piperidines and Dementia--Vascular

The objective of this study was to determine whether treatment with acetylcholinesterase inhibitors would provide cognitive benefit for patients with vascular dementia.. Studies in patients with vascular dementia, who had not taken acetylcholinesterase inhibitors or memantine for at least 6 weeks, were included.. Twelve studies were included in the final analysis. Donepezil showed significant improvement in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) as compared to placebo, at the doses tested, that is, 5 and 10 mg/day (difference in means -1.389 and -1.680, respectively, p ≤ 0.008), but not on the Mini Mental State Examination (MMSE) (p ≥ 0.259). Galantamine also improved the ADAS-cog in comparison to the placebo (difference in means -2.191, p < 0.001), whereas, rivastigmine did not show any benefit on ADAS-cog. However, the findings with rivastigmine are difficult to interpret, given there were only 2 studies. Treatment with cholinesterase inhibitors was associated with a twofold increase in the odds of discontinuation, due to adverse events (pooled OR 1.966, 95% CI 1.630-2.371, p < 0.001).. The present results reveal the therapeutic benefits of donepezil and galantamine in patients with vascular dementia. Interestingly, the ADAS-cog and MMSE varied considerably in detecting cognitive improvement.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Galantamine; Humans; Indans; Neuropsychological Tests; Piperidines; Rivastigmine

Chinese herbal medicine has been extensively used in the treatment of vascular dementia (VaD), but lacked systematic review on its efficacy and safety. So we conducted a systematic review to assess the efficacy and safety of Chinese herbal medicine in treating VaD.. CNKI, CBM, PubMed, and Wiley Online Library were retrieved for randomized trials (RCTs) on Chinese herbal medicine treating VaD patients. Randomized parallel control trials by taking Chinese herbal medicine as one treatment method and placebos/cholinesterase inhibitors/Memantine hydrochloride as the control were included. Quality rating and data extraction were performed. RevMan5.2.0 Software was used for meta-analysis. Standardized mean difference (SMD) at 95% confidence interval (CI) was used to indicate effect indicators of results.. Seven RCTs met the inclusive criteria. Totally 677 VaD patients were randomly assigned to the treatment group and the control group. Descriptive analyses were performed in inclusive trials. The cognitive function was assessed in all trials. Results showed Mini-Mental state examination (MMSE) score was better in the Chinese herbal medicine group than in the placebo group, but with no significant difference when compared with the donepezil group (P > 0.05). Adverse reactions were mainly manifested as gastrointestinal symptoms such as abdominal pain in the Chinese herbal medicine group. But they occurred more in the donepezil group than in the Chinese herbal medicine group.. The methodological quality of included trials was poor with less samples. Results of different trials were lack of consistency. Present evidence is not sufficient to prove or disapprove the role of Chinese herbal medicine in improving clinical symptoms and outcome indicators of VaD patients. Their clinical efficacy and safety need to be supported by more higher quality RCTs.

Topics: Complementary Therapies; Dementia, Vascular; Donepezil; Drugs, Chinese Herbal; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

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

Hyperbaric oxygen therapy (HBOT) has been used to treat a variety of conditions and has shown possible efficacy for treating vascular dementia (VaD) in experimental and preliminary clinical studies.. To assess the efficacy and safety of HBOT for VaD, used alone or as an adjuvant treatment.. We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group Specialised Register on 20 December 2011 using the terms: hyperbaric OR oxygen OR HBO OR HBOT. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. We also searched the Chinese Biomedical Database (CBM), the Chinese National Knowledge Infrastructure (CNKI) and the VIP Chinese Science and Technique Journals Database on 10 November 2011 using the terms 'gaoyayang', 'xueguanxingchidai' and 'chidai'. In addition, we contacted authors of included studies for additional information.. Trials were eligible for inclusion if they were randomised controlled trials comparing HBOT to no intervention or to sham HBOT, or comparing HBOT plus another treatment to the same other treatment in patients with VaD.. Two review authors independently assessed trial quality and extracted data.. One study involving 64 patients was included. It compared HBOT as an adjuvant to donepezil with donepezil alone. This one included study was judged to be of poor methodological quality. Patients receiving HBOT plus donepezil had significantly better cognitive function than the donepezil only group after 12 weeks of treatment, measured by the Mini-Mental State Examination (MMSE) (WMD 3.50; 95% CI 0.91 to 6.09) or by Hasegawa's Dementia Rating Scale (HDS) (WMD 3.10; 95% CI 1.16 to 5.04). There were no deaths or withdrawals, and the study did not mention safety assessment at all. Global function, behavioral disturbance and activities of daily living were not investigated in the study.. There is insufficient evidence to support HBOT as an effective treatment for patients with VaD. Future trials should be randomised, double-blind comparisons of HBOT to sham HBOT.

Topics: Cognition; Combined Modality Therapy; Dementia, Vascular; Donepezil; Humans; Hyperbaric Oxygenation; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.Acta Pharmacologica Sinica (2009) 30: 879-888; doi: 10.1038/aps.2009.82.

Topics: Acetylcholine; Alkaloids; Animals; Anti-Inflammatory Agents; Cholinergic Agents; Cholinesterase Inhibitors; Dementia, Vascular; Disease Models, Animal; Donepezil; Galantamine; Humans; Indans; Inflammation; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, Cholinergic; Rivastigmine; Sesquiterpenes; Signal Transduction

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

Cholinesterase inhibitors and memantine do not have regulatory approval in most of the world for treatment of vascular dementia. A systematic review and meta-analysis was undertaken to assess the evidence for efficacy and safety of cholinesterase inhibitors and memantine in vascular dementia.. PubMed, BIOSIS, International Pharmaceutical Abstracts, and Cochrane registries were searched for randomised, placebo-controlled trials on cholinesterase inhibitors and memantine in patients with vascular dementia. Trial methods, clinical characteristics, outcomes, and adverse events were extracted and checked. Meta-analytic methods using fixed-effects models were used to give summaries of each drug's effects.. Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer's Disease Assessment scale were significant for all drugs, ranging from a -1.10 point mean difference (95% CI -2.15 to -0.05) for rivastigmine to -2.17 for 10 mg daily donepezil (95% CI -2.98 to -1.35). Only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale (odds ratio 1.51 [95% CI 1.11-2.07]). No behavioural or functional benefits were observed, except for a -0.95 point difference (95% CI -1.74 to -0.16) with 10 mg daily donepezil on the Alzheimer's Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse events (anorexia, nausea, vomiting, diarrhoea, and insomnia) occurred with the cholinesterase inhibitors, but not with memantine.. Cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance in patients with mild to moderate vascular dementia. Data are insufficient to support widespread use of these drugs in vascular dementia. Individual patient analyses are needed to identify subgroups of patients with vascular dementia who might benefit.

Topics: Cholinesterase Inhibitors; Databases, Bibliographic; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Odds Ratio; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Time Factors; Treatment Outcome

Accurate diagnosis of vascular cognitive impairment (VCI) is important but may be difficult. VCI diagnoses depend on determinations of the presence of both cognitive impairment and cerebrovascular disease (CVD), temporal causal links between cognitive impairment and CVD, and the presence or absence of other potential contributors to cognitive impairment, such as Alzheimer's disease (AD). Diagnostic criteria differ across currently utilized systems, resulting in widely differing VCI prevalence rates. Also, current systems may not be able to differentiate "pure" VCI from "mixed" AD and CVD. National Institute of Neurological Disorders and Stroke harmonization criteria for VCI have been developed for study and validation to help bridge gaps in our understanding of VCI diagnosis. VCI management begins with atherogenic risk factor control. Current VCI treatment options demonstrate statistical improvement but not consistent global clinical efficacy. Future clinical trials should concentrate on both primary risk factor control and development of new therapeutic agents to treat patients already diagnosed with VCI.

Topics: Central Nervous System Agents; Clinical Trials as Topic; Cognition Disorders; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine

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

Vascular dementia (VaD) is the second leading cause of dementia and is often underdiagnosed. Stroke is the leading cause of VaD, although it may also develop secondary to a variety of other cerebrovascular or cardiovascular conditions. Currently, no drugs are approved for the treatment of VaD. However, because cholinergic deficits have been found in patients with VaD, similar to those found in patients with Alzheimer disease (AD), it is believed that cholinesterase inhibitors, which are indicated for the treatment of mild to moderate AD, may also provide benefit for patients with VaD. Clinical trials of donepezil, galantamine, and rivastigmine have supported this idea, although as yet, large-scale, prospective studies in VaD have only been reported for donepezil. Donepezil was shown to provide benefits in cognition, global function, and activities of daily living compared with placebo. The N-methyl-D-aspartate receptor antagonist memantine may also provide some cognitive benefit in VaD, particularly in patients with more advanced disease. These data suggest that antidementia drugs currently used for treatment of AD should be considered for treatment of VaD as well.

Topics: Cholinesterase Inhibitors; Dementia, Vascular; Diagnosis, Differential; Donepezil; Dopamine Agents; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Stroke

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

Patients with vascular dementia (VaD) and Alzheimer's disease with cerebrovascular disease (AD + CVD) have dementia associated with underlying CVD. Although diagnosis of VaD is challenging, VaD is typically characterized by a stepwise progression of dementia that is closely associated with stroke and focal neurological findings, and a symptom profile that often includes executive dysfunction leading to decreased ability to perform instrumental activities of daily living (IADL). In contrast, AD + CVD patients typically present with progressive deterioration of cognition/memory that may also be influenced by concurrent cerebrovascular events. Early diagnosis and intervention are desirable to prevent further decline due to subsequent vascular events. Management of CVD can limit deterioration of cognitive symptoms in VaD patients, and treatment benefits with cholinesterase inhibitors may be realized as improvement above baseline levels in dementia symptoms. Results from a combined analysis of two 24-week, placebo-controlled clinical trials show that donepezil-treated VaD patients improve in cognition, global function, and performance of IADL. In contrast, AD + CVD patients may continue to decline despite management of CVD, and treatment benefits should be recognized as initial improvements followed by stabilization or slowed decline of dementia symptoms over time. In post-marketing studies, donepezil-treated AD and AD + CVD patients show similar benefits in cognition, global function, and quality of life. The results of these studies support the use of donepezil in treatment of patients with VaD or AD + CVD.

Topics: Cerebrovascular Disorders; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Diagnosis, Differential; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Parasympathetic Nervous System; 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

Vascular disease is the second commonest cause of dementia after Alzheimer's disease. There are difficulties in classifying patients with this type of cognitive impairment owing to varied clinical presentation and different types of arterial disease. There is some degree of overlap in the neuropathology of Alzheimer's and vascular dementia. Deficient cholinergic neurotransmission, a characteristic of Alzheimer's disease, has been postulated to contribute to the cognitive impairment of vascular disease of the brain. Cholinesterase inhibitors, such as donepezil, may therefore be a rational treatment.. To assess the clinical efficacy and tolerability of donepezil on cognitive function, clinical global impression, activities of daily living and social functioning of people with vascular cognitive impairment.. Relevant randomized controlled trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group Specialized Register on 21 July 2003 using the terms donepezil, E2020 and Aricept. This Register consists of records from all major healthcare databases and many ongoing trials databases. Unpublished trials were requested from the drug company Eisai Inc and they provided us with the required data.. All unconfounded randomized double-blind trials comparing donepezil with placebo were eligible for inclusion. Trials using combinations of donepezil with other pharmacological interventions were excluded.. Both reviewers assessed studies against the criteria for inclusion and extracted data. Data were pooled where appropriate, and weighted mean differences or Peto odds ratios with 95% confidence intervals calculated. Intention-to-treat analysis was undertaken when possible.. Two large-scale, randomized, double-blind, parallel-group controlled trials were identified for inclusion. A total of 1219 people with mild to moderate cognitive decline due to probable or possible vascular dementia (according to the NINCDS/AIREN criteria and the Hachinski Ischemia Scale) were recruited. Donepezil, at doses of 5 or 10 mg a day was compared with placebo for 24 weeks. For each outcome measure, mean change from baseline at weeks 12 and 24, using a last observation carried forward analysis, was calculated. Cognitive function: The donepezil groups showed statistically significantly better performance than the placebo groups on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) at 12 and 24 weeks. The donepezil groups produced statistically significantly better scores than the placebo groups on the Mini-Mental State Examination (MMSE) at 12 and 24 weeks. Global function: The sum of the boxes of the Clinical Dementia Rating (CDR-SB) showed at 24 weeks a statistically significant benefit of 10 mg donepezil daily over both placebo and a 5 mg daily dosage. The Clinician's Interview-Based Impression of Change-plus version (CIBIC-plus) showed improved global function of participants taking 5 mg of donepezil daily compared with the placebo group but this was not seen in the higher dose group. Activities of daily living and social behaviour: On the Instrumental Activity of Daily Living (IADL) scale, there was no statistically significant difference between the groups taking donepezil 5mg per day donepezil and placebo, but the group taking 10 mg of donepezil a day showed benefit compared with placebo There were statistically significant benefit for donepezil at either dosage compared with placebo on the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS). Tolerability and adverse effects: Broad range of adverse events were reported in the studies and data confirmed that donepezil was well tolerated, and most of the side effects were transient and were resolved by stopping the medication. Some of these events, especially nausea, diarrhoea, anorexia and cramp appeared more frequently on the 10 mg dose where there was a statistically significant difference compared with placebo. Drop-out: The drop-out rate was similar between the groups, 84.2% (330) patients completed the studies. The withdrawal rate was low and due mainly to side effects.. Evidence from the available studies support the benefit of donepezil in improving cognition function, clinical global impression and activities of daily living in patients with probable or possible mild to moderate vascular cognitive impairment after 6 months treatment. Extending studies for longer periods would be desirable to establish the efficacy of donepezil in patients with advanced stages of cognitive impairment. Moreover, there is an urgent need for establishing specific clinical diagnostic criteria and rating scales for vascular cognitive impairment.

Topics: Activities of Daily Living; Cognition Disorders; Dementia, Vascular; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Topics: Activities of Daily Living; Anticoagulants; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Humans; Indans; Patient Care Team; Piperidines; Quality of Life; Secondary Prevention; Selective Serotonin Reuptake Inhibitors; Warfarin

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living.

Topics: Aged; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Nootropic Agents; Parasympathetic Nervous System; Phenylcarbamates; Piperidines; Rivastigmine

Topics: Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Neuropsychological Tests; Piperidines; Randomized Controlled Trials as Topic

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

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second most common form of dementia after Alzheimer's disease (AD). Donepezil, an acetylcholinesterase inhibitor currently indicated for use in patients with mild to moderate AD, has recently been evaluated in VaD. Donepezil 5 or 10mg once daily provided significant improvements in cognition, as determined by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), relative to placebo, after 24 weeks in patients with VaD. Pooled data from two, randomised, double-blind, phase III trials showed that the least-squares mean change from baseline score effect size for the ADAS-cog was -1.79 for donepezil 5mg once daily (p < 0.001) and -2.28 for donepezil 10mg once daily (p < 0.001) at 24 weeks (observed cases). Significant improvement in global functioning occurred with donepezil 5mg once daily compared with placebo (p = 0.003), but not with donepezil 10mg once daily, as measured by the Clinician's Interview-Based Impression of Change-plus version score (pooled data, observed cases). Donepezil was generally well tolerated in patients with VaD. Most adverse events were mild to moderate in nature, with diarrhoea and nausea being the most common.

Topics: Administration, Oral; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Indans; Piperidines; Psychiatric Status Rating Scales

Cholinergic deficits are clinicopathological hallmarks of Alzheimer's disease (DAT) and during the past decade have been the sole target for clinically effective treatments. By contrast, vascular dementia subtypes (VaD) are heterogeneous clinical syndromes, and therapeutic approaches have been directed toward control of vascular risk factors. Little attention has been paid to cholinergic deficits as a mechanism contributing to cognitive impairments in VaD as a potential target for treatment. The purpose of the study was to determine whether there are therapeutic benefits from long-term treatment with cholinesterase inhibitors among VaD patients. Ten VaD patients were diagnosed according to DSM-III-R and NINDS-AIREN criteria and classified into subtypes by neuroimaging. All were treated with titrated doses of donepezil for a mean interval of 15 months. At baseline and follow-up clinic visits, patients underwent medical and neurological examinations, as well as neuropsychological testing including Mini-Mental Status Examinations (MMSE) and Cognitive Capacity Screening Examinations (CCSE). Cognitive statuses of 10 treated patients were then compared before and after treatment. Net changes were expressed as annual MMSE score changes (DeltaMMSE/year) and annual CCSE score changes (DeltaCCSE/year). Of the 10 treated VaD patients, cognitive improvements were found when comparisons were made before and after treatment. Ten treated patients also showed greater cognitive improvements, while untreated patients showed continued cognitive decline. This study suggests that cholinergic deficits in VaD are due to neuronal ischemic damage with loss of acetylcholine and that treatment of VaD with cholinesterase inhibitors is a rational therapy.

Topics: Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

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

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

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

We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria.. This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method.. Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference, -1.156; 95% CI, -1.98 to -0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group.. Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

Topics: Adult; Aged; Aged, 80 and over; Cognition; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Hippocampus; Humans; Indans; Male; Middle Aged; Nootropic Agents; Organ Size; Piperidines; Radiography

To study the efficacy and safety of the combined treatment with compound Reinhartdt and Sea Cumber Capsule (RSC, a Chinese medicinal preparation consisted mainly of Reinhartdt and Sea Cumber) and Donepezil for vascular dementia (VD), and its effect on thyroid function axis.. Sixty-three patients with VD were treated respectively with RSC, Donepezil and the combined treatment. MMSE, ADAS-Cog and ADL scales were used to evaluate the condition of patients before treatment as well as at 3 months and 6 months after treatment. Meanwhile, levels of thyroid hormones, including (TSH, FT3, FT4, TT3, TT4) were measured with radioimmunoassay.. 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, P<0.01), the improvement in the Donepezil group was more significant than that in the RSC group after 6 months of treatment (P < 0.05), but the combined treatment group showed the best efficacy (P < 0.01). After 3 months of treament, the levels of FT3 and FT4 in the combined treatment group increased, but showed no statistical significance (P >0.05). However, significant changes were found at 6 months after combined treatment (P < 0.01). No significant changes were seen at all in levels of TSH, TT3 and TT4 (P > 0.05). FT3, FT4 increased without statistical significance after 6 months Donepezil treatment, TSH, TT3 and TT4 also showed no significant difference in the Donepezil group and no other significant changes of thyroid hormones was seen in patients treated with RSC (P > 0.05). No obvious adverse reaction occurred in any of the three groups.. Combined treatment of RSC and Donepezil was effective and safe on VD patient, with the efficacy much better than either of them alone. No significant adverse reaction was observed. The regulation on thyroid hormones may one of the mechanisms of the combined treatment in improving cognitive function.

Topics: Aged; Aged, 80 and over; Capsules; Dementia, Vascular; Donepezil; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Materia Medica; Medicine, Chinese Traditional; Middle Aged; Nootropic Agents; Piperidines; Treatment Outcome

After Alzheimer's disease (AD), vascular dementia (VaD) is the most common cause of dementia among the elderly. Abnormalities in neurotransmitter pathways are common pathogenic mechanisms shared by AD and VaD. For one month we studied the effects of donepezil, an acetylcholinesterase inhibitor (5 mg daily), on the cognitive system using P300 auditory event-related potentials (P300) and neuropsychological tests in 10 patients affected by probable VaD according to the NINDS-AIREN criteria. Our data showed a significant improvement of neuropsychological items and P300 latency after one month of donepezil treatment. In conclusion both P300 and neuropsychological tests are indicated in patients with VaD to confirm the efficacy of donepezil treatment during follow-up.

Topics: Acoustic Stimulation; Aged; Dementia, Vascular; Donepezil; Electroencephalography; Event-Related Potentials, P300; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines

There are currently no drugs approved to treat vascular dementia (VaD). The objective of this study was to determine if treatment with donepezil, an acetylcholinesterase inhibitor, may provide benefit for VaD patients.. Combined analysis of 2 identical randomized, double-blind, placebo-controlled, 24-week studies involving 1,219 patients enrolled at 109 investigational sites in the USA, Europe, Canada and Australia. Patients were randomized to receive donepezil 5 mg/day (n = 406) or 10 mg/day (after brief titration; n = 421) or placebo (n = 392). Patients were assessed on cognition [Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE)], global function [Clinician's Interview-Based Impression of Change plus (CIBIC-plus), Clinical Dementia Rating-Sum of the Boxes (CDR-SB)] and function [Alzheimer's Disease Functional Assessment and Change Scale (ADFACS); instrumental activities of daily living (ADFACS-IADL)].. Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p < 0.01). Significant global function benefits were seen on the CIBIC-plus in the 5 mg/day group (placebo vs. 5 mg/day, p < 0.001; vs. 10 mg/day, p = 0.006) and on the CDR-SB in the 10 mg/day group (placebo vs. 5 mg/day, p = 0.09; vs. 10 mg/day, p < 0.01). Significant functional benefits were also seen (ADFACS, placebo vs. 5 mg/day, p = 0.08; vs. 10 mg/day, p = 0.02; ADFACS-IADL, p < 0.05 for both donepezil groups). Donepezil was well tolerated, with low withdrawal rates due to adverse events.. This combined analysis of the largest trial on VaD to date showed that donepezil-treated patients had significant benefits in cognition, global function and ability to perform IADL. Based on these findings and reported tolerability, donepezil should be considered as an important therapeutic element in the overall management of patients with VaD.

Topics: Activities of Daily Living; Aged; Cholinesterase Inhibitors; Clinical Protocols; Dementia, Vascular; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Humans; Indans; Male; Piperidines

To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD).. Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks.. Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer's Disease Assessment Scale-cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, -1.65 [p = 0.003]; 10 mg, -2.09 [p = 0.0002]). Greater improvements on the Clinician's Interview-Based Impression of Change-plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% (p = 0.004) of the 5 mg group and 32% (p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%).. Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Risk Factors; Smoking; Stroke; Treatment Outcome

Clinical observations suggest that patients with vascular dementia (VaD) may benefit from treatment with cholinesterase inhibitors. This study evaluated the efficacy and safety of donepezil for relieving symptoms of dementia in VaD.. Patients (n=603; mean age, 73.9 years; 55.2% men) with probable (70.5%) or possible (29.5%) VaD, according to criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), were randomized to 24 weeks of treatment with donepezil 5 mg/d (n=198), donepezil 10 mg/d (5 mg/d for first 28 days; n=206), or placebo (n=199). Analyses were based on the intent-to-treat population.. At week 24, both donepezil groups showed significant improvement in cognition versus placebo on the Alzheimer's Disease Assessment Scale-cognitive subscale (mean change from baseline score effect size: donepezil 5 mg/d, -1.90; P=0.001; donepezil 10 mg/d, -2.33; P<0.001). Significant improvements in patients' global function were seen versus placebo at week 24 (observed cases), on the Clinician's Interview-Based Impression of Change-Plus version only for patients on donepezil 5 mg/d (P=0.014), and on the Sum of the Boxes of the Clinical Dementia Rating only for patients on 10 mg/d (P=0.007). Donepezil-treated patients showed significant benefits in activities of daily living over placebo on the Alzheimer's Disease Functional Assessment and Change Scale (mean change from baseline score effect size at week 24: donepezil 5 mg/d, -1.31, P=0.02; donepezil 10 mg/d, -1.31, P=0.02). Donepezil was well tolerated. Withdrawal rates due to adverse events were relatively low (placebo, 11.1%; donepezil 5 mg/d, 11.1%; donepezil 10 mg/d, 21.8%; P=0.005 versus placebo).. These data demonstrate that donepezil is an effective and well-tolerated treatment for VaD and show it may have an important place in the management of this condition.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Cardiovascular System; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Diarrhea; Donepezil; Double-Blind Method; Female; Headache; Humans; Indans; Internationality; Male; Middle Aged; Nausea; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; 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

There is increasing evidence to suggest that patients with vascular dementia (VaD) exhibit a cholinergic deficit. These patients may therefore benefit from treatment with cholinesterase (ChE) inhibitors such as donepezil. However, there are difficulties in accurately defining patients with VaD. Clinical trials to assess the efficacy and tolerability of donepezil in patients with VaD have been completed. National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria were used to establish inclusion and exclusion criteria: evidence of dementia (impaired memory and two other cognitive domains), and evidence of cerebrovascular disease (CVD) from neuroimaging and physical examination and a possible or probable relationship between dementia and CVD were required for enrollment. Patients with a diagnosis of Alzheimer's disease (AD) or dementia caused by other conditions not associated with the cardiovascular system (e.g., MS, chronic infections, hypothyroidism) were excluded. These criteria ensured that only patients with probable or possible VaD were enrolled. Enrolled patients had a mean Hachinski score of 9.7, with memory impairment the most prominent feature of their dementia. Sixty percent of patients had a history of at least one stroke and 18% of patients had a history of transient ischemic attack (TIA) pre-dementia. Cortical and subcortical infarcts were among the lesions observed on computer-assisted tomography and magnetic resonance imaging scans with significant white matter lesions also present in some patients. Placebo-treated patients demonstrated stable cognitive and global function over the 24 weeks of the study. These observations suggest that the patients enrolled in these trials have a broad range of CVD, and are different from those enrolled in AD trials.

Topics: Aged; Brain; Cerebrovascular Circulation; Cognition; Cohort Studies; Dementia, Vascular; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychometrics; Research Design; Risk Factors

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Patient Selection; Piperidines; Time Factors

We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown.. The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test.. Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus.. Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cerebrovascular Circulation; Dementia, Vascular; Disks Large Homolog 4 Protein; Excitatory Amino Acid Antagonists; Hippocampus; Hypertension; Malathion; Male; Maze Learning; Memory; Piperidines; Posterior Cerebral Artery; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Ultrasonography, Doppler; Vitamin B 6; Vitamin B Complex

Topics: Aged; Antidepressive Agents; Brain; Cholinesterase Inhibitors; Cognitive Reserve; Dementia, Vascular; Depression; Donepezil; Female; Humans; Indans; Magnetic Resonance Imaging; Piperidines; Treatment Outcome

This study was designed to investigate the effects of fisetin (FST) on hyperhomocysteinemia (HHcy)-induced experimental endothelial dysfunction (ED) and vascular dementia (VaD) in rats. Wistar rats were randomly divided into 8 groups: control, vehicle control, l-methionine, FST (5, 10, and 25 mg/kg, p.o.), FST-per se (25 mg/kg, p.o.), and donepezil (0.1 mg/kg, p.o.). l-Methionine administration (1.7 g/kg, p.o.) for 32 days induced HHcy. ED and VaD induced by HHcy were determined by vascular reactivity measurements, behavioral analysis using Morris water maze and Y-maze, along with a biochemical and histological evaluation of thoracic aorta and brain tissues. Administration of l-methionine developed behavioral deficits; triggered brain lipid peroxidation (LPO); compromised brain acetylcholinesterase activity (AChE); and reduced the levels of brain superoxide dismutase (SOD), brain catalase (CAT), brain reduced glutathione (GSH), and serum nitrite; and increased serum homocysteine and cholesterol levels. These effects were accompanied by decreased vascular NO bioavailability, marked intimal thickening of the aorta, and multiple necrotic foci in brain cortex. HHcy-induced alterations in the activities of SOD, CAT, GSH, AChE, LPO, behavioral deficits, ED, and histological aberrations were significantly attenuated by treatment with fisetin in a dose-dependent manner. Collectively, our results indicate that fisetin exerts endothelial and neuroprotective effects against HHcy-induced ED and VaD.

Topics: Acetylcholinesterase; Animals; Aorta; Brain; Catalase; Cholesterol; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Endothelium, Vascular; Flavonoids; Flavonols; Glutathione; Homocysteine; Hyperhomocysteinemia; Indans; Lipid Peroxidation; Male; Maze Learning; Methionine; Necrosis; Nitric Oxide; Nitrites; Piperidines; Rats; Superoxide Dismutase

Estrogen deficiency and increase in protein tyrosine phosphatase (PTPase) activity may be a key mechanism in postmenopausal dyslipidemia-induced vascular dysfunction and dementia. Thus, the present study has been designed to investigate the effect of biochanin A (BCA, a phytoestrogen) and sodium orthovanadate (SOV), an inhibitor of PTPase in dyslipidemia-induced vascular dementia in ovariectomized rats.. Female Wistar rats were ovariectomized and fed on high fat diet for 4 weeks to produce dyslipidemia. Dyslipidemia was assessed by estimation of serum lipid levels including total cholesterol, triglyceride, HDL, and LDL levels. Dementia was assessed in terms of increase in brain acetylcholinesterase (AChE) activity and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Vascular dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), mRNA expression of endothelial nitric oxide synthase, and increase in serum thiobarbituric acid reactive species, superoxide anion level. Neurodegeneration was assessed in hippocampus by hematoxylin and eosin staining. BCA (2.5 and 5 mg/kg) and SOV (5 and 10 mg/kg) were administered alone and in low-dose combination to ovariectomized dyslipidemic rats.. BCA (2.5 and 5 mg/kg), SOV (5 and 10 mg/kg), and donepezil (1 mg/kg) significantly improves vascular function, and learning and memory ability and decreases the neuronal cell death, oxidative stress, and AChE in ovariectomized dyslipidemic rats.. Thus, it may be concluded that BCA and SOV attenuate vascular dysfunction and dementia in dyslipidemic ovariectomized rats.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Brain; Dementia, Vascular; Donepezil; Dyslipidemias; Enzyme Inhibitors; Female; Gene Expression Regulation; Genistein; Indans; Lipids; Mental Recall; Nitric Oxide Synthase Type III; Ovariectomy; Oxidative Stress; Phytoestrogens; Piperidines; Rats; Rats, Wistar; Reaction Time; Vanadates

Neurodegenerative disorders are associated with different neurochemical and morphological alterations in the brain leading to cognitive and behavioural impairments. New therapeutic strategies comprise multifunctional drugs. The aim of the presented studies is to evaluate in vivo the novel compounds - ASS188 and ASS234 - which combine the benzylpiperidine moiety of the acetylcholinesteras (AChE) inhibitor donepezil and the indolyl propargylamino moiety of the monoaminooxidase (MAO) inhibitor, N-[(5-benzyloxy-1- methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine, with respect to their influence on cerebral amine neurotransmitters systems and neuroprotective activity. The presumed therapeutic potential of these compounds has been evaluated following their administration to rats with experimental vascular dementia. A rat model of the permanent bilateral occlusion of the common carotid arteries (BCCAO) and the holeboard memory test were employed for this purpose. Wistar rats were used, either intact or 1 day after BCCAO. ASS188 (1 mg/kg) and ASS234 (5 mg/kg) were given s.c. for 5 consecutive days. Working and reference memory in rats was evaluated by holeboard tests before- and 7 and 12 days after BCCAO. The activities of MAOs, AChE and histamine N-methyltransferase (HMT), as well as cerebral amines concentrations were assayed. A significant inhibition of brain MAO A (>95%) and weaker MAO B (ca 60%) and HMT (<30%) and reduced AChE activities were recorded with a pronounced (2 - 10 fold) increase in the cerebral concentrations of serotonin, dopamine, and noradrenaline and smaller rises (up to 30%) of histamine. The BCCAO rats treated with ASS188 or ASS234 tended to perform holeboard tests better than the BCCAO untreated group, indicating a beneficial effect of the administered therapeutics.

Topics: Acetylcholinesterase; Animals; Biogenic Monoamines; Brain; Cholinesterase Inhibitors; Cholinesterases; Dementia, Vascular; Disease Models, Animal; Indoles; Male; Memory; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Time Factors

The effect of dehydroepiandrosterone (DHEA) on memory and cognition in experimental animals is well known, but its efficacy in clinical dementia is unproven. So, the aim of the present study was to investigate the effect of DHEA on learning and memory activities in a rat model of vascular dementia (VD). Forty-eight male rats that positively passed the holeboard memory test were chosen for the study before bilateral permanent occlusion of the common carotid artery. They were divided into four groups (n=12, each) as follows (i) untreated control, (ii) rats exposed to surgical permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion, (iii) rats exposed to BCCAO then received DHEA (BCCAO + DHEA) and (i.v.) rats exposed to BCCAO then received donepezil (BCCAO + DON). Holeboard memory test was used to assess the time, latency, working memory and reference memory. Central level of acetylcholine, norepinephrine and dopamine in the hippocampus were measured. Furthermore, the expression of brain derived neurotrophic factor (BDNF) in the hippocampus was determined. Histopathological studies of the cerebral cortex and transmission electron microscope of the hippocampus were performed. BCCAO decreased the learning and memory activities in the holeboard memory. Also, it decreased the expression of BDNF as well as the central level of acetylcholine, noradrenaline and dopamine as compared to control rats. Treatment with DHEA and donepezil increased the working and reference memories, BDNF expression as well as the central acetylcholine in the hippocampus as compared to BCCAO rats. DHEA produced neuroprotective effects through increasing the expression of BDNF as well as increasing the central level of acetylcholine and catecholamines which are non-comparable to donepezil effects.

Topics: Acetylcholine; Animals; Brain-Derived Neurotrophic Factor; Carotid Artery, Common; Dehydroepiandrosterone; Dementia, Vascular; Donepezil; Dopamine; Hippocampus; Indans; Male; Memory; Neuroprotective Agents; Neuropsychological Tests; Norepinephrine; Piperidines; Rats; Rats, Sprague-Dawley

Vascular dementia (VaD) is the second most common form of dementia caused by cerebrovascular disease. Several recent reports demonstrated that cholinergic deficits are implicated in the pathogenesis of VaD and that cholinergic therapies have shown improvement of cognitive function in patients with VaD. However, the precise mechanisms by which donepezil achieves its effects on VaD are not fully understood. Donepezil hydrochloride is an acetylcholinesterase inhibitor (AChEI) currently used for the symptomatic treatment of Alzheimer's disease (AD). Several lines of evidence have demonstrated that AChEIs such as donepezil promote neurogenesis in the central nervous system. We investigated whether donepezil regulated hippocampal neurogenesis after bilateral common carotid artery occlusion (BCCAO) in rats, a commonly used animal model of VaD. To evaluate the effect of donepezil on neurogenesis, we orally treated rats with donepezil (10mg/kg) once a day for 3weeks, and injected BrdU over the same 3-week period to label newborn cells. The doses of donepezil that we used have been reported to activate cholinergic activity in rats. After 3weeks, a water maze task was performed on these rats to test spatial learning, and a subsequent histopathological evaluation was conducted. Donepezil improved memory impairment and increased the number of BrdU-positive cells in the dentate gyrus (DG) of BCCAO animals. These results indicated that donepezil improves cognitive function and enhances the survival of newborn neurons in the DG in our animal model of VaD, possibly by enhancing the expression of choline acetyltransferase and brain-derived neurotropic factor.

Topics: Animals; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Dentate Gyrus; Disease Models, Animal; Donepezil; Indans; Male; Maze Learning; Memory; Neurogenesis; Piperidines; Rats; Rats, Wistar

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

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

Cognitive impairment and dementia treatment costs are significant for health systems. According to national and international guidelines, recommended drugs for treatment of dementias are cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Despite these guidelines recommendations, other nootropics, vasodilators and antioxidants are often used in Argentina. The purpose of this study was to describe and compare the prescription pattern of commonly used drugs for the treatment of cognitive disorders and dementia in different regions of Argentina. An observational, retrospective study of 1814108 recipes prescribed to National Institute of Social Services for Retired and Pensioners outpatients during the during the second half of 2008 and the first and second half of 2009 was performed, taking in count the whole country and also different Argentina's regions. Demographic variables, quantity and rate of prescriptions, dosage forms and strengths were analyzed. Considering the entire country, memantine was the most prescribed drug in these periods (570893 packages). An increase in the memantine, donepezil, rivastigmine and idebenone rates of prescription was observed. Prescription rate of memantine increased in the North-West and North-East regions, that of idebenone in the North-East region and Patagonia and donepezil in the North-East region. Non recommended drugs were highly prescribed in all the analyzed regions. Some of them were indicated to young and middle-aged patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Argentina; Child; Child, Preschool; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Dementia, Vascular; Donepezil; Drug Prescriptions; Female; Galantamine; Humans; Indans; Infant; Male; Memantine; Middle Aged; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine; Young Adult

Topics: Affective Symptoms; Aged; Crying; Dementia, Vascular; Excitatory Amino Acid Antagonists; Humans; Laughter; Male; Piperidines; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

There is considerable evidence that pro-cholinergic agents can cause depressed mood. However, there are also published case reports of a rare association between cholinesterase inhibitors and mood elevation in patients with pre-existing major functional psychiatric disorders, or organic disorders other than dementia. This report adds to the literature by describing a case of mood elevation in a patient without pre-existing psychiatric disorder.

Topics: Aged; Bipolar Disorder; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Humans; Indans; Piperidines; Treatment Outcome

The acetylcholinesterase inhibitor donepezil hydrochloride improves cognitive function in patients with Alzheimer's disease and vascular dementia. Given acetylcholine's important actions on the heart, we undertook a retrospective cohort investigation to assess whether donepezil usage affects cardiovascular mortality. In patients treated with donepezil, hazard ratios for total and cardiovascular mortality were 0.68 (P = 0.045, 95% confidence interval 0.46-0.99) and 0.54 (P = 0.042, 95% confidence interval 0.30-0.98), respectively. The apparent survival benefit in donepezil-treated patients should not be overinterpreted. Prospective clinical trials are warranted.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Cohort Studies; Dementia, Vascular; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Nootropic Agents; Piperidines; Proportional Hazards Models; Retrospective Studies

Topics: Brain; Dementia, Vascular; Diagnostic Imaging; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.

Topics: Animals; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Memantine; Neuroprotective Agents; Patient Selection; Piperidines; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Stroke

Topics: Dementia, Vascular; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Cerebrovascular Disorders; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Galantamine; Humans; Indans; Male; Piperidines; Risperidone

Sixteen patients with Alzheimer's disease (AD) and 15 patients with vascular dementia (VaD) associated with subcortical white matter lesions or subcortical cardiovascular accidents (CVAs) were treated with donepezil for 16 weeks. Within-group analyses for the AD group revealed significant improvement on some tests of working memory, and marginal improvement on the Mini-Mental State Examination and on tests of immediate free recall from a serial list-learning task. Identical analyses for the VaD group revealed substantial gains on tests of working memory and delayed recognition memory. These data suggest that medication such as donepezil may act to improve the working memory deficits known to be associated with dementia patients with subcortical vascular lesions. The clinical implications of these findings are discussed.

Topics: Aged; Alzheimer Disease; Blood Vessels; Brain; Dementia; Dementia, Vascular; Donepezil; Female; Humans; Indans; Male; Memory; Memory, Short-Term; Mental Recall; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Stroke

Topics: Aged; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Double-Blind Method; Humans; Indans; Multicenter Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Reproducibility of Results

Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD).. Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence.. From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Topics: Carbamates; Cardiovascular Diseases; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Controlled Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine; Stroke; Terminology as Topic

In a pilot study designed as a case control study the efficacy of donepezil treatment was investigated in patients with Alzheimer's disease (AD). Patients were stratified according to radiological criteria into patients without (AD group) and with subcortical vascular lesions (AD+SVD group). Changes in cognition were assessed as the primary outcome measurement after 6 and 18 months of treatment by the Mini-Mental Status Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. After 6 months, patients had improved from baseline by 0.7 points in MMSE score in the AD group and by 1.8 in the AD+SVD group. After 18 months of treatment, the AD+SVD group performed significantly worse in one CERAD subscore, whereas a deterioration in two subscores was observed in the AD group. A comparison between the 2 groups revealed that treatment did not lead to statistically significant differences between the AD and AD+SVD groups in any of CERAD parameters following 6 or 18 months of treatment. These data support previous observations that donepezil therapy is effective in AD patients with and without subcortical vascular lesions.

Topics: Aged; Alzheimer Disease; Case-Control Studies; Comorbidity; Dementia, Vascular; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Registries; Treatment Outcome

Topics: Alzheimer Disease; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Dementia, Vascular; Diagnosis, Differential; Donepezil; Galantamine; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Terminology as Topic; Treatment Outcome

Topics: Anticholesteremic Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indans; Piperidines; Stroke

Topics: Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Treatment Outcome

Topics: Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Piperidines

Topics: Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Piperidines

Topics: Administration, Oral; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Indans; Piperidines; Psychiatric Status Rating Scales

(1) The standard treatment for mild to moderately severe Alzheimer's disease is donepezil, an anticholinesterase with some beneficial effects (progression is slowed in about 10% of patients, by six months on average) and mainly gastrointestinal adverse effects. (2) Memantine, a drug first developed several decades ago, belongs to the family of NMDA glutamate receptor inhibitors. Marketing authorisation was recently granted for memantine in moderately severe and severe Alzheimer's disease. (3) The clinical evaluation dossier on memantine is poor. Marketing approval was obtained thanks to only one placebo-controlled trial. It included only 252 patients treated for 28 weeks. Patients with moderately severe Alzheimer's disease were not analyzed separately from those with severe forms, even though the response criteria are different for the two categories of patients. (4) According to the chosen endpoint, 5% to 19% of patients were clinically improved by memantine. It is not known whether this benefit persists beyond six months. (5) The report of a trial comparing memantine + donepezil with placebo + donepezil does not analyse the response rate. Use of this combination is not currently justified. (6) In clinical trials the main adverse effects of memantine were neurological (dizziness and headache). Fairly lengthy pharmacovigilance data from Germany are relatively reassuring. (7) In practice, donepezil remains the reference option for moderately severe Alzheimer's disease. Memantine is a second-line option, as its adverse effects differ from those of anticholinesterases. There is still no drug offering a clear benefit for patients with severe forms of the disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cost-Benefit Analysis; Dementia, Vascular; Drug Approval; Drug Therapy, Combination; Europe; Evaluation Studies as Topic; Humans; Indans; Memantine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome; United States

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Feasibility Studies; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Humans; Indans; Male; Piperidines

Topics: Aged; Aged, 80 and over; Aggression; Alzheimer Disease; Dementia; Dementia, Vascular; Female; Humans; Isoxazoles; Male; Piperidines; Psychotropic Drugs; Risperidone; Treatment Outcome