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Journal of Pharmaceutical Sciences Nov 2022Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is...
Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is not clear in the literature. BCS is one of the accepted criteria used to grant biowaiver (waiver of in vivo bioequivalence studies) of new drug products. So, the purpose of this work was to elucidate the BCS classification of DH and to raise the discussion about the possibility of biowaiver for new medicines containing it. The polymorphic form was previously identified as form III of DH. The drug showed high solubility in the entire pH range evaluated (1.2 to 6.8, at 37 °C) with a pH-dependent solubility profile. The effective permeability (P) values obtained with different DH concentrations, using in situ closed-loop perfusion model were statistically similar (p > 0.05), even when compared to high permeability control used (ketoprofen), demonstrating that DH has high permeability which, associated with its high solubility, allows to classify DH as BCS class 1. Relevant data to evaluate for granting a biowaiver for new medicines were also reviewed from the literature. Based on information reunited new immediate-release drug products containing DH should be eligible for BCS-based biowaiver.
Topics: Biopharmaceutics; Donepezil; Ketoprofen; Permeability; Solubility; Therapeutic Equivalency
PubMed: 35787368
DOI: 10.1016/j.xphs.2022.06.023 -
Clinical Medicine (London, England) Mar 2019
Topics: Accidental Falls; Arrhythmias, Cardiac; Donepezil; Humans; Long QT Syndrome; Torsades de Pointes
PubMed: 30872310
DOI: 10.7861/clinmedicine.19-2-189 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2020Donepezil is the most commonly used drug of the group of cholinesterase inhibitors. It is recommended for tretament of Alzheimer's disease. Donepezil is also used to...
Donepezil is the most commonly used drug of the group of cholinesterase inhibitors. It is recommended for tretament of Alzheimer's disease. Donepezil is also used to treat dementia in Lewy body disease, Parkinson's disease with dementia, and vascular dementia. In Russia, donepezil is not used as often, which is facilitated by the concern of doctors about the possibility of serious side-effects. Clinical studies demonstrate the safety and good tolerability of donepezil. Our study included 62 patients with dementia due to various neurodegenerative diseases (Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia). Thirty-seven patients (59.7%) started to receive donepezil. Side-effects, including bradycardia, hypertension, aggressive behavior, increased tremor, were observed in 7 patients (18.9%). There was no correlation between the development of side-effects and polymorphisms of the and genes.
Topics: Cholinesterase Inhibitors; Donepezil; Humans; Indans; Piperidines; Russia
PubMed: 33081459
DOI: 10.17116/jnevro2020120091137 -
Recent Patents on Biotechnology 2022Alzheimer's disease (AD) is a kind of neuropsychiatric illness that affects the central nervous system. In this disease, the accumulation of amyloid-beta increases, and... (Review)
Review
Alzheimer's disease (AD) is a kind of neuropsychiatric illness that affects the central nervous system. In this disease, the accumulation of amyloid-beta increases, and phosphorylated tau (P-tau) protein is one of the ways to treat this disease is to reduce the accumulation of amyloid-beta. Various studies have demonstrated that pharmacological approaches have considerable effects in the treatment of AD, despite the side effects and challenges. Cholinesterase inhibitors and the NMDA receptor antagonist memantine are presently authorized therapies for AD. Memantine and Donepezil are the most common drugs for the prevention and therapy of AD with mechanisms such as lessened β-amyloid plaque, affecting N-Methyl-D-aspartate (NMDA) receptors. Diminution glutamate and elevated acetylcholine are some of the influences of medications administrated to treat AD, and drugs can also play a role in slowing the progression of cognitive and memory impairment. A new pharmacological approach and strategy are required to control the future of AD. This review appraises the effects of memantine, donepezil, rivastigmine, and aducanumab in clinical trials, in vitro and animal model studies that have explored how these drugs versus AD development and also discuss possible mechanisms of influence on the brain. Research in clinical trials has substantial findings that support the role of these medications in AD treatment and ameliorate the safety and efficacy of AD therapy, although more clinical trials are required to prove their effectiveness.
Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal, Humanized; Donepezil; Indans; Memantine; Patents as Topic; Piperidines; Rivastigmine
PubMed: 35236274
DOI: 10.2174/1872208316666220302115901 -
Translational Research : the Journal of... Apr 2021Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity is associated with left ventricular (LV) dysfunction in cases of...
Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity is associated with left ventricular (LV) dysfunction in cases of cardiac ischemia/reperfusion (I/R) injury. Electrical stimulation to increase vagal activity has been shown to reduce infarct size and decrease fatal arrhythmias in cardiac I/R injury. However, the benefits of a parasympathomimetic drug on the heart during I/R are unclear. We hypothesized that administration of donepezil provides cardioprotection in cardiac I/R injury via reducing cellular apoptosis, oxidative stress, mitochondrial dysfunction, mitochondrial dynamic imbalance, increasing autophagy, and mitophagy. Fifty-four male Wistar rats were randomly assigned into sham and I/R groups. Acute cardiac I/R injury was induced by 30-minutes left anterior descending (LAD) coronary artery occlusion followed by 120-minutes reperfusion. These rats with induced I/R injury were randomly assigned to be treated with either: (1) Saline (vehicle group) or donepezil 3 mg/kg via intravenous injection given (2) before ischemia, (3) during ischemia, or (4) at the onset of reperfusion. Rats with cardiac I/R injury showed an increase in infarct size and arrhythmia score, LV dysfunction, impaired mitochondrial dynamic balance, autophagy and mitophagy, mitochondrial dysfunction, and increased apoptosis. All the donepezil-treated rats, regardless of the time of administration, showed a similar reduction in these impairments, and rebalancing in cardiac mitochondrial dynamics, leading to reduced myocardial infarct size and arrhythmia, and improved LV function. These findings suggested that donepezil effectively protected the heart against I/R injury through cardiac mitochondrial protection regardless of the time of administration.
Topics: Animals; Autophagy; Cholinesterase Inhibitors; Donepezil; Male; Mitochondria, Heart; Mitophagy; Myocardial Infarction; Myocardial Reperfusion Injury; Random Allocation; Rats; Rats, Wistar
PubMed: 33137536
DOI: 10.1016/j.trsl.2020.10.010 -
Expert Review of Neurotherapeutics Jun 2024Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically... (Review)
Review
INTRODUCTION
Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers.
AREAS COVERED
In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments.
EXPERT OPINION
While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.
Topics: Humans; Donepezil; Alzheimer Disease; Cholinesterase Inhibitors; Administration, Cutaneous; Transdermal Patch; Rivastigmine; Severity of Illness Index
PubMed: 38785454
DOI: 10.1080/14737175.2024.2355981 -
Clinical Toxicology (Philadelphia, Pa.) Mar 2021The neurocognitive benefits of donepezil are well recognised, but the potential side effects on cardiac conduction remain unclear.
BACKGROUND
The neurocognitive benefits of donepezil are well recognised, but the potential side effects on cardiac conduction remain unclear.
OBJECTIVE
To investigate whether long-term donepezil therapy is associated with electrocardiographic (ECG) changes and in particular to assess its effects on the QT interval.
METHODS
We conducted a single centre retrospective analysis of patients admitted to our trust on donepezil therapy over a 12-month period. An admission resting 12-lead ECG was obtained and compared to their ECG prior to commencement of donepezil therapy to assess for any significant difference in ECG parameters.
RESULTS
We identified 59 patients suitable for analysis. PR (177.0 ± 29.0 ms vs. 186.1 ± 34.2 ms, = 0.04), QRS (101.7 ± 20.3 ms vs. 104.7 ± 22.3 ms, = 0.04) and QT (393.3 ± 35.6 ms vs. 411.9 ± 44.6 ms, = 0.002) interval prolongation were all associated with donepezil use. The increase in QT intervals remained significant on correction for heart rate; resulting in 8 (13.6%) patients developing high arrhythmogenic risk based on assessment using QT nomogram plots. Concomitant use of tricyclic antidepressants was associated with significant QT prolongation (QTcB: = 0.344, = 0.008, QTcFred: = 0.382, = 0.003, QTcFram: = 0.379, = 0.003, QTcH: = 0.352, = 0.006), while the use of rate-limiting calcium channel blockers was associated with significant PR prolongation ( = 0.314, = 0.030), and beta-blockers with a reduction in heart rate ( = 0.256, = 0.050).
CONCLUSION
Our results clearly demonstrate that long-term use of donepezil is associated with prolongation of the QT interval. We suggest ECG evaluation should take place before and after donepezil initiation, and clinicians should be even more vigilant in those prescribed tricyclic antidepressants.
Topics: Aged, 80 and over; Alzheimer Disease; Donepezil; Electrocardiography; Female; Heart Rate; Humans; Long QT Syndrome; Male; Nootropic Agents; Retrospective Studies; Time Factors
PubMed: 32609550
DOI: 10.1080/15563650.2020.1788054 -
Alzheimer's & Dementia : the Journal of... May 2023During hospital admissions, patients with dementia are at risk for developing delirium, an acute state of brain failure associated with significant morbidity. There are...
INTRODUCTION
During hospital admissions, patients with dementia are at risk for developing delirium, an acute state of brain failure associated with significant morbidity. There are currently no pharmacologic tools to treat or prevent delirium. Decreased cholinergic signaling plays a role in the pathophysiology of both disorders. Whether enhanced pre-hospital cholinergic signaling in patients with dementia improves outcomes during critical illness remains unknown.
METHODS
We utilized the Medical Information Mart for Intensive Care III (MIMIC-III) database to determine whether pre-hospital donepezil use was associated with improved outcomes during critical illness in dementia patients.
RESULTS
We identified 2734 subjects with dementia admitted to the intensive care unit (ICU; 447 received donepezil). After adjusting for confounders, patients with dementia who were receiving donepezil had a significantly reduced in-hospital and 90-day mortality, ICU length of stay, and duration of mechanical ventilation. Donepezil use was associated with, and its benefit was mediated by, reduced delirium.
DISCUSSION
Patients with dementia who are treated with donepezil have improved outcomes during critical illness and reductions in delirium.
HIGHLIGHTS
No pharmacologic treatments exist to reduce delirium in patients with dementia. Donepezil improves outcomes during critical illness in patients with dementia. Improved outcomes are mediated by a reduction in hospital delirium. Future studies in patients with dementia should prospectively evaluate donepezil in the prevention of delirium.
Topics: Humans; Donepezil; Critical Illness; Delirium; Cholinergic Agents; Dementia
PubMed: 36218161
DOI: 10.1002/alz.12807 -
British Journal of Hospital Medicine... Jan 2022
Topics: Cholinesterase Inhibitors; Donepezil; Drug Overdose; Humans; Medication Adherence; Piperidines
PubMed: 35129390
DOI: 10.12968/hmed.2021.0243 -
Chemical Research in Toxicology Apr 2020Oxidized low-density lipoprotein (ox-LDL)- induced endothelial insults plays an important role in the pathogenesis of atherosclerosis. Donepezil is a well-known...
Oxidized low-density lipoprotein (ox-LDL)- induced endothelial insults plays an important role in the pathogenesis of atherosclerosis. Donepezil is a well-known acetylcholinesterase inhibitor with its primary application being the treatment of Alzheimer's disease. More recently, there has been increased interest in donepezil as an antiatherosclerosis treatment as it possesses a host of relevant and potentially beneficial properties. In the present study, we found that donepezil could reduce the expression of lectin-type oxidized low-density lipoprotein receptor-1 (LOX-1) in human aortic endothelial cells (HAECs). We found that donepezil could suppress the expression of intercellular adhesion molecule-1 (ICAM-1), which recruits monocytes to adhere to the endothelium, by more than half. Another key finding of our study is that donepezil could reduce the expression of tumor necrosis factor receptor-α (TNF-α) and interleukin-6 (IL-6) by more than half at both the mRNA and protein transcriptional levels. Donepezil also reduced the expression of tissue factor (TF), which is considerably upregulated in atherosclerotic lesions, by more than half. Finally, we turned our attention to the early growth response protein-1 (Egr-1) for its potential role in mediating the effects of donepezil. Through our Egr-1 overexpression experiment, we found that overexpression of Egr-1 almost completely abolished the effects of donepezil described above. Thus, the effects of donepezil are likely mediated through downregulation of Egr-1. These findings provide evidence that donepezil may exert protective effects against atherosclerosis.
Topics: Aorta; Cells, Cultured; Donepezil; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Lipoproteins, LDL; Molecular Structure; Monocytes; Protective Agents; Structure-Activity Relationship
PubMed: 32174113
DOI: 10.1021/acs.chemrestox.9b00509