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Drugs & Aging Nov 2023The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia.
OBJECTIVES
While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined.
METHODS
We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia.
RESULTS
A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine.
CONCLUSIONS
Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia.
CLINICAL TRIAL REGISTRATION
The study was pre-registered on PROSPERO (CRD42021258376).
Topics: Humans; Acetylcholinesterase; Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Donepezil; Galantamine; Parkinson Disease; Phenylcarbamates; Randomized Controlled Trials as Topic; Rivastigmine; Sleep Initiation and Maintenance Disorders
PubMed: 37682445
DOI: 10.1007/s40266-023-01065-x -
Ageing Research Reviews Mar 2022Psychotic symptoms of dementia are highly prevalent and lead to poor medical outcomes and substantial dysfunction. To date, which drug to use remains controversial... (Meta-Analysis)
Meta-Analysis Review
Psychotic symptoms of dementia are highly prevalent and lead to poor medical outcomes and substantial dysfunction. To date, which drug to use remains controversial without a summary of all direct or indirect comparisons of pharmacotherapy. Therefore, we conducted a systematic review with pairwise and network meta-analysis to examine efficacy and tolerability outcomes of pharmacological treatments in dementia patients. MEDLINE, Cochrane Library, EMBASE, and PubMed were searched systematically up to August 31, 2020. We included trials of cholinesterase inhibitors (ChEIs), memantine, antipsychotics, antidepressants, and mood stabilizers, with final approval from the U.S. Food and Drug Administration. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities. This analysis is based on 34 trials, which included 10,415 patients randomly assigned to 15 commonly used drug regimens. Donepezil (standardized mean difference [SMD] -0.30, 95% credible interval [CrI] -0.50 to -0.12; SUCRA, 0.85), memantine (SMD -0.20, 95%CrI -0.34 to -0.07; SUCRA, 0.68) and aripiprazole (SMD -0.17, 95% CrI -0.32 to -0.02; SUCRA, 0.62) showed greater benefit than placebo, and with relatively good tolerability in network meta-analyses. Risperidone was also found to be more efficacious than placebo (SMD -0.16, 95% CrI -0.28 to -0.05; SUCRA, 0.60), but with poor tolerability (odds ratios [OR] 1.50, 95% CrI 1.06-2.26). Donepezil, memantine, haloperidol, aripiprazole and risperidone were more efficacious than quetiapine (SMDs ranged from -0.36 to -0.22). Besides, donepezil, memantine and mirtazapine were more efficacious than sertraline (SMDs ranged from -0.47 to -0.36). Most of the results were rated as "low" to "very low". Several effective treatment choices for psychotic symptoms are available across drug classes. Donepezil, memantine and aripiprazole are probably the appropriate options to consider when a pharmacological treatment is indicated. Given the limitations of the meta-analytic approach and the low methodological quality of the majority of studies, our results should be cautiously interpreted.
Topics: Aripiprazole; Dementia; Donepezil; Humans; Memantine; Network Meta-Analysis; Risperidone; United States
PubMed: 35051646
DOI: 10.1016/j.arr.2022.101568 -
Mini Reviews in Medicinal Chemistry 2023Alzheimer's disease (AD) is a multifactorial, irreversible, and age-related neurodegenerative disorder among the elderly. AD attracts attention due to its complex... (Review)
Review
Alzheimer's disease (AD) is a multifactorial, irreversible, and age-related neurodegenerative disorder among the elderly. AD attracts attention due to its complex pathogenesis, morbidity and mortality rates, and the limitations of drugs used in the treatment of AD. Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are used in the clinic. While tacrine, donepezil, galantamine, and rivastigmine are cholinesterase inhibitors, memantine is a non-competitive NMDA receptor antagonist. However, these drugs could not delay the progress of AD. The traditional clinical approach which is the one drug-one target concept is not entirely effective in the treatment of AD. Also, it is of high-priority to develop potent and novel anti-AD drugs by the design concept of multitarget directed ligands (MTDLs) which combine pharmacophores interacting with different pathways in AD. This article provides an overview of the noteworthy structural modifications made to tacrine to develop novel candidates for anti-Alzheimer drugs. Due to the complex pathology of AD, multifunctional tacrine-based ligands targeting different hallmarks, β-amyloid, tau protein, N-methyl-Daspartate receptor, cholinesterases, monoamine oxidases, secretases, have been studied. Here, tacrinebased derivatives including heterocyclic structures such as dihydroxypyridine, chromene, coumarin, pyrazole, triazole, tetrahydroquinolone, dipicolylamine, arylisoxazole were reported with promising anti-AD effects compared to tacrine. In vitro and in vivo assays showed that new tacrine-based hybrids, which are selective, neuroprotective, and non-hepatotoxic, might be considered as remarkable anti-AD drug candidates for further clinical studies.
Topics: Aged; Humans; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Donepezil; Ligands; Tacrine
PubMed: 36464869
DOI: 10.2174/1389557523666221201145141 -
Journal of Enzyme Inhibition and... Dec 2023Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The...
Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that was a reversible and selective BChE inhibitor (IC = 0.53 μM), and the docking provided the possible mechanism. Compound also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, was a potential multifunctional lead compound against AD.
Topics: Humans; Aged; Donepezil; Rivastigmine; Alzheimer Disease; Cholinesterase Inhibitors; Neuroprotective Agents; Acetylcholinesterase; Structure-Activity Relationship
PubMed: 37414563
DOI: 10.1080/14756366.2023.2231661 -
AAPS PharmSciTech Feb 2022The current research work aims to study the pharmacokinetic and nasal ciliotoxicity of donepezil liposome-based in situ gel to treat Alzheimer's disease. The...
The current research work aims to study the pharmacokinetic and nasal ciliotoxicity of donepezil liposome-based in situ gel to treat Alzheimer's disease. The physicochemical properties and first-pass metabolism of donepezil HCl result in low concentrations reaching the brain post oral administration. To overcome this problem, donepezil HCl-loaded liposomes were formulated using the ethanol injection method. The donepezil HCl-loaded liposomes were spherical with a size of 103 ± 6.2 nm, polydispersity index of 0.108 ± 0.008, and entrapment efficiency of 93 ± 5.33 %. The optimized in situ gel with donepezil HCl-loaded liposomes showed 80.11 ± 7.77 % drug permeation than donepezil HCl solution-based in situ gel (13.12 ± 4.84 %) across sheep nasal mucosa. The nasal ciliotoxicity study indicated the safety of developed formulation for administration via nasal route. The pharmacokinetics and biodistribution study of developed formulation showed higher drug concentration (1239.61 ± 123.60 pg/g) in the brain after nasal administration indicating its better potential via the nasal pathway. To treat Alzheimer's disease, the administration of liposome-based in situ gel through the nasal pathway can therefore be considered as an effective and promising mode of drug delivery.
Topics: Administration, Intranasal; Animals; Brain; Donepezil; Drug Delivery Systems; Drug Liberation; Liposomes; Nasal Mucosa; Sheep; Tissue Distribution
PubMed: 35149912
DOI: 10.1208/s12249-022-02209-9 -
Bioorganic Chemistry Mar 2024Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure-activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD.
Topics: Humans; Alzheimer Disease; Cholinesterase Inhibitors; Ligands; Donepezil; Rivastigmine; Acetylcholinesterase
PubMed: 38290187
DOI: 10.1016/j.bioorg.2024.107152 -
Neurotoxicology May 2022The current study elucidates pharmacological evaluation of bromelain as a bioactive compound obtain from pineapple stem belongs to family Bromeliaceae in AlCl and D -...
The current study elucidates pharmacological evaluation of bromelain as a bioactive compound obtain from pineapple stem belongs to family Bromeliaceae in AlCl and D - galactose induced mice. In mice, co-administration of AlCl at dose 5 mg/kg b.w., via the oral route, and D - galactose at dose 60 mg/kg b.w., via intraperitoneal route for 90 days resulted in cognitive impairment, spatial learning, and memory deficits, as well as neurotoxicity. However, 30 consecutive days, treatments via an intraperitoneal route with bromelain low dose (Brm L) at dose 10 mg/kg b.w., bromelain high dose (Brm H) at dose 20 mg/kg b.w., donepezil (Dnpz) at dose 2 mg/kg b.w., and Brm L + Dnpz at doses 10, 2 mg/kg b.w. were considerably reversed the effect of AlCl and D - galactose induced AD mice. Consequences of behavioral parameters (Morris water maze, elevated plus maze and locomotor), biochemical estimation (MDA, GSH, SOD, CAT, Nitrite and AChE), and ELISA tests (mouse BACE, Aβ, TNF-α, IL-6, and BDNF) confirmed significant (p < 0.05) neuroprotective effect of treatments in AlCl and D - galactose induced mice. Additionally, hematoxylin and eosin staining of the cerebral cortex and the hippocampus exposed eosinophilic lesions and hyperchromatic nuclei in AD mice, but these neurodegenerative effects were eliminated by Brm L, Brm H, Dnpz, and Brm L + Dnpz treatments. Thus, bromelain alone and in combination with donepezil prevent AlCl and D - galactose induced spatial learning and memory deficits, as well as cognitive impairment, by increasing cholinergic activity and synaptic plasticity, as well as reducing oxidative damage, neuroinflammation, Aβ aggregations, and histopathological damage, according to our findings. The present study consequences indicate that bromelain alone and in combination with donepezil appears to have neuroprotective properties. Henceforward, this may be a promising treatment option for Alzheimer's disease.
Topics: Aluminum Chloride; Alzheimer Disease; Animals; Bromelains; Disease Models, Animal; Donepezil; Galactose; Hippocampus; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Oxidative Stress
PubMed: 35219781
DOI: 10.1016/j.neuro.2022.02.009 -
Current Alzheimer Research 2022Alzheimer's disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many...
BACKGROUND
Alzheimer's disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many acetylcholinesterase inhibitors, such as donepezil, are widely used for the treatment of AD. On the other hand, the efficacy of long-term donepezil use is limited. SIP3, a mixture of three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine.
OBJECTIVE
We assessed the synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice.
METHODS
In this study, a Drosophila AD model and SH-SY5Y clles were used to assess the toxicity of SIP3, and APPswe/PS1dE9 (APP/PS1) transgenic mice were used to evaluate the cognitive-behavioral and depression-like behavior effect of SIP3 and donepezil co-treatment on symptoms of AD. The cerebral cortex or hippocampus transcriptomes were analyzed by RNA sequencing and miRNA to investigate the molecular and cellular mechanisms underlying the positive effects of SIP3 on AD.
RESULTS
In the passive avoidance test (PAT) and Morris water maze (MWM) test, the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice in the mid-stage of AD compared to the group treated with donepezil only. In addition, co-administration of SIP3 and donepezil effectively reduced the depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of the cerebral cortex transcriptome and miRNA of the hippocampus showed that the gene expression profiles after a low dose SIP3 co-treatment were more similar to those of the normal phenotype mice than those obtained after the donepezil treatment alone. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, showed that differentially expressed genes were involved in the locomotor behavior and neuroactive ligand-receptor interactions. These results suggest that a co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.
CONCLUSION
Co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Depression; Disease Models, Animal; Donepezil; Herbal Medicine; Hippocampus; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Neuroblastoma
PubMed: 35422218
DOI: 10.2174/1567205019666220413082130 -
CNS & Neurological Disorders Drug... 2022Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous... (Review)
Review
Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous system at the site of cholinergic neurotransmission. It is involved in the pathophysiology of Alzheimer's diseasecausing dementia, cognitive impairment, behavioral and psychological symptoms. Recent findings involved the inhibition of AchE that could aid in the treatment of Alzheimer's. Many drugs of different classes are being analyzed in the clinical trials and examined for their potency. Drugs that are used in the treatment of Alzheimer's disease are donepezil, galantamine, tacrine, rivastigmine showing major adverse effects. To overcome this, researchers work on novel drugs to elicit inhibition. This review comprises many hybrids and non-hybrid forms of heteroaromatic and nonheteroaromatic compounds that were designed and evaluated for AchE inhibition by Ellman's method of assay. These novel compounds may assist future perspectives in the discovery of novel moieties against Alzheimer's disease by the inhibition of AchE.
Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Rivastigmine
PubMed: 34602041
DOI: 10.2174/1871527320666210928160159 -
Journal of Psychopharmacology (Oxford,... Dec 2020A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological...
BACKGROUND
A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological profile beyond cognition remains unclear. The zebrafish () is rapidly becoming a powerful novel model organism in neuroscience and central nervous system drug screening.
AIM
Here, we characterize the effects of 24-h donepezil administration on anxiety-like behavioral and endocrine responses in adult zebrafish.
METHODS
We evaluated zebrafish anxiety-like behaviors in the novel tank, the light-dark and the shoaling tests, paralleled by assessing brain acetylcholinesterase activity and whole-body cortisol levels.
RESULTS
Overall, donepezil dose-dependently decreased zebrafish locomotor activity in the novel tank test and reduced time in light in the light-dark test, likely representing hypolocomotion and anxiety-like behaviors. Donepezil predictably decreased brain acetylcholinesterase activity, also increasing whole-body cortisol levels, thus further linking acetylcholinesterase inhibition to anxiety-like behavioral and endocrine responses.
CONCLUSION
Collectively, these findings suggest negative modulation of zebrafish affective behavior by donepezil, support the key role of cholinergic mechanisms in behavioral regulation in zebrafish, and reinforce the growing utility of zebrafish models for studying complex behavioral processess and their neuroendocrine and neurochemical regulation.
Topics: Animals; Anxiety; Behavior, Animal; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Female; Hydrocortisone; Locomotion; Male; Zebrafish
PubMed: 32854587
DOI: 10.1177/0269881120944155