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Brain Sciences Jul 2023Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely... (Review)
Review
OBJECTIVE
Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed.
DESIGN
A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised.
RESULTS
In patients with Alzheimer's Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson's Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects.
CONCLUSIONS
Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital.
PubMed: 37508993
DOI: 10.3390/brainsci13071061 -
Scientific Reports Aug 2023Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this... (Randomized Controlled Trial)
Randomized Controlled Trial
Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.
Topics: Humans; Female; Breast Neoplasms; Metformin; Ventricular Function, Left; Stroke Volume; Donepezil; Cardiotoxicity; Leukocytes, Mononuclear; Doxorubicin; Natriuretic Peptide, Brain; Peptide Fragments
PubMed: 37550350
DOI: 10.1038/s41598-023-40061-4 -
Age and Ageing Nov 2023Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits.
OBJECTIVE
To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders.
METHODS
Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis.
RESULTS
Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures.
CONCLUSION
In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.
Topics: Humans; Cholinesterase Inhibitors; Donepezil; Rivastigmine; Accidental Falls; Galantamine; Accidental Injuries; Cognitive Dysfunction; Fractures, Bone; Syncope
PubMed: 37993407
DOI: 10.1093/ageing/afad205 -
Journal of Enzyme Inhibition and... Dec 2023Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three... (Review)
Review
Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.
Topics: Humans; Monoamine Oxidase; Acetylcholinesterase; Alzheimer Disease; Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Cholinesterase Inhibitors; Structure-Activity Relationship
PubMed: 37955252
DOI: 10.1080/14756366.2023.2270781 -
Experimental and Therapeutic Medicine Sep 2023Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with the process of... (Review)
Review
Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with the process of global ageing. Although extensive research has been carried out on AD, the etiology and pathological mechanism of the disease are still unclear, and there is no specific drug to cure or delay AD progression. The exploration of enhancing nerve regeneration in AD has gradually attracted increasing attention. In the current review, the existing therapeutic strategies were summarized to induce nerve regeneration which can increase the number of neurons, and improve the survival of neurons, the plasticity of synapses and synaptic activity. The strategies include increasing neurotrophic expression (such as brain-derived neurotrophic factor and nerve growth factor), inhibiting acetylcholinesterase (such as donepezil, tacrine, rivastigmine and galanthamine), elevating histone deacetylase levels (such as RGFP-966, Tasquinimod, CM-414 and 44B), stimulating the brain by physiotherapy (such as near-infrared light, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation) and transplanting exogenous neural stem cells. However, further evaluations need to be performed to determine the optimal treatment. The present study reviews recent interventions for enhancing adult neurogenesis and attempts to elucidate their mechanisms of action, which may provide a theoretical basis for inducing nerve regeneration to fight against AD.
PubMed: 37614437
DOI: 10.3892/etm.2023.12143 -
Journal of Forensic and Legal Medicine Jan 2024Donepezil is one of the primary treatments options for patients suffering from Alzheimer's Disease. In a review of more than 2200 postmortem donepezil positive blood... (Review)
Review
Donepezil is one of the primary treatments options for patients suffering from Alzheimer's Disease. In a review of more than 2200 postmortem donepezil positive blood specimens, 76% of concentrations were higher than the proposed therapeutic range. Means and medians were similar between central blood specimens and peripheral specimens, indicating minimal postmortem redistribution. Postmortem concentrations may not reflect those circulating antemortem. Mean and median postmortem blood concentrations were approximately 3-fold higher than those in antemortem blood specimens. Additionally, in cases where antemortem blood was available for testing, large increases in donepezil concentrations were reported between antemortem and postmortem specimens without documented administration by medical personnel. Elevated blood donepezil concentrations have been reported in multiple postmortem cases where cause of death was unrelated. The blood concentrations reported in cases where donepezil did not contribute to death overlapped with those in suspected drug overdose cases where other drugs may have been present. In 4 out of 5 suspected donepezil overdose cases, blood concentrations greater than 1000 ng/mL were reported, whereas less than 1% of all postmortem blood samples reviewed achieved these concentrations. Blood concentrations greater than 1000 ng/mL should be considered contributory when a drug overdose is suspected. Postmortem donepezil concentrations should be interpreted with caution in the context of a comprehensive case history.
Topics: Humans; Donepezil; Postmortem Changes; Autopsy; Drug Overdose
PubMed: 38043240
DOI: 10.1016/j.jflm.2023.102625 -
Biomedicines Dec 2023Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive... (Review)
Review
Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR) knock-out mice or by LPAR antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer's disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome.
PubMed: 38255163
DOI: 10.3390/biomedicines12010056 -
Expert Opinion on Pharmacotherapy 2023The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with... (Review)
Review
INTRODUCTION
The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with available antipsychotics. The purpose of the present manuscript is to provide an updated overview of novel pharmacotherapy targeting positive symptoms in schizophrenia.
AREAS COVERED
A comprehensive research on the main database sources (PubMed, PsychINFO, Isi Web of Knowledge, MEDLINE, and EMBASE) was performed to obtain original articles published till 31 January 2023 about new pharmacological strategies for the treatment of positive symptoms in schizophrenia.
EXPERT OPINION
The most promising compounds include: lamotrigine, pro-cognitive-compounds (donepezil - in the short term, idazoxan and piracetam) and drugs acting partially or totally outside the Central Nervous System (CNS) (anti-inflammatory drugs: celecoxib, methotrexate; cardiovascular compounds: L-theanine, mononitrate isosorbide, propentofylline, sodium nitroprusside; metabolic regulators: diazoxide, allopurinol; others: bexarotene, raloxifene [in women]). The effectiveness of the latter compounds indicates that other biological systems, such as immunity or metabolism can be object of future research to identify pharmacological targets for positive symptoms of schizophrenia. Mirtazapine could be useful for treating negative symptoms without increasing the risk of a worsening of delusions/hallucinations. Nevertheless, the lack of replication of studies prevents to draw definitive conclusions and future studies are needed to confirm the findings presented in this overview.
Topics: Humans; Female; Schizophrenia; Antipsychotic Agents
PubMed: 37401388
DOI: 10.1080/14656566.2023.2231346 -
Drug Development Research Dec 2023Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying... (Review)
Review
Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aβ aggregation.
Topics: Humans; Rivastigmine; Carbamates; Acetylcholinesterase; Pharmacophore; Cholinesterase Inhibitors; Alzheimer Disease
PubMed: 37694498
DOI: 10.1002/ddr.22113 -
Biomedicine & Pharmacotherapy =... Dec 2023Alzheimer's disease (AD) stands as the predominant age-related neurodegenerative disorder, for which efficacious treatment remains elusive. An auspicious avenue for this...
Alzheimer's disease (AD) stands as the predominant age-related neurodegenerative disorder, for which efficacious treatment remains elusive. An auspicious avenue for this disease lies in natural compounds sourced from tranditional medicine and plant origins. Parthenolide (PTN) is a natural product with multiple biological functionsand. Recent investigations have illuminated PTN's protective properties against neurological maladies; however, its potential therapeutic role against AD remains uncharted. This study aims to explore the role of PTN in treating AD. Our in vitro findings underscore PTN's bioactivity, as evidenced by its capacity to curtail apoptosis, reduce reactive oxygen species (ROS) production, and restore mitochondrial membrane potential in PC12 cells. Moreover, PTN treatment demonstrates a capacity to ameliorate deficits in spatial learning and memory in the 3 ×Tg-AD murine model. Notably, PTN's therapeutic efficacy surpasses that of a clinical agent, donepezil. Mechanistically, PTN's neuroprotective effects stem from its adept regulation of the AMPK/GSK3β(ser9)/Nrf2 signaling pathway and protection on neuronal cells from ROS-related apoptosis. Although the molecular target and the pre-clinical evaluations of PTN need to be further explored, this study indicates PTN as a potential agent or lead compound for the drug development against AD.
Topics: Rats; Mice; Animals; Reactive Oxygen Species; NF-E2-Related Factor 2; AMP-Activated Protein Kinases; Glycogen Synthase Kinase 3 beta; Signal Transduction; Alzheimer Disease; Cognitive Dysfunction; Neuroprotective Agents; Neurotoxicity Syndromes; Amyloid beta-Peptides
PubMed: 37992573
DOI: 10.1016/j.biopha.2023.115909