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TheScientificWorldJournal 2013Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage.
OBJECTIVES
This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD.
METHOD
Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007-2012.
RESULTS AND CONCLUSION
Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of "adequacy and representativeness." Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24-52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Memantine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 24288512
DOI: 10.1155/2013/925702 -
ACS Biomaterials Science & Engineering Jul 2023Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug...
Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo experiments. In this scenario, organ-on-a-chip is gaining attention as it couples a state-of-the art in vitro approach to the recapitulation of key in vivo physiological features such as fluidodynamics and a tri-dimensional cytoarchitecture. We implemented a novel liver-on-a-chip (LoC) device based on an innovative dynamic device (MINERVA 2.0) where functional hepatocytes (iHep) have been encapsulated into a 3D hydrogel matrix interfaced through a porous membrane with endothelial cells (iEndo)]. Both lines were derived from human-induced pluripotent stem cells (iPSCs), and the LoC was functionally assessed with donepezil, a drug approved for Alzheimer's disease therapy. The presence of iEndo and a 3D microenvironment enhanced the expression of liver-specific physiologic functions as in iHep, after 7 day perfusion, we noticed an increase of albumin, urea production, and cytochrome CYP3A4 expression compared to the iHep static culture. In particular, for donepezil kinetics, a computational fluid dynamic study conducted to assess the amount of donepezil diffused into the LoC indicated that the molecule should be able to pass through the iEndo and reach the target iHep construct. Then, we performed experiments of donepezil kinetics that confirmed the numerical simulations. Overall, our iPSC-based LoC reproduced the in vivo physiological microenvironment of the liver and was suitable for potential hepatotoxic screening studies.
Topics: Humans; Induced Pluripotent Stem Cells; Alzheimer Disease; Donepezil; Endothelial Cells; Liver; Lab-On-A-Chip Devices
PubMed: 37318190
DOI: 10.1021/acsbiomaterials.3c00346 -
Journal of Enzyme Inhibition and... Dec 2020The symptoms of Alzheimer's disease (AD) do not include only memory loss and cognitive decline but also neuropsychiatric manifestation. These AD-related symptoms are...
The symptoms of Alzheimer's disease (AD) do not include only memory loss and cognitive decline but also neuropsychiatric manifestation. These AD-related symptoms are usually treated with the aid of antipsychotics; however, their effects on cognition and safety remain unexplored. The present study determines the effects of quetiapine, an atypical antipsychotic, and two imidazo[1,2-a]pyrimidine-based inhibitors of PDE10A on the activity of human cholinesterases. Quetiapine moderately inhibited BuChE (IC = 6.08 ± 1.64 µmol/L) but improved the anti-BuChE properties of donepezil by decreasing its IC value. Both PDE10A inhibitors were found to possess moderate anti-AChE properties. The combined mixtures of donepezil and imidazo[1,2-a]pyrimidine analogues produce a synergistic anti-BuChE effect which was greater than either compound alone, improving the IC value by approximately six times. These favourable interactions between quetiapine, PDE10A inhibitors and clinically approved donepezil, resulting in improved anti-BuChE activity, can lead to a wider variety of potent AD treatment options.
Topics: Acetylcholinesterase; Antipsychotic Agents; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Quetiapine Fumarate; Structure-Activity Relationship
PubMed: 32938236
DOI: 10.1080/14756366.2020.1818739 -
Scandinavian Journal of Pain Oct 2023Chronic pain is defined as pain that persists or recurs for more than 3 months. This study focuses on neuropathic pain (NP) and fibromyalgia (FM) which are chronic pain...
Analysis of Japanese nationwide health datasets: association between lifestyle habits and prevalence of neuropathic pain and fibromyalgia with reference to dementia-related diseases and Parkinson's disease.
OBJECTIVES
Chronic pain is defined as pain that persists or recurs for more than 3 months. This study focuses on neuropathic pain (NP) and fibromyalgia (FM) which are chronic pain states, and aims to identify lifestyle habits associated with their prevalence. Other neurological disorders are also analyzed as references.
METHODS
Association between the variable referring to disease prevalence (number of claims for reimbursement of marker drugs) and the variable for lifestyle habits/health examination results (collected from insured individuals aged 40-74 years) was determined by analyzing Japanese nationwide datasets, which were collected in 2018 and aggregated by prefecture. Pregabalin, donepezil, and levodopa were used as marker drugs for the chronic pain states, dementia-related diseases (Alzheimer's disease and Lewy body dementia) and Parkinson's disease (PD), respectively. Pearson's correlation analysis and multiple linear regression analysis were conducted.
RESULTS
Variables showing correlation coefficient (||)>0.5 were put into the multiple linear regression. Exercise habits (ꞵ=-0.3182), smoking habits (0.3218), daily drinking (0.2683), and alanine aminotransferase>51 U/L (0.2309) were finally incorporated in the equation for pregabalin ( =0.7268). Walking speed (-0.4543) and daily drinking (0.5077) were incorporated in the equation for donepezil ( =0.5718).
CONCLUSIONS
The prevalence of chronic pain states is associated with lifestyle habits, just like the dementia-related diseases. Exercise in daily life is negatively associated with the prevalence of the chronic pain states, although excessive alcohol drinking, smoking, and high serum ALT are positively associated with it. The prevalence of PD seems less associated with lifestyle habits.
Topics: Humans; Alzheimer Disease; Chronic Pain; Donepezil; East Asian People; Fibromyalgia; Habits; Life Style; Neuralgia; Parkinson Disease; Pregabalin; Prevalence; Japan; Datasets as Topic; Dementia; Levodopa; Health Risk Behaviors
PubMed: 37439280
DOI: 10.1515/sjpain-2023-0010 -
Biomedicine & Pharmacotherapy =... May 2022Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced...
BACKGROUND
Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN.
METHODS
using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities. The involvement of muscarinic M2 acetylcholine receptors (m2AChRs) in analgesic effects was investigated at the spinal level. The absence of interference of donepezil with the cytotoxic effect of chemotherapy has been controlled in cancer cell lines.
RESULTS
the analgesic efficacy of donepezil was demonstrated for all CIPN models, mainly on tactile hypersensitivity (maximal efficacy at 60 min, p < 0.05 vs. vehicle group). This effect was suppressed by an intrathecal injection of methoctramine (m2AChR antagonist). Regarding preventive effects, donepezil limited tactile hypersensitivity induced by paclitaxel, but not for other CIPN models. Donepezil did not modify the viability of cancer cells or the efficacy of anticancer drugs.
CONCLUSIONS
donepezil had a broad analgesic effect on animal models of CIPN and this effect involved spinal m2AChRs. This work validates the repositioning of donepezil in the management of CIPN.
Topics: Acetylcholine; Analgesics; Animals; Antineoplastic Agents; Cholinesterase Inhibitors; Donepezil; Leukemia, Myeloid, Acute; Models, Animal; Paclitaxel; Peripheral Nervous System Diseases; Rats; Receptor, Muscarinic M2; Receptors, Muscarinic
PubMed: 35635358
DOI: 10.1016/j.biopha.2022.112915 -
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 -
Alzheimer Disease and Associated...Dyadic enrollment of a participant and study partner is required in mild cognitive impairment (MCI) clinical trials, despite participants being functionally independent....
BACKGROUND
Dyadic enrollment of a participant and study partner is required in mild cognitive impairment (MCI) clinical trials, despite participants being functionally independent. Research examining how the study partner requirement impacts MCI trials remains limited.
METHODS
Using the Alzheimer's Disease Cooperative Study donepezil and vitamin E MCI trial data, we quantified the proportions of enrolled spouse, adult child, and other dyads. We used multinomial regression to identify which baseline participant characteristics (age, sex, race and ethnicity, apolipoprotein E ε4 status, education, residence type) were associated with dyad type.
RESULTS
Among 769 randomized dyads, 73% were spousal, 14% adult child, and 13% other dyads. Adjusting for multiple comparisons, underrepresented racial and ethnic background (eg, comparing Hispanic to non-Hispanic White participants: adult child vs. spouse odds ratio = 5.86; 95% confidence interval: 2.09, 16.5; other vs. spouse odds ratio = 4.95; 95% confidence interval: 1.83, 13.4), female sex, age, nonhouse residence, and apolipoprotein E ε4 noncarriage were each associated with a higher odds of having an adult child, as well as an other, study partner at enrollment.
DISCUSSION
Increasing participation among nonspousal dyads may facilitate more inclusive and representative MCI trial samples.
Topics: Adult Children; Alzheimer Disease; Apolipoprotein E4; Clinical Trials, Phase III as Topic; Cognitive Dysfunction; Donepezil; Female; Humans; Male; Patient Participation; Spouses
PubMed: 35482891
DOI: 10.1097/WAD.0000000000000506 -
Phytomedicine : International Journal... Jan 2024The pathogenesis of Alzheimer's disease (AD) is complex, resulting in unsatisfactory effects of single-target therapeutic drugs. Accumulation evidence suggests that low...
BACKGROUND
The pathogenesis of Alzheimer's disease (AD) is complex, resulting in unsatisfactory effects of single-target therapeutic drugs. Accumulation evidence suggests that low toxicity multi-target drugs may play effective roles in AD. Ginseng is the root and rhizome of Panax ginseng Meyer, which can be used not only as herbal medicine but also as a functional food to support body functions. Ginsenoside RK1 (RK1), obtained from ginseng plants through high-temperature treatment, has antiapoptotic, antioxidant, anti-inflammatory effects and these events are involved in the development of AD. So, we believe that RK1 may be an effective drug for the treatment of AD.
HYPOTHESIS/PURPOSE
We aimed to investigate the potential protective effects and mechanisms of RK1 in AD.
METHODS
Neuronal damage was detected by MTT assay, LDH assay, immunofluorescence and western blotting. Oxidative stress was measured by JC-1 staining, reactive oxygen species (ROS) staining, superoxide dismutase (SOD) and malonaldehyde (MDA). The cognitive deficit was measured through morris water maze (MWM) and novel object recognition (NOR) tests.
RESULTS
RK1 attenuated Aβ-induced apoptosis, restored mitochondrial membrane potential (ΔΨm), and reduced intracellular levels of ROS in both PC12 cells and primary cultured neurons. In vivo, RK1 significantly improved cognitive deficits and mitigated AD-like pathological features. Notably, RK1 demonstrated superior efficacy compared to the positive control drug, donepezil. Mechanistically, our study elucidates that RK1 modulates the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, NF-E2-related factor 2 (Nrf2), leading to the optimization of mitochondrial membrane potential, reduction of ROS levels, and mitigation of AD-like pathology. It's noteworthy that blocking the AMPK signaling pathway attenuated the protective effects of RK1.
CONCLUSION
RK1 demonstrates superior efficacy in alleviating cognitive deficits and mitigating pathological changes compared to donepezil. These findings suggest the potential utility of RK1-based therapies in the development of treatments for AD.
Topics: Rats; Animals; Alzheimer Disease; Reactive Oxygen Species; AMP-Activated Protein Kinases; NF-E2-Related Factor 2; Donepezil; Signal Transduction; Oxidative Stress; Cognitive Dysfunction
PubMed: 37925892
DOI: 10.1016/j.phymed.2023.155168 -
International Journal of Molecular... Jun 2023Liposomes modified with tetradecyltriphenylphosphonium bromide with dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal...
Liposomes modified with tetradecyltriphenylphosphonium bromide with dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal administration. Physicochemical characteristics of cationic liposomes such as the hydrodynamic diameter, zeta potential, and polydispersity index were within the range from 105 to 115 nm, from +10 to +23 mV, and from 0.1 to 0.2, respectively. In vitro release curves of donepezil hydrochloride were analyzed using the Korsmeyer-Peppas, Higuchi, First-Order, and Zero-Order kinetic models. Nanocontainers modified with cationic surfactant statistically better penetrate into the mitochondria of rat motoneurons. Imaging of rat brain slices revealed the penetration of nanocarriers into the brain. Experiments on transgenic mice with an Alzheimer's disease model (APP/PS1) demonstrated that the intranasal administration of liposomes within 21 days resulted in enhanced learning abilities and a reduction in the formation rate of Aβ plaques in the entorhinal cortex and hippocampus of the brain.
Topics: Mice; Rats; Animals; Alzheimer Disease; Liposomes; Donepezil; Brain; Mice, Transgenic; Mitochondria; Disease Models, Animal
PubMed: 37445673
DOI: 10.3390/ijms241310494 -
Journal of Pharmacological Sciences Oct 2022Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to...
Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal function, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic efficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects.
Topics: Acetylcholinesterase; Animals; Anorexia; Donepezil; Drugs, Chinese Herbal; Ghrelin; Humans; Kaolin; Medicine, Kampo; Mice; Nausea; Pica; Receptors, Ghrelin; Vomiting
PubMed: 36055750
DOI: 10.1016/j.jphs.2022.08.001