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Journal of Arrhythmia Dec 2023Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious...
BACKGROUND
Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database.
METHODS
From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP.
RESULTS
Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3).
CONCLUSIONS
This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.
PubMed: 38045460
DOI: 10.1002/joa3.12936 -
3 Biotech Sep 2023The goal was to evaluate the effect of resveratrol (RS) and combination therapy of RS and donepezil (DPZ), on the numerical expression of microglial cells and...
Effect of resveratrol and combination of resveratrol and donepezil on the expression of microglial cells and astrocytes in albino rats of colchicine-induced Alzheimer's disease.
AIM
The goal was to evaluate the effect of resveratrol (RS) and combination therapy of RS and donepezil (DPZ), on the numerical expression of microglial cells and astrocytes, in the frontal cortex, regions of the hippocampus in colchicine-induced Alzheimer's disease (AD) model.
METHODS
The study involved male albino rats of three months, age and consisted of 6 groups, with six animals each. The immunohistochemical staining with mouse monoclonal anti-human CD 68 and mouse monoclonal anti-GFAP was performed to assess the number of microglial cells and astrocytes, respectively.
RESULTS
AD group showed an increase in the number of microglia, and the numbers declined in the treatment groups, RS 10, RS 20, RS10/10 and DPZ + RS ( < 0.001). Astrocyte count was increased in the treatment groups in contrast to the AD group ( < 0.05). The DPZ + RS combination group revealed substantial elevation in the number of astrocytes and decreased microglial number among all the groups ( < 0.001).
CONCLUSION
RS administration has diminished the microglial number and elevated the number of astrocytes. The elevated reactive astrocytes have decreased the microglial population. However, the limitation of our study is utilizing the colchicine for the induction of neurodegeneration. Using the transgenic models of AD may give a better insight into the pathogenesis and effect of RS. Another limitation of this study is the administration of RS and DPZ through different routes. The prospects of this research include studying the probiotic nature of RS and the effect of RS in other neurodegenerative disorders.
PubMed: 37641690
DOI: 10.1007/s13205-023-03743-4 -
IBRO Neuroscience Reports Jun 2023Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must concentrate on symptom management. Astrocytes and microglia are now known to play distinct physiological roles in synaptic function, the blood-brain barrier, and neurovascular coupling. Consequently, the search for drugs that can slow the degenerative process in dementia sufferers continues because existing drugs are designed to alleviate the symptoms of Alzheimer's disease. Drugs that address pathological changes without interfering with the normal function of glia, such as eliminating amyloid-beta deposits, are prospective treatments for neuroinflammatory illnesses. Because neuron-astrocytes-microglia interactions are so complex, developing effective, preventive, and therapeutic medications for AD will necessitate novel methodologies and strategic targets. This review focused on existing medications used in treating AD amongst which include Donepezil, Choline Alphoscerate, Galantamine, Dextromethorphan, palmitoylethanolamide, citalopram, resveratrol, and solanezumab. This review summarizes the effects of these drugs on neurons, astrocytes, and microglia interactions based on their pharmacokinetic properties, mechanism of action, dosing, and clinical presentations.
PubMed: 36593897
DOI: 10.1016/j.ibneur.2022.11.005 -
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 -
Journal of Alzheimer's Disease : JAD 2022Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia...
BACKGROUND
Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan.
OBJECTIVE
To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data.
METHODS
Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation.
RESULTS
We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94-1.07) for patients with support needs, 1.12 (1.06-1.18) for patients with low long-term care needs, and 1.31 (1.21-1.40) for patients with moderate-to-high long-term care needs relative to independent patients.
CONCLUSION
Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients.
Topics: Humans; Female; Aged; Aged, 80 and over; Donepezil; Cholinesterase Inhibitors; Alzheimer Disease; Japan; Indans; Piperidines
PubMed: 36213993
DOI: 10.3233/JAD-220200 -
International Journal of Molecular... May 2020Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer's disease (AD). In contrast to these failures,... (Review)
Review
Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer's disease (AD). In contrast to these failures, acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors slow the clinical progression of the disease and randomized, placebo-controlled trials in prodromal and mild to moderate AD patients have shown AChE inhibitor anti-neurodegenerative benefits in the cortex, hippocampus, and basal forebrain. CNS neurodegeneration and atrophy are now recognized as biomarkers of AD according to the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria and recent evidence shows that these markers are among the earliest signs of prodromal AD, before the appearance of amyloid. The current AChE inhibitors (donepezil, rivastigmine, and galantamine) have short-acting mechanisms of action that result in dose-limiting toxicity and inadequate efficacy. Irreversible AChE inhibitors, with a long-acting mechanism of action, are inherently CNS selective and can more than double CNS AChE inhibition possible with short-acting inhibitors. Irreversible AChE inhibitors open the door to high-level CNS AChE inhibition and improved anti-neurodegenerative benefits that may be an important part of future treatments to more effectively prevent, delay the onset, or slow the progression of AD.
Topics: Acetylcholinesterase; Alzheimer Disease; Cerebral Cortex; Cholinesterase Inhibitors; Humans; Neurodegenerative Diseases
PubMed: 32414155
DOI: 10.3390/ijms21103438 -
Frontiers in Psychiatry 2022This report aims to introduce a rare case of a dramatic recovery by donepezil with a patient with schizophrenia who suffered from remaining psychotic symptoms despite...
OBJECTIVES
This report aims to introduce a rare case of a dramatic recovery by donepezil with a patient with schizophrenia who suffered from remaining psychotic symptoms despite proper treatment and had a cognitive impairment by carbon monoxide (CO) poisoning sequelae.
CASE REPORT
A 38-year-old male who developed schizophrenia 2 years ago had attempted suicide CO inhalation due to his uncontrolled symptoms. He was hospitalized with delayed neurological sequelae (DNS). Though hyperbaric oxygen therapy (HBOT) was applied 10 times, his cognitive impairment did not recover. Surprisingly, with 5-10 mg donepezil, both cognitive function and the psychotic symptoms of the patient remarkably improved.
CONCLUSION
This case showed a good response of donepezil for a patient with schizophrenia and CO-induced DNS after ineffective HBOT. Although the mechanism of the phenomenon is unclear, it can be possible reasons that the neuroprotective effect of donepezil and white matter insult by CO poisoning.
PubMed: 36465281
DOI: 10.3389/fpsyt.2022.1071417 -
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 -
Therapeutic Advances in Infectious... 2023Donepezil is a front-line treatment for Alzheimer's disease. Donepezil treatment is associated with decreased risk of all-cause mortality. Specific protection is...
BACKGROUND AND AIM
Donepezil is a front-line treatment for Alzheimer's disease. Donepezil treatment is associated with decreased risk of all-cause mortality. Specific protection is observed in pneumonia and cardiovascular disease. We hypothesized that donepezil treatment would improve mortality among Alzheimer's patients following infection with COVID-19. The objective of this study is to assess the influence of ongoing donepezil treatment on survival in Alzheimer's disease patients after polymerase chain reaction (PCR)-confirmed COVID-19 infection.
METHODS
This is a retrospective cohort study. We conducted a national survey of Veterans with Alzheimer's disease to assess the influence of ongoing donepezil treatment on survival in Alzheimer's disease patients after PCR-confirmed COVID-19 infection. We assessed all-cause 30-day mortality stratified by COVID-19 infection and donepezil use, estimating odds ratios using multivariate logistic regression.
RESULTS
Among people with Alzheimer's disease and COVID-19, all-cause 30-day mortality was 29% (47/163) for people taking donepezil compared with 38% (159/419) for those who were not. Among people with Alzheimer's disease without COVID-19, all-cause 30-day mortality was 5% (189/4189) for people taking donepezil compared with 7% (712/10,241) for those who were not. Adjusting for covariates, the decrease in mortality associated with donepezil did not differ between people with and without COVID-19 (interaction = 0.710).
CONCLUSION
The known survival benefits of donepezil were retained but not found to be specific to COVID-19 among people with Alzheimer's disease.
PubMed: 37234745
DOI: 10.1177/20499361231174289