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CNS & Neurological Disorders Drug... 2020Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were... (Review)
Review
Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were previously enjoyed, behavioral changes, and memory loss. Alzheimer's disease and other types of dementia affect almost 46.8 million people globally and are estimated to strike about 131.5 million people in 2050. It has been reported that Alzheimer's is the sixth main cause of mortality. The most used drugs, which are currently approved by the Food, and Drug Administration for Alzheimer's disease are donepezil, rivastigmine, galantamine, memantine, and the combination of donepezil and memantine. However, most of the drugs present various adverse effects. Recently, the transdermal drug delivery route has gained increasing attention as an emerging tool for Alzheimer's disease management. Besides, transdermal drug delivery systems seem to provide hope for the management of various diseases, due to the advantages that they offer in comparison with oral dosage forms. Herein, the current advancements in transdermal studies with potent features to achieve better Alzheimer's disease management are presented. Many researchers have shown that the transdermal systems provide higher efficiency since the first-pass hepatic metabolism effect can be avoided and a prolonged drug release rate can be achieved. In summary, the transdermal administration of Alzheimer's drugs is an interesting and promising topic, which should be further elaborated and studied.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Delivery Systems; Humans; Memantine; Rivastigmine
PubMed: 32552655
DOI: 10.2174/1871527319666200618150046 -
CNS & Neurological Disorders Drug... 2020Alzheimer's Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral... (Review)
Review
Alzheimer's Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer's disease. The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease. Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Mice; Phytotherapy; Plant Preparations; Rats; Rivastigmine
PubMed: 32679025
DOI: 10.2174/1871527319666200717091513 -
Current Alzheimer Research 2022Considering the lack of direct comparison between cholinesterase inhibitors and memantine in patients with vascular cognitive impairment (VCI), determining how to choose... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Considering the lack of direct comparison between cholinesterase inhibitors and memantine in patients with vascular cognitive impairment (VCI), determining how to choose the best treatment plan remains inconclusive. Hence, we conducted the network meta-analysis to compare the efficacy and acceptability of these drugs.
METHODS
PubMed, the Cochrane Central Register of Controlled Trials, Embase and Web of Science were searched for double-blind randomized controlled trials (RCTs) for the treatment of VCI, which involved donepezil, galantamine, rivastigmine, and memantine, from database inception to January 1, 2020. Then, a network meta-analysis based on the frequency method was conducted.
RESULTS
Eleven RCTs were included. Compared with the placebo, in terms of efficacy, donepezil 5 mg (standardized mean difference = -1.11, 95% confidence interval = -1.88 to -0.34), donepezil 10 mg (-1.44, -2.31 to -0.56), galantamine 24 mg (-1.99, -3.03 to -0.95), and memantine 20 mg (-1.89, -2.93 to -0.86) were more effective for the cognition of ADAS-cog, and donepezil 5 mg (0.46, 0.12 to 0.81), donepezil 10 mg (0.76, 0.34 to 1.17), and rivastigmine 12mg (0.60, 0.10 to 1.10) exhibited superior benefits for the cognition of MMSE. Donepezil 10 mg (-0.25, -0.44 to -0.06; -1.47, -2.79 to -0.15) exhibited improvements for CDR-SB and EXIT25, respectively. In terms of acceptability, memantine was found to be the best.
CONCLUSION
Donepezil 5 mg, donepezil 10 mg, galantamine 24 mg, memantine 20 mg, and rivastigmine 12 mg exerted beneficial effects on cognition, and donepezil 10mg provided beneficial effects for executive function and global status. Based on the network meta-analysis, donepezil 10 mg might be the best choice, considering the benefits on cognition function, executive function and global status, but doserelated adverse reactions need to be noted. In the meantime, memantine is a better comprehensive choice in terms of efficacy and safety.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Galantamine; Humans; Indans; Memantine; Network Meta-Analysis; Nootropic Agents; Randomized Controlled Trials as Topic; Rivastigmine
PubMed: 35048806
DOI: 10.2174/1567205019666220120112301 -
Therapeutic Drug Monitoring Jun 2021Donepezil is one of the most commonly prescribed drugs for the treatment of Alzheimer disease. It is predominantly metabolized through CYP2D6 and to a lesser extent by...
BACKGROUND
Donepezil is one of the most commonly prescribed drugs for the treatment of Alzheimer disease. It is predominantly metabolized through CYP2D6 and to a lesser extent by CYP3A4/5. There are conflicting reports regarding the influence of CYP2D6, CYP3A5, and ABCB1 polymorphisms on the plasma concentration of donepezil. This study investigated the influence of these polymorphisms and sex on the plasma concentrations of donepezil and its active metabolite, 6-O-desmethyl donepezil (6ODD), in 47 patients with Alzheimer disease.
METHODS
Plasma donepezil and 6ODD concentrations were measured using liquid chromatography tandem mass spectrometry. Sex, the concomitant use of psychotropics, and CYP2D6, CYP3A5, and ABCB1 polymorphisms were analyzed as possible influencers.
RESULTS
The mean plasma concentrations of donepezil and 6ODD were well correlated (R2 = 0.418). The mean plasma concentration ratio of donepezil to 6ODD (metabolic ratio) was significantly lower in intermediate metabolizers of CYP2D6 than in extensive metabolizers. The metabolic ratio in patients receiving psychotropics was significantly lower than in those not receiving psychotropics. Among intermediate metabolizers, patients positive for CYP3A5 *3/*3 showed a significant increase in plasma mean 6ODD concentrations when compared with those who did not express this gene (CYP3A5 *1/*1 or *1/*3).
CONCLUSIONS
Results indicate that the mean plasma concentration ratio of donepezil to 6ODD is associated with CYP2D6 polymorphism and the concomitant use of psychotropics in patients with Alzheimer disease. In intermediate metabolizers, CYP3A5 may play a significant role in the metabolism of donepezil.
Topics: ATP Binding Cassette Transporter, Subfamily B; Alzheimer Disease; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Donepezil; Humans; Polymorphism, Genetic
PubMed: 33065613
DOI: 10.1097/FTD.0000000000000823 -
British Journal of Community Nursing Mar 2020
Review
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Male; Treatment Outcome
PubMed: 32160022
DOI: 10.12968/bjcn.2020.25.3.148 -
Pharmaceutical Biology Dec 2022Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are...
CONTEXT
Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD.
OBJECTIVE
To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the therapeutic effect on AD in a zebrafish model.
MATERIALS AND METHODS
Aaptamine was isolated from the sponge Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE . Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10 and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed.
RESULTS
The IC values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%.
DISCUSSION AND CONCLUSIONS
Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Humans; Kinetics; Molecular Docking Simulation; Naphthyridines; Zebrafish
PubMed: 35968601
DOI: 10.1080/13880209.2022.2102657 -
Drug Design, Development and Therapy 2020The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system,...
BACKGROUND
The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil. polymorphisms can cause altered enzyme activity resulting in lower or higher than expected drug concentrations of donepezil.
OBJECTIVE
We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of genotype or gene dose-dependent metabolism of donepezil.
METHODS
Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography - tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess genotype and gene dose.
RESULTS
Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (β=0.465; p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on gene dose.
CONCLUSION
Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from genotyping or treatment with an AChE-I independent of CYP metabolism.
Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Donepezil; Drug Monitoring; Female; Genotype; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Rivastigmine; Tandem Mass Spectrometry
PubMed: 32848364
DOI: 10.2147/DDDT.S247259 -
Journal of Pharmaceutical and... Oct 2023Alzheimer's disease (AD) is a progressive disease with continuous brain changes and has caused a severe burden on families and society. Huanglian Jiedu Decoction (HLJD)...
Alzheimer's disease (AD) is a progressive disease with continuous brain changes and has caused a severe burden on families and society. Huanglian Jiedu Decoction (HLJD) is a classic traditional Chinese medicine formula that can improve AD animals' cognitive impairment. This study recruited 50 AD patients who were divided into two groups, one receiving donepezil (DON) treatment and the other receiving DON + HLJD treatment for 3 months. The curative effect, inflammatory and oxidative stress levels were analyzed. The PES-D/11, MMSE, and ADL scales were used to evaluate traditional Chinese medicine syndrome elements, cognitive function, mental state, and life ability. There were no significant differences between the two groups in baseline characteristics and vital sign indicators. After drug treatment, the results showed that AD patients with HLJD combined with DON treatment didn't increase the adverse effects and had good compliance. HLJD combined with DON could improve the disease syndrome, making the differences in PES-D/11, MMSE, and ADL scores before and after the intervention larger. Furthermore, both DON and DON+HLJD treatment inhibited the levels of IL-6, IL-1β, TNF-α, and MDA, raised SOD level, and HLJD enhances the inhibitory effect of DON on inflammation and oxidative stress. IL-6, IL-1β, TNF-α, and MDA levels were significantly correlated with curative effect. Moreover, this study found 107 (206) up-regulated metabolites and 1430 (145) down-regulated metabolites in urine (serum) and conducted differential metabolite screening and correlation analysis suggesting that HLJD may interfere with oxidative stress and inflammation in AD by regulating lipid metabolism and glutamic acid metabolism. Arachidonic acid, diaminopimelic acid, and 1-Aminocyclopropanecarboxylic acid may play an important role in HLJD to improve AD.
Topics: Animals; Alzheimer Disease; Donepezil; Tumor Necrosis Factor-alpha; Interleukin-6; Drugs, Chinese Herbal; Metabolomics; Inflammation
PubMed: 37542831
DOI: 10.1016/j.jpba.2023.115610 -
Current Alzheimer Research 2019Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge... (Review)
Review
Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Donepezil; Humans; Protein Aggregation, Pathological
PubMed: 30819078
DOI: 10.2174/1567205016666190228122956 -
Pathology International Nov 2023This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in...
This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in vitro models of UC were established using dextran sodium sulfate (DSS)-induced mice and NCM460 cells, respectively. Following oral administration of DNPZ, body weight, disease activity index (DAI) scores and colon lengths of mice were recorded. Histopathological damage was detected employing hematoxylin and eosin (H&E) staining. Inflammatory factors were tested using enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction, respectively. Apoptosis was estimated utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot. Low-density lipoprotein receptor-related protein 1 (LRP1)/AMP activated protein kinase (AMPK)/nuclear factor-κB (NF- κB) signaling proteins were detected utilizing western blot. NCM460 cell viability was assessed by cell counting kit (CCK)-8. We found that DNPZ partially restored body weight, reduced DAI scores and attenuated intestinal pathological damage in DSS-induced mice. Additionally, inflammatory factors decreased significantly after DNPZ treatment, accompanied by reduced apoptosis level. Phosphorylation (p)-AMPK increased and p-p65 decreased after DNPZ treatment, whereas LRP1 knockdown showed the opposite effect. Moreover, DNPZ treatment greatly restored NCM460 cell viability after DSS stimulation. DNPZ attenuated DSS-induced inflammation and apoptosis in NCM460 cells, which was reversed by LRP1 knockdown. In summary, DNPZ hydrochloride attenuates inflammation and apoptosis in UC via LRP1/AMPK/NF-κB signaling.
Topics: Mice; Animals; Colitis, Ulcerative; NF-kappa B; AMP-Activated Protein Kinases; Donepezil; Colon; Inflammation; Apoptosis; Body Weight; Disease Models, Animal; Colitis; Mice, Inbred C57BL
PubMed: 37830504
DOI: 10.1111/pin.13380