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British Journal of Pharmacology Dec 2022Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including...
BACKGROUND AND PURPOSE
Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non-depolarising neuromuscular blockers during surgery. Here, we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve-muscle preparations from mice.
EXPERIMENTAL APPROACH
We measured effects of therapeutic concentrations of donepezil (10 nM to 1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles from CD01 or C57BlWld mice.
KEY RESULTS
Donepezil inhibited muscle AChE with an approximate IC of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil prolonged post-tetanic muscle contractions. Preliminary Fluo4-imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca transients at motor endplates. Donepezil prolonged spontaneous miniature EPP (MEPP) decay time constants by about 65% and extended evoked EPP duration almost threefold. The mean frequency of spontaneous MEPPs was unaffected but the incidence of 'giant' MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 μM.
CONCLUSION AND IMPLICATIONS
Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are probably due to inhibition of AChE at NMJs, prolonging the action of ACh on postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.
Topics: Humans; Mice; Animals; Acetylcholinesterase; Donepezil; Neuromuscular Junction; Synaptic Transmission; Muscle, Skeletal
PubMed: 36028305
DOI: 10.1111/bph.15940 -
Neurotherapeutics : the Journal of the... Oct 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1 mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.
Topics: Humans; Mice; Animals; Amyotrophic Lateral Sclerosis; Donepezil; Nebivolol; Phosphatidylinositol 3-Kinases; HeLa Cells; Quality of Life; Spinal Cord; Disease Progression; Disease Models, Animal; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37782409
DOI: 10.1007/s13311-023-01444-7 -
PloS One 2023Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug...
A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.
Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.
Topics: Humans; Alzheimer Disease; Donepezil; Memantine; Hospitals; Emergency Service, Hospital
PubMed: 37708117
DOI: 10.1371/journal.pone.0291362 -
Alzheimer's Research & Therapy Jun 2023Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.
METHODS
From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.
RESULTS
Donepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.
CONCLUSIONS
Our data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.
TRIAL REGISTRATION
ClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.
Topics: Humans; Donepezil; Cognitive Dysfunction; Magnetic Resonance Imaging; Alzheimer Disease; Atrophy
PubMed: 37353809
DOI: 10.1186/s13195-023-01253-2 -
Biosensors Aug 2022Fast and reliable determination of enzyme inhibitors are of great importance in environmental monitoring and biomedicine because of the high biological activity and...
Fast and reliable determination of enzyme inhibitors are of great importance in environmental monitoring and biomedicine because of the high biological activity and toxicity of such species and the necessity of their reliable assessment in many media. In this work, a flow-through biosensor has been developed and produced by 3D printing from poly(lactic acid). Acetylcholinesterase from an electric eel was immobilized on the inner walls of the reactor cell. The concentration of thiocholine formed in enzymatic hydrolysis of the substrate was monitored amperometrically with a screen-printed carbon electrode modified with carbon black particles, pillar[5]arene, electropolymerized Methylene blue and thionine. In the presence of thiocholine, the cathodic current at -0.25 V decreased because of an alternative chemical reaction of the macrocycle. The conditions of enzyme immobilization and signal measurements were optimized and the performance of the biosensor was assessed in the determination of reversible (donepezil, berberine) and irreversible (carbofuran) inhibitors. In the optimal conditions, the flow-through biosensor made it possible to determine 1.0 nM-1.0 μM donepezil, 1.0 μM-1.0 mM berberine and 10 nM to 0.1 μM carbofuran. The AChE biosensor was tested on spiked samples of artificial urine for drugs and peanuts for carbofuran. Possible interference of the sample components was eliminated by dilution of the samples with phosphate buffer. Easy mounting, low cost of replaceable parts of the cell and satisfactory analytical and metrological characteristics made the biosensor a promising future application as a point-of-care or point-of-demand device outside of a chemical laboratory.
Topics: Acetylcholinesterase; Berberine; Biosensing Techniques; Carbofuran; Carbon; Donepezil; Electrodes; Enzymes, Immobilized; Methylene Blue; Phosphates; Soot; Thiocholine
PubMed: 36140061
DOI: 10.3390/bios12090676 -
Therapeutic Advances in Drug Safety 2020Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer's disease (AD). This study aimed to evaluate...
BACKGROUND
Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer's disease (AD). This study aimed to evaluate evidence from the case report literature for an association between these agents and risk of QT interval prolongation and (TdP) arrhythmia.
METHODS
Published literature was mined with predetermined MeSH terms for each of donepezil, galantamine and rivastigmine, to identify cases of QT interval prolongation and TdP. Case reports were analysed using causality scales and a QT interval nomogram.
RESULTS
A total of 13 case reports were found (10 for donepezil, 2 for galantamine and 1 for rivastigmine) with rate corrected QT interval (QT) prolongation. Five cases with donepezil exhibited TdP. TdP was not reported in the cases with galantamine and rivastigmine. The use of a QT heart rate nomogram highlighted risk with donepezil compared with the other two drugs and the application of the Naranjo causality scale suggested probable or possible causation for all donepezil cases. All patients had at least two other risk factors for TdP, including modifiable risk factors such as electrolyte disturbances, bradycardia, co-administration of QT prolonging drugs. A number of recent cases involved recent changes in medication.
CONCLUSION
Our evaluation of the case report literature suggests that there is evidence for a causal association between donepezil and QT/TdP risk. Attention to risk factors for QT prolongation/TdP should be exercised when prescribing donepezil and modifiable risk factors corrected. Owing to the low number of cases with galantamine and rivastigmine, further work is needed to establish whether these drugs may be more suitable than donepezil for patients with other risk factors for TdP.
PubMed: 32874532
DOI: 10.1177/2042098620942416 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
Journal of Alzheimer's Disease : JAD 2023Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the...
BACKGROUND
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.
OBJECTIVE
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.
RESULTS
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.
CONCLUSION
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: Humans; Cholinesterase Inhibitors; Acetylcholinesterase; Dementia; Piperidines; Indans; Phenylcarbamates; Parkinson Disease; Rivastigmine; Alzheimer Disease; Galantamine; Cognition; Perfusion; Cerebrovascular Circulation
PubMed: 37182871
DOI: 10.3233/JAD-221125 -
Clinical Interventions in Aging 2024Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC).
BACKGROUND
Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC).
OBJECTIVE
This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.
MATERIAL AND METHODS
According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ- patients using a logistic regression analysis.
RESULTS
The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95).
CONCLUSION
The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.
Topics: Humans; Donepezil; Alzheimer Disease; Polymorphism, Single Nucleotide; Female; Male; Aged; Aged, 80 and over; Genotype; Logistic Models; Cholinesterase Inhibitors; Mental Status and Dementia Tests
PubMed: 38894884
DOI: 10.2147/CIA.S462786 -
Environmental Health Perspectives Apr 2021Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used...
BACKGROUND
Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).
OBJECTIVES
The objective of the current study was to identify environmental chemicals that inhibit AChE activity using and models.
METHODS
To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.
RESULTS
A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.
CONCLUSIONS
Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Humans; Insecticides; Molecular Docking Simulation
PubMed: 33844597
DOI: 10.1289/EHP6993