whereas there is no significant trend in the treated group.. Donepezil affects the relationship between hippocampal volume and cognitive function and may therefore have a pharmacologic effect as a disease modifier.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Case-Control Studies; Donepezil; Female; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Organ Size; Piperidines; Regression Analysis; Treatment Outcome

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Hep G2 Cells; Humans; Hydroxyquinolines; Indans; Male; Memory; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Piperidines; Propylamines; Rats

Donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease, has been widely cited in media and bioethics literature on cognitive enhancement (CE) as having the potential to improve the cognitive ability of healthy individuals. In both literatures, this claim has been repeatedly supported by the results of a small study published by Yesavage et al. in 2002 on non-demented pilots (30-70 years old). The factors contributing to this specific interpretation of this study's results are unclear.. We examined print media and interdisciplinary bioethics coverage of this small study, aiming to provide insight into how evidence from research may be shaped within different discourses, potentially influencing important policy, ethics, and clinical decisions. Systematic qualitative content analysis was used to examine how this study was reported in 27 media and 22 bioethics articles. Articles were analyzed for content related to: (1) headlines and titles; (2) colloquialisms; and, (3) accuracy of reporting of the characteristics and results of the study.. In media and bioethics articles referencing this small study, strong claims were made about donepezil as a CE drug. The majority of headlines, titles, and colloquialisms used enhancement language and the majority of these suggest that donepezil could be used to enhance intellectual ability. Further, both literatures moved between reporting the results of the primary study and magnifying the perceived connection between these results and the CE debate that was alluded to in the primary study. Specific descriptions of the results overwhelmingly reported an improvement in performance on a flight simulator, while more general statements claimed donepezil enhanced cognitive performance. Further, a high level of reporting accuracy was found regarding study characteristics of the original study, but variable levels of accuracy surrounded the presentation of complex characteristics (i.e., methods) or contentious properties of the CE debate (i.e., initial health status of the study subjects).. Hyped claims of CE effects cannot be completely accounted for by sheer inaccuracy in reporting. A complex interaction between the primary and secondary literature, and expectations and social pressures related to CE appears to drive enthusiastic reports.

Topics: Adult; Aerospace Medicine; Aged; Alzheimer Disease; Aviation; Cholinesterase Inhibitors; Computer Simulation; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Patient Safety; Piperidines; Psychomotor Performance; Reaction Time; Research Design; User-Computer Interface

Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Attention Deficit and Disruptive Behavior Disorders; Behavior, Animal; Disease Models, Animal; Female; HEK293 Cells; Humans; In Vitro Techniques; Male; Maze Learning; Membrane Potentials; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Synapses

Episodic memory retrieval is reliant upon cognitive control systems, of which 2 have been identified with functional neuroimaging: a cingulo-opercular salience network (SN) and a frontoparietal executive network (EN). In Alzheimer's disease (AD), pathology is distributed throughout higher-order cortices. The hypotheses were that this frontoparietal pathology would impair activity associated with verbal memory recall; and that central cholinesterase inhibition (ChI) would modulate this, improving memory recall.. Functional magnetic resonance imaging was used to study normal participants and 2 patient groups: mild cognitive impairment (MCI) and AD. Activity within the EN and SN was observed during free recall of previously heard sentences, and related to measures of recall accuracy.. In normal subjects, trials with reduced recall were associated with greater activity in both the SN and EN. Better recall was associated with greater activity in medial regions of the default mode network. By comparison, AD patients showed attenuated responses in both the SN and EN compared with either controls or MCI patients, even after recall performance was matched between groups. Following ChI, AD patients showed no modulation of activity within the SN, but increased activity within the EN. There was also enhanced activity within regions associated with episodic and semantic memory during less successful recall, requiring greater cognitive control.. The results indicate that in AD, impaired responses of cognitive control networks during verbal memory recall are partly responsible for reduced recall performance. One action of symptom-modifying treatment is partially to reverse the abnormal function of frontoparietal cognitive control and temporal lobe memory networks.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Executive Function; Female; Frontal Lobe; Functional Neuroimaging; Humans; Indans; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Parietal Lobe; Piperidines; Speech Perception; Young Adult

Cistanche tubulosa (Schenk) R. Wight (CT) is commonly used to treat forgetfulness by traditional Chinese physicians. This study presents the ameliorating effects of CT extract which was quantified with three phenylpropanoid glycosides in Alzheimer's disease (AD)-like rat model.. Amyloid β peptide 1-42 (Aβ 1-42) intracisternally infused to rats by osmotic pump (Alzet 2002) was used as an AD-like rat model. The major pathological makers were measured including Aβ 1-42 immunohistochemical stain, behavioral tests (inhibitory avoidance task and Morris water maze) and central neurotransmitter functions.. Aβ 1-42 caused the cognitive deficits, the increase in the amyloid deposition and acetylcholinesterase activities, and the decrease in the levels of brain's acetylcholine and dopamine. Daily administration of CT extract throughout Aβ 1-42 infusion periods ameliorated the cognitive deficits, decreased amyloid deposition and reversed cholinergic and hippocampal dopaminergic dysfunction caused by Aβ 1-42. Donepezil also ameliorated the cognitive dysfunction, but only blocked the amyloid deposition and cholinergic dysfunction caused by Aβ 1-42.. We suggest that CT extract, containing enough echinacoside and acteoside, ameliorated the cognitive dysfunction caused by Aβ 1-42 via blocking amyloid deposition, reversing cholinergic and hippocampal dopaminergic neuronal function.

Topics: Alzheimer Disease; Amyloid; Animals; Brain; Brain Chemistry; Cistanche; Disease Models, Animal; Donepezil; Exploratory Behavior; Indans; Male; Maze Learning; Neurotransmitter Agents; Piperidines; Plant Extracts; Rats; Rats, Sprague-Dawley

Recent neuroimaging studies in humans support the clinical observations that the motor cortex is affected early in the course of Alzheimer's disease (AD).. We used transcranial magnetic stimulation to measure the active cortical motor threshold (ACMT) in AD patients in the very early stage of the disease, and we explored whether and in which way the pharmacologic manipulation of the cholinergic system could have a direct effect on the excitability of the motor cortex.. An increase of the ACMT was observed in AD patients in the early stage in comparison to controls. After 2 months of treatment with donepezil, the threshold did not differ significantly from normal subjects.. The results suggest an early functional impairment of cholinergic neurotransmission in AD, which is associated to early changes in the excitability of the motor system.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Motor Cortex; Piperidines; Severity of Illness Index; Transcranial Magnetic Stimulation; Treatment Outcome

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Auditory Perception; CA1 Region, Hippocampal; Choline O-Acetyltransferase; Cholinergic Neurons; Disease Models, Animal; Donepezil; Electrodes, Implanted; Evoked Potentials, Auditory; Indans; Male; Nerve Degeneration; Neuroprotective Agents; Neuropsychological Tests; Piperidines; Psychomotor Performance; Rats, Sprague-Dawley; Ribosome Inactivating Proteins, Type 1; Saporins

Positron emission tomography (PET) imaging using 5-HT1A receptor radioligands shows a decreased expression of this serotonin receptor in the hippocampus of patients with Alzheimer's disease (AD) at advanced stages. However, previous 5-HT1A receptor radioligands used in human imaging were antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the functional state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radioligand, which binds selectively to the functional state of the receptors, with the PET imaging obtained using an antagonist radioligand would therefore provide original information on 5-HT1A receptor impairment during AD.. Quantitative autoradiography using (18) F-F15599 and (18) F-MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of 18 patients with AD.. Functional 5-HT1A receptors, labeled by (18) F-F15599, represented ~35% of total receptors, as estimated by (18) F-MPPF labeling. (18) F-F15599 binding decreased in dentate gyrus of patients with AD, as indicated by Braak's stages. In contrast, binding of (18) F-MPPF was statistically unchanged.. These in vitro results support testing the concept of functional PET imaging using agonist radioligands in clinical studies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Autopsy; Autoradiography; Binding Sites; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Protein Binding; Pyrimidines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Chlorocebus aethiops; Cholinesterase Inhibitors; Cognition; COS Cells; Cyclosporine; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Kinetics; Ligands; Mice; Permeability; Piperidines; Receptors, Serotonin, 5-HT4; Rhodamine 123; Serotonin 5-HT4 Receptor Agonists; Solubility; Task Performance and Analysis

To report an uncommon adverse event in an elderly patient related to the cholinesterase inhibitor, donepezil.. An 80-year-old Greek woman with Alzheimer disease was admitted to the hospital with a sudden onset of myoclonus in both upper and lower extremities after receiving 30 mg of donepezil daily for 25 days. After 36 hours of donepezil remission, the frequency of the myoclonic jerks was sharply reduced. The patient remains asymptomatic after 6 months of follow-up.. Our literature search yielded only 2 cases of myoclonus in relation to memantine, which has a different action with donepezil; to our knowledge, this is the first report of generalized myoclonus induced by donepezil overdosing. Based on the Naranjo probability scale it was probable that the patient's myoclonus was related to donepezil because of clear temporal proximity and lack of alternative explanations.. Clinicians should take into consideration therapeutic drug monitoring in the event of a potentially rare serious adverse reaction. Further studies are needed to clarify the possible role of donepezil in the pathophysiology of myoclonus.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Myoclonus; Piperidines

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Medication Adherence; Piperidines; Time Factors

Topics: Aged; Alanine Transaminase; Alzheimer Disease; Antidepressive Agents, Second-Generation; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Donepezil; Fluoxetine; Humans; Indans; Male; Piperidines

Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD.. In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion.. A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups.. FOXO1 may influence the clinical response to AChEIs in AD patients.

Topics: Aged; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Galantamine; Gene Frequency; Genetic Loci; Genotype; Haplotypes; Humans; Indans; Male; Oxidative Stress; Phenylcarbamates; Piperidines; Prospective Studies; Rivastigmine

The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Drug Design; Humans; Indans; Models, Molecular; Molecular Structure; Monoamine Oxidase Inhibitors; Piperidines; Pyridines; Quantitative Structure-Activity Relationship; Recombinant Proteins

Cholinesterase inhibitors can delay the progression of Alzheimer's disease (AD). Several clinical trials of the drug in moderate to severe AD have consistently reported clinically positive effects. A combining effect with psychosocial intervention was reported in mild to moderate AD patients. Since a therapeutic approach or rehabilitation combined with cholinesterase inhibitors for severe AD patients remains controversial, we performed a prospective intervention for patients in Long-Term Care Health Facilities (LTCHF).. Two LTCHFs (N1, N2) were enrolled. N1 is a 126-bed facility that does not treat with donepezil but rather with psychosocial intervention (reality orientation and reminiscence). N2 is a 150-bed facility with a 50-bed special dementia unit, in which the physician can prescribe donepezil. On top of the similar psychosocial intervention, rehabilitation is performed in N2. Thirty-two severe AD patients (MMSE < 6) in N1 and N2 (16 vs. 16) were compared for the effect of donepezil (10 mg/d for 3 months) with or without psychosocial intervention (n = 8 vs. 8 for each facility). The Vitality Index was used to assess daily activities and the introduction of rehabilitation.. The response ratio (MMSE 3+) of donepezil was 37.5% in N2. The combination of donepezil with the psychosocial intervention improved the Vitality Index total score, and Communication, Eating, and Rehabilitation subscores (Wilcoxon, p = 0.016, 0.038, 0.023, and 0.011, respectively). Most of them were smoothly introduced to rehabilitation, and the proportion of accidental falls decreased. Psychosocial intervention in N1 without the drug only improved the total score (Wilcoxon, p = 0.046).. A combined therapeutic approach of donepezil and psychosocial intervention can have a positive effect, even for severe patients through the introduction of rehabilitation and decreasing accidental falls. However, these findings require replication in a larger cohort.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Disease Progression; Donepezil; Female; Humans; Indans; Long-Term Care; Male; Nursing Homes; Piperidines; Prospective Studies; Severity of Illness Index; Treatment Outcome

To analyze the possibility of using MMSE and CGIS as well as the Clock drawing test for the objectification of treatment efficacy in Alzheimer's disease (AD).. Authors examined 765 patients with mild and moderate dementia treated with donepezil during 3 months. The efficacy was assessed using the MMSE and CGIS.. The methods demonstrated the reproducibility compared to those used in earlier clinical trials and efficacy of donepezile in the treatment of mild and moderate AD, the Clock drawing test can be recommended as an additional technique for assessment of treatment efficacy in relation to opticospatial function.. Цель исследования - анализ возможности использования врачами из различных регионов РФ шкал MMSE и CGIS, а также теста рисования часов для объективизации оценки результатов лечения болезни Альцгеймера (БА). Материал и методы. Обследовали 765 больных БА с мягкой и умеренной деменцией, лечившихся донепезилом на протяжении 3 мес. Эффективность терапии деменции оценивали по шкалам MMSE и CGIS. Результаты и заключение. Предложенные методы показали воспроизводимость результатов, полученных ранее в клинических исследованиях эффективности донепезила при мягкой и умеренной БА. Полученные данные позволяют рекомендовать перечисленные шкалы в качестве объективных показателей эффекта терапии в клинической практике; тест рисования часов может быть предложен в качестве дополнительной методики для оценки эффективности терапии по отношению к расстройствам оптико-пространственной деятельности.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Effectiveness of donepezil hydrochloride treatment for elderly patients with Alzheimer's and vascular dementia types depending on the ApoE genotype.. To study the effectiveness of donepezil hydrochloride (Almer "Actavis") for elderly patients with Alzheimer's and vascular dementia types depending on the ApoE genotype.. The 3-month clinical study included 38 elderly patients (mean age- (71.03 ± 1.20) years) with dementia. All patients have undergone clinical, neurological, laboratory, instrumental (electrocardiography, CT/MRI brain), neuropsychological examination, ApoE genotype determination. Identified certain characteristics of response to treatment of donepezil hydrochloride (acetylcholinesterase inhibitor) with dementia according to ApoE genotype. The effectiveness of donepezil hydrochloride was more pronounced in patients ε4 allele carriers compared with ε3/ε3 group the results of the scale parameter ADAScog, describing episodic memory and complex types of praxis.. The effectiveness of the treatment of donepezil hydrochloride for elderly patients with dementia largely be associated with ApoE genotype available that makes it worthwhile carrying determine ApoE 2, 3, 4 allele in patients with cognitive deficits before starting pharmacotherapy.

Topics: Aged; Alzheimer Disease; Apolipoproteins E; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Humans; Indans; Male; Piperidines; Polymorphism, Genetic; Treatment Outcome

Anticholinesterase, such as neostigmine, was used to be a standard drug at the end of surgery for reversal of nondepolarizing neuromuscular block. Neostigmine decreases the metabolism of acetylcholine (ACh) at the neuromuscular junction and allows its concentration to increase and overcome the effect of the muscle relaxant. But this approach is ineffective against profound block. Rapid reversal from deep block is not possible and giving a reversal agent early will not speed up the recovery time. Anticholinesterases have actions both at the nicotinic and the muscarinic receptors, and even when accompanied by an antimuscarinic agent, they produce undesirable autonomic responses. Some anticholinesterase, like donepezil, exhibits high specificity for centrally active acetylcholinesterase and raise ACh levels in the brain. The deficiency in cholinergic neurotransmission in Alzheimer's disease (AD) has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. In addition to donepezil, two other cholinesterase inhibitors have recently been approved for the treatment of AD patients. The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. Donepezil can also reverse opioid-induced respiratory depression.

Topics: Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Neostigmine; Neuromuscular Blocking Agents; Neuromuscular Junction; Piperidines

It is largely unknown how the medical treatment of patients diagnosed with dementia is followed up in primary care. Therefore, we studied patient medical records from two dementia clinics and from the referring primary care centres.. A retrospective study of 241 patients was conducted from April to October 2011 in north west Stockholm, Sweden. Over half (51.5%) of the patients had Alzheimer's disease (AD), the remainder had mixed AD/vascular dementia (VaD). Eighty-four medical reports from primary care (35% of the study group) were analysed at follow-up 18 months after diagnosis.. All four dementia drugs available on the Swedish market (three cholinesterase inhibitors [donepezil, rivastigmine and galantamine] and memantine) were prescribed at the two dementia clinics. The most commonly used dementia drug was galantamine. There were differences between the two dementia clinics in preference and combination of drugs and of treatment given to male and female patients. At follow-up, 84% were still on dementia medication. Drug use was followed up by the general practitioners (GPs) in two-thirds of the cases. Eighteen per cent of the GPs' medical records made no reference to the patient's dementia or treatment even though dementia drugs were included in the list of medications prescribed.. The results indicate that the Swedish guidelines for treatment of cognitive symptoms in AD are being followed in primary care. However, documentation of follow-up of drug treatment was sometimes insufficient, which calls for development of guidelines for complete medical records and medication lists.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Dementia, Vascular; Donepezil; Female; Galantamine; Humans; Indans; Male; Medical Records; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Practice Guidelines as Topic; Practice Patterns, Physicians'; Primary Health Care; Retrospective Studies; Rivastigmine; Sweden; Treatment Outcome

Currently available treatment used in Alzheimer's disease is based on acetylcholinesterase inhibitors, e. g. donepezil, tacrine, galantamine, and rivastigmine. In the present study some derivatives of donepezil were synthesized, and their potential anticholinesterase properties were investigated using the colorimetric Ellman's method. These compounds were synthesized by condensation between indanone derivatives and the hydrazine nicotinated moiety (Hynic). For received derivatives, the selectivity and the IC50 values for acetylcholinesterase and butyrylcholinesterase were calculated. All the tested compounds exhibited lower affinity for AChE than donepezil and higher affinity for BChE than donepezil. Compound 33 showed the most selectivity for AChE among the obtained indanone derivatives.

Topics: Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Colorimetry; Donepezil; Indans; Inhibitory Concentration 50; Niacinamide; Piperidines

2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BuChE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.

Topics: Acetylcholinesterase; Alzheimer Disease; Binding, Competitive; Biocatalysis; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Piperidines; Protein Binding; Protein Structure, Tertiary; Pyridazines; Structure-Activity Relationship

The aim of this study was to describe the evolution of a cost-utility model used to inform the UK National Institute for Health and Clinical Excellence's (NICE) most recent decisions on the cost-utility of drug treatments for Alzheimer's disease (AD), and to explore the impact of structural assumptions on the cost-utility results.. Changes informed by noted limitations of the decision model used in NICE's previous decisions (in 2006) were made cumulatively to the original decision model for donepezil compared with best supportive care (for patients with mild to moderate AD). Deterministic and probabilistic analyses were undertaken for each cumulative change of the model. The expected value of perfect information (EVPI) of parameter estimates and structural assumptions was also calculated.. Cumulative changes to the decision model highlighted how the results of the original model (incremental cost-effectiveness ratio of £81,000 per quality-adjusted life-year gained) related to those of the new model (where donepezil was estimated to be cost-saving), mainly due to uncertainty in the incremental cost of donepezil treatment over best supportive care (ranging from -£600 to £3,000 per patient). The partial EVPI analysis reflected this finding where further information on treatment discontinuations and cost parameter estimates were shown to be valuable in terms of reducing decision uncertainty.. Assessing the evolution of the cost-utility model helped to identify and explore structural differences between cohort-based models and is likely to be useful for decision models in other disease areas. This approach makes the structural uncertainty explicit, forcing decision makers to address structural uncertainty in addition to parameter uncertainty.

Topics: Alzheimer Disease; Costs and Cost Analysis; Decision Support Techniques; Donepezil; Humans; Indans; Models, Economic; Models, Statistical; Nootropic Agents; Piperidines; Uncertainty; United Kingdom

Acetylcholinesterase (AChE) inhibition is one of the most currently available therapies for the management of Alzheimer's disease (AD) symptoms. In this context, NMR spectroscopy binding studies were accomplished to explain the inhibition of AChE activity by Salvia sclareoides extracts. HPLC-MS analyses of the acetone, butanol and water extracts eluted with methanol and acidified water showed that rosmarinic acid is present in all the studied samples and is a major constituent of butanol and water extracts. Moreover, luteolin 4'-O-glucoside, luteolin 3',7-di-O-glucoside and luteolin 7-O-(6''-O-acetylglucoside) were identified by MS(2) and MS(3) data acquired during the LC-MS(n) runs. Quantification of rosmarinic acid by HPLC with diode-array detection (DAD) showed that the butanol extract is the richest one in this component (134 μg mg(-1) extract). Saturation transfer difference (STD) NMR spectroscopy binding experiments of S. sclareoides crude extracts in the presence of AChE in buffer solution determined rosmarinic acid as the only explicit binder for AChE. Furthermore, the binding epitope and the AChE-bound conformation of rosmarinic acid were further elucidated by STD and transferred NOE effect (trNOESY) experiments. As a control, NMR spectroscopy binding experiments were also carried out with pure rosmarinic acid, thus confirming the specific interaction and inhibition of this compound against AChE. The binding site of AChE for rosmarinic acid was also investigated by STD-based competition binding experiments using Donepezil, a drug currently used to treat AD, as a reference. These competition experiments demonstrated that rosmarinic acid does not compete with Donepezil for the same binding site. A 3D model of the molecular complex has been proposed. Therefore, the combination of the NMR spectroscopy based data with molecular modelling has permitted us to detect a new binding site in AChE, which could be used for future drug development.

Topics: Alzheimer Disease; Binding Sites; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Cinnamates; Depsides; Donepezil; Glucosides; Indans; Luteolin; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Plant Extracts; Portugal; Rosmarinic Acid; Salvia

A potential anti-inflammatory role for acetylcholinesterase inhibitors (AChEIs) has been supported by animal studies. As very limited data exist from individuals with Alzheimer's disease (AD), the aim of this study was to assess the potential influence of AChEIs on blood pro-inflammatory cytokines. We hypothesized that pro-inflammatory cytokine concentrations were lower in individuals with AD stabilized on AChEIs.. Blood interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were assessed using specific enzyme-linked immunosorbent assays in three groups of participants: patients with AD stabilized on a therapeutic dose of an AChEI (n = 42); AChEIs drug naïve patients (n = 24); and a cognitively unimpaired control group (n = 35). Patients in the AChEIs group had received medication for an average of one year.. Patients stabilized on an AChEI did not differ significantly from drug naïve patients in relation to the concentrations of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p = 0.874, 0.225, and 0.978, respectively). Within the group taking AChEIs, the levels of cytokines did not differ between those taking donepezil, rivastigmine, or galantamine (p = 0.368, 0.851, and 0.299, respectively).. Results from animal studies suggesting a modulatory anti-inflammatory role for AChEIs was not advanced in this study. In individuals with AD, very limited evidence currently exists to support the hypothesis that AChEIs may influence inflammatory blood markers and function beyond the enhancement of neuronal transmission. However, further studies assessing a wider range of inflammatory markers and processes are still needed before this hypothesis can be ruled out.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Enzyme-Linked Immunosorbent Assay; Female; Galantamine; Humans; Indans; Interleukin-1beta; Interleukin-6; Male; Phenylcarbamates; Piperidines; Rivastigmine; Sex Factors; Tumor Necrosis Factor-alpha

As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between α4β2, α7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (Aβ)42 oligomers, which are believed to be the synaptotoxic Aβ-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the α4β2 nAChR agonist TC-1827 and the α7 nAChR partial agonist SSR180711 to reverse Aβ42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of Aβ42 oligomer induced impairment of early LTP, and had no effect on Aβ42 oligomer induced impairment of late LTP. The same was demonstrated for the α4β2 nAChR agonist TC-1827. In contrast, the α7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by Aβ42 oligomers. As activating α7 nAChRs was found to be most efficacious in restoring Aβ42 oligomer induced LTP deficits, targeting α7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cholinesterase Inhibitors; Donepezil; Hippocampus; Indans; Long-Term Potentiation; Male; Nicotinic Agonists; Piperidines; Rats; Rats, Wistar; Receptors, Nicotinic

To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD).. This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.. During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.. Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Chi-Square Distribution; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Home Care Services; Humans; Indans; Linear Models; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Phenylcarbamates; Piperidines; Proportional Hazards Models; Prospective Studies; Risk Factors; Rivastigmine; Treatment Outcome

Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Databases, Factual; Donepezil; Drug Prescriptions; Excitatory Amino Acid Antagonists; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Retrospective Studies; Survival Rate; United States; United States Department of Veterans Affairs

To highlight the utility of using an effect size analysis to communicate the effectiveness of treatment interventions.. Secondary analysis.. Previously published systematic review on cholinesterase inhibitors (ChEIs) in Alzheimer's disease.. Individuals with mild to moderate Alzheimer's disease.. Six-month randomized controlled trials involving a placebo group and a ChEI group (donepezil, galantamine, or rivastigmine).. Cognitive function was assessed according to performance on the cognition subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog). Global Function was quantified using the Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus). Harm was defined as withdrawal from a trial because of an adverse event. Several effect size indices were computed based on these domains: the success rate difference (SRD), the harm rate difference (HRD), the number needed to treat (NNT) or harm (NNH), and the area under the curve (AUC). Harm:benefit ratios were also computed to compare effect size indices across domains of function.. In terms of benefit, the NNT for cognition ranged from 4 to 14 (corresponding AUC values: 0.64-0.54), and the NNT for global function ranged from 6 to 100 (corresponding AUC 0.59-0.51). In terms of harm, the NNH ranged from 6 to 20 (corresponding AUC 0.58-0.53). Only one of the four studies had favorable harm:benefit ratios in both the cognition and global function domains.. Effect size indices should be reported in clinical trials because they provide important insight into the clinical meaningfulness of results. Additional benefit is gained by comparing effect size indices across domains of function to reveal harm:benefit ratios.

Topics: Aged; Alzheimer Disease; Area Under Curve; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Acetylcholinesterase inhibitors (AChEIs) are approved to treat the symptoms of mild to moderate Alzheimer's disease by restoring acetylcholine levels at synapses where the neurotransmitter has been depleted due to neurodegeneration. This assumption is challenged by more recent clinical studies suggesting the potential for disease-modifying effects of AChEIs as well as in vitro studies showing neuroprotective effects. However, few preclinical studies have assessed whether the improvement of cognitive symptoms may be mediated by reductions in Abeta or Tau pathology.. The objective of the present study was to determine whether short-duration treatment with donepezil could improve spatial learning and memory in transgenic mice overexpressing mutant human amyloid precursor protein (hAPP) and presenilin 1 (PS1) (Dewachter et al., J Neurosci 20(17):6452-6458, 2000) after amyloid pathology has fully developed, consistent with early stages of Alzheimer'sdisease in humans. In parallel, the effect of donepezil treatment on brain amyloid, Tau, and glial endpoints was measured.. This study showed a significant improvement in reference memory in hAPP/PS1 mice along with dose-dependent reductions in brain amyloid-β (Aβ).. These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer's disease may be due, at least in part, to reduction of brain Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Presenilin-1; Synapses

The aim of the present study was to elucidate the differences in the plasma concentration of two enantiomers of donepezil in Chinese patients with Alzheimer's disease (AD) and investigate in vitro stereoselective metabolism and transport. Donepezil enantiomers were separated and determined by LC-MS/MS using D5-donepezil as an internal standard on a Sepax Chiralomix SB-5 column. In vitro stereoselective metabolism and transport of donepezil were investigated in human liver microsomes and MDCKII-MDR1 cell monolayer. Pre-dose (Css-min) plasma concentrations were determined in 52 patients. The mean plasma level of (R)-donepezil was 14.94 ng/ml and that of (S)-donepezil was 23.37 ng/ml. One patient's plasma concentration of (R)-donepezil was higher than (S)-donepezil and the ratio is 1.51. The mean plasma levels of (S)-donepezil were found to be higher than those of (R)-donepezil in 51 patients and the ratio of plasma (R)- to (S)-donepezil varies from 0.34 to 0.85. In the in vitro microsomal system, (R)-donepezil degraded faster than (S)-donepezil. V(max) of (R)-donepezil was significantly higher than (S)-donepezil. The P-gp inhibition experiment shown that the P(app) of the two enantiomers was higher than 200 and the efflux ratios were 1.11 and 0.99. The results of the P-gp inhibition identification experiment showed IC50 values of 35.5 and 20.4 μM, respectively, for the two enantiomers. The results indicate that donepezil exhibits stereoselective hepatic metabolism that may explain the differences in the steady-state plasma concentrations observed. Neither (R)- nor (S)-donepezil was a P-gp substance and the two enantiomers are highly permeable through the blood-brain barrier.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Drug Stability; Female; Humans; Indans; Male; Microsomes, Liver; Piperidines; Stereoisomerism

The clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain "reserve capacity." A possible association between the cholinergic system and reserve is suggested by preclinical observations that the cholinergic system allows cortical plasticity and by clinical observations of variable responses to cholinergic treatments depending on the patient's educational level. The aim of this study was to investigate the association of reserve proxies, that is, education and occupation, with acetylcholinesterase (AChE) activity, measured voxelwise by [(11)C]-MP4A and positron emission tomography (PET), in 9 healthy controls (HC), 7 patients with early probable AD, and 9 subjects with mild cognitive impairment (MCI) at the time of PET imaging, who progressed to AD at follow-up (prodromal AD). The analysis of prodromal and early AD showed positive correlations between education and AChE activity in the hippocampus, bilaterally, and between occupation and AChE activity in the right posterior cingulate gyrus. The significant correlation between AChE activity in structures belonging to the memory network and reserve proxies suggests that the brain reserve in AD is associated with a preserved/stimulated cholinergic neurotransmission.

Topics: Acetates; Acetylcholine; Aged; Aged, 80 and over; Alzheimer Disease; Carbon Isotopes; Cognitive Dysfunction; Cognitive Reserve; Educational Status; Employment; Female; Fluorodeoxyglucose F18; Humans; Male; Mental Status Schedule; Middle Aged; Piperidines; Positron-Emission Tomography; Radiography; Statistics, Nonparametric; Tomography Scanners, X-Ray Computed

The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Drug Design; Humans; Mice; Microsomes, Liver; Models, Molecular; Piperidines; Triazoles

Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical γ-secretase modulators affect the processing of APP by the γ-secretase complex and the production of the amyloid-beta peptide Aβ42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both γ- and ε-cleavage sites, by raising the Aβ42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to γ-secretase modulators, which shift Aβ42 production towards the shorter Aβ38, but unequivocally spare the ε-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its γ-site, modifying at the same time, the solvation of the ε-site.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Humans; Imidazoles; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Mutation; Piperidines; Protein Structure, Tertiary; Proteolysis; Receptors, Notch

With the recent approval of several new drugs, pharmacological management of Alzheimer's disease has become more complicated in Japan. The efficacy and safety of increasing the dose of donepezil to 10 mg daily were assessed in an open-label study of patients with mild to moderate Alzheimer's disease who were showing a diminished response to 5 mg daily.. The subjects included 27 patients with mild to moderate probable Alzheimer's disease whose primary caregivers had confirmed progression of symptoms during treatment with donepezil 5 mg daily. The dose of donepezil was increased to 10 mg daily, and the Alzheimer's disease assessment scale-cognitive subscale (Japanese version), Neuropsychiatric Inventory, and Zarit caregiver burden interview scores were compared before and after dose escalation. Adverse events were also investigated.. Efficacy was evaluated in 24 patients; three dropped out because of adverse reactions. The Alzheimer's disease assessment scale score showed significant improvement after dose escalation of donepezil (P = 0.006). The total score of the Neuropsychiatric Inventory and the Zarit score showed no significant changes. However, the anxiety score of the Neuropsychiatric Inventory showed a significant increase (P = 0.028). Safety assessment revealed that the dropout rate was 11.1% and adverse reactions occurred in 40.7%. Nausea (29.6%) and loss of appetite (22.2%) were common adverse reactions.. Because cognitive function showed improvement after increasing the dose of donepezil, the dosage of this drug should probably be adjusted based on the overall severity of Alzheimer's disease as well as the progression of cognitive dysfunction.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Japan; Male; Middle Aged; Piperidines; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.

Topics: Alzheimer Disease; Antioxidants; Apoptosis; Blood-Brain Barrier; Cell Line, Tumor; Cell Survival; Cells, Cultured; Humans; Indoles; Neurons; Piperidines

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Azoles; Butyrylcholinesterase; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Donepezil; Electrophorus; Glutathione Peroxidase; Humans; Indans; Isoindoles; Kinetics; Ligands; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Organoselenium Compounds; Peptide Fragments; Peroxynitrous Acid; Piperidines; Protein Multimerization; Protein Structure, Secondary; Thioredoxin-Disulfide Reductase; Toxicity Tests, Acute

Zinc Finger Nucleases (ZFNs), famous for their ability to precisely and efficiently modify specific genomic loci, have been employed in numerous transgenic model organism and cell constructions. Here we employ the ZFNs technology, with homologous recombination (HR), to construct sequence-specific Amyloid Precursor Protein (APP) knock-in cells. With the use of ZFNs, we established APP knock in cell lines with gene-modification efficiencies of about 7%. We electroporated DNA fragment containing the promoter and the protein coding regions of the zinc finger nucleases into cells, instead of the plasmids, to avoid problems associated with off target homologous recombination, and adopted a pair of mutated FokI cleavage domains to reduce the toxic effects of the ZFNs on cell growth. Since over-expression of APP, or a subdomain of it, might lead to an immediately lethal effect, we used the Cre-LoxP System to regulate APP expression. Our genetically transformed cell lines, w5c1 and s12c8, showed detectable APP and Amyloid β (Aβ) production. The Swedish double mutation in the APP coding sequence enhanced APP and Aβ abundance. What is more, the activity of the three key secretases in Aβ formation could be modulated, indicating that these transgenic cells have potential for drug screening to modify amyloid metabolism in cells. Our transformed cells could readily be propagated in culture and should provide an excellent experimental medium for elucidating aspects of the molecular pathogenesis of Alzheimer's disease, especially those concerning the amyloidogenic pathways involving mutations in the APP coding sequence. The cellular models may also serve as a tool for deriving potentially useful therapeutic agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; BALB 3T3 Cells; Base Sequence; Cholinesterase Inhibitors; Deoxyribonucleases; DNA Cleavage; Donepezil; Drug Evaluation, Preclinical; Galantamine; Gene Expression; Genetic Engineering; Green Fluorescent Proteins; Homologous Recombination; Humans; Ibuprofen; Indans; Mice; Molecular Sequence Data; Peptide Fragments; Piperidines; Recombinant Proteins; Zinc Fingers

As life expectancy increases, it is imperative that health care providers recognize the importance of safe medication use within an aging geriatric population. Dealing with a cohort that has different biological and medical demands requires pharmacists to pay particular attention to details when treating this subset of individuals. In particular, this manuscript will focus on Alzheimer's disease (AD) and considerations when dealing with new treatment options. The Food and Drug Administration's recent approval of the increased dosage strength, donepezil 23 mg, previously only available in 5 mg and 10 mg strengths, has raised efficacy and safety concerns. Reservations stem from unproven superiority along with an increased incidence of adverse events. The purpose of the manuscript is to provide a brief insight into these concerns and provide readers the knowledge necessary to make a clinically sound decision when treating patients with moderate-to-severe AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Treatment Outcome

It is difficult to confirm a diagnosis of early-onset Alzheimer's disease (EOAD) because patients sometimes have non-specific cortical features, such as psychiatric symptoms, executive functional impairment, and pyramidal symptoms, along with typical symptoms, such as recent memory impairment and disorientation. We encountered a patient with multiple psychotic symptoms, finally diagnosed with EOAD on genetic testing. A right-handed sixty-year-old man, whose mother was suspected of having dementia, developed memory impairment at the age of fifty, disorientation at the age of fifty-six, and both visual hallucination and dressing apraxia at the age of fifty-nine. After admission to a psychiatric hospital for treatment, his symptoms disappeared with antipsychotic medication. However, his ADL were declining and so he was referred to our university hospital. He had frontal lobe symptoms, pyramidal signs, and extrapyramidal signs with severe dementia. Neuropsychological examinations were not possible because of sedation. On brain MRI, he showed diffuse atrophy of the cerebral cortex and hippocampus. HMPO-SPECT showed hypoperfusion of cerebral cortices diffusely. We decided to perform genetic testing because he had both family and alcohol abuse histories. He showed EOAD with V717I mutation of the amyloid precursor protein gene. After the discontinuation of antipsychotics, excessive sedation and extrapyramidal signs disappeared. A dose of 10 mg of donepezil was effective to improve motivation and activity, and his mini mental examination score was calculable after recovery. The case supports usefulness of applying genetic testing for Alzheimer's disease to patients with early onset dementia, even when they do not have a family history.

Topics: Alzheimer Disease; Brain; Donepezil; Genetic Testing; Humans; Indans; Male; Middle Aged; Mutation; Piperidines

(i) To describe patient and public involvement (PPI) in a network promoting research in dementia and neurodegenerative diseases, in terms of activity at the different stages of the research cycle and within the different levels of the research network. (ii) To use case studies to try and answer the question: what benefits (if any) does PPI in research bring to the research process?. PPI in health research is a central part of government policy, but the evidence base underpinning it needs strengthening. PPI allows exploration of feasibility, acceptability and relevance of hypotheses, assists in the precise definition of research questions and increases accrual to studies. However, the measurement of outcomes is methodologically difficult, because the impact of lay researchers may occur through team interactions and be difficult to untangle from the efforts of professional researchers. Opportunities for PPI in rapidly progressive diseases may be limited, and involvement of people with marked cognitive impairment is particularly challenging.. (i) Description of PPI within the DeNDRoN network. (ii) Case studies of three research projects which asked for extra help from centrally organized PPI.. PPI in research projects on the DeNDRoN portfolio may function at different levels, occurring at project, local research network and national level. Case studies of three research projects show different roles for PPI in research and different functions for centrally organized PPI, including contribution to remedial action in studies that are not recruiting to target, solving problems because of the complexity and sensitivity of the research topic, and linking researchers to PPI resources.. The case studies suggest that centrally organized PPI can have 'diagnostic' and remedial functions in studies that are struggling to recruit and serve as reinforcement for study-level PPI in the complex and sensitive research topics that are typical in neurodegenerative diseases research. PPI may be actively sought by researchers, but the infrastructure of PPI is not yet so widespread in the research community that lay researchers are easy to find; a centrally organized PPI resource can assist in this situation.

Topics: Alzheimer Disease; Biomedical Research; Community Participation; Dementia; Donepezil; Humans; Indans; Memantine; Neurodegenerative Diseases; Nootropic Agents; Organizational Case Studies; Patient Participation; Piperidines

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Piperidines

The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.. Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow.. PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies.. These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.

Topics: Allosteric Regulation; Alzheimer Disease; Animals; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Macaca fascicularis; Macaca mulatta; Male; Mice; Piperidines; Quinolizines; Rats; Rats, Wistar; Receptor, Muscarinic M1; Regional Blood Flow; Scopolamine; Species Specificity

As perturbations in auditory filtering appear to be a candidate trait marker of schizophrenia, there has been considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in sensory gating. This is the first study to investigate the effects of the non-selective muscarinic antagonist scopolamine, the muscarinic M1 antagonist biperiden and the cholinesterase inhibitor donepezil (also in combination with scopolamine and biperiden) on auditory evoked potentials (AEPs) and sensory gating. In the saline condition, only the N50 peak displayed sensory gating. Scopolamine and biperiden both disrupted sensory gating by increasing N50 amplitude for the S2 click. Donepezil was able to fully reverse the effects of biperiden on N50 sensory gating, but had residual effects when combined with scopolamine; i.e., it enhanced sensory gating by increasing N50 amplitude of the S1 stimulus. Donepezil by itself improved sensory gating by enhancing N50 amplitude of S1, and reducing N50 amplitude of the S2 click. In conclusion, due to its relatively more selective effects biperiden is to be preferred over scopolamine as a means for pharmacologically inducing cholinergic impairments in auditory processing in healthy rats. Changes in auditory processing and sensory gating induced by cholinergic drugs may serve as a translational model for aging instead of schizophrenia.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Biperiden; Cholinergic Neurons; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Electroencephalography; Evoked Potentials, Auditory; Hippocampus; Indans; Male; Muscarinic Antagonists; Nerve Tissue Proteins; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M1; Schizophrenia; Scopolamine; Sensory Gating

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Piperidines; Torticollis

Given that amyloid-β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ-Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ-cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque-free 5.5-month-old Tg2576 AD model mice. Here, we investigated the effects of GSM-2 on 10-, 14-, and 18-month-old mice which had age-dependent increase in amyloid plaques. Eight-day treatment with GSM-2 significantly ameliorated cognitive deficits measured by Y-maze task in the mice of any age. However, GSM-2 reduced brain soluble Aβ42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Aβ42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque-associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens.

Topics: Acetates; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Antibodies; Chromatography, Liquid; Cognition Disorders; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Hippocampus; Humans; Mass Spectrometry; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Piperidines

Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. Significant deficits in working and spatial memory were observed from 4 and 6 months of age, respectively. Acute single-dose administrations of memantine, a low-to-moderate-affinity N-methyl-d-aspartate (NMDA) antagonist, showed improvements in working memory deficits at 4 months of age, whereas donepezil, an acetylcholinesterase (AChE) inhibitor, did not. However, both drugs improved spatial memory dysfunction at 6 months of age at therapeutically relevant doses. No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics.

Topics: Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Female; Indans; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Transgenic; Nootropic Agents; Piperidines; Receptors, AMPA

Topics: Aged; Alzheimer Disease; Antioxidants; Chromatography, High Pressure Liquid; Citrus; Disease Progression; Donepezil; Flavones; Humans; Indans; Japan; Medicine, Kampo; Phytotherapy; Piperidines; Statistics, Nonparametric; Treatment Outcome

A simple and sensitive capillary zone electrophoresis (CZE) with UV detection (214 nm) was developed and validated for the simultaneous determination of the acetylcholinesterase inhibitors (AChEI), donepezil, and rivastigmine, with antipsychotic drugs in plasma. A sample pretreatment by liquid-liquid extraction and subsequent quantification by CZE with field-amplified sample injection (FASI) was used. The optimum separation for these analytes was achieved in <20 min at 25 °C with a fused-silica capillary column of 60.2 cm × 50 μm I.D. (effective length 50 cm) and a run buffer containing 120 mM phosphate (pH 4.0) with 0.1 % γ-cyclodextrin, 40 % methanol (MeOH), and 0.02 % polyvinyl alcohol as a dynamic coating to reduce analytes' interaction with the capillary wall. Using phenformin as an internal standard (40.0 ng/mL), the linear ranges of the proposed method for the simultaneous determination of donepezil, rivastigmine, aripiprazole, quetiapine, risperidone, clozapine, ziprasidone, and trazodone were over the range 4.0-80.0 ng/mL, and olanzapine was over the range 1.0-20.0 ng/mL. The method was applied for concentrations monitoring of AChEIs and antipsychotic drugs in ten Alzheimer's disease patients with behavioral and psychological symptoms of dementia after oral administration of the commercial products.

Topics: Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Electrophoresis, Capillary; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine

Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with aging. This study aimed to explore new markers for AD as total homocysteine (tHcy), insulin, insulin like growth factor-1 (IGF-1), interlukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α); to determine the modulatory effects of vitamin E (VE), acetyl-L-carnitine (ALC) and α-lipoic acid (LA) on the investigated parameters and to evaluate the possible therapeutic role of these nutraceutical in AD-induced in rats. Our results revealed that brain acetylcholine esterase (AChE) activity and tHcy levels were significantly increased in AD model. Folic acid, vitamin B(12) levels and Na(+)/K(+) ATPase activity were markedly reduced. Plasma insulin and IGF-1 levels were noticeably decreased but plasma TNF-α and IL-1β concentrations were significantly increased, confirming that abnormal inflammatory response is associated with AD. Treatment by VE, ALC and LA restored the above mentioned parameters to about normal levels comparable to those of donepezil, indicating that tHcy, insulin, IGF-1, IL-1β and TNF-α may be considered as new biomarkers for AD. The study points to the potential restoring effects of VE, ALC and LA in AD model. Our study provides evidence for the importance of dietary supplementation in delaying the progression of age-related neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Antioxidants; Biomarkers; Brain; Carnitine; Cholinesterase Inhibitors; Dietary Supplements; Disease Models, Animal; Donepezil; Enzyme-Linked Immunosorbent Assay; Homocysteine; Indans; Insulin-Like Growth Factor I; Interleukin-1beta; Male; Piperidines; Rats; Rats, Sprague-Dawley; Thioctic Acid; Tumor Necrosis Factor-alpha; Vitamin E

Diagnosing and treating patients with Alzheimer's disease (AD) at an early stage should improve the quality of life of the patient and caregiver. In the United Kingdom, cost-effectiveness of early assessment of individuals presenting with subjective memory complaints and treating those with AD with donepezil was evaluated.. A discrete event simulation of AD progression and the effect of treatment interventions was developed. Patient-level data from donepezil trials and a 7-year follow-up registry were used to model correlated longitudinal rates of change in cognition, behavior, and function. Other epidemiological and health services data, including estimates of undiagnosed dementia and delays in diagnosis, were based on published sources. Simulated individuals were followed up for 10 years.. In the base-case estimates, 17 patients need to be assessed to diagnose one patient with AD, resulting in an average assessment cost of £4100 ($6000; $1 US = £0.68 UK) per patient diagnosed (2007 cost year). In comparison with a scenario without early assessment or pharmacologic treatment, early assessment reduces health care costs by £3600 ($5300) per patient and societal costs by £7750 ($11,400). Savings are also substantial compared with treatment without early assessment, averaging £2100 ($3100) in health care costs, and £5700 ($8400) in societal costs. Results are most sensitive to estimates of patient care costs and the probability of patients reporting subjective memory complaints. In probabilistic sensitivity analysis, early assessment leads to savings or is highly cost-effective in the majority of cases.. Although early assessment has significant up-front costs, identifying AD patients at an early stage results in cost savings and health benefits compared with no treatment or treatment in the absence of early assessment.

Topics: Alzheimer Disease; Caregivers; Cognition Disorders; Cost-Benefit Analysis; Disease Progression; Donepezil; Female; Health Care Costs; Humans; Indans; Longitudinal Studies; Male; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Quality of Life; Statistics as Topic; United Kingdom

Improved data and methods are needed for modeling disease progression in Alzheimer's disease (AD) for economic evaluation of treatments. The aim is to estimate prediction models for long-term AD progression and subsequently economic outcomes.. Three-year follow-up data on 435 patients treated with the cholinesterase inhibitor donepezil in clinical practise were analyzed. Regression models were estimated for long-term prediction of decline in cognitive function (ADAS-cog) and activities in daily living (ADL) ability, risk of institutionalization and costs of care.. The cognitive deterioration was estimated at between 1.6 and 4 ADAS-cog points per every 6 months, increasing with disease severity. Cognitive function was an important predictor of ADL-ability, which itself was the most important predictor of the risk of institutionalization and costs of care. Combining all models in a cross-validation process generated accurate predictions of costs of care at each 6 months follow-up.. The proposed methods for representing AD progression and economic outcomes can be used in micro-simulation models for the economic evaluation of new treatments.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cognition; Disease Progression; Donepezil; Female; Health Care Costs; Health Status Indicators; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Models, Economic; Nootropic Agents; Piperidines; Psychometrics; Regression Analysis; Severity of Illness Index; Sweden

Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid-β protein precursor (AβPP), is a therapeutic target for Alzheimer's disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are described in different species such as mouse, rat, and guinea pigs. All these models have their value in testing compounds with amyloid lowering properties, however, compound characteristics and pharmacokinetic properties, as well as other species characteristics such as limited sampling volumes of cerebrospinal fluid (CSF), recommended the use of a larger, non-rodent animal species. For this purpose, a screening model in dogs was developed for testing GSIs and GSMs. We showed that GSIs and GSMs had a dose- and time-dependent effect on Aβ(37), Aβ(38), Aβ(40), and Aβ(42) in CSF. Changes in liver function were evidenced by a transient increase in bilirubin with the GSMs and incidental increases in alanine aminotransferase for GSMs as well as GSIs. Microarray analysis of liver biopsies enabled to elucidate potential mechanisms behind the liver function changes. The relevance of the liver findings should be further evaluated in chronic pre-clinical safety studies and in humans. Based on our data, we can conclude that the dog is a very appropriate species to assess efficacy and safety of compounds which have an effect on AβPP processing such as GSMs, GSIs, and BACE-inhibitors.

Topics: Alanine; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Azepines; Dogs; Drug Evaluation, Preclinical; Female; Imidazoles; Models, Animal; Piperidines; Treatment Outcome

Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L.

Topics: Acetylcholinesterase; Alzheimer Disease; Azo Compounds; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Indoles; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Models, Chemical; Models, Molecular; Molecular Conformation; Piperidines; Spiro Compounds; Structure-Activity Relationship; Temperature; Thiazoles; Thiosemicarbazones; Triazoles

The aim of this study was to develop a taste-masked oral disintegrating film (ODF) containing donepezil, with fast disintegration time and suitable mechanical strength, for the treatment of Alzheimer's disease. Hydroxypropyl methylcellulose, corn starch, polyethylene glycol, lactose monohydrate and crosspovidone served as the hydrophilic polymeric bases of the ODF. The uniformity, in vitro disintegration time, drug release and the folding endurance of the ODF were examined. The in vitro results showed that 80% of donepezil hydrochloride was released within 5 minutes with mean disintegration time of 44 seconds. The result of the film flexibility test showed that the number of folding time to crack the film was 40 times, an indication of sufficient mechanical property for patient use. A single-dose, fasting, four-period, eight-treatment, double-blind study involving 16 healthy adult volunteers was performed to evaluate the in situ disintegration time and palatability of ODF. Five parameters, namely taste, aftertaste, mouthfeel, ease of handling and acceptance were evaluated. The mean in situ disintegration time of ODF was 49 seconds. ODF containing 7 mg of sucralose were more superior than saccharin and aspartame in terms of taste, aftertaste, mouthfeel and acceptance. Furthermore, the ODF was stable for at least 6 months when stored at 40°C and 75% relative humidity.

Topics: Administration, Oral; Alzheimer Disease; Chemistry, Pharmaceutical; Donepezil; Double-Blind Method; Drug Carriers; Female; Humans; Indans; Male; Piperidines; Solubility; Sweetening Agents; Taste; Tensile Strength; Young Adult

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer's disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Topics: Aged; Alzheimer Disease; Cerebrovascular Circulation; Cholinergic Fibers; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Neural Pathways; Piperidines; Regional Blood Flow; Severity of Illness Index; Time Factors

We describe a 62-year-old female diagnosed with Alzheimer's disease, who had been treated with donepezil for approximately 1 year. When she developed a low-grade fever and digestive complaints, her family physician interpreted these symptoms as side effects of the drug and ordered donepezil to be discontinued. Not only was there no improvement of the somatic symptoms after discontinuation of donepezil, but there was also a worsening of the dementia symptoms, culminating in delirium. When donepezil was re-prescribed, the delirium resolved and the patient's mental state stabilized. The authors urge great caution in discontinuing treatment with acetylcholinesterase inhibitors such as donepezil.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Delirium; Dementia; Donepezil; Female; Humans; Indans; Middle Aged; Piperidines; Substance Withdrawal Syndrome; Withholding Treatment

Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD) progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function.. Rates of change were modeled using trial and registry-based patient level data. A discrete event simulation projected outcomes for three identical patient groups: donepezil 10 mg, memantine 20 mg and no therapy. Patient mix, mortality and costs were developed using Germany-specific sources.. Treatment of patients with mild to moderately severe AD with donepezil compared to no treatment was associated with 0.13 QALYs gained per patient, and 0.01 QALYs gained per caregiver and resulted in average savings of €7,007 and €9,893 per patient from the healthcare system and societal perspectives, respectively. In patients with moderate to moderately-severe AD, donepezil compared to memantine resulted in QALY gains averaging 0.01 per patient, and savings averaging €1,960 and €2,825 from the healthcare system and societal perspective, respectively.In probabilistic sensitivity analyses, donepezil dominated no treatment in most replications and memantine in over 70% of the replications. Donepezil leads to savings in 95% of replications versus memantine.. Donepezil is highly cost-effective in patients with AD in Germany, leading to improvements in health outcomes and substantial savings compared to no treatment. This holds across a variety of sensitivity analyses.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Dopamine Agents; Germany; Humans; Indans; Memantine; Piperidines; Quality-Adjusted Life Years

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Piperidines

Current treatment of Alzheimer's disease rests on cholinergic and anti-glutamatergic substances. It has been suggested that acetylcholine is required for memory acquisition but is less important for memory retrieval. It was our goal to investigate the effects of treatment with donepezil, memantine, and a combination thereof on spatial memory. We assessed spatial memory of male wild type and B6C3-Tg(APPswe,PSEN1dE9)85Dbo (APP23) transgenic animals in a complex dry-land maze. Animals were treated with donepezil (1 mg/kg) and memantine (10 mg/kg). Total time to escape from the maze decreased in 4.5 month old sham-treated wild-type animals and, to a lesser extent, in APP23 animals. Analysis of time spent moving and resting revealed that the treatment effect is conferred by a reduction of the moving time for donepezil and a reduction of the resting time for memantine. Combination treatment with donepezil and memantine fostered a greater improvement than treatment with either substance alone. We conclude that enhancement of spatial learning in a dry-land maze on cholinergic or anti-glutamatergic treatment is differentially conferred during moving of the animals, possibly reflecting acquisition of spatial information, and resting of the animals, possibly reflecting retrieval of spatial information. Combination treatment with donepezil and memantine exerts a synergistic effect improving both moving time and resting time and thus possibly both spatial learning and retrieval.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Drug Synergism; Excitatory Amino Acid Antagonists; Indans; Male; Maze Learning; Memantine; Memory; Mice; Mice, Transgenic; Motor Activity; Piperidines; Rest; Spatial Behavior

Topics: Alzheimer Disease; Donepezil; Drug Approval; Drug Labeling; Evidence-Based Medicine; Humans; Indans; Marketing; Nootropic Agents; Piperidines; United States; United States Food and Drug Administration

This case report describes a new adverse drug event due to use of donepezil in a patient with probable Alzheimer's Disease.. While receiving a 10-mg dose of donepezil nightly, an 87-year old veteran of World War II experienced irrepressible memories of a kamikaze strike. This symptom did not occur at a 5-mg dose of donepezil and resolved with downward titration of this agent.. This sequence of dosage and symptoms suggests acetylcholinesterase inhibition was the trigger for release of these memories, which are otherwise mostly chronically repressed in this individual.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Male; Memory, Episodic; Piperidines; Stress Disorders, Post-Traumatic

The mode of action of acetylcholinesterase inhibitors (AChEIs) in Alzheimer's disease (AD) is mainly by potentiating neuronal transmission. Animal studies have also consistently described a role for AChEIs in enhancement of antioxidants and attenuation of oxidative stress. The influence of AChEIs on blood antioxidants in AD patients has not been established before. Furthermore, AChEI treatment, or lack of it, may have contributed to the inconsistent antioxidant data reported by other studies so far. Here we sought to investigate the potential modulation effect of AChEIs on blood antioxidants in AD patients. Catalase (CAT) and glutathione reductase (GR) activities were analyzed in 25 drug naïve patients (Group A), 43 patients receiving AChEIs (Group B) and 34 cognitively unimpaired controls (Group C). A statistically significant difference for CAT and GR was observed between the two AD groups (A and B) when compared to the control group C (KW-H = 36.530, p < 0.001; post hoc tests p < 0.001 and KW-H = 37.814, p < 0.001; post hoc tests p < 0.001, respectively). In contrast, CAT and GR activities did not differ significantly between the two AD groups, and were not influenced by AChEI treatment. Hence, these results do not replicate the extensively reported data from animal studies and question whether AChEI efficacy in AD is mediated by processes beyond neuron to neuron enhancement of transmission. Studies assessing a wider range of oxidative/inflammatory markers taking into account type, dosage, and treatment duration of the various acetylcholinesterase inhibitors are now needed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Catalase; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Glutathione Reductase; Humans; Indans; Male; Oxidative Stress; Phenylcarbamates; Piperidines; Rivastigmine

Alzheimer's disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients' genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95% CI]: 1.74 [1.01-3.00], p = 0.04). Rs1080985 might be useful as predictor of poor response to short-term donepezil treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cytochrome P-450 CYP2D6; DNA Replication; Donepezil; Female; Follow-Up Studies; Genetic Markers; Humans; Indans; Male; Piperidines; Polymorphism, Genetic; Treatment Outcome

Recent studies have reported the presence of acetylcholine (ACh) receptor subtypes in bone tissue, and have demonstrated that inhibition of the ACh receptors has negative effects on bone mass and fracture healing capacity. However, little is known about the potential clinical effects that increased ACh signaling might have on bone. Accordingly, this study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate ACh receptors and are used to treat Alzheimer's disease (AD), is associated with a decreased risk of hip fracture in AD patients. To accomplish this objective, a case-control analysis was performed using the AD population, aged above 75 years, based in the local health area of the Carlos Haya Hospital, in Malaga, Spain. The cases were 80 AD patients that suffered a hip fracture between January 2004 and December 2008. The controls were 2178 AD patients without hip fracture followed at our health care area during the same period of time. Compared with patients who did not use AChEIs, the hip fracture adjusted odds ratio (OR) for users of AChEIs was 0.42 (95% confidence interval [CI], 0.24-0.72), for users of rivastigmine was 0.22 (95% CI, 0.10-0.45), and for users of donepezil was 0.39 (95% CI, 0.19-0.76). Data were adjusted for the following parameters: body mass index, fall risk, smoking habits, cognition, dependence, degree of AD, comorbidity score, treatment with selective serotonin reuptake inhibitors, age, and gender. Our data suggests that use of AChEIs donepezil and rivastigmine is associated with a reduced risk of fractures in AD patients. Many elderly patients with AD disease who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEIs donepezil and rivastigmine.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Female; Hip Fractures; Humans; Indans; Male; Odds Ratio; Phenylcarbamates; Piperidines; Regression Analysis; Risk; Rivastigmine

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Brain; Enzyme Inhibitors; Mice; Peptide Fragments; Piperidines

We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Biomarkers; Brain; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Piperidines; Treatment Outcome

Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Brain; Calcium; Calcium-Binding Proteins; Cell Survival; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Egtazic Acid; Enzyme Inhibitors; Glycoproteins; Humans; Indans; Isoxazoles; Ligands; Maze Learning; Memory Disorders; Metalloproteases; Mice; Mice, Transgenic; Microfilament Proteins; Mutation; Neuroblastoma; Nootropic Agents; Panax; Peptide Fragments; Phytotherapy; Piperidines; Plant Proteins; Presenilin-1; Propionates; Protein Binding; Receptors, Lysophosphatidic Acid; Signal Transduction; Time Factors; Transfection

Cholinesterase inhibitors (ChEIs) are widely used for the treatment of Alzheimer's disease (AD); however, their cholinergic side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the side effects caused by donepezil, rivastigmine, and galantamine on cardiac rhythm and postural blood pressure changes in elderly patients with AD.. Of 204 consecutive elderly patients who were newly diagnosed with AD, 162 were enrolled and underwent comprehensive geriatric assessments. The electrocardiographs (ECGs) and blood pressures were recorded at the baseline and 4 weeks after the dose of 10 mg/d of donepezil, 10 cm(2)/d of rivastigmine, and 24 mg/d of galantamine.. There were no changes relative to the baseline in any of the ECG parameters or arterial blood pressure with any of the administered ChEIs.. It was demonstrated that none of the 3 ChEIs were associated with increased negative chronotropic, arrhythmogenic, and hypotensive effects for the elderly patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Blood Pressure; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Heart; Humans; Indans; Male; Phenylcarbamates; Piperidines; Rivastigmine

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Piperidines

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Excitatory Amino Acid Antagonists; Female; Humans; Indans; Male; Memantine; Piperidines

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the AβPP/PS1 transgenic mouse model is a commonly used experimental model to mimic the pathological and cognitive impairments in AD. As a classic method to evaluate spatial learning and memory, the Morris water maze is widely applied to study the cognitive deficits in rodent AD models. However, the assay procedure is relatively complicated and requires a properly equipped environment. The novel object recognition test is a relatively simple and straightforward method to test working memory in rodents. However, whether the latter can be used as a common tool for evaluating the therapeutic effects of drugs in the AβPP/PS1 transgenic AD mouse model remains unclear. In the present study, we assessed the cognitive impairment of AβPP/PS1 AD mice with the novel object recognition test. In parallel, Morris water maze was performed and compared with the novel object recognition study. Both assays worked equally well in evaluating the cognitive defect of AβPP/PS1 mice. Furthermore, we drew similar conclusions from the novel object recognition assay as from the Morris water maze in assessing the therapeutic effects of two previously reported compounds, donepezil and naltrindole, on AD. We found the novel object recognition to be a facile assay with almost no stress to mice and think it could be used as an ideal primary screening assay to evaluate drug effects on AβPP/PS1 AD model.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Female; Humans; Indans; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Naltrexone; Pattern Recognition, Visual; Piperidines; Presenilin-1; Random Allocation

Mild cognitive impairment (MCI) is defined as 'a condition between a normal state and dementia indicated by a cognitive decline in comparison to previous results'. MCI groups as a whole are not necessarily in the prodromal stage of dementia. However, when patients are notified of their condition, communication must be cautious and account for the patient's personality, mental status, and examination findings. Hurriedly notifying patients may give the incorrect impression that they will certainly have dementia in the future and cause worry or emotional tension. The efficacy of pharmacotherapy and non-pharmacotherapy, such as cognitive function training, in preventing dementia in MCI patients has not yet been confirmed. As no particular types of intervention are currently shown to be effective for MCI, it is believed that periodically monitoring patients and providing lifestyle guidance, while also treating lifestyle-related diseases, is an appropriate treatment strategy for those with MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Combined Modality Therapy; Donepezil; Health Behavior; Humans; Indans; Japan; Life Style; Middle Aged; Nootropic Agents; Patient Education as Topic; Physician-Patient Relations; Piperidines; Treatment Outcome; Truth Disclosure

Rocuronium bromide is a muscle relaxant used in general anesthesia, inhibiting cholinergic neurotransmission of neuromuscular junction. Donepezil used for the treatment of Alzheimer's disease inhibits decomposition of acetylcholine. We describe a case in which donepezil most obviously weakened the muscle relaxation induced by rocuronium. Because the interaction may impair intubation and surgery conditions, anesthesiologists should be aware of it. Prior to general anesthesia, a 2-4-week pause in anticholinesterase medication has been recommended. So far, reliable scientific data on the subject is lacking.

Topics: Alzheimer Disease; Androstanols; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Neuromuscular Nondepolarizing Agents; Piperidines; Rocuronium

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients.

Topics: Alzheimer Disease; Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Drug Inverse Agonism; Male; Mice; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Drug Therapy, Combination; Humans; Indans; Memantine; Piperidines

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Neuropsychological Tests; Piperidines; Randomized Controlled Trials as Topic

The crystal structures of a very large number of compounds with biological relevance are known. Application of the invariom formalism provides the aspherical electron density distribution.. The electron density distribution of the anti-Alzheimer's disease drug donepezil was derived from its x-ray structure reported in the literature, using the invariom database. The electrostatic potential mapped on the electron density isosurface shows how the positive charge of the donepezilium cation is distributed over a wide surface range. The presence of intermolecular contacts can be illustrated by the Hirshfeld surface. Comparable interactions are found in both the small-molecule structure and an acetylcholinesterase complex with donezepil from the literature.. The electron density of donepezil in the small-molecule crystal structure mimics the intermolecular interactions within the receptor site. Complementing steric properties with electronic information can be a valuable procedure in the examination of molecular recognition of systems with biological activity.

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Databases, Factual; Donepezil; Electrons; Humans; Indans; Molecular Conformation; Piperidines; Static Electricity; X-Ray Diffraction

We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer's disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Functional Laterality; Hippocampus; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Nootropic Agents; Piperidines; Prefrontal Cortex

The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; CHO Cells; Cognition Disorders; Cricetinae; Cricetulus; Cyclic AMP; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver; Permeability; Piperidines; Protein Isoforms; Pyrans; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism; Structure-Activity Relationship

The efficacy of donepezil 10 mg/day against Alzheimer's disease (AD) was examined, with a primary focus on changes in cerebral blood flow (CBF) as determined by single-photon emission computed tomography imaging.. The subjects were 24 outpatients who had been diagnosed with probable AD, which had progressed to advanced AD. Mini-Mental State Examination and Alzheimer's Disease Assessment Scale (ADAS) scores were determined before and after the donepezil dosage increase. (99m) Tc-ethylcysteinate dimer single-photon emission computed tomography was performed to evaluate changes in CBF. Then, a comparative study evaluated changes after the donepezil dosage increased.. After the donepezil dosage increase, adverse effects associated with gastrointestinal symptoms were observed in one patient, and irritability was observed in three. The average Mini-Mental State Examination score changed from 15.25 ± 6.24 to 14.67 ± 6.07; significant changes were not observed. Seventeen subjects were evaluated with the Alzheimer's Disease Assessment Scale-cognitive subscale. After the dosage increase, the average subscale score decreased from 24.52 ± 13.39 to 21.56 ± 9.14, and significant improvement was observed (P = 0.021). With respect to changes in the CBF, the values of all three indicators decreased after the higher dosage increased CBF. However, no significant differences were observed in CBF. Analysis performed after the donepezil dosage increase revealed significant increases in CBF in the right occipital and temporal lobes, left temporal lobe, right parietal lobe, and both parts of the posterior cerebellum.. Increasing the donepezil dosage from 5 mg/day to 10 mg/day is effective for the treatment of AD.

Topics: Aged; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

The aim of this study was to investigate the pathological changes in a rat model of Alzheimer's disease (AD) and the effect of donepezil hydrochloride (HCl) treatment. The rat model of AD was established by the bilateral injection of amyloid β₁₋₄₀ (Aβ₁₋₄₀) into the hippocampus. Changes in spatial learning and memory functions were examined using the Morris water maze test and changes in catalase (CAT) and glutathione peroxidase (GSH-Px) activities were determined using chemical colorimetry. Moreover, the changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) expression were analyzed using immunohistochemical staining. The mRNA expression levels of the amyloid precursor protein (APP) and β-secreted enzyme 1 (BACE1) were evaluated using RT-PCR. The effects of donepezil HCl on the aforementioned indices were also observed. The rat memories of the platform quadrants in the blank, sham and donepezil HCl groups were improved compared with those of the rats in the model group. The ratio of swim distance in the fourth platform quadrant (l₄) to the total swim distance (l total) for the model group rats (l₄/l total) was significantly decreased compared with that for the blank and sham group rats. Following donepezil HCl treatment, the ratio of l₄/l total significantly increased. AD modeling caused a significant decrease in the CAT and GSH-Px activities in the brain tissues of the rats. The CAT and GSH-Px activities in the AD model rats significantly increased following donepezil HCl treatment. Moreover, donepezil HCl treatment significantly decreased the AChE, APP and BACE1 mRNA expression levels and increased the ChAT expression levels. Therefore, donepezil HCl was able to significantly decrease learning and memory damage in a rat model of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Catalase; Choline O-Acetyltransferase; Disease Models, Animal; Donepezil; Glutathione Peroxidase; Hippocampus; Indans; Learning; Male; Memory; Piperidines; Rats; Rats, Sprague-Dawley

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dystonia; Female; Humans; Indans; Memory Disorders; Piperidines; Postural Balance; Sensation Disorders

The synthesis, biological assessment and molecular modeling of new pyridonepezils1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC(50) (hAChE) = 9.4 ± 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminopyridines; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Enzyme Assays; Humans; Indans; Models, Biological; Models, Molecular; Nitriles; Permeability; Piperidines; Protein Binding; Pyridines; Structure-Activity Relationship

Alzheimer's disease (AD) is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL) is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ) associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning, and memory in AD animals. Although the molecular mechanisms underlying the beneficial effects produced by MAGL inhibition remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD, and thus is a promising therapeutic target for the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Astrocytes; Benzodioxoles; Disease Models, Animal; Down-Regulation; Hippocampus; Humans; Mice; Mice, Transgenic; Microglia; Monoacylglycerol Lipases; Neuronal Plasticity; Piperidines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Synapses

Previous studies using magnetic resonance imaging (MRI) showed that dementia with Lewy bodies (DLB) had less atrophy in some medial temporal structures than Alzheimer's disease (AD). However, very few studies have focused on the entorhinal cortex, which is closely related to episodic memory. We compared the degree of entorhinal cortex atrophy between the two types of dementia using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region.. The subjects consisted of 60 patients with DLB and 210 patients with AD. The degree of entorhinal cortex atrophy was quantified by application of the VSRAD to MRI data, and a Z score >2 was defined as significant atrophy.. The DLB group had significantly lower Z scores than the AD group (mean ± SD: 2.25 ± 1.10 vs. 2.85 ± 1.33, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z scores were significantly lower in the DLB group than in the AD group (p < 0.01). The proportion of patients with atrophy was significantly lower in the DLB group than in the AD group (53 vs. 72%, p < 0.01).. The present study using the VSRAD suggests that DLB shows less atrophy in the entorhinal cortex than AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Data Interpretation, Statistical; Donepezil; Entorhinal Cortex; Female; Humans; Image Processing, Computer-Assisted; Indans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Sex Characteristics

To identify risk factors for early nursing home placement (NHP) in Alzheimer's disease (AD), focusing on the impact of longitudinal change in cognition, activities of daily living (ADL), service utilization, and cholinesterase inhibitor treatment (ChEI).. In an open, 3-year, prospective, multicenter study in a routine clinical setting, 880 AD patients were treated with either donepezil, rivastigmine, or galantamine. At baseline and every 6 months, they were assessed with several rating scales including Mini-Mental State Examination, Instrumental Activities of Daily Living scale (IADL), and Physical Self-Maintenance scale. Moreover, the dose of ChEI, the amount of weekly assistance (home help service and adult day care), and the date of NHP were recorded. Cox regression models were constructed to predict the risk of NHP. . During the study, 206 patients (23%) were admitted to nursing homes. Factors that precipitated institutionalization were lower cognitive and functional abilities at baseline, faster rate of decline in IADLs, female gender, solitary living, and a lower mean dose of ChEI. The men living alone and patients with a substantial increase in adult day care also demonstrated shorter time to NHP.. The rate of functional but not cognitive decline was a strong risk factor for NHP. The results could be used to identify the care recipients that might risk early NHP to ensure that these individuals receive a sufficient level of assistance. Furthermore, higher doses of ChEI might postpone institutionalization in AD.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Galantamine; Humans; Indans; Kaplan-Meier Estimate; Male; Middle Aged; Nursing Homes; Phenylcarbamates; Piperidines; Proportional Hazards Models; Prospective Studies; Risk Factors; Rivastigmine; Severity of Illness Index; Sex Factors; Sweden

This study sought to examine the trends in the prescribing of subsidized and unsubsidized cognition enhancing drugs (CEDs) in Australia over five years from 2002 to 2007. Subsidized cholinesterase inhibitor medication could be prescribed to people with mild to moderate Alzheimer's disease (AD) once a specialist physician had confirmed this diagnosis. Memantine was available for use in moderately severe AD but not subsidized.. We analyzed the Medicare Australia and Drug Utilisation Sub-Committee databases for CED prescription data, 2002-2007, by gender, age and prescriber class. Aggregated prescription data for each medication were converted to defined daily doses (DDD) per 1000 persons per day using national census data.. There were 1,583,667 CED prescriptions dispensed during the study period. CED use increased 58% from 0.91 to 1.56 DDD/1000 persons/day between 2002 and 2007. Peak use was in those aged 85-89 years. Age-adjusted utilization was slightly higher in females than males. Donepezil was the most widely used CED (66%), followed by galantamine (27%) then memantine (4%). General practitioners prescribed the majority of CEDs. Geriatricians exhibited a greater preference for galantamine than other prescribers. CED dispensing peaked towards the end of each calendar year, reflecting stockpiling by patients under the influence of a federal safety net subsidy.. Despite subsidized access to CEDs in Australia, only a minority of people with AD was prescribed these drugs during the period of the study. It is likely that the combination of complex prescribing rules and negative perceptions about efficacy or cost-effectiveness might have contributed to these findings.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Australia; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Nootropic Agents; Piperidines; Practice Patterns, Physicians'; Sex Factors

Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these.. As part of the development of the Statistical Analysis Plan for the DOMINO trial, investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures, the Standardised Mini-mental State Examination (sMMSE), Bristol Activities of Daily Living Scale (BADLS) and Neuropsychiatric Inventory (NPI). Only standard deviations (SD) were presented to investigators who remained blind to treatment allocation.. Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE, BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE, 3.5 for BADLS and 8.0 for NPI.. Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Data Interpretation, Statistical; Decision Making; Donepezil; Dopamine Agents; Humans; Indans; Memantine; Outcome Assessment, Health Care; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic

Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD.. In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis.. Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667).. Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.

Topics: Alzheimer Disease; Cohort Studies; Cytochrome P-450 CYP2D6; Donepezil; Female; Genetic Variation; Humans; Indans; Male; Nootropic Agents; Piperidines; Polymorphism, Genetic

The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome.. Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured.. Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively].. Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Alzheimer Disease; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Donepezil; Female; Genotype; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Polymorphism, Single Nucleotide; Treatment Outcome; Young Adult

The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain.. Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding (123)I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system.. The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with (123)I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation.. BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid; Animals; Autoradiography; Brain; Butyrylcholinesterase; Evaluation Studies as Topic; Immunohistochemistry; Iodine Radioisotopes; Iodobenzoates; Kinetics; Ligands; Male; Molecular Conformation; Molecular Imaging; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Tissue Distribution; Trialkyltin Compounds

Donepezil has been approved for the treatment for mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A higher oral dosage was suggested to have a better therapeutic response in reported results, but the plasma concentration of donepezil was not examined with respect to the therapeutic outcomes in those studies. Therefore, we analyzed the therapeutic responses, measured by neuropsychological assessments, among 70 newly diagnosed AD patients taking donepezil (5 mg daily) in relation to their plasma concentration of donepezil, apolipoprotein E genotype, and demographic characteristics. Our results have showed 60% of recruited AD patients improved in cognition, measured by Mini-Mental Status Examination (MMSE), and 57.1% in global status, by Clinical Dementia Rating Scale (CDR) sum of boxes (CDR-SB). In cognition, compared to the improving group, the clinically worsening group had a significantly higher donepezil concentration [p = 0.022, odds ratio (OR) = 1.024, 95% CI = 1.003-1.045] and higher initial MMSE score (p = 0.007, OR = 1.330, 95% CI = 1.080-1.639). In global status, initially higher CDR-SB (p = 0.028, OR = 2.318, 95% CI = 1.096-4.903) and initially higher MMSE (p = 0.036, OR = 1.201, 95% CI = 1.012-1.425), not donepezil concentration (p = 0.883), were significantly associated with clinical worsening. Our results have indicated that the dosage of donepezil should be reconsidered for AD patients, especially those clinically worsening in cognition.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Piperidines; Taiwan; Treatment Outcome

FK962 is a member of a novel class of compounds that promote somatostatin production in the brain, and is being developed as a treatment for patients with Alzheimer's disease. As acetylcholinesterase inhibitors such as Aricept© (donepezil) are widely used to treat these patients, it is important to confirm that potential new medicines in this disease area can be co-administered with drugs such as Aricept. To study the effect of FK962 in combination with donepezil, touchscreen methodology was used to measure the effect on cognition in rats. Doses of FK962 and donepezil were identified that resulted in minimal cognition enhancement when given separately. There was strong evidence (p=0.002) of a treatment difference between the combination of FK962/donepezil and FK962 alone: the estimated treatment difference is 5.47 (95% CI: 2.19-8.75). There was also evidence (p=0.017) of a treatment difference between the combination of FK962/donepezil and donepezil alone: the estimated treatment difference is 4.01 (95% CI: 0.77-7.26). Therefore, a combination of low doses of FK962 and donepezil showed a significantly greater effect on cognition than low doses of either compound alone. This is the first time that FK962 has shown activity in a reward-based model of cognition. In addition, these data suggest that this compound could beneficially be given in addition to Aricept to treat Alzheimer's disease patients.

Topics: Alzheimer Disease; Animals; Benzamides; Cholinesterase Inhibitors; Cognition; Discrimination Learning; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Humans; Indans; Male; Models, Animal; Nootropic Agents; Photic Stimulation; Piperidines; Rats; Reward

A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.. An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.. General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.. A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Topics: Advisory Committees; Alzheimer Disease; Amyloidogenic Proteins; Biomarkers; Clinical Trials as Topic; Cognition; Consensus; Disease Progression; Donepezil; Drug Industry; Early Diagnosis; Europe; Humans; Indans; International Cooperation; Nootropic Agents; Outcome Assessment, Health Care; Patient Selection; Piperidines; Positron-Emission Tomography; Research Design; Treatment Outcome; United States; United States Food and Drug Administration; Vitamin E

Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Motor Cortex; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Transcranial Magnetic Stimulation