piperidines and Parkinson-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

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

Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a comprehensive review of the existing literature to investigate the association between bipolar disorder and Parkinson's disease, focusing on the dopaminergic hypothesis and potential therapeutic options. The dopaminergic hypothesis suggests that both bipolar disorder and Parkinson's disease involve impairments in the nigrostriatal or mesolimbic dopaminergic pathways. Studies have demonstrated alterations in dopamine regulation during manic and depressive phases of bipolar disorder. Similarly, Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms. Recent analyses have highlighted a predisposition to Parkinson's disease in individuals with bipolar disorder. Longitudinal studies and meta-analyses have demonstrated an increased risk of developing Parkinson's disease in patients with bipolar disorder. However, differentiating idiopathic Parkinson's disease from parkinsonism induced by medications used in bipolar disorder can be challenging. Dopamine transporter (DAT) scans can aid in making a differential diagnosis. Treatment options for patients with both bipolar disorder and Parkinson's disease are limited. Neuroleptics, commonly used to manage psychotic symptoms in Parkinson's disease, may worsen motor symptoms and have limitations in bipolar disorder patients. Clozapine has shown efficacy in treating psychosis without worsening motor symptoms. Pimavanserin, an inverse agonist of the 5-HT2A receptor can offer new opportunities. However, its efficacy in bipolar disorder patients with Parkinson's disease remains unexplored. In conclusion, the association between bipolar disorder and Parkinson's disease is supported by the involvement of the dopaminergic system in both conditions. The identification of shared mechanisms opens new avenues for potential therapeutic interventions. Further research is needed to investigate the efficacy of pimavanserin and explore other treatment options for individuals with both bipolar disorder and Parkinson's disease.

Topics: Bipolar Disorder; Dopamine; Drug Inverse Agonism; Humans; Parkinson Disease; Piperidines

Dementia-related psychosis (DRP) is prevalent across dementias and typically manifests as delusions and/or hallucinations. The mechanisms underlying psychosis in dementia are unknown; however, neurobiological and pharmacological evidence has implicated multiple signaling pathways and brain regions. Despite differences in dementia pathology, the neurobiology underlying psychosis appears to involve dysregulation of a cortical and limbic pathway involving serotonergic, gamma-aminobutyric acid ergic, glutamatergic, and dopaminergic signaling. Thus, an imbalance in cortical and mesolimbic excitatory tone may drive symptoms of psychosis. Delusions and hallucinations may result from (1) hyperactivation of pyramidal neurons within the visual cortex, causing visual hallucinations and (2) hyperactivation of the mesolimbic pathway, causing both delusions and hallucinations. Modulation of the 5-HT2A receptor may mitigate hyperactivity at both psychosis-associated pathways. Pimavanserin, an atypical antipsychotic, is a selective serotonin inverse agonist/antagonist at 5-HT2A receptors. Pimavanserin may prove beneficial in treating the hallucinations and delusions of DRP without worsening cognitive or motor function.

Topics: Dementia; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

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

There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden. To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD. After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.

Topics: Antipsychotic Agents; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: Animals; Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).. Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.. NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease) versus discontinuation due to an adverse event.. Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

Topics: Clinical Trials as Topic; Humans; Numbers Needed To Treat; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Syndromes of delusional misidentification consist of disordered familiarity and have been reported in diverse diagnoses, including Parkinson's disease. Although the most common delusional misidentification is Capgras syndrome, in which the sufferer believes a familiar person has been replaced by an identical imposter, other forms have been also described. The pathogenesis of delusions of misidentification appears to require dysfunction of or connection to a left cerebral cortical area involved in recognition of familiarity, and also right frontal cortex serving belief evaluation. Two cases of Parkinson's disease with an unusual delusional misidentification, intermetamorphosis, are presented, along with their improvement with pimavanserin, a novel atypical antipsychotic medication.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Delusions; Female; Humans; Male; Parkinson Disease; Piperidines; Urea

We discuss features of Parkinson's disease psychosis (PDP) including symptomology and pathophysiology. Treatment options, including non-pharmacologic strategies, dose reduction of offending agents, and the addition of non-dopaminergic antipsychotics, are addressed. The efficacy of second-generation antipsychotics and novel agents is examined.. Pimavanserin, a 5-HT

Topics: Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required.. This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed.. Clozapine and pimavanserin have proven efficacy for Parkinson's disease psychosis (PDP), without impairing motor function. In clozapine's favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4-6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials.

Topics: Antipsychotic Agents; Clozapine; Dopamine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

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

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Topics: Antiparkinson Agents; Antipsychotic Agents; Consensus; Drug Substitution; Humans; Off-Label Use; Parkinson Disease; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of pimavanserin for the treatment of hallucinations and delusions of Parkinson's disease psychosis (PDP).. A comprehensive PubMed search (1966 to January 2017) was conducted using the search terms Parkinson's disease psychosis, hallucinations, delusions, pimavanserin, and ACP-103. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling and website, and Clinicaltrials.gov.. All English-language trials evaluating pimavanserin in PDP were included. Data from review articles were included if relevant to clinical practice. One phase II and 3 phase III trials are discussed.. Pimavanserin was approved in April 2016 for the treatment of delusions and hallucinations of PDP. One phase II and 2 phase III trials reported no difference for primary outcomes when pimavanserin was compared with placebo. The pivotal phase III ACP-103-020 trial adapted a scale to target more specific symptoms prevalent in PDP and showed that least-squares mean differences of the total PD-adapted Scale for the Assessment of Positive Symptoms score were significantly improved for pimavanserin-treated patients as compared with placebo-treated patients (difference = -3.06; 95% CI [-4.91 to -1.20]; P = 0.0014]). Pimavanserin's adverse effect profile includes urinary tract infections, falls, peripheral edema, hallucinations, confusion, nausea, and headaches.. Pimavanserin is a novel 5-HT

Topics: Antiparkinson Agents; Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

To summarize and evaluate the existing literature regarding medications to treat Parkinson's disease (PD) psychosis.. MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL (1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the following terms: Parkinson disease, Parkinson's disease, psychotic disorders, psychosis, delusions, and hallucinations.. The search was limited to randomized controlled trials (RCTs) reporting human outcomes. Data extracted included the following: study design, population, setting, intervention, control, outcomes related to psychosis and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of 235 studies were included; 11 articles reported comparisons between active drug and placebo, whereas 5 compared clozapine and an active comparator. Placebo-controlled trials demonstrated benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies demonstrated improved efficacy in symptom scores when clozapine or comparator agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1, ziprasidone) was assessed alone. However, no comparator data suggest that one agent is better than another, and none are yet available for pimavanserin. Overall risk of bias across all studies was moderate to high.. Despite lack of rigor in study designs, published data to date suggest that clozapine and pimavanserin should be considered drugs of choice to treat PD psychosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Evidence-Based Medicine; Humans; Olanzapine; Parkinson Disease; Piperazines; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Thiazoles; Urea

To summarize the US Food and Drug Administration's (FDA's) review of the safety and effectiveness for pimavanserin, an atypical antipsychotic, for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. We describe the regulatory and clinical issues important to the FDA's approval of this New Drug Application, with special focus on the risk-benefit balance. We also describe a new labeling feature that presents additional efficacy data to clinicians.. Data sets for all relevant clinical trials of pimavanserin and the Applicant's and FDA's analyses of these data were considered in this review. Data were available from 616 patients with Parkinson's disease with hallucinations and delusions who received at least 1 dose of pimavanserin, with a total exposure of 825 patient-years in the Parkinson's disease psychosis population.. Pimavanserin 34 mg/d was effective in treating hallucinations and delusions associated with Parkinson's disease. In the Applicant's single pivotal trial, 80.5% of pimavanserin patients experienced at least some improvement in symptoms compared to 58.1% of patients taking placebo. Pimavanserin did not worsen motor function, an adverse effect commonly observed with other antipsychotics, probably because of a lack of consequential dopamine binding.. Pimavanserin is the only FDA-approved treatment for the hallucinations and delusions seen in patients with psychosis of Parkinson's disease. Although pimavanserin appears to have a pharmacologic mechanism that is different from other atypical antipsychotics, concern remained that the increased risk of death seen with antipsychotic use in elderly demented patients, and described in all approved antipsychotic labels, would also occur with pimavanserin. Pimavanserin bears the same boxed warning about the risk of death associated with antipsychotic use in elderly patients with dementia.

Topics: Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; United States; United States Food and Drug Administration; Urea

A panel of experts drawn from neurology, psychiatry, geropsychiatry, geriatrics, and pharmacy representatives of 3 health plans convened in New York City on July 30, 2016, with the objective of sharing opinions, ideas, and information regarding the optimal management of Parkinson's disease psychosis (PDP). Three key points emerged from the discussion: (1) Because of the nature of Parkinson's disease and PDP, finding appropriate treatment can prove challenging; (2) emerging therapies may present an opportunity for effective disease management; and (3) moving forward, provider and patient education regarding PDP and available treatment options is essential for well-managed symptoms and better quality of life. The panel reviewed current practices and formulated recommendations on moving forward in the treatment of PDP.. This project and manuscript was funded by ACADIA Pharmaceuticals and developed by Magellan Rx Management. Lopes and Farnum are employees of Magellan Rx Management. Kremens has received consulting/speaker fees from Teva Pharmaceuticals, UCB, Sunovion, Impax, Lundbeck, ACADIA, USWorldMeds, Merz, Acorda, Kyowa, Neurocrine, and GE Healthcare. Pagan reports consulting/speaker fees from Teva Nanoscience, AbbVie, Impax, ACADIA, Medtronic, USWorldMeds, Merz, and Cynapsus and research and educational grants from USWorldMeds, Teva, and Medtronic. Patel has received consultant/speaker fees from ACADIA, Allergen, and Avanir. Alva reports research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech and consultant/speaker fees from ACADIA, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. The other authors report no potential conflicts of interest, financial or otherwise.

Topics: Animals; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with a decrease in the neurotransmitter dopamine and characterized by the cardinal motor hallmarks of resting tremor, rigidity, bradykinesia/akinesia, and postural instability. Lesser-known features of PD revolve around nonmotor concerns including psychosis, dementia, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Parkinson's disease psychosis (PDP) contributes significantly to morbidity, mortality, nursing home placement, and quality of life (QOL). PDP management suffers from a lack of safe, effective pharmacological agents and the opposing nature of atypical antipsychotics and dopaminergic therapies. Pimavanserin, the only atypical antipsychotic currently approved by the FDA for treating PDP-related hallucinations and delusions, has no appreciable affinity for dopaminergic receptors, and a controlled clinical study demonstrated its efficacy in treating PDP-associated hallucinations and delusions without affecting motor function. A recent analysis of all health resource utilization (HRU) and total costs attributable to PD and PDP found that mean 12-month HRU services per patient were 2.3 times higher and costs were 2.1 times higher in the PDP cases, while falls were 3.4 times higher and fractures 2.3 times higher, respectively. Products or services that prevent, delay, or lessen the severity of PDP may contribute to reduced healthcare system costs and improve the QOL of patients with PDP and of their caregivers.

Topics: Antipsychotic Agents; Cost of Illness; Health Care Costs; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

Topics: alpha-Synuclein; Cholinesterase Inhibitors; Disease Management; Genetic Therapy; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Stem Cell Transplantation; Urea

Parkinson's disease psychosis (PDP) may develop in up to 60% of Parkinson's patients and is associated with increased morbidity and mortality. It also correlates with depression and dementia, and can contribute to caregiver stress and burnout. Pimavanserin is the first FDA approved drug for the treatment of hallucinations and delusions associated with PDP. Areas covered: For this review, a MEDLINE literature search (via PubMed) and information provided by ACADIA Pharmaceuticals were used. This review will discuss the pathophysiology and current management of PDP. In addition, this review will focus on the rationales behind the development of pimavanserin, mechanism of action, pharmacokinetics, pharmacodynamics, and the clinical trials evaluating the efficacy and safety of pimavanserin. Last, the review will address the drug's package insert warning. Expert commentary: Pimavanserin, a 5HT2A receptor inverse agonist, is the first FDA approved drug for the treatment of PDP which has been shown to reduce psychosis in PD through its unique mechanism of action. Pimavanserin, does not worsen PD motor symptoms and has an acceptable safety profile. The development of pimavanserin as an antipsychotic opened a new therapeutic avenue in the treatment of PDP as well as targeting psychosis in other disorders such as Alzheimer's disease.

Topics: Antipsychotic Agents; Delusions; Drug Inverse Agonism; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

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

Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis.

Topics: Antipsychotic Agents; Delusions; Drug Approval; Drug Discovery; Drug Evaluation, Preclinical; Hallucinations; Humans; Molecular Structure; Parkinson Disease; Piperidines; Randomized Controlled Trials as Topic; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP.. A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders.. Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP. The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.

Topics: Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Urea

Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion: Rivastigmine, a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase, is effective for dementia, whereas the use of Donepezil is still in the realm of investigation. Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.

Topics: Animals; Cholinergic Agents; Cholinergic Neurons; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Gait; Humans; Indans; Nerve Degeneration; Parkinson Disease; Piperidines; Psychotic Disorders

Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Humans; Molecular Targeted Therapy; Neurotransmitter Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptor intended to treat patients with Parkinson's disease psychosis (PDP). Currently there are no FDA-approved medications in the United States for the treatment of PDP, although on September 2, 2014, the United States Food and Drug Administration granted breakthrough therapy status to pimavanserin, highlighting the unmet need for therapeutics in this class. Most antipsychotic medications worsen motor dysfunction due to dopamine antagonism, and all carry a black box warning for an increased risk of mortality in elderly patients with dementia-related psychosis. Data from phase II and phase III clinical trials suggest that pimavanserin is a safe and effective treatment option for PDP. Trial results indicate a significant reduction in hallucinations and delusions in patients with PDP without worsening motor symptoms. Additional studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia and insomnia. Such promising outcomes warrant a review of the available literature regarding pimavanserin and its use in the treatment of PDP symptoms.

Topics: Animals; Clinical Trials as Topic; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Parkinson's disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson's patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician's clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson's disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Topics: Drug Discovery; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Parkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks.. Information from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism.. Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP.

Topics: Animals; Antiparkinson Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Topics: Benzazepines; Diabetes Mellitus, Type 2; Heart Valve Diseases; Humans; Molecular Structure; Obesity; Parkinson Disease; Piperidines; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement.. To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease).. The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials.. Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD).. Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0.. Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms. The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.

Topics: Amantadine; Excitatory Amino Acid Antagonists; Humans; Indans; Memantine; Monoamine Oxidase; Monoamine Oxidase Inhibitors; N-Methylaspartate; Parkinson Disease; Piperidines; Selegiline

Dementia associated with Parkinson's disease (PDD) is a common problem and one that is associated with significant morbidity and mortality. Over the past decade, increasing research efforts and funding have been directed toward an improved understanding of PDD. Despite these efforts, fundamental gaps remain in our knowledge. Consequently, therapeutic progress has been frustratingly slow and incomplete. To significantly affect PDD, novel "disease-modifying" agents, rather than more traditional neurotransmitter replacement approaches, likely will be required.

Topics: Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia; Diagnosis, Differential; Humans; Parkinson Disease; Piperidines; Urea

Excessive stimulation of NMDA receptors is involved in various CNS pathologies such as Parkinson's disease, acute and chronic pain and cerebral ischaemia. The use of NMDA antagonists as therapeutic agents has been restricted as a result of unwanted side effects including hallucinations and loss of co-ordination. NR2B subtype selective antagonists have previously shown a therapeutic effect without causing the side effects of broad spectrum NMDA antagonists. Considerable research has since been devoted to the development of orally bioavailable, selective NR2B antagonists and their applications in various neurological diseases. The improved therapeutic index of these compounds is expected to be the result of the subtype selectivity and cellular location of the NR2B receptors within the CNS. This review describes recent advances in the development of NR2B antagonists as well as their therapeutic applications.

Topics: Animals; Benzamidines; Brain Ischemia; Chemistry, Pharmaceutical; Excitatory Amino Acid Antagonists; Humans; Mice; Pain; Parkinson Disease; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are the two most common types of dementing neurodegenerative disease after Alzheimer's disease (AD). Both of these conditions are often diagnosed late or not at all.. Selective literature review.. The severe cholinergic and dopaminergic deficits that are present in both DLB and PDD produce not only motor manifestations, but also cognitive deficits, mainly in the executive and visual-constructive areas, as well as psychotic manifestations such as visual hallucinations, delusions, and agitation. The intensity of these manifestations can fluctuate markedly over the course of the day, particularly in DLB. Useful tests for differential diagnosis include magnetic resonance imaging and electroencephalography; in case of clinical uncertainty, nuclear medical procedures and cerebrospinal fluid analysis can be helpful as well. Neuropathological studies have revealed progressive alpha-synuclein aggregation in affected areas of the brain. In DLB, beta-amyloid abnormalities are often seen as well.. DLB should be included in the differential diagnosis of early dementia. If motor manifestations arise within one year (DLB), dopaminergic treatment should be initiated. On the other hand, patients with Parkinson's disease should undergo early screening for signs of dementia so that further diagnostic and therapeutic steps can be taken in timely fashion, as indicated. Cholinesterase inhibitors are useful for the treatment of cognitive deficits and experiential/behavioral disturbances in both DLB (off-label indication) and PDD (approved indication).

Topics: Aged; Brain; Cholinesterase Inhibitors; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Early Diagnosis; Humans; Indans; Lewy Body Disease; Mental Disorders; Neuropsychological Tests; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

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

Pimavanserin tartrate is the first 5-HT(2A) inverse agonist to enter clinical trials as a treatment for L-dopa-induced psychosis in Parkinson's disease and for augmentation of low-dose risperidone treatment in schizophrenia. Pimavanserin is also being evaluated as a possible anti-insomnia drug.. To discuss the potential of pimavanserin to fill multiple therapeutic needs.. The problems with currently approved antipsychotics and sleep agents are explored to highlight how pimavanserin might address some longstanding issues in the treatment of psychosis and insomnia.. In Phase II clinical trials, pimavanserin seemed to be safe, well-tolerated and efficacious in treating L-dopa-induced psychosis without worsening motor symptoms. Pimavanserin also potentiated the therapeutic effects of low-dose risperidone, reduced haloperidol-induced akathisia, and increased slow-wave sleep in older individuals.

Topics: Clinical Trials as Topic; Humans; Molecular Structure; Parkinson Disease; Piperidines; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

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 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

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

It is generally accepted that patients with a tremor-dominant type of idiopathic Parkinson's disease progress more slowly than the ones with the rigid-akinetic type. On the other hand successful treatment of Parkinsonian tremor is a challenge. German neurologists use anticholinergics, budipine, beta-blockers, clozapine, dopaminergic substances and for most severe cases deep brain stimulation. Budipine is an enigma because its main mode of action is still unknown, although it is mostly listed under glutamate antagonists. There is however no other anti-Parkinsonian drug available with such a broad spectrum of action as shown for budipine. Budipine has been studied in open and double-blind studies as monotherapy and adjunct therapy. In both instances the drug showed beneficial effects to the patients. It may well be that the non-dopaminergic mode of action of budipine is helpful even for patients who are on stable medication. When 3 years ago reports on budipine-induced prolongation of the QT interval in the ECG emerged larger trials were stopped and nowadays there are strict rules on how to use budipine. Nonetheless, budipine in our hands is a most useful and safe drug to treat tremor and other main symptoms of Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Humans; Parkinson Disease; Piperidines; Tremor

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

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMP

Topics: Adult; Aged; Animals; Benzothiadiazines; Brain-Derived Neurotrophic Factor; Cognition Disorders; Depressive Disorder; Excitatory Amino Acid Agonists; Humans; Neuronal Plasticity; Parkinson Disease; Piperidines; Pyrrolidinones; Receptors, AMPA

The diagnosis of Parkinson's disease (PD) is clinical and is based on the identification of a combination of the cardinal motor signs of bradykinesia plus at least one of the following: rigidity, tremor or postural instability. There are many causes of parkinsonism such as drug induced parkinsonism, subcortical vascular disease, and multisystem atrophy. PD is a well characterised syndrome which represents only a part of the various causes of parkinsonism. A good response to dopaminergics is an important diagnostic criteria for PD. Pharmacotherapy for PD relies primarily on levodopa and dopamine agonists. Deep brain stimulation is increasingly used in the management of patients with severe dopa fluctuations and dyskinesias. Cholinesterase inhibitors are introduced for dementia in parkinsonism. Neuroprotective compounds, nerve growth factors such as GDNF and the implantation of dopaminergic cells are studied in clinical trials.

Topics: Aged; Amantadine; Antiparkinson Agents; Apomorphine; Botulinum Toxins; Catechols; Cholinesterase Inhibitors; Clinical Trials as Topic; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Enzyme Inhibitors; Ergot Alkaloids; Family Practice; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Piperidines

Several lines of evidence suggest that substitution of the dopaminergic striatal deficit only represents one important aspect of the treatment of Parkinson's disease (PD) because neurotransmitter systems other than the dopaminergic one also degenerate and aggravate parkinsonian motor, vegetative and cognitive symptoms. Thus, regulation and balance of altered non-dopaminergic neurotransmission could provide an additional benefit for parkinsonian patients (PP). Moreover, onset of motor complications, psychosis and loss of drug efficacy increasingly reduce parkinsonian quality of life in the course of long-term dopamine substitution. Indirect stimulation of the dopaminergic neurotransmission via non-dopaminergic systems is an upcoming interesting strategy to solve these problems. Treatment of L-dopa-associated dyskinesias represents a further important future task of non-dopaminergic drug therapy. NMDA antagonists are a promising therapeutic option but further trials are necessary to elucidate their efficacy. A further peripheral effect of L-dopa/dopa decarboxylase inhibitor (DDI) application is increased homocysteine synthesis with its putative hypothetical additional central impact on neurodegeneration and progression of PD. Long-term monitoring with subsequent therapeutic decrease of homocysteine levels with folic acid could result in substantial clinical benefits at reasonable costs for PP. Also, it could hypothetically influence altered dopaminergic and non-dopaminergic neurotransmission beside its impact on occurrence of vascular disease and altered striatal microvascularisation in PD. The interesting field of non-dopaminergic drug therapy is emerging and will hopefully lead to a better understanding of PD and subsequently improve drug therapy of parkinsonian symptoms, which do not respond to dopaminergic substitution or are long-term complications of dopamine substitution.

Topics: Adenosine; Adrenergic alpha-Antagonists; Body Weight; Cholinergic Antagonists; Homocysteine; Humans; Levodopa; Methionine; N-Methylaspartate; Parkinson Disease; Piperidines; Serotonin Receptor Agonists

The lipophilic t-butyl analog of 1-alkyl-4,4-diphenyl piperidine, budipine, possesses a polyvalent spectrum of mechanisms of action. Budipine experimentally increased the brain content of norepinephrine, serotonine, dopamine and histamine in reserpine treated rats. Budipine did not alter the receptor affinity of these neurotransmitters but antagonizes the effect of NMDA at its receptor binding site in vitro. Budipine reduced MPP+ toxicity in the nigrostriatal system of mice. This complex pharmacologic profile is not comparable to the one of convenient antiparkinsonian drugs. In clinical trials budipine reduced tremor, akinesia and rigidity. Budipine induced a relevant additional positive effect in patients with an optimal dopaminergic therapy based on levodopa and dopamine agonists, such as bromocriptine. Current available data suggest that the need for levodopa application in early stages of the disease may be postponed by budipine and that the long-term application of budipine may induce a levodopa-sparing effect.

Topics: Animals; Antiparkinson Agents; Clinical Trials as Topic; Humans; Parkinson Disease; Piperidines

11C-NMPB is a useful ligand which is used to measure brain muscarinic cholinergic receptors (mAChRs) for its high affinity and high brain uptake. PET images of 11C-NMPB uptake had the highest accumulations in the cerebral cortex and striatum and the lowest in the cerebellum, both in patients with Parkinson's disease (PD) and normal subjects. 11C-NMPB uptake was homogeneous throughout the cerebral cortex in the normal subjects but greater in the frontal cortex of about one half of the PD patients as compared with other cerebral cortical areas. Quantitative analysis showed that the PD patients had high K3 values, an index of mAChR binding, in the frontal cortex. In PD, increased mAChR binding in the frontal cortex may be related to frontal lobe dysfunction. This technique should prove useful for detecting subclinical impairment of the central cholinergic system in PD.

Topics: Animals; Benzilates; Brain; Carbon Radioisotopes; Humans; Parkinson Disease; Piperidines; Receptors, Muscarinic; Tomography, Emission-Computed

Several lines of evidence demonstrate that glutamate antagonists can reverse experimental parkinsonism in animals. However, few clinical studies have been undertaken, principally because there is a shortage of glutamate antagonists which are considered safe for human use. This paper details the results of preliminary studies carried out on dextromethorphan, an anti-tussive agent and a weak open-channel blocker of the NMDA receptor; and the cerebral anti-ischaemic drug ifenprodil, a novel non-competitive inhibitor of the polyamine modulatory site on the NMDA receptor. Trials with these two compounds in small groups of parkinsonian volunteers have not demonstrated conclusive symptomatic improvement. These results do not exclude a possible role for NMDA receptor antagonists in the pharmacotherapy of Parkinson's disease, but rather point to the need for developing more potent and safe NMDA antagonists, with better pharmacodynamic and pharmacokinetic profiles.

Topics: Antiparkinson Agents; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Parkinson Disease; Piperidines; Receptors, Glutamate

Topics: Antiparkinson Agents; Dopamine Agonists; Humans; Parkinson Disease; Piperidines

Most patients with Parkinson's disease develop response fluctuations after several years of chronic treatment with levodopa. Accumulating evidence suggest that pharmacokinetic mechanisms are the cause of some subtypes of response fluctuations, especially the "delayed-on" and "no-on" phenomena. Evaluation of gastric emptying in Parkinson patients with and without response fluctuations revealed that those with fluctuations had a significant delay in gastric emptying compared to patients without fluctuations. Treatment with cisapride, a prokinetic drug, causes amelioration of these fluctuations. The optimal solution is to bypass the stomach completely and deliver levodopa parenterally. This was done by levodopa ethylester injections, which reduced latency to "on" and prolonged "on" duration in patients with severe response fluctuations. These data emphasize the role of the stomach as one of the causes for deterioration in Parkinson's disease.

Topics: Administration, Oral; Antiparkinson Agents; Cisapride; Drug Therapy, Combination; Gastric Emptying; Humans; Injections, Intramuscular; Intestinal Absorption; Levodopa; Parasympathomimetics; Parkinson Disease; Piperidines

In this paper an overview of the present state of monoamine oxidase inhibitors (MAOIs) is presented. The irreversible inhibitors are firstly considered. They have been divided into four chemical types: substituted hydrazine, cyclopropylamine, propargylamine and allylamine derivatives. Moreover, a tetrahydropyridine derivative (MPTP), recently described as an irreversible inhibitor of MAO-B, has been included among the irreversible MAOIs. The reversible inhibitors such as tetrahydro-beta-carbolines and salsolinol, phenylalkylamines: amphetamine, amiflamine and 2,3-dichloro-alpha-methyl-benzylamine. Among the short acting or reversible inhibitors the 4-(2-benzofuranyl) piperidine series and the morpholinoethylamino derivatives are discussed. Finally the oxazolidinone series is presented separately, as in this series reversible or irreversible inhibitors of the A or B form of MAO have been obtained.

Topics: Animals; Benzamides; Humans; Hydrazines; Isoquinolines; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Parkinson Disease; Phenethylamines; Piperidines; Selegiline; Structure-Activity Relationship

Topics: 1-Propanol; Acids; Alcohols; Amines; Amino Alcohols; Analgesics; Anesthetics, Local; Animals; Anti-Inflammatory Agents; Anticonvulsants; Antihypertensive Agents; Biperiden; Cats; Central Nervous System Stimulants; Diuretics; Dogs; Esters; Ethers, Cyclic; Ganglionic Blockers; Guinea Pigs; Humans; Hypnotics and Sedatives; Ketones; Mice; Muscles; Parasympatholytics; Parkinson Disease; Piperidines; Rabbits; Rats; Vasodilator Agents

Laryngeal mask airways have been widely used in clinical practice. The aim of this study was to investigate whether the remifentanil requirement for facilitation of i-gel insertion in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery was different from that in non-PD (NPD) patients undergoing intracranial surgery.. An up-and-down sequential allocation trial.. Male patients aged between 40 and 64 years old were enrolled. The first patient in each group (PD and NPD) group received an effect-site concentration (Ce) of remifentanil (Minto pharmacokinetic model) of 4.0 ng.ml. The PD group included 24 patients and the NPD group included 23. The EC. The remifentanil requirement for successful i-gel insertion is reduced in male PD patients undergoing DBS implantation during propofol TCI induction. Clinicians should closely monitor the remifentanil requirement in patients with PD.. Registered at http://www.chictr.org.cn ( ChiCTR1900021760 ).

Topics: Adult; Anesthetics, Intravenous; Brain; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Propofol; Remifentanil

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

Topics: Drug Evaluation; Humans; Parkinson Disease; Phenyl Ethers; Piperidines

This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit.. Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT. We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis.. Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin.. In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Dementia; Double-Blind Method; Female; Hallucinations; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Parkinson Disease; Piperidines; Proportional Hazards Models; Psychotic Disorders; Recurrence; Urea

Parkinson's disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP.. Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study.. Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales.. Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was - 3.4 (6.3); p < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (-6.9 vs. -6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE.. Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

Many patients with Parkinson's disease (PD) experience depression.. Evaluate pimavanserin treatment for depression in patients with PD.. Pimavanserin was administered as monotherapy or adjunctive therapy to a selective serotonin reuptake inhibitor or serotonin/noradrenaline reuptake inhibitor in this 8-week, single-arm, open-label phase 2 study (NCT03482882). The primary endpoint was change from baseline to week 8 in Hamilton Depression Scale-17-item version (HAMD-17) score. Safety, including collection of adverse events and the Mini-Mental State Examination (MMSE) and Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) scores, was assessed in patients who received ≥1 pimavanserin dose.. Efficacy was evaluated in 45 patients (21 monotherapy, 24 adjunctive therapy). Mean (SE) baseline HAMD-17 was 19.2 (3.1). Change from baseline to week 8 (least squares [LS] mean [SE]) in the HAMD-17 was -10.8 (0.63) (95% CI, -12.0 to -9.5; p < 0.0001) with significant improvement seen at week 2 (p < 0.0001) and for both monotherapy (week 8, -11.2 [0.99]) and adjunctive therapy (week 8,-10.2 [0.78]). Most patients (60.0%) had ≥50% improvement at week 8, and 44.4% of patients reached remission (HAMD-17 score ≤7). Twenty-one of 47 patients experienced 42 treatment-emergent adverse events; the most common by system organ class were gastrointestinal (n = 7; 14.9%) and psychiatric (n = 7; 14.9%). No negative effects were observed on MMSE or MDS-UPDRS Part III.. In this 8-week, single-arm, open-label study, pimavanserin as monotherapy or adjunctive therapy was well tolerated and associated with early and sustained improvement of depressive symptoms in patients with PD.

Topics: Aged; Depression; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Serotonin and Noradrenaline Reuptake Inhibitors; Urea

Delayed gastric emptying may impair l-dopa absorption, contributing to motor fluctuations. We evaluated the effect of camicinal (GSK962040), a gastroprokinetic, on the absorption of l-dopa and symptoms of PD.. Phase II, double-blind, placebo-controlled trial. Participants were randomized to receive camicinal 50 mg once-daily (n = 38) or placebo (n = 20) for 7 to 9 days.. l-dopa exposure was similar with coadministration of camicinal compared to placebo. Median time to maximum l-dopa concentration was reduced, indicating more rapid absorption of l-dopa. Camicinal resulted in significant reduction in OFF time (-2.31 hours; 95% confidence interval: -3.71, -0.90), significant increase in ON time (+1.88 hours; 95% confidence interval: 0.28, 3.48) per day, and significant decrease in mean total MDS-UPDRS score (-12.5; 95% confidence interval: -19.67, -5.29). Camicinal treatment was generally well tolerated.. PD symptom improvement with camicinal occurred in parallel with more rapid absorption of l-dopa. This study provides evidence of an improvement of the motor response to l-dopa in people with PD treated with camicinal 50 mg once-daily compared with placebo, which will require further evaluation. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antiparkinson Agents; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperazines; Piperidines; Statistics, Nonparametric; Treatment Outcome

PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms.. To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications.. Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms.. Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors.. The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort.. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics.. Primary and secondary care medical centers in the United States, Canada, Europe, and India.. A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis.. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications.. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs).. There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant.. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Topics: Accidental Falls; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Drug Therapy, Combination; Edema; Female; Humans; Hypotension, Orthostatic; Infections; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Stroke; Thromboembolism; Urea

Here we conducted a randomized and double-blind study attempting to explore the safety and efficacy of combined therapy of Di-Huang-Yi-Zhi (DHYZ) with donepezil in treating Parkinson's disease dementia (PDD). Sixty PDD patients were included and randomly divided into control group and DHYZ group. All patients were given donepezil (5 mg last for a month, then 10 mg for the rest months, once daily), while patients in DHYZ group were additionally administrated with DHYZ (150 ml, twice daily). The measurement subjects included mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Barthel Index for activities of daily living (ADL) and Traditional Chinese medical (TCM) symptoms before and after treatment in this study. The whole study lasted for six months. Significant differences were observed on MMSE, MoCA, ADAS-Cog, ADL and TCM in both control and DHYZ group (P<0.05 or P<0.01) before and after drug treatment. Furthermore, there were more obvious changes of MMSE, MoCA, ADAS-Cog, ADL and TCM scores compared the DHYZ group with the control group (P<0.01) which suggested the DHYZ group showed a more effective improvement on cognition, behavior as well global function. In conclusion, the combined therapy of DHYZ with donepezil showed a more effective improvement in PDD and the underlying mechanism may be related to the synergic amelioration of cholinergic system between them.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Dementia; Donepezil; Double-Blind Method; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines

Impaired mobility and falls are clinically important complications of Parkinson's disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait.. The study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD. Each treatment period will be 6 weeks with a 6-week washout between treatments for a total of 18 weeks for each subject. Donepezil in 2.5 mg capsules or identical appearing placebo capsules will be increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks, if tolerated. Subjects will have idiopathic Parkinson's disease, Hoehn and Yahr stages 2 to 4. We anticipate recruiting up to 100 subjects for screening to have 54 enrolled and 44 subjects complete both phases of treatment. Dropouts will be replaced. As this is a crossover trial, all subjects will be exposed to both donepezil and to placebo. The primary outcome measures will be the root mean square of the mediolateral sway when standing and the variability of the stride duration when walking for two minutes. Secondary outcomes will be the computerized Attention Network Test to examine three domains of attention and the Short-latency Afferent Inhibition (SAI), a physiological marker obtained with transcranial magnetic stimulation as a putative marker of cholinergic activity.. The results of this study will be the most direct test of the hypothesized role of cholinergic neurotransmission in gait and balance. The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. We hypothesize that change in cholinergic activity, as measured with SAI, will predict the relative effectiveness of donepezil on gait and balance. Our immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurotransmission in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility.. This trial is registered at clinical trials.gov ( NCT02206620).

Topics: Cholinesterase Inhibitors; Cross-Over Studies; Donepezil; Double-Blind Method; Gait Disorders, Neurologic; Humans; Indans; Parkinson Disease; Piperidines; Postural Balance

Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population.. In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004.. Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.. Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease.. ACADIA Pharmaceuticals.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB).. This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout.. In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear.. The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.

Topics: Aged; Aged, 80 and over; Data Interpretation, Statistical; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Lewy Body Disease; Male; Nootropic Agents; Parkinson Disease; Piperidines; Treatment Outcome

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Cholinesterase Inhibitors; Dementia; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT(2A)) receptor blockade. We postulated that pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of pimavanserin was compared with placebo in 60 patients with L-DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to pimavanserin, the SAPS total domain score, only showed a trend. However, the pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT(2A) receptor antagonism.

Topics: Aged; Analysis of Variance; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Motor Activity; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Severity of Illness Index; Urea

To investigate if a central cholinesterase inhibitor will reduce falling frequency in subjects with Parkinson disease (PD) with advanced postural instability.. Falling due to postural instability is a significant problem in advancing PD, and is minimally impacted by dopaminergic therapy. Anticholinergic medications increase falling in the elderly. Further, CNS cholinergic neuron loss occurs in PD. We hypothesized that acetylcholine augmentation may reduce frequent falling in subjects with PD.. We enrolled 23 subjects with PD who reported falling or nearly falling more than 2 times per week. In a randomized, placebo-controlled, crossover design, subjects were given 6 weeks of donepezil or placebo with a 3-week washout between phases. The primary outcomes were daily falls and near falls reported on postcards. Secondary outcomes included scores on the Activities of Balance Confidence Scale, Berg Balance Scale, Clinical Global Impression of Change, Folstein Mini-Mental State Examination, and the motor section of the Unified Parkinson's Disease Rating Scale.. Fall frequency per day on placebo was 0.25 ± 0.08 (SEM) compared with 0.13 ± 0.03 on donepezil (p < 0.05). The frequency of near falls was not significantly different between phases. The secondary outcomes did not differ; however, there was a trend to improvement on the subject-completed Global Impression of Change scale.. Subjects with PD fell approximately half as often during the 6 weeks on donepezil than on placebo. Larger trials of cholinergic augmentation are warranted in subjects with PD with frequent falls.. This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).

Topics: Aged; Cholinesterase Inhibitors; Cross-Over Studies; Disability Evaluation; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Postural Balance; Sensation Disorders; Severity of Illness Index; Statistics, Nonparametric

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Combinations; Female; Humans; Hypertension; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Piperidines; Pyrimidines; Receptors, N-Methyl-D-Aspartate

We examined attention-enhancing effects of the cholinesterase inhibitor donepezil in Dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) by means of open label study.. 22 DLBs and 23 PDDs were assessed over 20 weeks using the Cognitive Drug Research Computerized Attentional Tasks. We examined how much closer our patients moved towards being normal for their age by comparing them to a non-demented elderly control sample (n = 183, aged 71-75 years).. Donepezil treatment improved power of attention, continuity of attention and reaction time variability. The deficit in responses was moved towards normal by 38 and 56% for power of attention and 22 and 10% for continuity of attention in PDD and DLB, respectively.. Improvements in attention were found with donepezil in PDD and DLB.

Topics: Aged; Aged, 80 and over; Attention; Chi-Square Distribution; Cholinesterase Inhibitors; Cognition; Dementia; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Mental Processes; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Reaction Time; Reference Values; Statistics, Nonparametric; Treatment Outcome

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

Anticholinesterase (AChE) drugs are being prescribed off label for nonmotor symptoms in Parkinson's disease (PD). Theoretically, these drugs can impair motor function. A small literature suggests AChE therapy has little effect on clinical motor evaluation; however, no study has made objective motor kinematic measures or evaluated brain function. We hypothesized that even if clinical examination was normal in PD patients on dopamine therapy, (1) sensitive kinematic measures would be abnormal during AChE therapy or (2) normal kinematic measures would be maintained by compensatory brain activation. We carried out a randomized, double-blind, placebo-controlled trial of 8 weeks donepezil (10 mg/day) in 17 PD subjects. Subjects carried out a computerized motor task during a positron emission tomography (PET) scan before starting the drug and again after 8 weeks of donepezil or placebo. Kinematic measures of motor function and PET scans were analyzed to compare the effects of donepezil and placebo. Neither placebo nor donepezil altered motor kinematic measures. Furthermore, movement integrity while on donepezil was maintained without compensatory brain activity. Donepezil 10 mg/day can be given for nonmotor symptoms in PD without adverse motor effects or compensatory brain activity.

Topics: Analysis of Variance; Biomechanical Phenomena; Brain; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Movement; Parkinson Disease; Piperidines; Positron-Emission Tomography

To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias.. Thirty-four PD patients had cabergoline up-titrated and their levodopa (L-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26).. Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean L-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious.. High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for L-dopa.

Topics: Adolescent; Adult; Aged; Amantadine; Antiparkinson Agents; Cabergoline; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Humans; Levodopa; Middle Aged; Nitriles; Parkinson Disease; Piperidines; Prospective Studies; Quality of Life; Selegiline; Severity of Illness Index; Treatment Outcome

Several evidences suggest that cholinergic deficits may significantly contribute to dementia in Parkinson's disease (PDD) and acetylcholinesterase inhibitors (ChEIs) have been reported to improve cognitive symptoms in PDD, without worsening parkinsonism. Nineteen PDD patients underwent brain perfusion SPECT with (99m)Tc-ethyl cysteinate dimer after 6 months ChEIs treatment in order to evaluate the functional correlates of clinical improvement. A clear-cut cognitive improvement was reported in PDD patients with a significant improvement of ADAS-cog total score as well as of subscores exploring executive functions (p<0.01). MMSE total score did not significantly change after ChEIs but the subscore of attention significantly improved after therapy (p<0.01). No difference in motor performance as evaluated by UPDRS was reported. SPM analysis showed a significant increase of perfusion (p < 0.0001) in bilateral cingulate, and frontal regions after ChEIs. Our data confirm the efficacy of ChEIs in the treatment of dementia associated with PD mainly on attention and executive functions, and the functional findings indicate that this cognitive improvement could be associated with a sort of pharmacological frontal "re-afferentation".

Topics: Aged; Antiparkinson Agents; Brain; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Image Processing, Computer-Assisted; Indans; Male; Neuropsychological Tests; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine; Tomography, Emission-Computed, Single-Photon

There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB.. We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms.. The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment.. Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Topics: Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Lewy Body Disease; Parkinson Disease; Piperidines; Treatment Outcome

Inhibition of acetylcholinesterase improves symptoms of dementia in patients with Parkinson's disease (PD). Dementia in PD has a cumulative incidence of up to 80% and is mainly caused by a distinct cholinergic deficit. Objectives of this investigator initiated multicenter open label trial were to confirm the efficacy of donepezil in the treatment of dementia in PD patients and to investigate the tolerability and safety of donepezil. The Mini Mental State Examination (MMSE)-score significantly increased in patients, who finished the trial. A detailed analysis of the various items of the MMSE revealed, that only task performance of orientation and recall significantly improved. Scores of the short syndrome test and the Clinical Global Impression Scale improved, motor impairment did not increase. Only 14 out of 24 PD patients finished the trial due to predominant onset of vomiting, nausea, dizziness and confusion. This may result from the titration regime of donepezil, that allows only 5 and 10 mg dosages. Participants with premature study termination had a significant longer duration of PD, less motivation and sleep disturbances at night. Treatment with donepezil was only effective in PD patients with dementia, who experience nearly no side effects from the drug.

Topics: Aged; Analysis of Variance; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Parkinson Disease; Piperidines; Time Factors

Previous studies demonstrated the efficacy of budipine on motor symptoms of treated patients with Parkinson's disease (PD) with rating scales. However rating procedures may be subjective and variable. Therefore additional use of instrumental motor tests are helpful to reflect therapeutic benefits. Objective was to test the efficacy of 20 mg budipine (t.i.d.) in 51 previously untreated idiopathic PD patients in a monocenter, double-blind, placebo-controlled trial with a 2:1 randomisation over a three month interval. Budipine was not superior to placebo application. However a detailed analysis of rating results shows, that budipine but not placebo treated patients significantly improved. Budipine caused significant better outcomes of motor tests with execution of complex movements, but did not change results of tasks, which demand for simple motions. Placebo significantly improved dopamine sensitive motor test results. These outcomes may result from improved non dopaminergic neurotransmission due to budipine. Placebo caused better results of dopamine sensitive tests, since placebo may release endogenous dopamine.

Topics: Adult; Aged; Antiparkinson Agents; Basal Ganglia; Disability Evaluation; Dopamine; Double-Blind Method; Female; Humans; Male; Middle Aged; Movement; Neurologic Examination; Parkinson Disease; Piperidines; Placebo Effect; Synaptic Transmission; Treatment Outcome

To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD).. This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog).. Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant.. Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cross-Over Studies; Dementia; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Piperidines; Treatment Outcome

To assess neurochemical deficits in patients with Parkinson disease (PD) associated dementia (PDD) in vivo.. The authors performed combined PET with N-[11C]-methyl-4-piperidyl acetate (MP4A) and 18F-fluorodopa (FDOPA) for evaluation of cholinergic and dopaminergic transmitter changes in 17 non-demented patients with PD and 10 patients with PDD. Data were compared to 31 age-matched controls by a combined region-of-interest and voxel-based Statistical Parametric Mapping analysis.. The striatal FDOPA uptake was significantly decreased in PD and PDD without differences between the groups. The global cortical MP4A binding was severely reduced in PDD (29.7%, p < 0.001 vs controls) and moderately decreased in PD (10.7%, p < 0.01 vs controls). The PDD group had lower parietal MP4A uptake rates than did patients with PD. Frontal and temporo-parietal cortices showed a significant covariance of striatal FDOPA reduction and decreased MP4A binding in patients with PDD.. While non-demented patients with Parkinson disease had a moderate cholinergic dysfunction, subjects with Parkinson disease associated dementia (PDD) presented with a severe cholinergic deficit in various cortical regions. The finding of a closely associated striatal FDOPA and cortical MP4A binding reduction suggests a common disease process leading to a complex transmitter deficiency syndrome in PDD.

Topics: Acetates; Acetylcholine; Acetylcholinesterase; Aged; Atrophy; Binding, Competitive; Brain; Brain Mapping; Dihydroxyphenylalanine; Dopamine; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Neuropsychological Tests; Parkinson Disease; Piperidines; Positron-Emission Tomography; Synaptic Transmission

To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD).. Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects.. Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases.. Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Pilot Projects; Piperidines; Treatment Outcome

The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa.. Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination.. The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo.. No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Cholinesterase Inhibitors; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Combinations; Drug Interactions; Female; Humans; Indans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines

This open label study was designed to assess the effects of donepezil treatment, its withdrawal and subsequent recommencement on cognitive functioning, behaviour and parkinsonian symptoms in patients with probable dementia with Lewy bodies (DLB) and with Parkinson's disease who subsequently developed dementia (PDD).. Eight patients with DLB and 11 with PDD were treated with up to 10 mg of donepezil daily for 20 weeks followed by a 6-week withdrawal period. The primary outcome measures were the Mini-Mental State Examination (MMSE), the total Neuropsychiatric Inventory (NPI) and the Unified Parkinson's Disease Rating Scale III. Testing was conducted before dosing, at week 20, at a withdrawal visit and 3 months after recommencement on donepezil.. Patients with DLB and PDD showed a significant improvement in cognition with treatment, loss of this improvement on withdrawal and restoration of treatment gains on recommencement. Both groups also demonstrated favourable, behavioural changes with treatment, PDD patients in particular deteriorating significantly after withdrawal. The only NPI symptom domain that showed a consistent significant response to both treatment (positive) and withdrawal (negative) was hallucinations. The medication was well tolerated and parkinsonian features did not alter significantly over the testing sessions.. Our results suggest that treatment with donepezil improves cognition and hallucinations without increasing parkinsonian symptoms, and its sudden withdrawal is usually detrimental, producing acute cognitive and behavioural decline. Although recommencement on donepezil appears to reverse this deterioration we do not advise its abrupt discontinuation in this population.

Topics: Cholinesterase Inhibitors; Dementia; Donepezil; Drug Administration Schedule; Humans; Indans; Lewy Body Disease; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

As cholinergic mechanisms may be at least partially responsible for hallucinations and delusions in Parkinson's disease (PD), we conducted an open study in 8 PD patients to assess the efficacy and tolerability of the cholinesterase inhibitor donepezil, 5 mg at bedtime for two months, in the treatment of these complications. Hallucinations and delusions improved significantly in all patients. Donezepil was overall well tolerated, but a deterioration in motor disability was noted in 2 out of 8 patients.

Topics: Aged; Aged, 80 and over; Basal Nucleus of Meynert; Cholinergic Fibers; Cholinesterase Inhibitors; Delusions; Donepezil; Female; Hallucinations; Humans; Indans; Male; Movement; Parkinson Disease; Piperidines; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Outcome

Topics: Cholinesterase Inhibitors; Cognition; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Parkinson Disease; Piperidines; Treatment Outcome

The complex pharmacological profile of the antiparkinsonian drug budipine influences neurotransmission beyond the dopaminergic system. Previous studies have demonstrated the therapeutic efficacy of budipine on motor symptoms in insufficiently treated patients with Parkinson disease.. To demonstrate the efficacy of 20 mg of budipine, 3 times daily, in addition to a stable, prior, optimum-titrated dopaminergic substitution consisting of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine mesylate, and optional selegiline hydrochloride in 99 patients with idiopathic Parkinson disease in a multicenter, double-blind, placebo-controlled trial.. Budipine significantly (P<.001) decreased the Columbia University Rating Scale sum score (median, 15.0; 95% confidence interval, 11.3-17.0) compared with placebo (median, 4.3; 95% confidence interval, 3.0-7.5) at study end point. Budipine reduced Columbia University Rating Scale subscores for tremor, rigidity, and akinesia.. The additional application of budipine provides further therapeutic benefit in subjects with Parkinson disease receiving a stable, prior, optimum-titrated dopaminergic drug regimen because of the hypothetical positive impact of budipine on altered nondopaminergic neurotransmission in patients with Parkinson disease.

Topics: Adult; Aged; Antiparkinson Agents; Bromocriptine; Dopamine Agents; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines; Treatment Outcome

To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment.. This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS).. Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score.. Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Piperidines; Treatment Outcome

In a randomised double blind parallel-group study in three centers budipine, a diphenylpiperidin derivate, was compared to amantadine with respect to efficacy and safety in the monotherapy of mild to moderate Parkinson's disease (PD). From 53 patients of either sex 27 patients were randomised to 3 x 20 mg/d budipine and 26 patients to 3 x 100 mg/d amantadine. The duration of treatment was 4 weeks in 1 center (21 patients) and 12 weeks in the other 2 centers (32 patients). Safety was measured by vital signs, ECG, adverse event recording and clinical laboratory. Both drugs caused a clinically relevant and statistically significant (p < 0.001) improvement of Parkinsonian symptoms according to the Webster-Rating-Scale (WRS) as compared to pretreatment values. With respect to the total WRS score sum there was no difference between the groups (p > 0.05; n.s.), while budipine showed a significantly (p < 0.05) better effect on the main symptom tremor after 12 weeks. During amantadine treatment more adverse events were observed than after budipine intake. Two patients left the study prematurely, one in the amantadine group due to psychiatric adverse events and one in the budipine group because of insufficient efficacy.

Topics: Aged; Aged, 80 and over; Amantadine; Antiparkinson Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines

Topics: Adult; Aged; Antiparkinson Agents; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; N-Methylaspartate; Parkinson Disease; Pilot Projects; Piperidines; Severity of Illness Index

In order to objectively quantify the tremorlytic activity of budipine in Parkinson's disease (PD) we performed longterm tremor recordings in a subset of patients enrolled in two clinical trials. Eleven PD patients with marked tremor participating in an open-label study underwent longterm recording before and during medication. Nine patients completed the study. Tremor occurrence was reduced from 52 +/- 18.6% to 34.7 +/- 19.3% (p < 0.05); tremor intensity decreased from 15.3 +/- 4.8 (SNR) to 11.3 +/- 4.8 (p < 0.01). UPDRS tremor subscores were also significantly improved. Fourteen patients who enrolled in a multicenter, double-blind, placebo-controlled study underwent longterm tremor analysis in addition to the Columbia University Rating Scale (CURS). Tremor occurrence was improved in the budipine group (n = 7) from 24.7 +/- 15.5% to 14.8 +/- 14.5% (p < 0.05). Tremor intensity decreased from 9.1 +/- 2.5 (SNR) to 7.2 +/- 1.6. However, the latter result was statistically not significant, probably due to the small patient number. In the placebo-group (n = 7) there was no reduction of tremor occurrence or of tremor intensity. The CURS sum score was improved from 5.7 to 3.0 in the budipine group, whereas there was only a smaller improvement in the placebo group (from 7.1 to 5.5). These data suggest that budipine is an effective tremorlytic agent in PD, which may be used as an alternative to anticholinergics.

Topics: Aged; Antiparkinson Agents; Double-Blind Method; Electromyography; Female; Humans; Levodopa; Male; Parkinson Disease; Piperidines; Tremor

Impaired gastric emptying may be the cause for some response fluctuations in Parkinson's disease (PD), especially the "delayed-on" and "no-on" phenomena. Cisapride is a prokinetic drug that enhances gastric emptying by releasing acetylcholine from the myenteric plexus. Tolerability and safety as well as efficacy of cisapride was studied in an open-label trial on 15 fluctuating PD patients. Twelve patients had "delayed-on" and six had "no-no" phenomena. They filled out daily diaries on times of levodopa intake and of turning "on" and "off" for 1 week on levodopa alone and for an additional week of pretreatment with cisapride, 30 min before early morning, early afternoon, and late evening doses of levodopa. Cisapride significantly shortened latency to "on" from 60 +/- 20 to 45 +/- 19 min after the morning dose and from 63 +/- 17 to 47 +/- 22 min after the evening doses. Patients with "no-no" phenomenon had a decreased number of dose failures from 23 before to nine during cisapride treatment. The drug was well tolerated, with no important side effects. Our study supports the role of impaired gastric emptying in some subtypes of motor fluctuations and indicates that they may be improved by prokinetic drugs.

Topics: Aged; Cisapride; Drug Therapy, Combination; Gastric Emptying; Humans; Levodopa; Middle Aged; Motor Activity; Parkinson Disease; Piperidines; Reaction Time

The tremorlytic activity of the novel antiparkinson agent budipine was quantified in an open trial. Eleven patients with Parkinson's disease (PD) were treated with individual doses of budipine added to stable conventional antiparkinsonian medication. Tremor activity was measured using long-term electromyogram (EMG) recordings. Tremor intensity was reduced by 25%, tremor occurrence by 34%, and conventional "Unified Parkinson's Disease Rating Scale" (UPDRS) scores improved by 20% with this medication. There were two dropouts because of side effects. One dropout appeared not to be related to budipine. Apart from those, the drug was well tolerated by all patients. We conclude that budipine is an effective and well-tolerated tremorlytic drug and that the method of long-term EMG recording is suitable for tremor quantification in clinical studies.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Electromyography; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Piperidines; Time Factors; Tremor

Disorders of autonomic regulation are common in patients with Parkinson's disease (PD). Patients most frequently complain of dysphagia and therapy resistant constipation, as far as the gastrointestinal tract is concerned. These symptoms have to be attributed to a neuronal degeneration. In a pilot study we therefore investigated the effect of stimulation of the myenteric plexus by cisapride. 11 women and 13 men were examined, the average age was 67.3 years, the Webster rating 17 points. In 2 out of 24 patients, colonic transit was prolonged up to the limit, both with and without therapy. The other 22 patients showed an acceleration in transit on response to cisapride. On average the colonic transit of 130 hours was reduced to 79 hours. This objective improvement was associated with a subjective improvement. Central side effects or a worsening of Parkinsonian symptoms were not found. We conclude that cisapride is effective in the treatment of constipation in idiopathic PD.

Topics: Aged; Aged, 80 and over; Cisapride; Colon; Constipation; Cross-Over Studies; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Myenteric Plexus; Parasympathomimetics; Parkinson Disease; Pilot Projects; Piperidines

The motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP, preclamol] were evaluated in nine patients with Parkinson's disease using a double-blind, placebo-controlled design. (-)-3-PPP monotherapy had an antiparkinsonian effect in five of nine patients at a mean dose of 37 +/- 10 mg intramuscularly. The co-administration of (-)-3-PPP and a mildly dyskinetic dose of levodopa, infused intravenously at steady-state, resulted in complete suppression of dyskinesias and reemergence of parkinsonian signs in two of seven patients. These dopamine antagonist effects of (-)-3-PPP occurred at relatively low (2.5 and 5 mg) doses. Our results suggest that partial dopamine agonists can exert agonist or antagonist activity in parkinsonian patients depending on concurrent dopaminergic tone. Although this dual action of (-)-3-PPP and other partial agonists could be therapeutically important on theoretical grounds, the small number of patients manifesting a clinically significant response and the frequently inconsistent effects could indicate that this class of agents may have relatively limited clinical utility.

Topics: Aged; Antiparkinson Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Levodopa; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Piperidines

Preclamol, the (-)enantiomer of 3-PPP (= 3(3-hydroxyphenyl)-N-n-propyl piperidine), has a selective dopamine autoreceptor- and postsynaptic mixed agonist-antagonist profile. Its action on patients with disabling on-off parkinsonian fluctuations has been studied and compared with those of placebo and subcutaneous apomorphine. Preclamol had a mild but unequivocal antiakinetic effect, less than that caused by subcutaneous apomorphine, but it provoked less dyskinesia. Further studies to explore the therapeutic potential of preclamol seem justified.

Topics: Antiparkinson Agents; Apomorphine; Blood Pressure; Dopamine Agonists; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Movement; Parkinson Disease; Piperidines; Receptors, Dopamine D1; Receptors, Dopamine D2

Budipine, a new 4,4-diphenylpiperidine derivative, and placebo were administered three times daily to 31 patients with Parkinson's disease over a period of 12 weeks. All patients in the two treatment groups received levodopa (plus benserazide) at an optimum and constant dose for at least 2 months before the start of the study and throughout the trial. The additional administration of budipine (daily dose 60 mg) was excellently tolerated by 14 patients, while 2 patients left the study because of mental confusion at an early stage of the trial. The budipine group showed a 22% improvement on the Columbia Rating Scale (median score). Compared with the placebo group (4% improvement), there was a highly significant difference (P less than 0.01, one-tailed test). Of the three main symptoms of Parkinson's disease, the best effect was seen on tremor, and less pronounced effects on bradykinesia and rigidity. Owing to its long half-life (31 h) with little plasma level fluctuations, budipine appears to be an effective agent in the treatment of Parkinson's disease.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Benserazide; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines

Topics: Adult; Aged; Amantadine; Antiparkinson Agents; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines; Random Allocation

In a single-blind trial of therapy in 20 patients with idiopathic Parkinson disease, domperidone prevented nausea and vomiting induced by bromocriptine without diminishing beneficial central effects. Combination of the two drugs permitted rapid increase in bromocriptine dosage from 22.5 mg per day to 148 mg per day, with 71% mean clinical improvement over baseline score; continuing efficacy of the regimen was evident for a mean follow-up of 2 months.

Topics: Benzimidazoles; Bromocriptine; Domperidone; Female; Humans; Levodopa; Male; Middle Aged; Nausea; Parkinson Disease; Piperidines; Vomiting

Patients with Parkinson's disease were treated with different antiparkinsonian drugs and the amino acid levels in serum and cerebrospinal fluid were determined. Results obtained in 43 patients (L-dopa [26]; prodipine [6]; amantadine [11]) are reported. All drugs investigated produced an increase in amino acids in serum and in CSF, this enhancement being most pronounced for neutral, long-chain amino acids. Amantadine, however, showed this effect for a short period, only. Our results lead us to assume that this increased pool of amino acids in the CSF facilities the biosynthesis of amines with transmitter function from their precursor amino acids.

Topics: Amantadine; Amino Acids; Antiparkinson Agents; Humans; Levodopa; Parkinson Disease; Piperidines

A peripheral dopaminergic blocking agent, domperidone (60 mg daily), or placebo was given, double-blind, to 17 parkinsonian patients who also received increasing doses of bromocriptine. Combined treatment with domperidone reduced total disability by 76% in 8 patients receiving a mean dose of 148 mg of bromocriptine daily. There was no vomiting and involuntary movements and psychic disturbances were similar to those in patients on levodopa and a peripheral decarboxylase inhibitor. In 9 patients taking placebo instead of domperidone, the average daily dose of bromocriptine could not be raised beyond 92 mg. The mean total disability score in this group was reduced by only 48%. Thus, peripheral blockade of dopamine receptors is a promising means of limiting the adverse side-effects of the treatment of parkinsonism with central dopaminergic receptor stimulating agents such as bromocriptine.

Topics: Adult; Antiparkinson Agents; Benzimidazoles; Bromocriptine; Clinical Trials as Topic; Disability Evaluation; Dopamine Antagonists; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Placebos; Receptors, Dopamine

Apomorphine in combination with a peripheral dopamine receptor blocker (domeperidone) was administered to four parkinsonian patients in a double-blind placebo-controlled study. The therapeutic efficacy of apomorphine was not reduced by domperidone, while nausea, drowsiness, sedation, and arterial hypotension were prevented. Combination of domperidone with dopamine agonists may result in more effective treatment of Parkinson's disease.

Topics: Apomorphine; Benzimidazoles; Blood-Brain Barrier; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Placebos; Receptors, Dopamine

Topics: Antiparkinson Agents; Bromocriptine; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Levodopa; Parasympatholytics; Parkinson Disease; Piperidines; Thioxanthenes; Trihexyphenidyl

24 hospitalized psychiatric patients with neuroleptic-induced tardive dyskinesia were treated with alpha-methyl-para-tyrosine (AMPT), 4 g daily for 3 days, and biperiden, 12 mg daily for 3 weeks. The results were evaluated blindly by means of videotape technique. The frequency of tardive dyskinesia was significantly reduced by AMPT and significantly increased by biperiden. The amplitude was reduced by AMPT in ten cases, unchanged in 12 cases and increased in two cases. Biperiden significantly increased the amplitude. The duration of each separate tongue protrusion and/or mouth opening was significantly increased by AMPT and reduced or unchanged by biperiden. It is concluded that a reduced dopaminergic activity (pharmacological or organic) may constitute the primary pathogenetic background for tardive dyskinesia, but that dopaminergic hypersensitivity and/or cholinergic hypofunction is necessary before the hyperkinetic element of the movement disturbances can minifest itself.

Topics: Adult; Aged; Biperiden; Cheek; Clinical Trials as Topic; Humans; Methyltyrosines; Middle Aged; Mouth; Movement Disorders; Parkinson Disease; Piperidines; Tongue; Tranquilizing Agents

The trial involved 69 female, long-stay inpatients of the Voorburg mental hospital, of a median age of 50 years. Two groups were formed at the start of the trial. The first group (51 patients) on a maintenance therapy with orphenadrine, were now put on oral dexetimide. Individually adapted dosages ranged from 0.5 to 1.5 mg daily. The control group (18 patients) of antiparkinsonian agents did not take any in the course of the study either. After three and six months (end of trial) biochemical and haematologic parameters were assessed. Clinical evaluation of extrapyramidal symptoms was made in the dexetimide group. All patients of the control group and 47 of the dexetimide group completed the trial. Both groups were shown to be comparable with regard to all parameters. Statistical analysis showed significant improvement in dexetimide-patients with regard to gross motor tremor, facial inexpressiveness, parkinsonian gait (after two weeks) + dyskinesia (after six months).

Topics: Adult; Aged; Dexetimide; Drug Evaluation; Female; Humans; Middle Aged; Parkinson Disease; Piperidines; Time Factors

In 10 parkinsonian patients the short-time effects of biperiden after slow, intravenous application were investigated in comparison with a placebo group. Immediately after infusion the patients, who were examined at fixed intervals using standardized tests of psychomotor function, mood, and affect, showed a marked impairment os psychomotor function and reaction time, which in time did not exceed the placebo effects. Simultaneously there could be demonstrated an increasing affective stimulation with an acceleration of operating time and improvement of mood. These findings demonstrate- analogously to the intravenous application of L-Dopa-a psychotropic effect independent of the eventual antiakinetic properties of biperiden. The frequency of exogenous psychotic reactions in patients with marked psychoorganic alteration restricts the applicability of anticholinergic drugs in the treatment of an akinetic crisis.

Topics: Affect; Biperiden; Drug Evaluation; Humans; Motor Skills; Parkinson Disease; Piperidines; Reaction Time; Time Factors

Topics: Adolescent; Adult; Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Biperiden; Clinical Trials as Topic; Humans; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines

Topics: Administration, Oral; Adult; Aged; Amantadine; Benzyl Compounds; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines

Topics: Adolescent; Adult; Age Factors; Aged; Child; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Movement Disorders; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Placebos; Psychotic Disorders; Sex Factors; Time Factors; Tranquilizing Agents; Trihexyphenidyl

Topics: 1-Propanol; Adult; Biperiden; Clinical Trials as Topic; Handwriting; Humans; Male; Middle Aged; Neurologic Examination; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines; Psychiatric Status Rating Scales

Topics: Adult; Aged; Atropa belladonna; Clinical Trials as Topic; Humans; Isoniazid; Middle Aged; Parasympatholytics; Parkinson Disease; Phytotherapy; Piperidines; Plants, Medicinal; Plants, Toxic; Trihexyphenidyl

Topics: Aged; Hospitalization; Humans; Parkinson Disease; Piperidines; Urea

Topics: Aged; Hospitalization; Humans; Parkinson Disease; Piperidines; Urea

Janus-activated kinases (JAKs) are well known to play a physiological as well as pathological role in several disease conditions such as autoimmune disorders. The present study evaluated the therapeutic potential of CP690550 (pan-JAK inhibitor) in 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP) model of Parkinson's disease. Intrastriatal administration of MPTP (30 micromol in 2 microl) produced a significant alteration in behavioural (bar test and block test). Biochemical investigations in serum and brain homogenate revealed a significant alteration in the JAK-mediated cytokine levels. MPTP administration also showed significant imbalance of inflammatory (increased TNF-α, IL-6 and NF-κb) versus anti-inflammatory cytokines (decreased IL-10 levels). MPTP-treated brain sections revealed alteration in the tissue architecture as well as undifferentiated bodies of varying contour and lesions. Chronic administration of CP690550 (3 and 10 mg/kg, po) for 7 days significantly reversed the behavioural, biochemical and histological alterations induced by MPTP. In conclusion, the findings of the present study govern the possible therapeutic potential of CP690550 in MPTP-treated mice and thus highlight the therapeutic potential of JAK inhibitors in treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cytokines; Disease Models, Animal; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Pyrimidines

Pimavanserin, a serotonin 5-HT. This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW).. Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients.. Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Topics: Aged; Antipsychotic Agents; Cohort Studies; Female; Humans; Male; Medicare; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; United States; Urea

Topics: Antipsychotic Agents; Dementia; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Dopamine; Dopaminergic Neurons; Ferroptosis; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Parkinson Disease; Piperidines; Pyrazoles; Quercetin; Reactive Oxygen Species

The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [. We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands.. We found no statistically significant difference of [. [

Topics: Humans; Male; Parasympathectomy; Parkinson Disease; Piperidines; Positron-Emission Tomography; REM Sleep Behavior Disorder

Topics: Alkaloids; alpha-Synuclein; Animals; Autophagy; Benzodioxoles; Ligand-Gated Ion Channels; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Receptors, Purinergic P2X4

Severe cholinergic degeneration is known to occur in Parkinson's disease (PD) and is thought to play a primary role in the cognitive decline associated with this disease. Although cholinergic losses occur in all patients with PD, cognitive performance remains normal for many of them, suggesting compensatory mechanisms in those.. This exploratory study aimed at verifying if normal cognition in PD may involve distinctive features of the brain cholinergic systems.. Following extensive neuropsychological screening in 25 patients with PD, 12 were selected and evenly distributed between a cognitively normal (PD-CN) group, and a mild cognitive impairment (PD-MCI) group. Each group was compared with matched healthy volunteers (HV) on standardized cognitive scales (MoCA, PDCRS), and PET imaging with [. [. These findings suggest a compensatory upregulation of the hippocampal cholinergic innervation in PD-CN, which might underly normal cognitive performances in spite of cortical cholinergic denervation in other regions.

Topics: Aged; Cholinergic Agents; Cognition; Cognitive Dysfunction; Female; Hippocampus; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Positron-Emission Tomography; Radioactive Tracers

Although there are numerous strategies to counteract the death of dopaminergic neurons in Parkinson's disease (PD), there are currently no treatments that delay or prevent the disease course, indicating that early protective treatments are needed. Targeting axonal degeneration, a key initiating event in PD, is required to develop novel therapies; however, its underlying molecular mechanisms are not fully understood. Here, we studied axonal degeneration induced by 6-hydroxydopamine (6-OHDA) in vitro and in vivo. We found that metabotropic glutamate receptor 5 (mGluR5) expression increased during 6-OHDA-induced axonal degeneration in primary neurons and that blockade of mGluR5 by its antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1, 3-thiazol-4-yl) ethynyl]-pyridine (MTEP) almost completely attenuated the degenerative process in vitro. Furthermore, a rapid increase in intra-axonal calcium levels following 6-OHDA treatment was visualized using a calcium-sensitive fluorescence probe and a calcium chelator prevented the axonal degenerative process induced by 6-OHDA in vitro, whereas application of the mGluR5 antagonist MPEP partially attenuated the increase in intra-axonal calcium. The screening of calcium targets revealed that calpain activation and an increase in phosphorylated extracellular signal-regulated kinase (p-ERK) were calcium dependent during 6-OHDA-induced axonal degeneration in vitro. Consistent with these in vitro findings, blockade of mGluR5 with MPEP attenuated the degeneration of dopaminergic axons induced by 6-OHDA injection into the striatum prior to soma death in the early stage of PD in an in vivo animal model. In addition, MPEP inhibited the increase in mGluR5 expression levels, calpain activation and the elevation of p-ERK in the striatum triggered by 6-OHDA injection in vivo. Taken together, these data identify an mGluR5-calcium-dependent cascade that causes axonal degeneration, and suggest that mGluR5 antagonists could provide effective therapy to prevent the disease process of PD.

Topics: Animals; Axons; Calcium Signaling; Cells, Cultured; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Female; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Thiazoles

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by

Topics: alpha-Synuclein; Butyrates; Cell Line; Dopamine Plasma Membrane Transport Proteins; Flavonols; Humans; Models, Biological; Oxidative Stress; Parkinson Disease; Piperidines; Protein Aggregates; Saccharomyces cerevisiae; tert-Butylhydroperoxide

Topics: Aged; Hospitalization; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

To determine the risk of hospitalization and death associated with pimavanserin use.. We conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively.. The study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06-1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99-1.24) or with 30-day mortality (aHR 0.76, CI 0.56-1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02-1.41) that persisted after 180 days (aHR 1.28, CI 1.13-1.45) and 1 year (aHR 1.56, CI 1.42-1.72).. Pimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease.. This study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

Topics: Aged; Hospitalization; Humans; Medicare; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; United States; Urea

Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.

Topics: Amidohydrolases; Analgesics; Animals; Benzamides; Brain; Cannabidiol; Capsaicin; Carbamates; Celecoxib; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Morphine; Nociception; Oxidopamine; Pain; Parkinson Disease; Piperidines; Pyrazoles; Thienamycins

Parkinson's disease (PD) related pain can be assigned to either nociceptive pain or neuropathic pain, in which Transient receptor potential vanilloid 1 (TRPV1) has been demonstrated to play a pivotal role. Yet little research has examined possible involvement of TRPV1 in pain in PD. Here, we show that TRPV1 is highly expressed in PD and blocking TRPV1 can alleviate pain in PD. The level of TRPV1 in 6-OHDA induced semi mice model of PD was evaluated. The effect of TRPV1 and involved serotonin (5-HT) was also examined in the model. Unilateral injection of 6-OHDA in striatum significantly decreased thermal pain threshold and induced mechanical allodynia without changes in conditioned place preference. Immunostaining revealed that great increased expression in TRPV1 in the Vc of 6-OHDA lesioned mice compared with sham mice. TRPV1 sensitization was maintained by 5-HT/5-HT3A. In 6-OHDA-lesioned mice model of PD, TRPV1 sensitization might be implicated in the maintenance of behavioral hypersensitivity by enhanced descending 5-HT pain facilitation and dorsal horn 5-HT3AR mechanism.

Topics: Acrylamides; Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Hyperalgesia; Male; Mice, Inbred C57BL; Oxidopamine; Pain Threshold; Parkinson Disease; Piperidines; Receptors, Serotonin, 5-HT3; Serotonin; Signal Transduction; Trigeminal Caudal Nucleus; TRPV Cation Channels

Topics: Cross-Sectional Studies; Genotype; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Sleep; Urea

A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds

Topics: Animals; Antiparkinson Agents; Caco-2 Cells; Disease Models, Animal; Humans; Indoles; Male; Nociceptin Receptor; Parkinson Disease; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Structure-Activity Relationship

Topics: Aged; Female; Humans; Narcolepsy; Parkinson Disease; Piperidines

Topics: Alkaloids; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship

This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS).. Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years).. Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Female; Hallucinations; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: Antipsychotic Agents; Death, Sudden; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Capsaicin; Disease Models, Animal; Dopaminergic Neurons; Humans; Indoles; Mice; Mice, Inbred C57BL; Neurogenic Inflammation; Neuroglia; Neuroprotection; Parkinson Disease; Piperidines; Pyrazoles; Receptor Cross-Talk; Receptors, Cannabinoid; Substantia Nigra; TRPV Cation Channels

This article is to investigate the effect of piperine on the small intestine of mice with Parkinson's disease with dementia(PDD). Ninety-six C57 BL/6 mice of SPF grade were randomly divided into 8 groups(male, 12 in each group): normal group, model group, autophagy inhibitor group(6-amino-3-methylpurine, 3 MA, 30 mg·kg~(-1)), autophagy activator group(rapamycin, 1 mg·kg~(-1)), low, medium, and high dose piperine groups(10, 20, 40 mg·kg~(-1)), and medopar group(112.5 mg·kg~(-1)). Except for the normal group, mice in each group were injected subcutaneously with reserpine(0.1 mg·kg~(-1)) once every 48 hours for 40 days. In addition, on the 20 th day of administration, except for the normal group, the mice in the other groups were subjected to bilateral common carotid artery occlusion to finally prepare PDD models. At the same time, each group was given the corresponding drug treatment once a day for 40 days. After the last administration, the behavioral changes of mice were observed by autonomic activity experiment and hot plate experiment. The expression levels of α-synuclein(α-syn) and tyrosine hydroxylase(TH) in the small intestine were detected by immunohistochemistry. The expression levels of beclin-1, microtubule-associated protein 1 light chain 3 B(LC3 B) and p62 in the small intestine were detected by immunofluorescence assay. Hematoxylin-eosin staining was used to observe the pathological morphology of small intestine tissues in each group. Enzyme-linked immunosorbent assay was adopted for detection of β-amyloid precursor protein(APP), p-tau, acetylcholine transferase(ChAT), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in small intestine. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of α-syn, TH, beclin-1, microtubule-associated protein 1 light chain 3(LC3), and p62 mRNA and mmu-miR-99 a-5 p in the small intestine. The results of this study showed that, as compared with the model group, the number of activities, the expression levels of ChAT, TH, and p62 were significantly increased in the 3 MA group, the various piperine dose groups, and the medopar group(P<0.05), and their first foot licking time was shortened; APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly reduced(P<0.05). However, as compared with the model group, the number of activities, ChAT, TH, and p62 expression levels in the rapamycin group were significantly reduce

Topics: Alkaloids; Animals; Autophagy; Benzodioxoles; Dementia; Intestine, Small; Male; Mice; Parkinson Disease; Piperidines; Polyunsaturated Alkamides

Psychosis is common among patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Limited data exist on the most effective therapies.. Retrospective cohort study comparing patients with PD or DLB initiated on quetiapine or pimavanserin for psychosis. Primary outcome was time to discontinuation of pimavanserin or quetiapine using Kaplan-Meier survival analysis. We hypothesized the rate of antipsychotic discontinuation would be lower in the pimavanserin group. Subjects were included if the indication for treatment was psychosis and excluded if there was a history of major mental illness or no follow up data were available.. Forty-seven patients were included in the quetiapine cohort and 45 in the pimavanserin cohort. Patients in the pimavanserin cohort were more likely to have a diagnosis of DLB (33% vs. 11%, P = 0.01) and to have been prescribed an antipsychotic previously (62% vs. 6%, P < 0.01); otherwise, the groups were similar. Time to discontinuation analysis, which accounts for efficacy, safety and tolerability, revealed a lower early pimavanserin discontinuation rate and a higher late pimavanserin discontinuation rate (HR < 1 before day 43, HR > 1 after day 43; P = 0.04). There was no difference in mortality in the pimavanserin group compared to the quetiapine group (HR 0.37, 95% CI 0.06 to 2.45; P = 0.88). More individuals had a documented secondary indication for taking quetiapine than pimavanserin (38% vs. 4%; P = 0.001).. Accounting for efficacy, safety and tolerability, pimavanserin may be more clinically useful for promptly managing psychosis, while quetiapine may confer additional secondary benefits long-term.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cohort Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Urea

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Pimavanserin is a first-in-class selective serotonin 5-HT2A receptor inverse agonist approved for the treatment of Parkinson disease psychosis. This article discusses pimavanserin's mechanism of action, which patients are appropriate candidates for therapy, adverse reactions, and appropriate dosing.

Topics: Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Psychosis is common in Parkinson's disease-related disorders and is associated with significant morbidity. Pimavanserin is a newly approved treatment for Parkinson's disease psychosis, but real-world experience with pimavanserin has been limited by small sample sizes and limited assessment of longitudinal outcomes.. The aim was to summarize the clinical experience with pimavanserin in a large cohort of patients with Parkinson's disease-related psychosis.. We conducted a retrospective chart review of patients who were prescribed pimavanserin at Vanderbilt University Medical Center in the southeast United States between May 2016 and July 2018. We used Chi-squared analyses to compare efficacy and tolerability of pimavanserin, considering patient diagnosis, presence of dementia or delusions, use of deep brain stimulation, and prior antipsychotic failure. Additionally, we compared the clinical characteristics of patients who started treatment and those who did not, to evaluate safety outcomes.. We identified 107 patients prescribed pimavanserin, and 91 began treatment. Clinical improvement in psychosis was documented in 76% of patients (69/91) and did not differ based on diagnosis, presence of dementia, delusions, use of deep brain stimulation, or prior antipsychotic failure. Adverse effects were reported in 20 patients (22%), the most common of which was worsening gait instability (5/91, 5%). Side effects led to cessation of therapy in 11 of the 91 patients (12%). At current follow-up, 50 (65%) of 77 living patients remain on treatment, with a mean treatment duration of 14.6 months. Although most of these patients are on pimavanserin monotherapy (33/50, 66%), 17 patients (34%) are on a dual-antipsychotic regimen. The living patients no longer on treatment stopped pimavanserin primarily because of a lack of perceived benefit (11/77, 14%), side effects (9/77, 12%), or both (1/77, 1%), though six patients (8%) stopped for reasons unrelated to medication effects, including the desire to reduce overall medication burden and negative media reporting on pimavanserin.. Study results emphasize long-term efficacy and tolerability of pimavanserin for psychosis in Parkinson's disease-related disorders, including patients with dementia, delusions, deep brain stimulation use, or prior antipsychotic failure.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; Urea

Topics: Brain; Humans; Parkinson Disease; Piperidines; Positron-Emission Tomography

Topics: Antiparkinson Agents; Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

REM sleep behaviour disorder (RBD) occurs frequently in patients with synucleinopathies such as Parkinson's disease, dementia with Lewy body, or multiple system atrophy, but may also occur as a prodromal stage of those diseases; and is termed idiopathic RBD (iRBD) when not accompanied by other symptoms. Cholinergic degeneration of the mesopontine nuclei have been described in synucleinopathies with or without RBD, but this has not yet been explored in iRBD. We sought to assess cholinergic neuronal integrity in iRBD using PET neuroimaging with the. The sample included 10 participants evenly divided between healthy subjects and patients with iRBD. Polysomnography and PET imaging with FEOBV were performed in all participants. Standardized uptake value ratios (SUVRs) were compared between the two groups using voxel wise t-tests. Non-parametric correlations were also computed in patients with iRBD between FEOBV uptake and muscle tonic and phasic activity during REM sleep.. Compared with healthy participants, significantly higher FEOBV uptakes were observed in patients with iRBD. The largest differences were observed in specific brainstem areas corresponding to the bulbar reticular formation, pontine coeruleus/subcoeruleus complex, tegmental periacqueductal grey, and mesopontine cholinergic nuclei. FEOBV uptake in iRBD was also higher than in controls in the ventromedial area of the thalamus, deep cerebellar nuclei, and some cortical territories (including the paracentral lobule, anterior cingulate, and orbitofrontal cortex). Significant correlation was found between muscle activity during REM sleep, and SUVR increases in both the mesopontine area and paracentral cortex.. We showed here for the first time the brain cholinergic alterations in patients with iRBD. As opposed to the cholinergic depletion described previously in RBD associated with clinical Parkinson's disease, increased cholinergic innervation was found in multiple areas in iRBD. The most significant changes were observed in brainstem areas containing structures involved in the promotion of REM sleep and muscle atonia. This suggests that iRBD might be a clinical condition in which compensatory cholinergic upregulation in those areas occurs in association with the initial phases of a neurodegenerative process leading to a clinically observable synucleinopathy.

Topics: Aged; Brain; Case-Control Studies; Cholinergic Neurons; Dementia; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Polysomnography; Positron-Emission Tomography; REM Sleep Behavior Disorder; Sleep, REM; Synucleinopathies

Topics: Antipsychotic Agents; Delusions; Drug Evaluation; Hallucinations; Humans; Parkinson Disease; Piperidines; United States; United States Food and Drug Administration; Urea

Topics: Antipsychotic Agents; Drug Approval; Humans; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; United States; United States Food and Drug Administration; Urea

In 2016, pimavanserin, a 5-hydroxytryptamine 2A inverse agonist, became the first U.S. Food and Drug Administration (FDA) approved medication for Parkinson disease psychosis (PDP) after demonstrating modest clinical improvement in a single positive trial as assessed by a novel PDP scale, the Scale for the Assessment of Positive Symptoms for Parkinson's Disease Psychosis (SAPS-PD). This followed three trials that demonstrated negative findings on established measures of psychosis widely used in PDP research, including the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, the Parkinson Psychosis Rating Scale, and the Clinical Global Impression-Severity Scale. This review article provides an overview of the scale construction of the SAPS-PD, a measure which has yet to be established as valid, reliable, or sensitive to change in PDP. Furthermore, this article reviews analyses completed by an FDA statistical reviewer that call into question whether pimavanserin demonstrated a clinically significant difference from placebo on the SAPS-PD. These findings underscore concerns regarding the clinical efficacy of pimavanserin.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Drug Approval; Humans; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Urea

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Survival Analysis; Treatment Outcome; Urea

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.

Topics: alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Neurons; Parkinson Disease; Piperidines; Protein Aggregation, Pathological; Protein Folding; Pyrazines; Pyrimidines; Retina

Pimavanserin is not curative, but can improve the quality of life remaining for the person with Parkinson's disease who typically has been suffering from this relentless neurodegenerative disease for years. Using pimavanserin effectively requires knowledge not only about the product itself, but also about the treatments pimavanserin is replacing.

Topics: Antipsychotic Agents; Consensus; Humans; Neurodegenerative Diseases; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Parkinson's disease psychosis (PDP) occurs commonly and can comprise the most troubling symptoms among the many that occur with this illness. Prior treatment options for PDP have been limited and unsatisfactory due to uneven efficacy data, burdensome monitoring, and lack of a specific FDA indication coupled with warnings of increased mortality. Pimavanserin, approved for the treatment of PDP by the FDA in 2016, overcomes some of these obstacles, with data proven efficacy and without the frequent monitoring required for clozapine. This presents an opportunity to transition patients with PDP to pimavanserin from older therapies. Black and colleagues provide their thoughtful recommendations on how to achieve this transition to pimavanserin while maintaining symptom control and minimizing disruptions that might occur with a medication change.

Topics: Antipsychotic Agents; Consensus; Humans; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson's disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Azepines; Blotting, Western; Cell Survival; Heterocyclic Compounds, Bridged-Ring; Interferon-Stimulated Gene Factor 3; Lactones; Lipopolysaccharides; Mice; Microglia; Mitogen-Activated Protein Kinases; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Parkinson Disease; Phosphorylation; Piperidines; Polymerase Chain Reaction

Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.. A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.. Forty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.. This study was limited by its retrospective study design and small sample size and with likely selection bias.. The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Olanzapine; Outcome and Process Assessment, Health Care; Parkinson Disease; Piperidines; Psychological Techniques; Psychotic Disorders; Quality of Life; Retrospective Studies; Urea

Sulfasalazine is an anti-inflammatory agent commonly used in the treatment of autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine is converted by gut bacteria into sulfapyridine and the clinically active metabolite 5-aminosalicylic acid (5-ASA), and its efficacy is proportional to the 5-ASA concentration within the intestinal lumen. Renal complications are commonly reported for the chemically similar 5-ASA derivative mesalamine, but are not well-known side effects of sulfasalazine therapy. We report a 72-year-old patient with Crohn's disease managed with sulfasalazine for more than 10 years who presented with severe acute kidney injury (serum creatinine, 9.7mg/dL). Renal ultrasound revealed calculi and he subsequently spontaneously voided innumerable stones, which were composed of sulfasalazine metabolites. His renal calculi cleared and serum creatinine concentration improved to 3.1mg/dL after discontinuing sulfasalazine therapy and intravenous fluid hydration. His kidney function eventually returned to baseline. This case demonstrates that renal complications, in particular nephrolithiasis, may be an under-reported but potentially serious phenomenon in patients with inflammatory bowel disease treated with sulfasalazine and that their hydration status may play an important role in this process.

Topics: Acute Kidney Injury; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antiparkinson Agents; Carbidopa; Cholinesterase Inhibitors; Crohn Disease; Donepezil; Drug Combinations; Fluid Therapy; Humans; Indans; Kidney Calculi; Levodopa; Male; Parkinson Disease; Piperidines; Severity of Illness Index; Sulfasalazine; Ultrasonography

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 ± 7.2; Hoehn and Yahr stage 2.6 ± 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [

Topics: Aged; Aged, 80 and over; Carbon Isotopes; Cognition Disorders; Cognitive Behavioral Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Parkinson Disease; Phosphinic Acids; Piperidines; Positron-Emission Tomography; Regression Analysis; Tetrabenazine

Topics: Aged, 80 and over; Anesthesia; Bronchoscopes; Bronchoscopy; Dentures; Etomidate; Foreign Bodies; Humans; Hypnotics and Sedatives; Levodopa; Male; Parkinson Disease; Piperidines; Remifentanil; Respiratory Aspiration; Trachea

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT

Topics: Animals; Benzylamines; Cholinesterase Inhibitors; Cognition; Cognitive Dysfunction; Corpus Striatum; Donepezil; Dopamine; Female; Gait; Indans; Indoles; Male; Parkinson Disease; Piperidines; Postural Balance; Rats, Sprague-Dawley; Receptors, Serotonin

The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD

Topics: Adenosine Triphosphate; Cells, Cultured; Electron Transport Complex I; F-Box Proteins; Humans; Iodoacetic Acid; Isoquinolines; Membrane Potential, Mitochondrial; Mitochondria; Mitophagy; NAD; Oxygen Consumption; Parkinson Disease; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Polymorphism, Single Nucleotide; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Sodium Cyanide

Parkinson's disease (PD) is a progressive neurodegenerative disorder with prominent motor and non-motor symptoms. Psychosis develops in over 40% of PD patients and it is one of the most distressing symptoms for patients and caregivers alike. Until recently, atypical antipsychotics, clozapine and quetiapine were used to treat psychotic symptoms, but treatment was associated with substantial concerns for side-effects of clozapine and unfounded efficacy for quetiapine. Extensive research has shown that the antipsychotic effect of these drugs could be attributed to serotonin 2a receptor (5-HT2A) triggered mechanisms. A selective 5-HT2A inverse agonist, pimavanserin, has been developed, investigated and has gained approval in April 2016 in the US for the treatment of hallucinations and delusions in PD. In this review we primarily focus on psychosis in PD, the current treatment possibilities and the new, emerging therapy, pimavanserin, a selective 5-HT2A inverse agonist. All articles were reviewed in this topic and indexed in PubMed with keywords: Parkinson's disease psychosis, serotonin 2a receptor inverse agonist, clozapine, quetiapine, pimavanserin.

Topics: Animals; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Urea

We report a 74-year-old female patient with Parkinson disease (PD). Around 2010, she developed depression and bradykinesia and was diagnosed as PD. In July 2014, she came to our hospital, of which she lived in the neighborhood. In the last part of December 2014, she felt uneasy about her fecal smell and saw a psychiatrist in the first part of January 2015. Quetiapine (25 mg/day) was added. In the last part of January, she complained of fecal smell everywhere and could not take a meal. No-one else could detect the smell. A diagnosis of olfactory hallucination was made. The next day after increasing to 75mg/day, however, she was admitted to our hospital because of refusing to take medicine. After introducing donepezil, olfactory hallucination subsided and her appetite was improved. Brain MRI showed atrophy of the bilateral temporal lobes and N-isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography (

Topics: Aged; Cerebrovascular Circulation; Donepezil; Female; Hallucinations; Humans; Indans; Iodine Radioisotopes; Iofetamine; Parkinson Disease; Piperidines; Radiopharmaceuticals; Temporal Lobe; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

To investigate systemic levels of acetylcholinesterase in early Parkinson disease (PD) with. This was a cross-sectional study with 19 patients with early-stage PD (disease duration 1.5 ± 0.6 years) and 16 age-matched controls who had clinical assessments, olfaction tests, and. The patients with PD showed significantly reduced. We found significantly decreased

Topics: Acetylcholinesterase; Aged; Area Under Curve; Carbon Radioisotopes; Cross-Sectional Studies; Donepezil; Female; Heart; Humans; Indans; Intestines; Kidney; Male; Middle Aged; Myocardium; Pancreas; Parkinson Disease; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; Time Factors

The placement of subthalamic nucleus (STN) deep brain stimulation (DBS) electrodes can be facilitated by intraoperative microelectrode recording (MER) of the STN.. Optimal anesthetic management during surgery remains unclear because of a lack of quantitative data of the effect of anesthetics on MER. Therefore, we measured the effects of dexmedetomidine (DEX) on MER measures of the STN commonly taken intraoperatively.. MER from 45 patients was retrospectively compared between patients treated with remifentanil (REMI) alone or both REMI and DEX, which are the 2 main standards of care at our center. The measures examined were population activity, such as root mean square, STN length, and number of passes yielding STN, and the single-neuron measures of firing rate and variability.. The addition of DEX does not affect population measures (number of passes: DEX+REMI, n = 68, REMI only, n = 154), or neuronal firing rates (number of neurons: DEX+REMI, n = 64, REMI only, n = 72), but firing rate variability was reduced.. In this cohort, population-based measures routinely used for electrode placement in the STN were unaffected by DEX when added to REMI. Neuronal firing rates were also unaffected, but their variability was reduced, even beyond 20 min after cessation.

Topics: Action Potentials; Aged; Deep Brain Stimulation; Dexmedetomidine; Female; Humans; Male; Microelectrodes; Middle Aged; Neurons; Parkinson Disease; Piperidines; Remifentanil; Retrospective Studies; Subthalamic Nucleus

Psychotic disorders in Parkinson's disease (PDPD) are common and significantly influence the quality of life and disability level. The pathogenesis of PDPD is complex and not yet fully understood. Taking into consideration the features of the Parkinson's disease (usually older patients with a risk of cognitive decline), and the pharmacodynamics of the antiparkinsonian and traditional antipsychotic drugs, the management of PDPD is a challenging issue of clinical neurology and psychiatry. In this systematic review, scientific publications for the period 2014-2016 were analyzed within two bibliographic databases: MEDLINE/PubMed and eLIBRARY.RU. Additionally, the guidelines of the International Parkinson and Movement Disorders Society, American Academy of Neurology and European Academy of Neurology were included in the analysis. Clozapine is recommended to use in the treatment of PDPD, quetiapine is possible to use, pimavanserin will probably become a remedy of choice. Nonpharmacological approaches have positive effects on the general condition of the patients with PDPD, however the efficacy of such approaches to treat psychosis is unclear.. Психотические расстройства при болезни Паркинсона (ПРБП) отмечаются у большого числа пациентов. Они оказывают значительное влияние на качество жизни и уровень инвалидизации. Патогенез ПРБП является сложным и до конца не изученным. Принимая во внимание специфику БП (как правило, пациенты пожилого возраста с риском появления когнитивных нарушений), а также фармакодинамические особенности антипаркинсонических и классических антипсихотических средств, лечение ПРБП требует особого внимания неврологов и психиатров. Представлен систематический обзор, в котором обобщены результаты научных публикаций за период 2014-2016 гг. в двух библиографических базах данных: MEDLINE/PubMed и eLIBRARY.RU, а также клинических рекомендаций Международного общества болезни Паркинсона и нарушений движения, Американской и Европейской академий неврологии. Из антипсихотических средств клозапин является препаратом, рекомендованным к применению, кветиапин - препарат, который признается возможным к применению, пимавансерин, вероятно, станет одним из препаратов выбора в терапии ПРБП. Нефармакологические методы лечения оказывают положительный эффект в плане улучшения общего состояния пациентов с ПРБП, однако их эффективность по лечению собственно ПРБП остается неясной.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Quetiapine Fumarate; Urea

Parkinson's disease (PD) is a common neurodegenerative disease affecting the quality of life in the elderly. We speculated that PD patients might have abnormal pharmacodynamics due to the degenerative neural system, and the present study was performed to investigate the pharmacodynamics of remifentanil in PD patients.. Two arms of patients were recruited, including 31 PD patients undergoing pulse generator placement after deep brain stimulator implantation and 31 pair-controlled patients undergoing intracranial surgery without PD (NPD). Patients were anesthetized with target-controlled infusion of propofol and remifentanil. The effective concentration of remifentanil to inhibit responses to intubation and skin incision in 50% and 95% patients (EC50 and EC95) was determined by the up and down method.. Demographic data, bispectral index, and hemodynamic values were similar between the PD and the NPD groups. The average remifentanil concentration used in the PD group for tracheal intubation is significantly lower than in the NPD group (P<0.001). The EC50 for inhibiting the response to tracheal intubation were 1.86 ng/mL (95% confidential interval [CI], 1.77-1.96 ng/mL) in the PD group and 3.20 ng/mL (95% CI, 3.13-3.27 ng/mL) in the NPD group. The average remifentanil concentration used in the PD group for skin incision is significantly lower than in the NPD group (P<0.001). EC50 for inhibiting the response to skin incision were 2.17 ng/mL (95% CI, 2.09-2.25 ng/mL) in the PD group and 3.09 ng/mL (95% CI, 3.02-3.17 ng/mL) in the NPD group.. The remifentanil concentrations required for inhibiting responses to tracheal intubation and skin incision are reduced markedly in PD patients undergoing pulse generator placement (NCT01992692).

Topics: Anesthetics, Intravenous; Deep Brain Stimulation; Female; Humans; Intubation, Intratracheal; Male; Middle Aged; Parkinson Disease; Piperidines; Prospective Studies; Remifentanil; Skin; Surgical Wound

Parkinson's disease psychosis (PDP) is a common and often very disturbing component of Parkinson's disease (PD). PDP consists of hallucinations that are mainly visual and delusions that are often of a paranoid nature. These symptoms can be the most troubling and disruptive of all the manifestations of Parkinson's disease. Current treatment methods include the reduction of anti-Parkinson's medications, a strategy that may worsen the motor problems the medications are prescribed to alleviate, and the introduction of selected antipsychotic medications that carry with them the potential for troubling side effects and serious consequences. Pimavanserin has been developed and studied in clinical trials to specifically address Parkinson's disease psychosis and has been submitted to the U.S. Food and Drug Administration for its approval for this purpose. If this is granted, we believe the evidence of Pimavanserin efficacy, safety and tolerability will position this medication as the first choice for treatment of Parkinson's disease psychosis.

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Tartrates

Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21-24.].

Topics: Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Topics: Antiparkinson Agents; Antipsychotic Agents; Drug Administration Schedule; Drug Costs; Drug Interactions; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

Topics: Antiparkinson Agents; Delusions; Drug Approval; Drug Labeling; Hallucinations; Humans; Parkinson Disease; Piperidines; Urea

To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil.. Forty-nine participants (25 PDD and 24 elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs).. We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor-naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks.. Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition.

Topics: Aged; Antiparkinson Agents; Brain; Brain Mapping; Cerebrovascular Circulation; Donepezil; Female; Humans; Indans; Linear Models; Male; Mental Status Schedule; Multivariate Analysis; Neural Pathways; Nootropic Agents; Parkinson Disease; Piperidines; Radiopharmaceuticals; Receptor, Muscarinic M1; Receptor, Muscarinic M4; Receptors, Muscarinic; Tomography, Emission-Computed, Single-Photon

Pimavanserin, a novel agent approved for the treatment of Parkinson's disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors.

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Urea

The effect of N1-dansylspermine, a polyamine analogue and competitive polyamine antagonist, and Ro25,6981, a noncompetitive polyamine antagonist with good affinity and selectivity for the GluN2B subunit, on locomotor activity in naive mice was investigated. Furthermore, the ability of the polyamine antagonists to reverse reserpine-induced hypokinesia was assessed, 24 h after injection of a catecholamine-depleting dose of reserpine (5 mg/kg, subcutaneous), to investigate the therapeutic potential of polyamine antagonists in Parkinson's disease. N1-dansylspermine significantly decreased locomotor activity in naive animals (P<0.001) but caused a mild, but significant increase in locomotor activity in reserpinized mice at the highest dose tested (P<0.05). Ro25,6981 significantly stimulated locomotor activity in naive animals (P<0.001) and had a slight significant stimulatory effect on reserpine-induced hypokinesia (P=0.05). N1-dansylspermine and Ro25,6981 had opposite effects on locomotor activity in naive mice, but both had a mild antiparkinsonian effect in the reserpine model. These findings suggest that antagonism of the polyamine binding site on the GluN2B subunit can reduce hypokinesia, albeit to a limited extent.

Topics: Animals; Antiparkinson Agents; Antipsychotic Agents; Dansyl Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Locomotion; Male; Mice; Parkinson Disease; Phenols; Piperidines; Reserpine

Parkinson's disease psychosis (PDP) is theoretically a serotonin-dopamine imbalance syndrome due to disruption of the normal balance between the serotonergic and dopaminergic neurotransmitter systems in key brain circuits.

Topics: Antiparkinson Agents; Antipsychotic Agents; Brain; Dopamine; Humans; Levodopa; Lewy Bodies; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Serotonin; Urea

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.

Topics: Acetylcholinesterase; Adult; Aged; Antiparkinson Agents; Brain; Case-Control Studies; Cholinesterase Inhibitors; Constipation; Digestive System; Donepezil; Female; Heart Rate; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Positron-Emission Tomography; Surveys and Questionnaires; Time Factors

Serotonin 5-HT1A receptor agonists reduce L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished L-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of L-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the L-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of L-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and L-DOPA dose-sparing effects in PD patients.

Topics: Adrenergic Agents; Animals; Antiparkinson Agents; Corpus Striatum; Disease Models, Animal; Dyskinesia, Drug-Induced; Female; Levodopa; Male; Motor Activity; Neurotransmitter Agents; Oxidopamine; Parkinson Disease; Piperidines; Psychomotor Performance; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Agonists; Tyrosine 3-Monooxygenase

Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6-hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of γ-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity-regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa.

Topics: Adrenergic Agents; Animals; Antiparkinson Agents; Apomorphine; Disease Models, Animal; Dopamine; Dopamine Agonists; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gene Expression Regulation; Indoles; Levodopa; Male; MAP Kinase Signaling System; Motor Activity; Neurokinin-1 Receptor Antagonists; Oxidopamine; Parkinson Disease; Piperidines; Rats; Rats, Sprague-Dawley; Substantia Nigra; Time Factors

Parkinson's disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. Neuroinflammation has been implicated in its pathogenesis. To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects. Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. The results expand the current understanding of the role that this signalling system has and its potential influence in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Arachidonic Acids; Benzodioxoles; Brain; Cell Death; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Furans; Gait Disorders, Neurologic; Glycerides; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Neurotoxins; Parkinson Disease; Piperidines; Time Factors; Tyrosine 3-Monooxygenase

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6‑tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1β, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Alkaloids; Animals; Anti-Inflammatory Agents; Apoptosis; Benzodioxoles; Disease Models, Animal; Dopaminergic Neurons; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rotarod Performance Test; Substantia Nigra; Tyrosine 3-Monooxygenase

Topics: Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Although cholinesterase inhibitors have been frequently used in the treatment of Alzheimer disease, its effects on serum cholinesterase concentrations have been rarely described. We described significant depression of serum cholinesterase levels due to cholinesterase inhibitor toxicity from redundant use of donepezil and rivastigmine in a 78-year-old man. Recovery of serum cholinesterase level was noted upon drug discontinuation and cholinergic symptom resolution. Serum cholinesterase level can be used as a biomarker for central cholinesterase inhibitor toxicity.

Topics: Aged; Bradycardia; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Humans; Indans; Lewy Body Disease; Male; Miosis; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine

The benefits of escalating the dose of donepezil in patients who are already receiving long-term treatment with it have not been well evaluated. Therefore, an exploratory study to assess the effects of donepezil dose escalation in patients with Parkinson's disease with dementia, and specifically on patients receiving long-term treatment with donepezil, was performed.. Patients treated with 5-mg/day donepezil for at least 3 months and having a Mini-Mental State Examination (MMSE) score between 10 and 26 were included in this study. Donepezil dosage was then increased to 10 mg/day for 12 weeks. The outcome measures were a modified form of the Neuropsychiatric Inventory (NPI) with an extra domain for additional evaluation of fluctuation in cognitive functions (NPI-11) and the MMSE.. Of the nine patients enrolled, two withdrew because of nausea and inability to be assessed on the predetermined date; this left seven participants (four men and three women) with a mean age of 74.6 ± 6.9 years, a mean period of Parkinson's disease of 11.7 ± 7.5 years, and median donepezil use of 7 months (range: 3-56 months). At baseline, the mean total NPI-11 and mean MMSE scores were 18.3 ± 5.6 points and 21.3 ± 5.3 points, respectively. At week 12, they improved by 8.3 points (P < 0.01) and 3.0 points (P = 0.08), respectively, from the baseline. The NPI symptom domains that improved by 1 or more points were hallucination (1.3 points), depression (1.0 points), anxiety (1.6 points), and aberrant motor behaviour (1.7 points). None of the patients withdrew because of worsening of parkinsonism.. The present results suggest that treatment with dose escalation of donepezil from 5 mg/day to 10 mg/day may be therapeutically useful for patients with Parkinson's disease with dementia who have taken donepezil 5 mg/day in the long term.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition; Dementia; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Long-Term Care; Male; Middle Aged; Parkinson Disease; Piperidines; Prospective Studies; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.

Topics: Adenosine A2 Receptor Antagonists; Animals; Cannabinoid Receptor Antagonists; Disease Models, Animal; Male; Neuroprotective Agents; Parkinson Disease; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Xanthines

To study the protective effect of puerarin on MPP(+) -induced SH-SY5Y cells by chaperone-mediated autophagy (CMA).. The Parkinson's disease cell model was established by injuring SH-SY5Y cells with 1 mmol x L(-1) MPP+. The CCK-8 staining was adopted to detect the effect the puerarin of different concentrations on the survival rate of MPP(+)-induced SH-SYSY cells. The autophagosome formation was observed under transmission electron microscope. The AO staining showed the changes in the lysosome activity. RT-PCR was used to detect the changes in Lamp2a and Hsc70 mRNA expressions. The western blotting was adopted to test the expressions of Lamp2a, Hsc70 and alpha-synuclein protein in cells.. Within the concentration range of 12. 5-50.0 micromol x L(-1), the pretreatment with puerain for 30 minutes could protect the injury of MPP+ in SH-SY5Y cells, and showed a certain dose-effect relationship. The AO staining and electron microscope showed the effect of puerain within the concentration range of 12.5-50.0 micromol x L(-1) on 1 mmol x L(-1) MPP(+)-induced SH-SY5Y cells; autophagosomes emerged in cells, and increased along with the rise in the puerarin dose. The results of the flow cytometry revealed that 50.0 micromol x L(-1) of puerarin could protect against the increase of the ROS level in 1 mmol x L(-1) MPP(+) -induced SH-SY5Y cells and prevent the oxidative injury. The results of RT-PCR and western blotting indicated that puerain within the concentration range of 12.5-50.0 micromol x L(-1) alleviated the MPP(+)-induced SH-SY5Y cell injury, and inhibited the accumulation of alpha-synuclein proteins in MPP(+) -induced SH-SY5Y cells by up-regulating Hsc70, Lamp2a mRNA and protein level.. Puerarin could protect against the MPP(+) -induced cell injury, whose protective mechanism may be related to the chaperone-mediated autophagy pathway of interventional molecules.

Topics: Autophagy; HSC70 Heat-Shock Proteins; Humans; Isoflavones; Lysosomal-Associated Membrane Protein 2; Molecular Chaperones; Parkinson Disease; Phagosomes; Piperidines; Pyrazoles; Tumor Cells, Cultured; Up-Regulation

Parkinson's disease is a frequent neurodegenerative disease, which typically occurs in older age. With progression of the disease, therapeutic complications, such as dyskinesias and fluctuations in the response to medication are common. To embed the medication of Parkinson's disease into a complex treatment plan of a patient suffering from multimorbidity can be challenging.. Not only the cardinal motor symptoms have to be treated properly but also the non-motor symptoms e.g. depression, dementia, autonomic dysregulations and gastrointestinal disorders. Pharmacological treatment and their risks are presented.. Especially in older patients the symptoms need to be treated with regard to multimorbidity and the risks of polypharmacotherapy. The therapeutic strategy needs to be carefully planned in order to achieve a high quality of life and social interaction.

Topics: Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Cholinergic Antagonists; Dopamine Agonists; Female; Humans; Levodopa; Male; Monoamine Oxidase Inhibitors; Parkinson Disease; Piperidines

There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.. To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.. Cross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.. There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (-0.98 ± 1.01) compared to the non-diabetics (-0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).. Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.

Topics: Aged; Butyrates; Carbon Isotopes; Cognition Disorders; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Piperidines; Positron-Emission Tomography; Severity of Illness Index; Tetrabenazine

Topics: Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

In the present study, we examined the molecular mechanism by which Piperine (bioactive compound of Piper nigrum) inhibits neuronal cell apoptosis. We further investigated the anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's disease. Consistent with its antioxidant properties, Piperine (10 mg/kg bwt) reduced 6-OHDA-induced lipid peroxidation and stimulated glutathione levels in striatum of rats. Furthermore, Piperine treatment diminished cytochrome-c release from mitochondria and reduced caspase-3 and caspase-9 activation induced by 6-OHDA. Treatment with Piperine markedly inhibited poly(ADP-ribose) polymerase activation, pro-apoptotic Bax levels and elevation of Bcl-2 levels. Piperine reduces contralateral rotations induced by apomorphine. Further narrow beam test and rotarod also showed improvement in motor coordination and balance behavior in rats treated with Piperine. In addition Piperine depletes inflammatory markers, TNF-α and IL-1β in 6-OHDA-induced Parkinson's rats. We propose that, in addition to its antioxidant properties Piperine exerts a protective effect via anti-apoptotic and anti-inflammatory mechanism on 6-OHDA induced Parkinson's disease.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Apomorphine; Apoptosis; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Male; Oxidative Stress; Oxidopamine; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Topics: Aged; Cholinesterase Inhibitors; Dementia; Donepezil; Dyskinesia, Drug-Induced; Female; Humans; Indans; Neck Muscles; Parkinson Disease; Piperidines; Posture

The contribution of non-dopaminergic degeneration to disability in Parkinson's disease (PD) is still debated. It has been argued that no additional advance can be expected in the management of PD by the development of new dopaminergic agents and suggested that future research should mainly focus on therapies targeting the non-dopaminergic systems involved in the pathogenesis of levodopa resistant motor and non-motor symptoms. We believe this is only partially true and the achievement of a stable dopaminergic restoration and modulation of the dopaminergic system is still an important, unmet need of current pharmacological therapies in PD. Currently available oral levodopa and dopamine agonist medications provide insufficient benefit, as the therapeutic window progressively narrows and motor fluctuations eventually develop in most patients. Conversely, the application of infusion and surgical therapies is limited by selective indications and possible irreversible adverse events and device-related problems. Research of new, safer and less invasive strategies, able to modulate the dopaminergic circuits, would certainly improve the management of motor complications, and most importantly such treatments would be also beneficial to axial and non-motor symptoms, which are universally regarded as the major cause of PD functional disability. Indeed, gait and balance problems may improve with dopaminergic treatment in most patients and they become unresponsive only at the very late stages of the disease. Moreover, several non-motor disturbances, including cognition and depression are often linked to oscillation of dopamine concentrations, and are frequently relieved by treatments providing continuous dopaminergic delivery. Finally, drug trials testing non-dopaminergic treatments for motor and non-motor symptoms of PD provided so far disappointing results. Despite the impressive advances of PD therapeutic strategy, we think there is still need for safe, non-invasive and easily manageable dopaminergic treatments able to provide constant dopamine receptor stimulation and ensure a more stable control of dopamine responsive motor and non-motor symptoms at any stage of the disease.

Topics: Antiparkinson Agents; Droxidopa; Humans; Parkinson Disease; Piperidines; Urea

Although levodopa and dopaminergic drugs remain the mainstay of therapy for the motor symptoms of Parkinson disease (PD), they fail to address many of the non-motor symptoms of PD including orthostatic hypotension, freezing of gait (FOG) and difficulty with balance, drug-induced paranoia and hallucinations, and drug-induced dyskinesias. Droxidopa, a drug that increases norepinephrine, treats orthostatic hypotension, cholinomimetic drugs sometimes help with FOG and difficulty with balance, pimavanserin, a drug that blocks serotonin receptors, treats paranoia and hallucinations, and anti-glutaminergic drugs treat dyskinesias. Thus, there are ample opportunities for non-dopaminergic drugs in PD.

Topics: Antiparkinson Agents; Droxidopa; Humans; Parkinson Disease; Piperidines; Treatment Outcome; Urea

The purpose of this study was to evaluate changes in subthalamic nucleus (STN) neuronal activity in Parkinson's disease (PD) patients during deep brain stimulation (DBS) surgery under general anesthesia, and to compare these data with those recorded in the same subjects during previous surgery under local anesthesia.. Five patients with advanced PD, who had previously undergone bilateral STN-DBS under local anesthesia, underwent re-implantation under general anesthesia (with an anesthetic protocol based on the intravenous infusion of remifentanyl and ketamine) owing to surgical device complications. The microelectrode recording (MER) data obtained were analyzed by an off-line spike-sorting software. Neurophysiological data (number of spikes detected, mean firing rate, pause index and burst index) obtained under local and general anesthesia were then evaluated and compared by means of statistical analysis.. We found no statistically significant difference between the first and second surgical procedures in any of the neurophysiological parameters analyzed.. Bilateral STN-DBS for advanced PD with MER guidance is possible and reliable under a ketamine-based anesthetic protocol.. General anesthesia can be proposed for those patients who do not accept an "awake surgery" for clinical reasons, such as excessive fear, poor cooperation or severe "off"-medication effects.

Topics: Aged; Anesthesia, General; Anesthesia, Local; Deep Brain Stimulation; Female; Humans; Ketamine; Male; Microelectrodes; Middle Aged; Parkinson Disease; Piperidines; Remifentanil; Subthalamic Nucleus; Treatment Outcome; Unconsciousness; Wakefulness

Although donepezil, an acetylcholinesterase inhibitor, has been proved to be effective in ameliorating cognitive impairment in Parkinson's disease with dementia (PDD), the responsiveness of patients to donepezil therapy varies. [5-(11)C-methoxy]donepezil, the radiolabeled form of donepezil, is a ligand for positron emission tomography (PET), which can be exploited for the quantitative analysis of donepezil binding to acetylcholinesterase and for cholinergic imaging.. To investigate the deficits of the cholinergic system in the brain in PDD and its association with response to donepezil therapy.. Twelve patients with PDD and 13 normal control subjects underwent [5-(11)C-methoxy]donepezil-PET imaging. For patients with PDD, daily administration of donepezil was started after [5-(11)C-methoxy]donepezil-PET imaging and continued for 3 months.. In the PDD group, the mean total distribution volume of the cerebral cortices was 22.7% lower than that of the normal control group. The mean total distribution volume of the patients with PDD was significantly correlated with improvement of visuoperceptual function after 3 months of donepezil therapy.. The results suggest that donepezil therapy is more effective in patients with less decrease in acetylcholinesterase, a binding site of donepezil, at least in the specific cognitive domain.

Topics: Aged; Antiparasitic Agents; Brain Mapping; Case-Control Studies; Cholinergic Agents; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Piperidines; Positron-Emission Tomography

A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498 nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8 μM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity.

Topics: Alkaloids; Animals; Benzodioxoles; Binding Sites; Blood-Brain Barrier; Cattle; Humans; Hydrogen Bonding; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Structure, Tertiary; Serum Albumin, Bovine

In the present study, effect of SR 57227A, a selective 5-hydroxytryptamine-3 (5-HT(3)) receptor agonist, on the firing activity of pyramidal neurons in the medial prefrontal cortex (mPFC) was studied in normal rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Systemic administration of SR 57227A (40-640 μg/kg, i.v.) decreased the mean firing rate of pyramidal neurons in normal and the lesioned rats. This inhibition was significant only at doses higher than 320 μg/kg and 640 μg/kg in normal and the lesioned rats, respectively, and was reversed by i.v. administration of 5-HT(3) receptor antagonist tropisetron or GABA(A) receptor antagonist bicuculline. Furthermore, local application of SR 57227A (0.01 μg) in the mPFC inhibited the firing rate of pyramidal neurons in normal rats while having no effect on firing rate in the lesioned rats. The i.v. administration of bicuculline excited the pyramidal neurons in normal rats, and then local application of SR 57227A did not alter the mean firing rate of these neurons. However, these two drugs did not affect the activity of the pyramidal neurons in the lesioned rats. We conclude that activation of 5-HT(3) receptors inhibited pyramidal neurons in the mPFC of normal rats via GABAergic interneurons, and degeneration of the nigrostriatal pathway decreased response of the pyramidal neurons to SR 57227A, suggesting the dysfunction of 5-HT(3) receptors and/or down-regulation of the expression on GABAergic interneurons in the lesioned rats.

Topics: Action Potentials; Analysis of Variance; Animals; Bicuculline; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; GABA-A Receptor Antagonists; Indoles; Male; Oxidopamine; Parkinson Disease; Piperidines; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin Agents; Statistics, Nonparametric; Substantia Nigra; Tropisetron; Tyrosine 3-Monooxygenase

Topics: Aged; Brain; Cholinesterase Inhibitors; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Early Diagnosis; Evidence-Based Medicine; Humans; Indans; Lewy Body Disease; Mental Disorders; Neuropsychological Tests; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dyskinesias; Fenfluramine; Fluorobenzenes; Hyperkinesis; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Psychotic Disorders; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sensory Gating; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Serotonin Receptor Agonists; Substantia Nigra; Tyrosine 3-Monooxygenase; Urea

Topics: Brain; Cholinesterases; Depth Perception; Donepezil; Humans; Indans; Nootropic Agents; Parkinson Disease; Piperidines; Proto-Oncogene Proteins c-bcl-2; Up-Regulation

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.

Topics: Administration, Oral; Animals; Benzopyrans; Biological Availability; Catalepsy; Cyclopentanes; Dogs; Drug Discovery; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Excitatory Amino Acid Antagonists; Female; Half-Life; Indicators and Reagents; Isomerism; Ligation; Macaca mulatta; Male; Neuralgia; Oxadiazoles; Parkinson Disease; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Nerves

The term neurological diseases includes a lot of disorders concerning both the central and peripheral nervous system. Low incidence on the one hand and anaesthetic relevance on the other hand requires special attention in preoperative preparing and management of general anaesthesia. The following paper presents special problems of neurodegenerative disorders, which anaesthetic relevance is of growing interest in the changed elderly population.

Topics: Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Autonomic Nervous System; Brain; Bromocriptine; Dopamine Agonists; Humans; Intubation; Levodopa; Monoamine Oxidase Inhibitors; Muscle Relaxants, Central; Nervous System Diseases; Neurodegenerative Diseases; Neurosurgery; Parkinson Disease; Piperidines; Premedication; Preoperative Care; Propofol; Remifentanil; Selegiline; Stereotaxic Techniques; Syndrome

In the present study, we examined changes in the firing rate and firing pattern of putative slow-spiking (SS) and fast-spiking (FS) interneurons in medial prefrontal cortex (mPFC) and the effect of 5-hydroxytryptamine-3 (5-HT(3)) receptor agonist SR 57227A on the neuronal firing in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) by using extracellular recording. The lesion of the SNc in rats decreased the firing rate of FS interneurons and the firing pattern of both SS and FS interneurons changed towards a more burst-firing. Systemic administration of SR 57227A (40-640 microg/kg, i.v.) increased the firing rate of SS interneurons, and decreased FS interneurons in sham-operated and the lesioned rats, respectively. The doses producing excitation or inhibition in the lesioned rats were higher than sham-operated rats. The local application of SR 57227A (0.01 microg) in mPFC excited SS interneurons, and inhibited FS interneurons in sham-operated rats, while having no effects on firing rate in the lesioned rats. Systemic administration of GABA(A) receptor antagonist bicuculline (2 mg/kg, i.v.) excited FS interneurons in sham-operated rats, whereas bicuculline did not change the activity of FS interneurons in the lesioned rats. Our findings indicate that the putative SS and FS interneurons activity is modulated through activation of 5-HT(3) receptor by direct or indirect action, and the lesion of the SNc leads to changes in firing activity of the SS and FS interneurons and decreased response of these interneurons to SR 57227A, suggesting dysfunction and/or down-regulation of 5-HT(3) receptor on interneurons in the 6-hydroxydopamine-lesioned rats.

Topics: Action Potentials; Animals; Cell Count; Dopamine; Interneurons; Male; Oxidopamine; Parkinson Disease; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Agonists; Substantia Nigra; Ventral Tegmental Area

Topics: Accidental Falls; Cholinesterase Inhibitors; Decision Making; Donepezil; Dopamine; Humans; Indans; Parkinson Disease; Piperidines

Acute injections of 8mg/kg of 3,4-dihydroxy-l-phenylalanine (l-DOPA) or 0.05mg/kg rimonabant equally improved contralateral forepaw stepping in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, and their combination improved stepping more than either drug alone. However, 0.05mg/kg rimonabant did not alter the changes in stepping produced by acute injections of a dyskinesic dose of 35mg/kg l-DOPA. Thus, not only is a cannabinoid antagonist monotherapeutic in this animal model of Parkinson's disease, but it also enhances the therapeutic effect of a moderate, but not a high, dose of l-DOPA.

Topics: Animals; Corpus Striatum; Disease Models, Animal; Hypokinesia; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Rimonabant

Animal models, consistent with the hypothesis of direct interaction of paraquat (PQ) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with specific areas of the central nervous system have been developed to study Parkinson's disease (PD) in mice. These models have necessitated the creation of an analytical method for unambiguous identification and quantitation of PQ and structurally similar MPTP and 1-methyl-4-phenylpyridinium ion (MPP+) in brain tissue. A method for determination of these compounds was developed using microwave-assisted solvent extraction (MASE) and liquid chromatography-mass spectrometry. Extraction solvent and microwave conditions such as power and time were optimized to produce recoveries of 90% for PQ 78% for MPTP and 97% for its metabolite MPP+. The chromatographic separation was performed on a C8, column and detection was carried out using an ion trap as an analyzer with electrospray ionization. Mass spectrometer parameters such as heated capillary temperature, spray voltage, capillary voltage and others were also optimized for each analyte. Analysis was done in selective ion-monitoring (SIM) mode using m/z 186 for PQ, m/z 174 for MPTP, and m/z 170 for MPP+. The method detection limit for paraquat in matrix was 100 pg, 40 pg for MPTP, and 20 pg MPP+.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Agents; Estrogen Receptor alpha; Herbicides; Mice; Microwaves; Paraquat; Parkinson Disease; Piperidines; Pyrazoles; Solvents; Tandem Mass Spectrometry

The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 microM MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12-24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death.

Topics: Adenosine Triphosphate; Animals; Biological Transport; Cell Death; Cell Line; Cyclin-Dependent Kinase 5; Down-Regulation; Electron Transport; Electron Transport Complex I; Gene Expression Regulation, Enzymologic; Humans; Mice; Mice, Inbred ICR; Mitochondria; Models, Biological; Nerve Tissue Proteins; Neurons; Parkinson Disease; Piperidines; Proteasome Endopeptidase Complex; Rats; Time Factors

It has been reported that the cholinesterase inhibitor, donepezil, improves cognitive decline in patients with Parkinson's disease dementia (PDD). However, this improvement was dominant for frontal lobe dysfunction, and the increase in the Mini-Mental State Examination (MMSE) score was minimal. We report a PDD patient with a decline of regional cerebral blood flow (rCBF) in the posterior cingulate cortex, precunei, and bilateral parietotemporal association cortex, as determined by single-photon emission computed tomography (SPECT) using the easy Z-scores imaging system (e-ZIS). Upon administration of donepezil, both the rCBF and MMSE score increased. The effectiveness of donepezil may vary based on the rCBF pattern in PDD.

Topics: Aged; Cerebrovascular Circulation; Dementia; Donepezil; Gyrus Cinguli; Humans; Indans; Male; Mental Status Schedule; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Piperidines; Regional Blood Flow; Treatment Outcome

We previously demonstrated that NMDA receptors containing the NR2A or NR2B subunits differentially regulate striatal output pathways. We now investigate whether such a differential control is altered under parkinsonian conditions and whether subunit selective antagonists have different abilities to attenuate parkinsonian-like motor deficits. Three microdialysis probes were simultaneously implanted in the dopamine-depleted striatum, globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats. The NR2A antagonist NVP-AAM077 perfused in the striatum reduced pallidal GABA, but not glutamate, levels whereas the NR2B antagonist Ro 25-6981 was ineffective. Neither antagonist affected striatal or nigral amino acid levels. To investigate whether these neurochemical responses were predictive of different antiparkinsonian activities, antagonists were administered systemically and motor activity evaluated in different motor tasks. Neither antagonist attenuated akinesia/bradykinesia in the bar and drag test. However, NVP-AAM077 dually modulated rotarod performance (low doses being facilitatory and higher ones inhibitory) while Ro 25-6981 monotonically improved it. Microdialysis revealed that motor facilitating doses reduced pallidal GABA levels while motor inhibiting doses increased them. We conclude that, under parkinsonian conditions, the striato-pallidal pathway is driven by striatal NR2A subunits. Motor improvement induced by NVP-AAM077 and Ro 25-6981 is accomplished by blockade of striatal NR2A and extrastriatal NR2B subunits, respectively.

Topics: Adrenergic Agents; Animals; Behavior, Animal; Corpus Striatum; Disease Models, Animal; Excitatory Amino Acid Antagonists; Globus Pallidus; Male; Microdialysis; Motor Activity; Neurons; Oxidopamine; Parkinson Disease; Phenols; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.

Topics: Animals; Benzamides; Benzoxazines; Cannabinoid Receptor Modulators; Carbamates; Disease Models, Animal; Dopamine; Dopamine D2 Receptor Antagonists; Endocannabinoids; Excitatory Postsynaptic Potentials; In Vitro Techniques; Long-Term Synaptic Depression; Mice; Mice, Transgenic; Morpholines; Naphthalenes; Neostriatum; Neuronal Plasticity; Oxidopamine; Parkinson Disease; Piperidines; Psychomotor Performance; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Reserpine; Synapses

(1) Three cholinesterase inhibitors are marketed in France for the treatment of Alzheimer's disease: donepezil, galantamine and rivastigmine. Tremor and dystonia are known adverse effects of cholinesterase inhibitors. (2) In patients with Parkinson's disease who have cognitive disorders, or in patients with Lewy body dementia, exacerbations of parkinsonism and tremor have been observed during treatment with cholinesterase inhibitors at normal doses. The disorders were reversible on withdrawal of the cholinesterase inhibitor. (3) Withdrawal of cholinesterase inhibitors should be considered if gait disorders, falls or parkinsonism occur or worsen during treatment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Dystonia; France; Galantamine; Humans; Indans; Lewy Body Disease; Parkinson Disease; Phenylcarbamates; Piperidines; Tremor

Recent evidence suggest that the blockade of cannabinoid CB1 receptors might be beneficial to alleviate motor inhibition typical of Parkinson's disease (PD). In the present study, we have explored the motor effects of rimonabant, a selective antagonist of CB1 receptors, in a rat model of PD generated by an intracerebroventricular injection of 6-hydroxydopamine. Compared with rats subjected to unilateral injection of this toxin in the medial forebrain bundle, this model allows nigral dopaminergic neurons be symmetrically affected. Dose-response studies with 6-hydroxydopamine revealed that the application of 200 microg per animal caused hypokinetic signs (decreased ambulatory activity, increased inactivity, and reduced motor coordination), which paralleled several signs of degeneration of nigrostriatal dopaminergic neurons (dopamine depletion in the caudate-putamen, and decreased mRNA levels for tyrosine hydroxylase and superoxide dismutase-1 and -2 in the substantia nigra). In these conditions, the degree of hypokinesia and dopaminergic degeneration may be considered moderate, comparable to the disturbances occurring in early and middle stages of PD in humans, a period that might be appropriate to test the effects of rimonabant. There is also degeneration of other dopaminergic pathways out of the basal ganglia, but this does not appear to interfere significantly with the hypokinetic profile of these rats. Higher doses of 6-hydroxydopamine elevated significantly animal mortality and lower doses failed in general to reproduce motor inhibition. Like other animal models of PD, these rats exhibited an increase in the density of CB(1) receptors in the substantia nigra, which is indicative of the expected overactivity of the cannabinoid transmission in this disease and supports the potential of CB1 receptor blockade to attenuate hypokinesia associated with nigral cell death. Thus, the injection of 0.1 mg/kg of rimonabant partially attenuated the hypokinesia shown by these animals with no effects in control rats, whereas higher doses (0.5-1.0 mg/kg) were not effective. We also found that the antihypokinetic effects of low doses of rimonabant did not influence the dopamine deficits of these animals, as well as it did not modify GABA or glutamate transmission in the caudate-putamen. In summary, rimonabant may have potential antihypokinetic activity in moderate parkinsonism at low doses, but this effect is not related to changes in dopaminergic, GABAergic, or glutama

Topics: Adrenergic Agents; Analysis of Variance; Animals; Autoradiography; Brain; Brain Chemistry; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Electrochemistry; gamma-Aminobutyric Acid; Gene Expression; Glutamic Acid; In Situ Hybridization; Injections, Intraventricular; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Protein Binding; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Rotarod Performance Test; Superoxide Dismutase; Superoxide Dismutase-1; Tyrosine 3-Monooxygenase

Topics: Aged; Analgesics, Opioid; Anesthesia; Anesthesia, General; Anesthetics, Intravenous; Coma; Deep Brain Stimulation; Humans; Male; Parkinson Disease; Piperidines; Propofol; Remifentanil

Topics: Cholinesterase Inhibitors; Comorbidity; Cross-Over Studies; Cross-Sectional Studies; Dementia; Donepezil; Double-Blind Method; Humans; Indans; Mental Status Schedule; Neuropsychological Tests; Outcome Assessment, Health Care; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) overlap in phenomenology and neurochemical deficits. We hypothesised they would not differ in their response to the cholinesterase inhibitor donepezil.. We recruited 70 subjects, 30 DLB and 40 PDD, in an open label study to compare the efficacy of donepezil in these two patient groups. They were assessed at baseline, 4, 12 and 20 weeks. The main outcome measures were the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and motor sub-section of the Unified Parkinson's Disease Rating Scale (UPDRS III).. PDD patients were younger than DLB and had more severe parkinsonism at baseline. The groups were similar on all other variables of interest. By 20 weeks the mean MMSE score increased by 3.9 points in the DLB group and by 3.2 points in PDD. The mean NPI score reduced by 14.6 points for DLB and 12.0 points for PDD. These treatment effects were all significant compared to baseline (p < 0.001) but there were no significant between-group treatment differences (MMSE p = 0.56, NPI p = 0.39). UPDRS III motor scores did not change significantly from baseline values in either group. Although adverse effects were common (69%) they were usually mild and 64 patients (91%) completed the study. The four patients who did withdraw with adverse effects all had a PDD diagnosis.. Donepezil produced similar improvements in cognition and behaviour in DLB and PDD. This supports the hypothesis that the two disorders are closely related clinically and neurobiologically. Larger scale, placebo controlled clinical trials are needed to provide an evidence base to guide the clinical use of cholinesterase inhibitors in Lewy body disease.

Topics: Age Factors; Aged; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Piperidines; Severity of Illness Index; Treatment Outcome

Alterations of striatal glutamate receptors are believed to be responsible, at least in part, for the pathogenesis of L-dopa-induced dyskinesias (LID). To evaluate whether co-administration of CI-1041, a novel NMDA receptor antagonist selective for the NR1A/NR2B subtype, with L-dopa might prevent the appearance of this side effect, eight de novo parkinsonian monkeys were treated chronically orally with either L-dopa alone or L-dopa plus CI-1041 (n= 4 for each group). After 4 weeks of treatment with L-dopa alone, all four animals developed moderate dyskinesias either choreic or dystonic in nature. CI-1041 co-treatment completely prevented the induction of dyskinesias in three animals and only one monkey developed mild dyskinesias at the end of the fourth week of treatment in the L-dopa + CI-1041 group. The magnitude and duration of the antiparkinsonian action of L-dopa was similar in both groups. These results suggest that selective NMDA receptor antagonism may be interesting for managing LID in Parkinson's disease patients.

Topics: Animals; Benzoxazoles; Corpus Striatum; Disease Models, Animal; Drug Interactions; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Levodopa; Macaca fascicularis; Parkinson Disease; Piperidines; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

The case presented highlights the difficult differential diagnosis of dementia with parkinsonism. Many disorders affecting the frontal-subcortical circuits produce the triad of impaired cognition, movement disorder, and neuropsychiatric symptoms. The 72-year-old patient whose case is reviewed here had abnormalities in all three domains.

Topics: Aged; Brain; Dementia; Diagnosis, Differential; Donepezil; Fatal Outcome; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Humans; Neurosurgical Procedures; Parkinson Disease; Piperidines; Remifentanil

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLUA1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLUA1, GLUA2, GLUA3, or GLUA4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amides; Animals; Biphenyl Compounds; Cells, Cultured; Corpus Striatum; Dioxoles; Disease Models, Animal; Excitatory Amino Acid Agonists; GAP-43 Protein; Hippocampus; Humans; Male; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Substantia Nigra

Visual hallucinations (VHs) are common psychiatric symptoms in patients with long-standing Parkinson's disease (PD). Treatment with neuroleptics or withdrawal of anti-PD drugs may improve VHs but will worsen motor dysfunctions. The authors report on 3 patients with long-standing PD who were treated with the cholinesterase inhibitor donepezil for the treatment of VHs. Each received a daily dose of 5 mg of donepezil, after reducing or discontinuing anti-PD medications had failed to relieve the VHs. In 2 patients (patient 1, 2), donepezil decreased VHs without worsening motor dysfunctions. In addition, the cognitive status of patient 2 improved. In patient 3, donepezil also resolved VHs, but delusions developed during treatment. After discontinuing donepezil, delusions disappeared and VHs reappeared. Donepezil may ameliorate visual hallucinations in PD patients, but controlled, double-blind trials are necessary to further clarify the effect of this drug on VHs in PD.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Hallucinations; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychomotor Disorders; Severity of Illness Index

A patient with Parkinson's disease refused both anti-Parkinson medication and general anaesthesia. Low dose remifentanil infusion suppressed her otherwise severe tremor, and the operation was performed uneventfully under local anaesthesia.

Topics: Aged; Anesthesia, Local; Anesthetics, Intravenous; Cataract Extraction; Female; Humans; Infusions, Intravenous; Parkinson Disease; Piperidines; Remifentanil; Tremor

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Delta 9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Behavior, Animal; Benzazepines; Benzoxazines; Brain Chemistry; Cannabinoid Receptor Modulators; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Antagonists; Drug Interactions; Dyskinesia, Drug-Induced; Dyskinesias; Endocannabinoids; Gas Chromatography-Mass Spectrometry; Levodopa; Male; Morpholines; Mouth; Naphthalenes; Oxidopamine; Parkinson Disease; Piperidines; Pyrazoles; Raclopride; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Substantia Nigra; Time Factors

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenoviridae; Animals; Blotting, Western; Chromatography, High Pressure Liquid; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Disease Models, Animal; Dopamine; Dopamine Agents; Flavonoids; Genes, Dominant; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neurons; Parkinson Disease; Piperidines; Time Factors

Pentifin and dopamine D1 receptor antagonist SCH-23390 possess similar pharmacological properties. In the present work we studied in vitro effects of Pentifin on dopamine receptors. Experiments on rat ductus deferents showed that Pentifin acts as a weak ligand of dopamine receptors. Our results indicate that the antihaloperidol effect of Pentifin is not related to the blockade of dopamine receptors.

Topics: Amino Alcohols; Animals; Brain; Cyclopentanes; Dopamine Antagonists; In Vitro Techniques; Intestine, Small; Male; Neurotransmitter Agents; Parkinson Disease; Piperidines; Rats; Receptors, Dopamine; Seminal Vesicles; Vas Deferens

Treatments for Parkinson's disease based on replacement of lost dopamine have several problems. Following loss of dopamine, enhanced N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the striatum is thought to be part of the cascade of events leading to the generation of parkinsonian symptoms. We determined the localisation and pharmacological characteristics of NMDA receptors that play a role in generating parkinsonian symptoms within the striatum. Rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and cannulae implanted bilaterally to allow injection of a range of NMDA receptor antagonists at different striatal sites. When injected rostrally into the dopamine-depleted striatum, the glycine site partial agonist, (+)-HA-966 (44-400 nmol) caused a dose-dependent contraversive rotational response consistent with an antiparkinsonian action. (+)-HA-966 (400 nmol) had no effect when infused into more caudal regions of the dopamine-depleted striatum, or following injection into any striatal region on the dopamine-intact side. To determine the pharmacological profile of NMDA receptors involved in inducing parkinsonism in 6-OHDA-lesioned rats, a range of NMDA receptor antagonists was infused directly into the rostral striatum. Ifenprodil (100 nmol) and 7-chlorokynurenate (37 nmol), but not MK-801 (15 nmol) or D-APV (25 nmol) elicited a dramatic rotational response when injected into the dopamine-depleted striatum. This pharmacological profile is not consistent with an effect mediated via blocking NR2B-containing NMDA receptors. The effect of intrastriatal injection of ifenprodil was increased in animals previously treated with levodopa (L-dopa) methyl ester. This was seen as an increase in on-time and in peak rotational response. We propose that stimulation of NR2B-containing NMDA receptors in the rostral striatum underlies the generation of parkinsonian symptoms. These studies are in line with previous findings suggesting that administration of NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients, when given de novo and following L-dopa treatment.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Levodopa; Male; Microinjections; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

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

Alzheimer's disease is the most common cause of dementia, but Parkinson's disease also shows dementia in the later stages. Donepezil is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. Variable responses to this drug suggest that Alzheimer's disease is clinically heterogeneous. In the clinical trial of tacrine, a first developed cholinesterase inhibitor, three cases markedly improved and, several years later, they were pathologically confirmed as dementia with Lewy bodies (DLB). In recent years, another cholinesterase inhibitor, rivastigmine, has also been reported to be effective for patients with DLB by a placebo-controlled, double-blind, multicenter study. Parkinson's disease with dementia, which is known to fulfill the pathological criteria of DLB, also shows a favorable response to donepezil. In some cases, not only does cognitive function improve, but also parkinsonism. Both DLB and Parkinson's disease with dementia show characteristic CBF patterns: While the parietal and temporal lobes are involved in Alzheimer's disease, the occipital lobe is additionally affected in these diseases. Alzheimer's disease and Parkinson's disease have been considered discrete disease entities. However, viewed from the aspects of response to donepezil treatment and CBF patterns, both diseases overlapped. A brain SPECT may be a useful tool to detect such treatable conditions.

Topics: Alzheimer Disease; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Parkinson Disease; Piperidines; Tomography, Emission-Computed, Single-Photon

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Comorbidity; Dementia; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Mental Status Schedule; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

In studies of dementia, crossover designs are controversial, reflecting concerns about temporal stability of disease, confounding of treatment effects with period by treatment interactions and/or carryover effects. Carryover effects are differences in the lingering effect of treatments (placebo) into subsequent periods. In the context of a trial to study the effect of donepezil on dementia in patients with Parkinson's disease, we examine two-sequence crossover studies with two or four periods, and a four-sequence design with two periods. We quantify bias in estimated treatment effects due to carryover effects and explore the use of biased estimators in hypothesis testing. For hypothesis testing, type I error rates are valid if (1) repeated administration of treatment alters the outcome only for effective treatments and (2) carryover effects due to placebo following treatment periods are nonzero only for effective treatments. For crossover and parallel group designs, sample sizes are adjusted for reduced statistical power due to carryover effects and temporal changes in variance. For the proposed clinical study, we estimate that a single-period parallel group design with baselines would require 104 patients and take about 23 months to complete. A two-sequence, four-period parallel group design with baselines would require about 80 patients and about 20 months to complete. We conservatively assume a carryover effect of 50% of the treatment effect for a two-sequence four-period crossover design. The estimated treatment effect for this model may underestimate the true treatment effect by up to 13%. The sample size/study length requirements are 28 patients or 12.4 months, respectively, a substantial saving over either parallel group design. The cost of allowing for carryover in the sample size calculation is about 1.2 months of study time.

Topics: Bias; Cognition; Cross-Over Studies; Dementia; Donepezil; Effect Modifier, Epidemiologic; Humans; Indans; Nootropic Agents; Parkinson Disease; Piperidines; Randomized Controlled Trials as Topic; Research Design; Sample Size

We present a 73-year-old man with probable dementia with Lewy bodies(DLB). At 65 years of age, he gradually developed bradykinesia, gait disturbance and mild amnesia. At 71 years of age, he noted resting tremor in bilateral hands, and amnesia and disorientation were exacerbated. He was diagnosed as having parkinsonism and took L-dopa/carbidopa at 100 mg/day. Since he developed hallucination and abnormal behavior 2 days after the initiation of the drug, he stopped taking L-dopa and was admitted to our hospital. A neurological examination on admission revealed moderate amnesia, disorientation, finger agnosia, constitutional apraxia, mask-like face, cogwheel rigidity, resting tremor in bilateral hands, and bradykinesia. Brain MRI showed mild brain atrophy, and single photon emission computerized tomography(SPECT) showed diffuse moderate hypoperfusion in bilateral cerebral cortex. As he had fluctuating cognitive dysfunction and parkinsonism, he was diagnosed to have probable DLB. As his dementia was exacerbated by trihexyphenidyl, an anti-cholinergic agent, at 2 mg/day, we treated him with donepezil, an anti-choline esterase agent, at 3-5 mg/day. His parkinsonism, including rigidity and bradykinesia, was markedly improved his dementia, consisting of amnesia and disorientation. Electroencephalography (EEG) improved in the organization of the dominant rhythm. The SPECT improved in the blood perfusion of the bilateral frontal lobe as well as cognitive function and parkinsonism were maintained by donepezil for 6 months after discharge. A therapeutic efficacy of donepezil for DLB has recently been reported. It is notable that donepezil was beneficial not only for cognitive dysfunction but also for parkinsonism in the present case with probable DLB.

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Humans; Indans; Lewy Body Disease; Male; Parkinson Disease; Piperidines

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia. In addition, treatment with (-)-OSU6162 for 5 consecutive days almost completely abolished the rotational behavior provoked by apomorphine and produced a transient subsensitization of such apomorphine-induced effects after it was discontinued. Moreover, pretreatment with (-)-OSU6162 in two monkeys augmented the rotational behavior elicited by the dopamine D1 receptor agonists, SKF-81297 (R(+)-6-chloro-7,8,dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ((-)-(1R, 3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran hydrochloride). The findings indicate that (-)-OSU6162 can exert indirect state-dependent effects that differentially affect dopamine D1 and dopamine D2 receptor agonist-induced behavior.

Topics: Adamantane; Animals; Apomorphine; Benzazepines; Benzopyrans; Callithrix; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Quinpirole; Rotation

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Callithrix; Dopamine Agents; Excitatory Amino Acid Antagonists; Levodopa; Motor Activity; Parkinson Disease; Parkinson Disease, Secondary; Piperidines

Topics: Aged; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Hallucinations; Humans; Indans; Parkinson Disease; Piperidines; Treatment Outcome

The atypical antipsychotic drug olanzapine has been proposed for treatment of dopaminergic psychosis in Parkinson's disease (PD). We report on a 68-year-old patient who developed a severe akinetic-rigid extrapyramidal syndrome, accompanied by additional paranoid symptoms, following olanzapine treatment of optic hallucinosis in PD. Olanzapine may also induce clinically relevant extrapyramidal side effects in PD patients.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Drug Therapy, Combination; Hallucinations; Humans; Levodopa; Male; Olanzapine; Paranoid Disorders; Parkinson Disease; Piperidines; Pirenzepine; Selegiline; Severity of Illness Index

Topics: Acetylcholine; Alzheimer Disease; Brain; Carbon Radioisotopes; Carrier Proteins; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Neuromuscular Depolarizing Agents; Neurons; Neuropeptides; Neurotransmitter Agents; Parkinson Disease; Piperidines; Tetrabenazine; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Transport Proteins

Topics: Antiparkinson Agents; Humans; Parkinson Disease; Piperidines

Topics: Aged; Antipsychotic Agents; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Therapy, Combination; Humans; Indans; Male; Parkinson Disease; Piperidines; Risperidone

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Disease Progression; Donepezil; Female; Humans; Indans; Parkinson Disease; Piperidines

To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease.. Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls.. The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST.. The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.

Topics: Aged; Benzilates; Brain; Brain Mapping; Carbon Radioisotopes; Cholinergic Fibers; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Parasympatholytics; Parkinson Disease; Piperidines; Receptors, Cholinergic; Receptors, Muscarinic; Supranuclear Palsy, Progressive; Tomography, Emission-Computed

Topics: Alzheimer Disease; Dementia; Diagnosis, Differential; Donepezil; Humans; Indans; Neurology; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatry; Societies, Medical

Topics: Aged; Aggression; Alzheimer Disease; Cholinesterase Inhibitors; Domestic Violence; Donepezil; Humans; Indans; Male; Paranoid Behavior; Parkinson Disease; Piperidines

In this study, we examined whether there is a long-term effect of cisapride on colonic transit in Parkinson's disease. Twenty-five patients (11 women, 14 men; average age, 64.4 years; moderate symptoms) were studied and treated initially with cisapride, 5 mg, twice a day, and after the first week with cisapride, 10 mg, twice a day. Colonic transit was measured by radioopaque markers at various stages: after 1 week, 6 months, and 1 year. In untreated patients, transit took 131 h; after 1 week with cisapride, it was accelerated to 81 h. After 6 months, colonic transit time amounted to 99 and 118 h, respectively, after 1 year. Cisapride seems to be highly effective initially. After 6 months, a significant but reduced effect was seen, and after 1 year, only a small effect could be demonstrated.

Topics: Aged; Cathartics; Cisapride; Constipation; Female; Humans; Male; Middle Aged; Parkinson Disease; Peristalsis; Piperidines; Severity of Illness Index; Treatment Outcome

Previous studies of radiolabelled vesamicol receptor (VR) ligands suggest that the latter may be used, in conjunction with dopamine D2 antagonists, to measure changes in striatal cholinergic function in vivo. In the present study, the radiolabelled VR ligand (+)-meta-[125I]iodobenzyltrozamicol {(+)-[125I]MIBT} was used to assess striatal cholinergic function in the unilateral 6-hydroxydopamine (6-OHDA)-treated rat. In control animals, the levels of this radiotracer monitored at 3 hr post injection displayed bilateral symmetry in the striatum, cerebral cortex and cerebellum. However, in animals pretreated with the dopamine antagonist spiperone (2 mg/kg ip), the radiotracer concentration in the striatal hemisphere ipsilateral to 6-OHDA lesion increased by 23% (p = 0.068) while the concentration in the contralateral striatum was elevated by 87% (p < 0.0001). Since the nigrostriatal dopaminergic system modulates striatal cholinergic function, and dopamine D2 receptor blockade is known to result in increased striatal cholinergic function, the refractoriness of striatal cholinergic neurons following the loss of nigrostriatal dopaminergic innervation confirms the existence of a dopaminergic-cholinergic imbalance in Parkinson's disease. Therefore the combination of a D2 antagonist and radiolabelled VR ligand may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson's disease.

Topics: Animals; Brain Diseases; Cholinergic Fibers; Corpus Striatum; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Iodine Radioisotopes; Iodobenzenes; Ligands; Male; Oxidopamine; Parkinson Disease; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Cholinergic; Spiperone

The non-competitive NMDA polyamine site antagonist, eliprodil, was examined for its effects on exploratory activity in non-habituated mice and for its antiakinetic potential in reserpine-treated mice. A low dose of eliprodil (5 mg/kg) weakly stimulated locomotion in naive animals, whilst higher doses depressed rearing (20-40 mg/kg) and grooming (40 mg/kg), consistent with a sedative action. At no dose did eliprodil cause ataxia. In 24 h reserpine-treated mice, eliprodil (10-40 mg/kg) reversed akinesia, but this effect was subject to considerable inter-animal variation and was not statistically significant. Eliprodil did not alter the motor recovery elicited by the dopamine D1 agonist SKF 38393, or the dopamine D2 agonist RU 24213, and suppressed the motor stimulation induced by L-DOPA. These results indicate that eliprodil displays a far lower propensity than many other NMDA receptor antagonists for disturbing posture and gait, but lacks the essential motor stimulant action required to make it a safe and effective antiparkinsonian agent, at least in the reserpine-treated mouse model of Parkinson's disease.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Biogenic Monoamines; Disease Models, Animal; Dopamine Agents; Dopamine Agonists; Dose-Response Relationship, Drug; Efferent Pathways; Excitatory Amino Acid Antagonists; Levodopa; Locomotion; Male; Mice; Mice, Inbred Strains; Motor Neurons; Parkinson Disease; Phenethylamines; Piperidines; Receptors, Dopamine D1; Reserpine; Sympatholytics

Topics: Antipsychotic Agents; Humans; Isoxazoles; Parkinson Disease; Piperidines; Risperidone

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Basal Ganglia Diseases; Dementia; Female; Humans; Isoxazoles; Lewy Bodies; Male; Middle Aged; Parkinson Disease; Piperidines; Risperidone

Cisapride (CIS) is a prokinetic agent that increases gastrointestinal motility in normal individuals and improves constipation in Parkinson's disease (PD). We studied the effects of CIS on the clinical response and the peripheral pharmacokinetics of orally administered L-dopa given to patients with PD. Twenty patients with idiopathic PD and chronic constipation, whose response to L-dopa was suboptimal or characterized by fluctuations, agreed to participate in an open study that lasted for 2 weeks. Fourteen patients completed the study (mean age 65 +/- 9.3 years, mean duration of treatment 5.7 +/- 4.2 years, mean L-dopa daily doses 658.9 +/- 269.9 mg); six patients were excluded due to lack of compliance or changes in medication during the study. The end points of the study included the mean levels of L-dopa, the height of the peak of L-dopa in plasma, mean plasma levels of 3-OM-dopa, and the speed and quality of gait and visuomanual coordination before and during treatment with CIS. CIS increased peak plasma levels of L-dopa by 37% and the mean plasma levels of L-dopa by 13% with respect to those obtained with the same dose of L-dopa before the addition of CIS. Therefore, CIS appears to increase early absorption of L-dopa through acceleration of gastric emptying. CIS also increased plasma 3-OM-dopa levels, improved visuomanual coordination, and reduced gait disability. CIS improves gastrointestinal function and response to L-dopa in patients with PD and could be a helpful add-on medication in these patients.

Topics: Aged; Cisapride; Female; Gait; Humans; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Piperidines; Psychomotor Performance

Topics: Aged; Antipsychotic Agents; Hallucinations; Humans; Isoxazoles; Levodopa; Parkinson Disease; Piperidines; Risperidone

Topics: Antipsychotic Agents; Humans; Isoxazoles; Parkinson Disease; Piperidines; Psychotic Disorders; Risperidone

Topics: Adrenergic alpha-Antagonists; Humans; Parkinson Disease; Piperidines; Receptors, N-Methyl-D-Aspartate

Constipation, a frequent symptom in Parkinson's disease (PD), is probably caused by degeneration of the autonomic nervous system, particularly the myenteric plexus. Cisapride is a drug that causes increased release of acetylcholine in the myenteric plexus. In a pilot study, cisapride therapy was investigated in 20 PD patients, 10 women and 10 men, who suffered from delayed intestinal transit. In all cases, cisapride therapy was associated with a significant acceleration of colonic transit, as measured by radioopaque pellets viewed on radiographs. Pellet count fell from a mean of 53.8 pretreatment to 30.4 after cisapride treatment. No adverse reaction and no "overshoot affects," such as diarrhea, were seen. Our findings suggest that cisapride may alleviate the constipation associated with Parkinson's disease.

Topics: Acetylcholine; Aged; Autonomic Nervous System; Cisapride; Constipation; Female; Humans; Male; Middle Aged; Myenteric Plexus; Parkinson Disease; Pilot Projects; Piperidines; Serotonin Antagonists

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18F-positron-emitting analogue of 3-fluoromethyl-1-[1-(2-benzothienyl)-cyclohexyl]-piperidine, [18F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. [18F]BTCP was obtained from cyclotron-produced n.c.a. [18F]fluoride (110 min half-life) and by nucleophilic substitution from 3-bromomethyl-BTCP with a radiochemical yield of 6% (decay-corrected). After intravenous injection, the cerebral distribution of the radioactivity was observed mainly in cortical areas and cerebral structures enriched in catecholamine reuptake sites such as the caudate-putamen complex and the thalamus. The binding ratio, defined with respect to the cerebellum (taken as a region of non-specific binding), was highest in the thalamus (1.42), intermediate in the putamen (1.36) and lowest in the caudate nucleus (1.17), suggesting that some specific binding occurs in these regions. After saturation of dopamine and norepinephrine transporters by nomifensine, the binding ratio in the thalamus, putamen and caudate nucleus striatum remained essentially unchanged in the non-lesioned hemisphere. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in the denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[18F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[18F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears rather limited.

Topics: Animals; Brain; Carrier Proteins; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Evaluation Studies as Topic; Fluorine Radioisotopes; Isotope Labeling; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Parkinson Disease; Piperidines; Radioligand Assay; Thiophenes; Tomography, Emission-Computed

Topics: Aged; Antiparkinson Agents; Drug Therapy, Combination; Humans; Levodopa; Neurologic Examination; Parkinson Disease; Pilot Projects; Piperidines; Receptors, N-Methyl-D-Aspartate

We measured the binding of the vesicular acetylcholine transport blocker [3H]vesamicol (2-[4-phenylpiperidino] cyclohexanol; AH-5183) to autopsied frontal cortex and amygdala of patients from 4 disorders having a marked brain cholinergic reduction, namely Alzheimer's disease, Parkinson's disease with dementia, dominantly inherited olivopontocerebellar atrophy and Down's syndrome. Although mean activity of the specific cholinergic marker enzyme choline acetyltransferase (ChAT) was markedly reduced by about 60% in frontal cortex in the 4 patient groups and by 80% or greater in amygdala of the Alzheimer's and Down's syndrome patients, [3H]vesamicol binding density was, on average, either normal or only slightly reduced as compared with the controls. This discrepancy suggests that in human brain [3H]vesamicol binding is either not preferentially localized to cholinergic nerve endings or, in these cholinergic deficiency syndromes, a substantial proportion of the vesamicol binding sites persist on cholinergic nerve terminals despite loss of ChAT activity.

Topics: Acetylcholine; Adult; Aged; Alzheimer Disease; Amygdala; Autonomic Nervous System Diseases; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Down Syndrome; Humans; Middle Aged; Neuromuscular Depolarizing Agents; Olivopontocerebellar Atrophies; Parasympathetic Nervous System; Parkinson Disease; Piperidines

[3H]Vesamicol binding was characterized in human brain post mortem. The number of binding sites was then determined in parallel with choline acetyltransferase activity in the temporal cortex of patients with Alzheimer's disease, demented and non-demented patients with Parkinson's disease, and in the cerebral cortex of rats with quisqualic acid lesions of the nucleus basalis magnocellularis. Whereas choline acetyltransferase activity decreased in patients with Alzheimer's or Parkinson's disease indicating loss of cholinergic innervation, the number of binding sites for [3H]vesamicol was the same as or higher than in controls. Similar results were obtained with the lesioned rats. It is suggested that the increase in binding sites may reflect compensatory regulation of the spared neurons at the level of the synaptic vesicle.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Brain Injuries; Choline O-Acetyltransferase; Female; Humans; Hydroxydopamines; Kinetics; Male; Neuromuscular Depolarizing Agents; Oxadiazoles; Oxidopamine; Parkinson Disease; Phencyclidine; Piperidines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine; Reference Values; Substantia Nigra; Temporal Lobe

Two sibling cases of cerebrotendinous xanthomatosis with parkinsonism were reported. One was a woman of 39 years old, and another was her sister of 36 years old. In both cases, febrile convulsion appeared on 1.5 year old, and mental deterioration, ataxic -spastic gait, cataract and swelling of Achilles tendons developed in order since entrance into elementary school. Five years ago, while they were in hospital at the first time, they were diagnosed as cerebrotendinous xanthomatosis by mental disturbance, cerebellar ataxia, pyramidal tract sign, histologically xanthomatous granuloma of Achilles tendons and hypercholestanolemia and family history of autosomal recessive trait. After the second admission, parkinsonism was noticed in addition to those findings above. Parkinsonism consisted of the following: Resting tremor of parkinsonian type, mild muscle rigidity of forearm and intrinsic-plus hand were observed in the elder sister, and generalized severe rigidity and bradykinesia in the younger sister. In both cases, brain CT showed the pontocerebellar atrophy, and the bilateral low density area in corona radiata, posterior portion of internal capsule, cerebral peduncle, tegmentum of midbrain and deep matter of cerebellum. Brain MRI also showed abnormal intensity in the same regions as on the brain CT. Administration of anti-parkinsonian drugs was challenged for the parkinsonism. Oral L-dopa test (500 mg) moderately improved parkinsonism in both cases. Therapy of diphenylpyraline hydrochloride (10 mg/day) entirely inhibited parkinsonian tremor and mild rigidity in the elder sister but was less effective for severe rigidity in the younger sister than administration of L-dopa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Achilles Tendon; Adult; Brain Diseases; Female; Humans; Magnetic Resonance Imaging; Parkinson Disease; Piperidines; Tomography, X-Ray Computed; Xanthomatosis

Sebum secretion was measured on the forehead of 47 patients with Parkinson's disease before and after treatment with anticholinergic (biperiden), levodopa + AAID and bromocriptine, by the osmic acid technique. Another 100 patients under biperiden, levodopa + AAID or association of both, for at least one year, were also evaluated. The male parkinsonian "de novo" patients have shown greater sebum secretion than female patients. It was also concluded that biperiden failed to reduce sebum secretion rate. On the other hand, it was found that L-dopa + AAID reduces the sebum secretion (CL = casual level and SER = sebum excretion rate) on both male and female patients. Bromocriptine (10mg/day) was the second dopaminergic therapy employed in the present work. Similarly to L-dopa, this dopaminergic agonist was able to significantly reduce sebum secretion (both CL and SER) of male patients. There was a positive and significant correlation for the 50-59 years old male patients "de novo" between CL and tremor, hypokinesia, gait and posture or functional incapacity, before treatment. After a period of treatment correlation was no more found. In relation to parkinsonians under chronic treatment was found a positive and significant correlation between sebum secretion and hypokinesia. The level of sebum secretion on parkinsonian "de novo" patients before treatment was equal to parkinsonian patients under chronic treatment regardless the treatment, except for greater than or equal to 60 years old parkinsonians who have shown CL and SER higher than "de novo" parkinsonian patients with the same age but without treatment. The treatment with L-dopa + AAID significantly decreased both CL and SER of "de novo" parkinsonian patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aged, 80 and over; Aromatic-L-Amino-Acid Decarboxylases; Biperiden; Bromocriptine; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines; Sebum; Sex Factors

A 74-year-old man with parkinsonism developed progressive cognitive and behavioral dysfunction suggesting coexistent Alzheimer's disease. The intellectual and behavioral disturbances were reversed following withdrawal of his anticholinergic antiparkinsonian medication. This case demonstrates that anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer's disease and suggests that these medications should be withdrawn for all parkinsonian patients who develop significant impairments of cognition or behavior.

Topics: Aged; Alzheimer Disease; Biperiden; Carbidopa; Drug Combinations; Humans; Levodopa; Male; Parkinson Disease; Piperidines

The density of high-affinity 3H-imipramine and 3H-paroxetine binding sites (two serotonin-uptake blockers) was decreased in the putamen of parkinsonian patients. The correlation between serotonin levels and the number of 3H-imipramine and 3H-paroxetine binding sites suggests that they are located on serotoninergic nerve terminals and could be used to study serotoninergic innervation in the human brain. Since imipramine and paroxetine are powerful antidepressants, these results furthermore suggest that decreased serotoninergic transmission may be implicated in the pathophysiology of depression in Parkinson's disease.

Topics: Aged; Binding Sites; Humans; Imipramine; Middle Aged; Parkinson Disease; Paroxetine; Piperidines; Putamen; Tritium

Topics: Aged; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Pilot Projects; Piperidines; Ritanserin

Topics: Antiparkinson Agents; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines

Topics: Adult; Aged; Biperiden; Delayed-Action Preparations; Drug Evaluation; Female; Humans; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Syndrome

Lisuride is a soluble ergolene derivative with endocrine effects similar to but more potent than those of bromocriptine. In nine subjects with idiopathic, postencephalitic, or drug-induced parkinsonism, lisuride at a dosage of 0.05 to 0.15 mg intravenously caused an immediate improvement in tremor, rigidity, akinesia, and postural deformity, but also caused chorea and orofacial dyskinesia. Improvement lasted 2 to 3 hours. Lisuride had little or no effect in a single patient with progressively supranuclear palsy. Oral lisuride therapy, 0.8 to 4.8 mg daily, had similar effects but occasionally caused reduced awareness and hallucinations.

Topics: Administration, Oral; Aged; Benzimidazoles; Chorea; Domperidone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Growth Hormone; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Paralysis; Parkinson Disease; Parkinson Disease, Postencephalitic; Parkinson Disease, Secondary; Piperidines; Prolactin

Topics: Aged; Basal Ganglia Diseases; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Thioxanthenes; Tremor

Thirty-seven parkinsonian patients treated with bromocriptine +/- domperidone were examined eighteen months later. Fifteen continued the same treatment; 10 also received L-DOPA plus a peripheral DOPA-decarboxylase-inhibitor; the others resumed L-DOPA therapy. Thus, by limiting peripheral side effects, domperidone permits effective doses of bromocriptine.

Topics: Aged; Aromatic Amino Acid Decarboxylase Inhibitors; Benzimidazoles; Bromocriptine; Domperidone; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines

Blood pressure and pulse rate were studied in 20 Parkinsonian patients on no treatment, and during treatment with bromocriptine (mean dosage 148 mg/day) as the sole anti-Parkinsonian therapy. The drug was shown to reduce erect systolic and diastolic and supine systolic blood pressure and to increase erect pulse rate, in a predictable dose-dependent manner. The occurrence of episodes of significant postural hypotension was less predictable and was a transitory phenomenon in all patients. Peripheral dopamine receptor blockade with domperidone did not alter the findings, suggesting that the principal mechanism for these cardiovascular effects is a central dopaminergic one.

Topics: Benzimidazoles; Blood Pressure; Bromocriptine; Domperidone; Humans; Parkinson Disease; Piperidines; Pulse

Topics: Apomorphine; Behavior; Benzimidazoles; Domperidone; Double-Blind Method; Drug Interactions; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Receptors, Dopamine

The nicotinic cholinergic amine piperidine diminished both the dyskinesia and the symptomatic control in some patients with Parkinson disease receiving levodopa. Since the piperdine configuration is contained in the molecules of the apomorphine and N-propylnoraporphine, it might be responsible for the antagonism of these drugs to some effects of levodopa in Parkinson disease and for the palliation by apomorphine of some dopamine-mediated symptoms in other extrapyramidal disorders.

Topics: Aged; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Drug Evaluation; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines

The author analyzes parkinsonism and hyperkinesia in psychiatric patients with tardive dyskinesia before and during treatment with alpha-methyl-p-tyrosine (AMPT, a dopamine antagonist), biperiden (an acetylcholine antagonist), and baclofen (a GABA agonist); and in patients with paralysis agitans and L-dopa-induced hyperkinesia. AMPT and baclofen had similar influences on oral dyskinesia, resulting in reduced frequency, unchanged or slightly reduced amplitude, and increased duration of each movement. The author concludes that: 1) reduced dopaminergic activity may be the primary pathogenetic background for tardive dyskinesia; 2) dopaminergic hypersensitivity and/or cholinergic hypofunction is necessary before hyperkinesia breaks through; and 3) the neurotoxic effects of neuroleptics may be associated with age-dependent changes in nigrostriatal regions representing oral innervation.

Topics: Age Factors; Aminobutyrates; Baclofen; Basal Ganglia; Biperiden; Choline; Dopamine; Dyskinesia, Drug-Induced; Humans; Levodopa; Methyltyrosines; Mouth; Parkinson Disease; Piperidines; Tranquilizing Agents

Topics: Antiparkinson Agents; Dioxoles; Dopamine; Drug Evaluation; Haloperidol; Homovanillic Acid; Humans; Levodopa; Parkinson Disease; Piperidines; Probenecid; Pyrimidines

Topics: Adult; Aged; Benzocycloheptenes; Dihydroxyphenylalanine; Ergolines; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Promethazine; Thiophenes; Tremor; Trihexyphenidyl

Topics: Antiemetics; Carbonates; Dihydroxyphenylalanine; Dinitrophenols; Humans; Nausea; Parkinson Disease; Piperidines; Vomiting

Topics: 1-Propanol; Animals; Central Nervous System; Ileum; Mice; Organ Culture Techniques; Parasympatholytics; Parkinson Disease; Peripheral Nerves; Piperidines; Rats; Stereoisomerism; Stomach; Synaptic Transmission; Tremor; Trihexyphenidyl

Topics: Amantadine; Amphetamine; Animals; Behavior, Animal; Chlorpheniramine; Dopamine; Dopamine Antagonists; Drug Synergism; Histamine H1 Antagonists; Injections, Intraperitoneal; Male; Orphenadrine; Parasympatholytics; Parkinson Disease; Piperidines; Rats; Trihexyphenidyl

Topics: Adult; Aged; Aniline Compounds; Antiparkinson Agents; Female; Humans; Indoles; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Tranquilizing Agents

Topics: Adult; Chlormethiazole; Humans; Male; Parkinson Disease; Piperidines; Psychoses, Substance-Induced; Sorbitol; Sympatholytics

Topics: Apomorphine; Dopamine; Humans; Parkinson Disease; Piperidines

Topics: Humans; Parasympatholytics; Parkinson Disease; Piperidines; Tremor

Topics: 1-Propanol; Adult; Age Factors; Aged; Bipolar Disorder; Follow-Up Studies; Humans; Middle Aged; Neurologic Manifestations; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Piperidines

Topics: 1-Propanol; Animals; Biperiden; Cerebral Decortication; Electromyography; Methamphetamine; Models, Neurological; Motor Neurons; Movement Disorders; Parasympatholytics; Parkinson Disease; Piperidines; Rats; Reserpine

Topics: Adult; Aged; Chemical Phenomena; Chemistry; Drug Synergism; Female; Humans; Male; Middle Aged; Muscles; Parkinson Disease; Piperidines; Propranolol; Tremor

Topics: Adolescent; Adult; Atropine; Female; Humans; Male; Middle Aged; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines; Schizophrenia; Xanthenes

Topics: Extrapyramidal Tracts; Humans; Parasympatholytics; Parkinson Disease; Piperidines; Spinal Cord Diseases

Topics: Humans; Imipramine; Parkinson Disease; Parkinsonian Disorders; Piperidines; Trihexyphenidyl

Topics: Anti-Allergic Agents; Biperiden; Histamine H1 Antagonists; Humans; Parasympatholytics; Parkinson Disease; Piperidines

Topics: Parasympatholytics; Parkinson Disease; Parkinsonian Disorders; Piperidines; Trihexyphenidyl

Topics: Glutethimide; Parkinson Disease; Parkinsonian Disorders; Piperidines

Topics: Chlorpromazine; Humans; Parkinson Disease; Parkinsonian Disorders; Piperidines; Reserpine; Syndrome

Topics: Electromyography; Humans; Parkinson Disease; Piperidines

Topics: Humans; Nervous System Diseases; Parkinson Disease; Piperidines; Trihexyphenidyl

Topics: Methylphenidate; Parasympatholytics; Parkinson Disease; Parkinsonian Disorders; Piperidines; Reserpine; Salts

Topics: Cardiovascular Agents; Muscle Relaxants, Central; Parkinson Disease; Piperidines; Trihexyphenidyl

Topics: Cardiovascular Agents; Muscarinic Antagonists; Muscle Relaxants, Central; Parkinson Disease; Piperidines

Topics: Cardiovascular Agents; Muscle Relaxants, Central; Parkinson Disease; Parkinsonian Disorders; Piperidines

Topics: Cardiovascular Agents; Muscle Relaxants, Central; Parasympatholytics; Parkinson Disease; Parkinsonian Disorders; Piperidines

Topics: Cardiovascular Agents; Muscle Relaxants, Central; Parkinson Disease; Parkinsonian Disorders; Piperidines