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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 -
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 -
CNS Drug Reviews 2001Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a... (Review)
Review
Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function. The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Clinical Trials, Phase III as Topic; Donepezil; Humans; Indans; Piperidines; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 11830754
DOI: 10.1111/j.1527-3458.2001.tb00204.x -
Drug Design, Development and Therapy 2022Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess...
PURPOSE
Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates.
METHODS
Mice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25-75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection.
RESULTS
Chronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels.
CONCLUSION
It is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.
Topics: Animals; Ascorbic Acid; Cognitive Dysfunction; Donepezil; Dopamine; Ethanol; Flavones; Hippocampus; Maze Learning; Mice; Norepinephrine
PubMed: 35665194
DOI: 10.2147/DDDT.S360677 -
Alzheimer's Research & Therapy Aug 2023There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have...
BACKGROUND
There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population.
OBJECTIVE
To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic.
METHODS
Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019.
RESULTS
Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020.
CONCLUSIONS
The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.
Topics: Humans; Male; Female; Alzheimer Disease; Donepezil; Rivastigmine; Memantine; Cholinesterase Inhibitors; Retrospective Studies; Pandemics; Prevalence; Piperidines; Phenylcarbamates; Indans; COVID-19; Galantamine
PubMed: 37537656
DOI: 10.1186/s13195-023-01271-0 -
International Journal of Nanomedicine 2023Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have...
INTRODUCTION
Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration.
METHODS
DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination.
RESULTS
DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology.
CONCLUSION
Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.
Topics: Rats; Animals; Drug Carriers; Donepezil; Alzheimer Disease; Antioxidants; Amyloid beta-Peptides; Brain; Nanostructures; Lipids; Particle Size
PubMed: 37534058
DOI: 10.2147/IJN.S417928 -
European Review For Medical and... Dec 2021To identify candidate differentially expressed genes (DEGs) and pathways in diabetic mice brain with metformin/donepezil, network pharmacology analysis was used and...
OBJECTIVE
To identify candidate differentially expressed genes (DEGs) and pathways in diabetic mice brain with metformin/donepezil, network pharmacology analysis was used and verified by experiments.
MATERIALS AND METHODS
We analyzed GSE62013 microarray datasets derived from the Gene Expression Omnibus (GEO) database for diabetic brain. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database. Subsequently, the protein-protein interaction network (PPI) and Cytoscape were used for visualizing the most significant module and hub genes. Metformin/donepezil were used to treat streptozotocin (STZ)-induced diabetic mice models. Blood glucose levels and Morris water maze test were measured. The apoptotic rate of diabetic brain tissue was analyzed using Annexin V/propidium iodide double staining. The levels of PI3K and AKT in the mice brain tissues were detected by Western blot.
RESULTS
DEGs included 214 up-regulated genes and 100 down-regulated genes in diabetic brain tissues of mice. The enriched GO functions were multicellular organism development, negative regulation of transcription from RNA polymerase II promoter, and extracellular region. The enriched pathways were PI3K-Akt signaling pathway, Linoleic acid metabolism and Arachidonic acid metabolism. Blood glucose levels and apoptosis were reduced in STZ-induced diabetic mice following metformin/donepezil treatment. Metformin/donepezil could reverse this neurocognitive deficiency. Protein levels of PI3K and AKT were significantly increased in STZ-induced diabetic mice.
CONCLUSIONS
Overall, we proposed that 10 genes (Cdc20, Fbxo32, Igtp, Atg7, Fbxo15, Trim37, Psmb8, Ifi47, Asb12, and Asb5) that might be novel hub genes strongly associated with diabetic mice brain. Metformin/donepezil ameliorates STZ-induced brain injury by activating the PI3K/AKT pathway and alleviating apoptosis.
Topics: Animals; Apoptosis; Brain; Cholinesterase Inhibitors; Computational Biology; Diabetes Mellitus, Experimental; Donepezil; Hypoglycemic Agents; Male; Metformin; Mice, Inbred C57BL; Neuroprotective Agents; Nootropic Agents; Phosphatidylinositol 3-Kinases; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Mice
PubMed: 34982428
DOI: 10.26355/eurrev_202112_27613 -
British Journal of Pharmacology Dec 2017Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the... (Review)
Review
Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid β, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Progression; Donepezil; Early Diagnosis; Humans; Indans; Neuroprotective Agents; Nootropic Agents; Piperidines; Time Factors
PubMed: 28901528
DOI: 10.1111/bph.14030 -
The Cochrane Database of Systematic... Jan 2012Antipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial effectiveness of the antipsychotics on cognitive and negative symptoms, the search is on for drugs that may improve these domains of functioning for someone suffering from schizophrenia. Acetylcholinesterase inhibitors have long been in use for treating cognitive symptoms of dementia.
OBJECTIVES
The aim of the review was to evaluate the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors for treating people with schizophrenia
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Register (February 2009), and inspected the references of all identified studies for further trials.
SELECTION CRITERIA
We included all clinical randomised trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat (ITT) basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model.
MAIN RESULTS
The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes.1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed).2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50).3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96).No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups.
AUTHORS' CONCLUSIONS
The results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.
Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Rivastigmine; Schizophrenia; Schizophrenic Psychology
PubMed: 22258978
DOI: 10.1002/14651858.CD007967.pub2