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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 -
Clinics (Sao Paulo, Brazil) 2024Summarize the evidence on drug therapies for obstructive sleep apnea. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Summarize the evidence on drug therapies for obstructive sleep apnea.
METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched on February 17th, 2023. A search strategy retrieved randomized clinical trials comparing the Apnea-Hypopnea Index (AHI) in pharmacotherapies. Studies were selected and data was extracted by two authors independently. The risk of bias was assessed using the Cochrane Risk of Bias tool. RevMan 5.4. was used for data synthesis.
RESULTS
4930 articles were obtained, 68 met inclusion criteria, and 29 studies (involving 11 drugs) were combined in a meta-analysis. Atomoxetine plus oxybutynin vs placebo in AHI mean difference of -7.71 (-10.59, -4.83) [Fixed, 95 % CI, I2 = 50 %, overall effect: Z = 5.25, p < 0.001]. Donepezil vs placebo in AHI mean difference of -8.56 (-15.78, -1.33) [Fixed, 95 % CI, I2 = 21 %, overall effect: Z = 2.32, p = 0.02]. Sodium oxybate vs placebo in AHI mean difference of -5.50 (-9.28, -1.73) [Fixed, 95 % CI, I2 = 32 %, overall effect: Z = 2.86, p = 0.004]. Trazodone vs placebo in AHI mean difference of -12.75 (-21.30, -4.19) [Fixed, 95 % CI, I2 = 0 %, overall effect: Z = 2.92, p = 0.003].
CONCLUSION
The combination of noradrenergic and antimuscarinic drugs shows promising results. Identifying endotypes may be the key to future drug therapies for obstructive sleep apnea. Moreover, studies with longer follow-up assessing the safety and sustained effects of these treatments are needed.
PROSPERO REGISTRATION NUMBER
CRD42022362639.
Topics: Humans; Sleep Apnea, Obstructive; Atomoxetine Hydrochloride; Donepezil; Norepinephrine
PubMed: 38341903
DOI: 10.1016/j.clinsp.2024.100330 -
CNS Neuroscience & Therapeutics May 2013To provide healthcare professionals with a comprehensive assessment of donepezil 23 mg and its role in treating Alzheimer's disease (AD), the Donepezil 23 mg Expert... (Review)
Review
To provide healthcare professionals with a comprehensive assessment of donepezil 23 mg and its role in treating Alzheimer's disease (AD), the Donepezil 23 mg Expert Working Group (EWG) convened in June 2011 to critically evaluate the clinical trial database for this higher dose formulation and the members' clinical experience with its use. Discussions were based on a large, 6-month, phase 3 clinical trial in patients with moderate to severe AD that compared continuing donepezil 10 mg/day versus switching to 23 mg/day. In this trial, donepezil 23 mg/day demonstrated significantly greater cognitive benefits (mean change in Severe Impairment Battery score, 2.11 points; P < 0.001). Prespecified analyses showed that benefits were significant irrespective of concomitant memantine use. The EWG considered integrating these new data into clinical practice approaches. Dementia severity, tolerability of the 10 mg dose, and need for additional therapy were key selection criteria, as was monitoring of gastrointestinal side effects, as consideration of titration strategies is an important aspect of implementation. The EWG concluded that donepezil 23 mg is an efficacious therapy for moderate to severe AD, with or without concomitant memantine, extending the treatment opportunities available to manage moderate to severe AD dementia. EWG guidelines offer assistance to clinicians in choosing and implementing treatment options.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Patient Selection; Piperidines; Practice Guidelines as Topic
PubMed: 23462265
DOI: 10.1111/cns.12076 -
Journal of the Formosan Medical... Jan 2022Donepezil was approved for the treatment of Alzheimer's disease (AD) but causes variable therapeutic responses. Thus, identifying specific genetic polymorphisms, which...
BACKGROUND/PURPOSE
Donepezil was approved for the treatment of Alzheimer's disease (AD) but causes variable therapeutic responses. Thus, identifying specific genetic polymorphisms, which can predict a therapeutic response to donepezil, would enable a development of personalized strategy to treatment for patients with AD. The research aimed to exam the impact of the cytochrome P450 2D6 (CYP2D6) single nucleotide polymorphism (SNP) rs1080985 on the concentration of and therapeutic response to donepezil in AD.
METHODS
In total, 40 newly diagnosed AD patients who had a clinical dementia rating (CDR) of 0.5-2 and who were on donepezil were enrolled and followed up. Plasma concentrations of donepezil were determined after 6 months of donepezil treatment. Cognitive and functional statuses were evaluated annually during follow-up. The response to therapy was defined based on the change in CDR.
RESULTS
At a mean of 21.8 ± 5.7 months of follow-up, 10 of 40 patients (25.0%) were nonresponders to donepezil treatment. Patients who were homozygous for the G allele exhibited a higher concentration of donepezil and concentration-to-dose ratio than those with other genotypes. Furthermore, a significantly higher proportion of patients with the G/G genotype were responders than nonresponders (90.0% vs 50.0%, P = 0.015, effect size of V: 0.457) to donepezil treatment. Conversely, patients carrying the C allele had a significantly high risk of poor responses to donepezil treatment (odds ratio: 9.00, 95% confidence interval: 1.611-50.275).
CONCLUSION
The CYP2D6 SNP rs1080985 might be a useful pharmacogenetic marker of the long-term therapeutic response to donepezil in patients with AD.
Topics: Alzheimer Disease; Cytochrome P-450 CYP2D6; Donepezil; Humans; Nucleotides; Polymorphism, Single Nucleotide
PubMed: 34120801
DOI: 10.1016/j.jfma.2021.05.026 -
Biomedicine & Pharmacotherapy =... Mar 2023The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of... (Randomized Controlled Trial)
Randomized Controlled Trial
The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer's disease.
BACKGROUND
The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate.
METHODS
Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points.
RESULTS
Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups.
CONCLUSION
The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.
Topics: Humans; Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Indans; Piperidines
PubMed: 36630846
DOI: 10.1016/j.biopha.2023.114223 -
The Journal of International Medical... Mar 2024To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia.
METHODS
Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software.
RESULTS
Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment.
CONCLUSION
Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.
Topics: Humans; Benzofurans; Dementia, Vascular; Donepezil; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 38546241
DOI: 10.1177/03000605231223081 -
BMC Neurology Apr 2014Cholinesterase inhibitors (ChEIs) such as donepezil have the effect of delaying progression of Alzheimer's disease (AD), but their effect on life expectancy is unclear....
BACKGROUND
Cholinesterase inhibitors (ChEIs) such as donepezil have the effect of delaying progression of Alzheimer's disease (AD), but their effect on life expectancy is unclear. We analyzed the influence of donepezil on life expectancy after onset of AD, together with the effects of antipsychotic drugs and residency in a nursing home.
METHODS
All outpatients at the Tajiri Clinic from 1999-2012 with available medical records and death certificates were included in a retrospective analysis. The entry criteria were a dementia diagnosis based on DSM-IV criteria and diagnosis of AD using NINCDS-ADRDA criteria; medical treatment for more than 3 months; and follow up until less than 1 year before death.
RESULTS
We identified 390 subjects with medical records and death certificates, of whom 275 had a diagnosis of dementia that met the entry criteria. Of 100 patients diagnosed with AD, 52 had taken donepezil and 48 patients had not received the drug due to treatment prior to the introduction of donepezil in 1999 in Japan. The lifetime expectancies after onset were 7.9 years in the donepezil group and 5.3 years in the non-donepezil group. There was a significant drug effect with a significant covariate effect of nursing home residency. Other covariates did not reach a significant level.
CONCLUSIONS
Although this report has the limitation of all retrospective analyses: the lack of randomization, we found a positive effect of donepezil on lifetime expectancy after onset of AD. This may be due to a decreased mortality rate caused by reduction of concomitant diseases such as pneumonia. The similar life expectancies in patients taking donepezil at home and those not taking donepezil in a nursing home indicated a positive health economic effect of the drug.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Japan; Life Expectancy; Male; Nursing Homes; Piperidines; Retrospective Studies
PubMed: 24720852
DOI: 10.1186/1471-2377-14-83