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Neurology Apr 2024The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer... (Comparative Study)
Comparative Study
The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid-related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision-making, and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer's Disease Assessment Scale-Cognitive 14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at 6 months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment, whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.
Topics: Humans; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Cognition; Donepezil; Randomized Controlled Trials as Topic
PubMed: 38484213
DOI: 10.1212/WNL.0000000000209320 -
The Senior Care Pharmacist Jul 2023Prevalence of dementia continues to increase with limited pharmacotherapy options available. Acetylcholinesterase inhibitors remain a mainstay of treatment. The US FDA... (Review)
Review
Prevalence of dementia continues to increase with limited pharmacotherapy options available. Acetylcholinesterase inhibitors remain a mainstay of treatment. The US FDA has approved three oral medications within this class- donepezil, galantamine, and rivastigmine. In 2022, the US Food and Drug Administration approved a novel patch formulation for donepezil that could be beneficial for patients with dysphagia as well as potentially decreasing the side effect burden. The purpose of this analysis is to review the efficacy, safety, tolerability, and clinical considerations related to this novel formulation.
Topics: Humans; Acetylcholinesterase; Donepezil; Drug-Related Side Effects and Adverse Reactions; Rivastigmine; United States; United States Food and Drug Administration
PubMed: 37381137
DOI: 10.4140/TCP.n.2023.300 -
Neurologia May 2022Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly... (Review)
Review
INTRODUCTION
Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.
DEVELOPMENT
We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.
CONCLUSIONS
Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.
Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Biomarkers; Donepezil; Humans; Pharmacogenomic Testing
PubMed: 35595404
DOI: 10.1016/j.nrleng.2018.03.022 -
ACS Chemical Neuroscience Jan 2019The discovery of acetylcholine and acetylcholinesterase provided the first insight into the intricacies of chemical signal transduction and neuronal communication.... (Review)
Review
The discovery of acetylcholine and acetylcholinesterase provided the first insight into the intricacies of chemical signal transduction and neuronal communication. Further elucidation of the underlying mechanisms led to an attendant leveraging of this knowledge via the synthesis of new therapeutics designed to control aberrant biochemical processes. The central role of the cholinergic system within human memory and learning, as well as its implication in Alzheimer's disease, has made it a point of focus within the neuropharmacology and medicinal chemistry communities. This review is focused on donepezil and covers the background, synthetic routes, structure-activity relationships, binding interactions with acetylcholinesterase, pharmacokinetics and metabolism, efficacy, adverse effects, and historical importance of this leading therapeutic in the treatment of Alzheimer's disease and true Classic in Chemical Neuroscience.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Nerve Degeneration; Structure-Activity Relationship
PubMed: 30372021
DOI: 10.1021/acschemneuro.8b00517 -
Brain and Nerve = Shinkei Kenkyu No... May 2023Alzheimer's disease (AD) treatment includes both non-pharmacological and pharmacological approaches. Current pharmacological approaches include symptomatic and... (Review)
Review
Alzheimer's disease (AD) treatment includes both non-pharmacological and pharmacological approaches. Current pharmacological approaches include symptomatic and disease-modifying therapies (DMTs). In Japan, DMTs have not yet been approved for treating AD; however, four drugs are currently available for symptomatic therapies, including cholinesterase inhibitors (ChEIs) such as donepezil for mild-to-severe dementia, galantamine and rivastigmine for mild-to-moderate dementia, and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, for moderate-to-severe dementia. In this review, we describe the use of four symptomatic anti-AD drugs in clinical practice for AD.
Topics: Humans; Cholinesterase Inhibitors; Alzheimer Disease; Donepezil; Rivastigmine; Galantamine; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 37194514
DOI: 10.11477/mf.1416202360 -
Psychiatria Danubina Dec 2015Parkinson's disease is the second most frequent neurodegenerative disorder. There is significantly elevated risk of cognitive decline and associated neuropsychiatric... (Review)
Review
Parkinson's disease is the second most frequent neurodegenerative disorder. There is significantly elevated risk of cognitive decline and associated neuropsychiatric symptoms. Dementia may develop insidiously several years after manifestation of Parkinson motor symptoms (dementia associated with Parkinson's disease; Parkinson's disease dementia) or in close temporal relationship (within one year) after onset of motor symptoms (Dementia with Lewy bodies). There are clinical, pathophysiological and therapeutic similarities between these two conditions. Men are more frequently affected than women. Risk factor or indicators are advanced age at disease onset, disease duration, rigidity, akinesia and posture and gait impairment and falls as opposed to tremor dominance, and associated neuropsychiatric symptoms (depression, apathy, hallucinosis, delirium). Dementia is treatable with cholinesterase inhibitors (rivastigmine, donepezil), memantine, and adjustment of the pharmacological regimen of parkinsonian motor symptoms. Concomitant autonomic nervous system symptoms and neuropsychiatric complications warrant early clinical awareness and are accessible to pharmacological therapy.
Topics: Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Humans; Memantine; Muscle Rigidity; Parkinson Disease; Risk Factors; Rivastigmine
PubMed: 26609664
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2023Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive... (Review)
Review
BACKGROUND
Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated.
OBJECTIVES
To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism.
SEARCH METHODS
In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence.
MAIN RESULTS
We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group.
AUTHORS' CONCLUSIONS
Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.
Topics: Child; Humans; Acetylcholine; Autism Spectrum Disorder; Cholinesterase Inhibitors; Donepezil; Galantamine; Risperidone; Rivastigmine; Child, Preschool; Adolescent
PubMed: 37267443
DOI: 10.1002/14651858.CD013851.pub2 -
Scientific Reports Jun 2023An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI)... (Clinical Trial)
Clinical Trial
An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by ≥ 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.
Topics: Animals; Mice; Acetylcholinesterase; Amblyopia; Donepezil; Visual Acuity
PubMed: 37349338
DOI: 10.1038/s41598-023-34891-5 -
Clinical Neurology and Neurosurgery Feb 2022This study intends to systematically evaluate the efficacy and safety of donepezil for improving cognitive function in patients with mild cognitive impairment (MCI), and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study intends to systematically evaluate the efficacy and safety of donepezil for improving cognitive function in patients with mild cognitive impairment (MCI), and to provide evidence-based foundation for donepezil in MCI treatment.
METHODS
We searched in PubMed, Embase, Cochrane Library, Clinical trials.gov, Web of Science, CQVIP, and CNKI databases, and then we summarized the interventional and observational studies on the use of donepezil for improving the cognitive function of MCI patients. The literature was collected according to the inclusion criteria for data extraction. We evaluated the quality of the selected literature and used Stata 15.0 for meta-analysis.
RESULTS
A total of 12 randomized controlled trials (RCTs) and 5 non-randomized concurrent controlled trials (CCTs) were included, and a total of 2847 patients were included. In terms of efficacy, meta-analysis showed that donepezil could significantly improve the MMSE (SMD: 0.85, 95%CI: 0.40-1.31) and MoCA (SMD: 1.88, 95%CI: 0.32-3.45) scores of MCI patients. Donepezil could not significantly reduce ADAS-cog score, nor could it significantly delay disease progression. The quality of the evidence was low overall. In terms of safety, donepezil could significantly increase the risk of adverse reactions such as nausea, vomiting, diarrhea in patients with MCI.
CONCLUSION
Donepezil can improve the cognitive function of MCI patients to a certain extent. However, there is no trend of significantly delaying the progression of the disease, and it is easy to lead to the occurrence of adverse reactions.
Topics: Cognition; Cognitive Dysfunction; Databases, Factual; Donepezil; Humans; Nootropic Agents; Randomized Controlled Trials as Topic
PubMed: 35078087
DOI: 10.1016/j.clineuro.2022.107134 -
Journal of Alzheimer's Disease : JAD 2022Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.
OBJECTIVE
To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.
METHODS
Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.
RESULTS
All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).
CONCLUSION
Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.
Topics: Adolescent; Adult; Humans; Middle Aged; Young Adult; Alzheimer Disease; Cross-Over Studies; Donepezil
PubMed: 36120781
DOI: 10.3233/JAD-220530