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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 -
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 Aug 2023Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this... (Randomized Controlled Trial)
Randomized Controlled Trial
Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.
Topics: Humans; Female; Breast Neoplasms; Metformin; Ventricular Function, Left; Stroke Volume; Donepezil; Cardiotoxicity; Leukocytes, Mononuclear; Doxorubicin; Natriuretic Peptide, Brain; Peptide Fragments
PubMed: 37550350
DOI: 10.1038/s41598-023-40061-4 -
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 -
Journal of Biomolecular Structure &... Jun 2022Donepezil is an acetylcholinesterase inhibitor (AChEI) in use to treat symptomatic patients of mild to moderate Alzheimer's disease (AD). Ferritin is an iron protein...
Donepezil is an acetylcholinesterase inhibitor (AChEI) in use to treat symptomatic patients of mild to moderate Alzheimer's disease (AD). Ferritin is an iron protein associated with storage and sequestration of excess ferrous iron in a way maintaining proper function of cellular processes and plays a key role in AD since steady-state dysregulation of metal ion metabolism is associated with AD pathology. In lieu of therapeutics importance of ferritin and donepezil in AD, this study aims at investigating the binding between these two employing molecular docking and molecular dynamics (MD) simulation. In this study, we performed structure-based docking of donepezil with human Ferritin. Primarily, the top pose based on the binding affinity was selected and then interaction analysis was carried out to find the stable pose. Structural annotations by docking analysis were further accompanied by all-atom MD simulation for 100 ns followed by principal component and free energy landscape analyses to investigate the conformational changes, stability, and interaction mechanism of ferritin with donepezil. MD simulation suggested that the binding of donepezil stabilizes the ferritin structure and leads to fewer conformational changes. This study gives an insight at the atomistic level into the interaction between donepezil and ferritin thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.
Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Ferritins; Humans; Iron; Molecular Docking Simulation; Molecular Dynamics Simulation
PubMed: 33228460
DOI: 10.1080/07391102.2020.1851302 -
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 -
European Journal of Medical Research Oct 2022The purpose of this study was to investigate the neuroprotective effect of donepezil against β-amyloid (Aβ)-induced neurotoxicity and the possible mechanism.
PURPOSE
The purpose of this study was to investigate the neuroprotective effect of donepezil against β-amyloid (Aβ)-induced neurotoxicity and the possible mechanism.
METHODS
PC12 cells were conventionally cultured. Serial concentrations of Aβ and donepezil (0, 0.5, 1, 5, 10, 20 and 50 μmol/L) were added to the PC12 cells, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) staining was performed to detect the effects of these treatments on PC 12 viability. The PC 12 cells were pretreated with 1, 5, 10, 20 or 50 μmol/L donepezil two hours before 20 μmol/L Aβ was added to pretreatment groups A, B, C, D and E. Normal control group I and the 20 μmol/L Aβ-treated group were selected. An MTT assay was used to detect PC12 cell viability, and the level of lactate dehydrogenase (LDH) was determined. PC12 cells were pretreated with 10 μmol/L GF109203X (a protein kinase C [PKC] antagonist) 30 min before 10 μmol/L donepezil was added to pretreatment group F, and normal control group II, the 10 μmol/L GF109203X-treated group and the 10 μmol/L donepezil-treated group were chosen. The expression of phosphorylation-PKC (P-PKC) and its major substrate phosphorylated myristoylated alanine-rich protein C kinase substrate (P-MARCKS) was measured by Western blotting. The effects of donepezil on the subcellular distribution of the PKCα and PKCε isoforms were detected by immunofluorescence staining.
RESULTS
Treatment with Aβ (5, 10, 20 or 50 μmol/L) for 24 h significantly (P < 0.05) decreased PC 12 cell viability in a dose-dependent manner. Compared with the PC12 cells in the control group, those in the 20 μmol/L Aβ-treated group exhibited lower viability but higher LDH release. Compared with the 20 μmol/L Aβ-treated group, pretreatment groups B, C, D and E exhibited significantly (P < 0.05) increased cell viability but significantly (P < 0.05) decreased LDH release. Western blotting demonstrated that compared with control, 10 μmol/L donepezil promoted PKC and MARCKS phosphorylation and that the expression of P-PKC and P-MARCKS in pretreatment group F was significantly (P < 0.05) lower than that in the donepezil-treated group. Immunofluorescence staining revealed that the PKCα and PKCε isoforms were located mainly in the cytoplasm of PC12 control cells, whereas donepezil increased the expression of the PKCα and PKCε isoforms in the membrane fraction. The Western blot results showed that donepezil altered the subcellular distribution of the PKCα and PKCε isoforms by decreasing their expression in the cytosolic fraction but increasing their expression in the membrane fraction.
CONCLUSION
Donepezil can antagonize Aβ-induced neurotoxicity in PC 12 cells, and PKC activation may account for the neuroprotective effect of donepezil.
Topics: Humans; Animals; Rats; Neuroprotective Agents; Donepezil; Peptide Fragments; Protein Kinase C-alpha; Apoptosis
PubMed: 36307893
DOI: 10.1186/s40001-022-00862-1 -
Journal of Chromatography. B,... May 2023Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the...
Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the brain function and behavior of various central nervous system diseases such as Alzheimer's disease (AD). In this study, metabolic profiling was used to investigate changes in plasma and urine metabolites following stereotactic injection of amyloid β (Aβ) and treatment with donepezil in rats. Aβ causes cognitive impairment, while donepezil treatment successfully improves memory impairment. Donepezil improves Aβ-induced plasma fatty acid and bile acid metabolism disorders, as well as Aβ-induced urine phenylalanine and tryptophan metabolism disorders in rats. More specifically, the plasma fatty acids improved by donepezil include alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, arachidonic acid, oleic acid, and palmitic acid, among others. Additionally, donepezil significantly restored the downregulation of bile acids such as ursodeoxycholic acid, cholic acid, and glycocholic acid caused by Aβ. As for urine metabolites, phenylacetylglycine, epinephrine, and other phenylalanine metabolites, as well as kynurenic acid, xanthurenic acid, and other tryptophan metabolites, were worsened by Aβ and improved by donepezil. These findings suggest that the cognitive impairment induced by Aβ and the improvement by donepezil are associated with changes in metabolic disorders in rats. This study provides basic data for the effects of Aβ and donepezil on plasma and urine metabolites in Aβ-induced AD rat models.
Topics: Rats; Animals; Alzheimer Disease; Amyloid beta-Peptides; Donepezil; Tryptophan; Fatty Acids; Disease Models, Animal
PubMed: 37263123
DOI: 10.1016/j.jchromb.2023.123766