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Alzheimers disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimers disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimers Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

In this study, donepezil hydrochloride (DZ HCl), a crucial medication for the treatment of Alzheimer's disease, is detected using a new sensor built on CuO-TiO 2 hybrid nanostructures. The sensor showed improved performance characteristics with a computed limit of quantitation of 0.211 and a limit of detection of 0.063. These qualities included improved stability, selectivity, and sensitivity. The fabrication process demonstrated repeatability, with a 4.27% relative standard deviation. After 10 successive readings, the sensor maintained 95% of its initial response, demonstrating its long-term stability. By quantifying DZ HCl in urine samples, the practical applicability of the sensor was confirmed. Remarkably, the sensor achieved a remarkable recovery rate of 97.00–99.41% and a suitable relative standard deviation range of 3.29–4.71%. The results of this work contribute to the development of trustworthy electrochemical sensors for medicinal chemicals and have prospective uses in pharmacological, biological, and therapeutic fields. [ABSTRACT FROM AUTHOR]

The dementia epidemic, attributed to aging populations, represents a growing socio-economic burden. It is estimated that in 2019 about 55 million people worldwide were living with dementia. With many possible causes of dementia and the possibility of mixed dementia combining Alzheimer's disease (AD) and vascular dementia the question is whether diagnostic uncertainty exists or whether diagnostic constructs based on single etiologies are incorrect. Vascular Cognitive Impairment and Dementia (VCID) designates the extent of cognitive dysfunctions from the most benign state to that of dementia, of vascular origin. We reviewed epidemiological, pathophysiological and clinical data on VCID with a focus on VaD, as well as key data on the development of a new therapeutic solution, SaiLuoTong (MLC-SLT). From documentary research executed on different web sources (PubMed, Clintrials.gov, Z-library and Google), our initial selection for the short review of VCID and VaD was based on keywords contained in each paragraph subtitles of this article with exclusion of publications in a language other than English or published before 2010. For the review of SaiLuoTong development, there was just the language exclusion criterion. Sorted by relevance and publication date, 47 references were selected from 140 shortlisted for review. With new evidence-based classification systems, vascular cognitive impairment was proposed as umbrella term covering all forms of cognitive deficits related to vascular causes. The scope of application expanded with the VCID which includes VaD and mixed pathologies. No drugs are approved for the treatment of VaD by major Western regulatory agencies, while some traditional Chinese medicines are registered in China. VCID treatment should have a dual focus: managing the underlying cerebrovascular disease and dementia symptoms. This is the objective set for the development of the MLC-SLT, the essential data of which are reviewed in detail. To strengthen VCID and VaD research, consensus groups should attempt to consolidate scattered local research initiatives into coordinated international programs. In two VaD clinical trials, MLC-SLT improved cognitive symptoms and activities of daily living, with good safety and potential diseasemodifying effect. In a placebo-controlled study in 325 patients with mild to moderate VaD and randomized according to a delayed-start design, MLC-SLT demonstrated significant improvement in memory tests and performance in executive function tasks, expanding its place in the management of VCID. At week 26, changes in VADAS-cog scores (SD) from baseline were 23.25 (0.45) for MLCSLT 180 mg bid), 23.05 (0.45) for MLC-SLT 120 mg bid (both p < 0.0001), and 20.57 (0.45) for placebo (p = 0.15). At week 52, differences between both groups MLCSLT and placebo were 2.67 and 2.48, respectively (p < 0.0001), without significant difference between MLC-SLT groups. [ABSTRACT FROM AUTHOR]

Background/aim: Alzheimer's disease (AD), one of the most common health issues, is characterized by memory loss, severe behavioral disorders, and eventually death. Despite many studies, there are still no drugs that can treat AD or stop it from progressing. Previous in vitro tests showed that O-demethyl galantamine (ODG) might have therapeutic potential owing to its 10 times higher acetylcholinesterase inhibitory activity than galantamine (GAL). Materials and methods: We aimed to assess the effect of ODG at the molecular level in a 12-month-old 5xFAD Alzheimer's mouse model. To this end, following the administrations of ODG and GAL (used as a positive control), protein alterations were investigated in the cortex, hippocampus, and cerebellum regions of the brain. Surprisingly, GAL altered proteins prominently in the cortex, while ODG exclusively exerted its effect on the cerebellum. Results: GNB1, GNB2, NDUFS6, PAK2, and RhoA proteins were identified as the top 5 hub proteins in the cerebellum of ODG-treated mice. Reregulation of these proteins through Ras signaling and retrograde endocannabinoid signaling pathways, which were found to be enriched, might contribute to reversing AD-induced molecular changes. Conclusion: We suggest that, since it targets specifically the cerebellum, ODG may be further evaluated for combination therapies for AD. [ABSTRACT FROM AUTHOR]

Background: Current evidence for the management of symptoms associated with dementia with Lewy bodies (DLB) using donepezil is limited. We conducted a meta‐analysis of three randomised controlled trials of donepezil in patients with DLB to investigate the overall efficacy of donepezil on Mini‐Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinician's Interview‐Based Impression of Change‐plus Caregiver Input (CIBIC‐plus). Methods: A meta‐analysis was performed using the data of 312 patients administered placebo or 10 mg donepezil. Overall mean score differences for MMSE, NPI‐2, and NPI‐10 from baseline to week 12 and their 95% confidence intervals (CI) were estimated. For CIBIC‐plus, which was transformed from a seven‐point grade to a dichotomous outcome (improvements/no improvements), odds ratio (OR) and its 95% CI were estimated. Random‐effects models were used, and heterogeneity was evaluated using the Cochrane's Q test and I2 statistic. Results: Heterogeneity was suspected for NPI‐2 (P < 0.05; I2 = 87.2%) and NPI‐10 (P < 0.05; I2 = 67.7%) while it was not suspected for MMSE (P = 0.23; I2 = 32.4%) and CIBIC‐plus (P = 0.26; I2 = 19.8%). The overall mean MMSE score difference (mean difference: 1.50; 95% CI, 0.67–2.34) and the overall odds of improving CIBIC‐plus (OR: 2.20; 95% CI, 1.13–4.26) from baseline to week 12 were higher in the donepezil group than in the placebo group. Conclusion: Results of our meta‐analysis indicated overall efficacy of donepezil on cognitive impairment and global clinical status in patients with DLB. [ABSTRACT FROM AUTHOR]

Background: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12‐week double‐blind phase. Methods: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview‐Based Impression of Change plus Caregiver Input (CIBIC‐plus). We also assessed four CIBIC‐plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini‐Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. Results: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42–2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI‐2: −0.2 (95% CI, −1.48 to 1.01), P = 0.710; NPI‐10: 0.1 (95% CI, −3.28 to 3.55), P = 0.937). Conclusion: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected. [ABSTRACT FROM AUTHOR]

Objective To explore the efficacy of combination therapy of Ginkgo biloba injection and donepezil in the treatment of Alzheimer's disease (AD) based on cerebral hemodynamics and inflammatory factors. Methods A total of 90 patients with AD in Zhangjiakou Shalingzi Hospital from March 2020 to January 2022 were randomly divided into a control group ( 45 cases) and a study group (45 cases) . Both groups received the conventional symptomatic treatment. On this basis, the control group was given donepezil treatment, and the study group was given ginkgo leaf injection combined with donepezil treatment. The therapeutic effects, cerebral hemodynamic parameters [mean flow velocity (MFV) and pulsatility index (PI) of bilateral middle cerebral arteries (bilateral MCA) and basilar arteries (BA)], inflammatory factors [interleukin-6 (IL-6), tumor necrosis factorα (TNF-α), IL-1β], s100β protein, Aβ-amyloid 1-42 ( Aβ1-42), bradykinin (BK), cognitive function, activities of daily living, and adverse reactions were compared between the two groups. Results Compared with the control group (77.78%), the total effective rate of the study group (93.33%) was significantly improved (P < 0.05); 1, 3, and 6 months after the treatment, the MFV of BA and bilateral MCA in the study group was higher than that in the control group, while the PI of BA and bilateral MCA was lower than that in the control group (P < 0.05); The levels of serum TNF-α, IL-6, and IL-1β in the study group were lower than those in the control group 1, 3, and 6 months after the treatment (P < 0.05); 1, 3, and 6 months after the treatment, the levels of serum s100β protein, Aβ1-42, and BK in the study group were lower than those in the control group（P< 0.05); 1, 3, and 6 months after the treatment, the score of the mini-mental state examination scale (MMSE) in the study group was higher than that in the control group, while the scores of the AD assessment subscale cognitive scale (ADAS-cog) and activities of daily living scale (ADL) were lower than those in the control group (P < 0.05); The incidence of adverse reactions in the study group (13.33%) was not significantly different from that in the control group (8.89%) (P > 0.05). Conclusion The efficacy of ginkgo biloba injection combined with donepezil in the treatment of AD is significant, which may be achieved by improving cerebral hemodynamics, downregulating inflammatory factors, and regulating the levels of serum s100β protein, Aβ1-42, and BK. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), one of the main causes of dementia, is a neurodegenerative disorder. Cholinesterase inhibitors are used in the treatment of AD, but prolonged use of these drugs can lead to serious side effects. Drug repurposing is an approach that aims to reveal the effectiveness of drugs in different diseases beyond their clinical uses. In this work, we investigated in vitro and in silico inhibitory effects of 11 different drugs on cholinesterases. The results showed that trimebutine, theophylline, and levamisole had the highest acetylcholinesterase inhibitory actions among the tested drugs, and these drugs inhibited by 68.70 ± 0.46, 53.25 ± 3.40, and 44.03 ± 1.20%, respectively at 1000 µM. In addition, these drugs are bound to acetylcholinesterase via competitive manner. Molecular modeling predicted good fitness in acetylcholinesterase active site for these drugs and possible central nervous system action for trimebutine. All of these results demonstrated that trimebutine was determined to be the drug with the highest potential for use in AD. [ABSTRACT FROM AUTHOR]

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood–CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day. [ABSTRACT FROM AUTHOR]

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Introduction: Donepezil enhances the function of cholinergic nerves by increasing the concentration of acetylcholine, thereby improving clinical symptoms in patients with Alzheimer’s disease (AD). However, the neural mechanisms of how donepezil modulates the effective connectivity (EC) network of cholinergic system in AD patients remain unknown. We speculated that the effective network of the cholinergic system changes in AD patients after donepezil intervention. Methods: We employed resting-state functional magnetic resonance imaging and Granger causality analysis approach to explore changes in the effective connectivity network of the basal forebrain in AD patients before and after donepezil intervention. This study included 32 participants, including 16 healthy controls (HCs) and 16 AD patients. In a 3T MRI scanner, the 16 AD patients were scanned before and after the donepezil intervention. To compare EC differences between the three groups of participants, ANOVA and post-hoc t-tests analysis were employed. Results: Compared to baseline status, AD patients after donepezil intervention had an increased EC from left middle occipital gyrus to right medial septum/diagonal bands. Compared to HCs, AD patients after donepezil intervention had an increased EC from right inferior frontal gyrus/orbit part to right medial septum/diagonal bands, AD patients before donepezil intervention had a reduced EC from right precuneus to right medial septum/diagonal bands. A significant positive correlation was found between EC values in right precuneus and Mini-Mental State Examination in pre-intervention AD patients (r = 0.7338, p = 0.0012). Discussion: Our study showed that effective connectivity of brain regions associated with the default mode network in the cholinergic pathway was enhanced after donepezil intervention. The results of this study will help us to better understand the neural mechanisms of donepezil intervention in AD and to find clinical targets for intervention. [ABSTRACT FROM AUTHOR]

Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases. [ABSTRACT FROM AUTHOR]

Plant-derived multitarget compounds may represent a promising therapeutic strategy for multifactorial diseases, such as Alzheimer's disease (AD). Artemisinin and its derivatives were indicated to beneficially modulate various aspects of AD pathology in different AD animal models through the regulation of a wide range of different cellular processes, such as energy homeostasis, apoptosis, proliferation and inflammatory pathways. In this review, we aimed to provide an up-to-date overview of the experimental evidence documenting the neuroprotective activities of artemi-sinins to underscore the potential of these already-approved drugs for treating AD also in humans and propose their consideration for carefully designed clinical trials. In particular, the benefits to the main pathological hallmarks and events in the pathological cascade throughout AD development in different animal models of AD are summarized. Moreover, dose- and context-dependent effects of artemisinins are noted. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of Fufang Huonaoshu capsule combined with Donepezil on cognitive function and serum brain neurotransmitters in patients with Parkinson's disease (PD) with mild cognitive impairment (PD-MCI). Methods: 128 patients with PD-MCI who received treatment in our hospital from March 2021 to December 2022 were selected. The patients were divided into a control group (treated with Donepezil) and a study group (treated with compound Huonaoshu capsule and Donepezil) according to the method of random number table, with 64 cases in each group. The efficacy, the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Activity of Daily Living Scale (ADL) and serum brain neurotransmitters [5-HT, Acetylcholine, dopamine] were compared between the two groups. Simultaneously observe the incidence of adverse reactions during treatment in both groups. Results: Compared with the control group, the clinical total effective rate of the study group was significantly increased (P<0.05). After 12 weeks of treatment, the MMSE, MoCA, and ADL scores of the study group were higher than those of the control group (P<0. 05). After 12 weeks of treatment, the 5-HT, Ach, and DA levels in the study group were higher than those in the control group (P<0.05). There was no difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion: Fufang Huonaoshu capsule combined with Donepezil can effectively improve the cognitive function of patients with PD-MCI, improve the serum brain neurotransmitter level, and improve the daily living ability of patients. [ABSTRACT FROM AUTHOR]

Background. Alzheimer's disease is a neurodegenerative disorder that worsens over time as more brain regions are affected and symptoms increase. It usually starts slowly and advances permanently. Ranolazine is a piperazine derivative used as a second-line treatment for people with chronic aortic stenosis who are unresponsive to other medications and have steady or ineffectively-managed angina pectoris. This study is intended to look into the possible neuroprotective effects of ranolazine scopolamine-induced Alzheimer's illness-like features in a mouse model. Methods. This is a randomized controlled animal study that has been carried out in Department of Pharmacology from College of Medicine of Al-Nahrain University. Mice were separated into five groups equally (each group with 10); a control group, and an induction group (mice were administered scopolamine 1 mg per kg intraperitoneally every 24hr for seven days to induce features similar to Alzheimer's disease). The mice in the remaining three treatment groups were given tested medications prophylactically for 14 days, then the induction was carried out with scopolamine 1 mg/kg i.p. once daily while the tested medication dosages were continued for an additional 7 days; these treatment groups included: donepezil group (5 mg/Kg/d), ranolazine group (40 mg/Kg/d), and combination groups donepezil (5 mg/Kg/d) with ranolazine (40 mg/Kg/d); all were administrated i.p. once daily. Behavioral parameters including the Y maze test and novel object recognition test were assessed for inflammatory cytokines and oxidative stress parameters. Result. Ranolazine exhibits significant improvement in behavior and memory, oxidative stress parameter level, as well as inflammatory cytokines. When the scopolamine induction group was compared to the control group, the spontaneous alteration considerably decreased (p ≤0.001). However, compared to the induction group, all three donepezil, ranolazine, and combination (donepezil + ranolazine) groups had a highly significant increase in the spontaneous alteration and when compared with the control group, there were no statistically significant changes (p>0.05). In comparison with a control group, the scopolamine (induction group) revealed a highly significant reduction (p ≤0.001) in the recognition index. In contrast to the induction group, all three donepezil, ranolazine, and combination (donepezil + ranolazine) groups demonstrated a highly statistically significant improvement in the recognition index. When compared with the control group, there were no statistically significant changes (p>0.05). Conclusion. The current investigation demonstrated ranolazine's neuroprotective action against scopolamine-induced AD-like characteristics in mouse models. The present work has demonstrated the considerable antioxidant and anti- inflammatory benefits of ranolazine, which may account for these positive results. [ABSTRACT FROM AUTHOR]

Donepezil hydrochloride (DPL) and Embelin (EMB) loaded Nanostructured Lipid Carriers (NLCs) have been developed and optimized to achieve optimal drug loading, safer nasal delivery, effective neuronal/cell uptake, enhanced brain accessibility, controlled release, and desired therapeutic effect. Molecular docking studies demonstrated that both drugs bind effectively to AchE with interaction energies of -48.5319 and − 65.7525, respectively, indicating a synergistic approach. The hydrophobic interactions with target proteins facilitate the transportation of drugs through brain hydrophobic channels to provide a desired pharmacological response. N2a cell line investigation advised a 1:1 ratio of DPL and EMB to have the greatest possible synergistic effect based on the MTT assay. NLCs were fabricated by hot emulsification probe sonication method and optimized using QbD-based Central Composite Rotatable Design (CCRD). Optimized NLCs with a diameter of 180.2 nm were suitable for axonal uptake. A low Polydispersity index (PDI) score of 0.37 and Zeta Potential (ZP) of -12 mV indicated a uniform monodisperse system with persistent and stable dispersion properties. The NLCs demonstrated sustained drug release, DPL released at 90.72 ± 1.00%, and EMB at 81.30 ± 0.52% in 24 h. The Korsemeyer-Peppas model proved to be the most accurate fit due to its strong correlation. Ex vivo permeation and CLSM studies revealed superior goat nasal mucosa penetration of NLCs over suspension with a higher fluorescence level, up to 35 μm. NLCs treated nasal mucosa exhibited no erosion or interstitial gaps in the histopathological study. Moreover, NLCs were nontoxic and non-irritating, with a HET CAM score of 0.68 ± 0.05, indicating safe nasal delivery. The cellular uptake study showed a preponderance of the NLCs in the Cell's cytoplasm, indicating ready uptake by N2a cells. Hence, intranasal therapy with the DPL and EMB-loaded NLCs could be a practical and promising implementation. Further in vivo, and clinical studies will be required to establish the formulation's efficacy in treating Alzheimer's disease (AD). Graphical Abstract [ABSTRACT FROM AUTHOR]

The oral administration of donepezil hydrochloride has low brain targeting efficiency especially due to the presence of the blood–brain barrier leading to poor quality of treatment. Hence, this study aimed to systematically design chitosan nanoparticles for direct nose-to-brain delivery of donepezil hydrochloride using the Quality by Design approach for better transport to the brain avoiding the blood–brain barrier. The optimized formulation showed 180.2 nm average particle size and 0.282 polydispersity index, + 16.6 mV zeta potential, more than 90% drug release, and more than 70% drug permeation in 24 h. The studies on in-vitro drug release and ex-vivo permeation showed a sustained release pattern fulfilling Korsemeyer Peppa's model. The confocal laser scanning micrographs showed the spherical nature of nanoparticles. The intranasal administration of donepezil hydrochloride nanoparticles in Wistar rats showed approximately 2.6 times more drug than donepezil hydrochloride solution given intranasally and approximately 10 times more drug than donepezil hydrochloride solution given orally in the brain respectively after 6 h. Further, confocal micrographs using Rhodamine B (fluorescent dye) loaded nanoparticles confirmed the localization of nanoparticles in the brain post-intranasal administration. The obtained results suggested that the chitosan nanoparticles are promising drug carriers for the nose-to-brain delivery of donepezil hydrochloride for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions. [ABSTRACT FROM AUTHOR]

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted. [ABSTRACT FROM AUTHOR]

Cholinesterases are important in ensuring hemostasis in our body. Excessive increase in cholinesterase function causes various cholinergic dysfunctions. Alzheimer's is a disease characterized by loss of cholinergic activity, which is especially common in the elderly. One of the cholinesterase inhibitors most commonly used to stop the progression of Alzheimer's disease is donepezil. Due to some side effects of donepezil, the synthesis and design of new analogues that may be alternatives to donepezil are reported in the literature. In this study, molecular docking studies were performed to compare the in silico AChE inhibitory potential of some new structural analogs of donepezil. Molecular docking studies were performed using Autodock4.2 tools. In this study, the hypothesis emerges that especially compound 1 and compound 5 have the potential to inhibit AChE at least as much as donepezil. In silico docking studies showed that donepezil derivatives designed with bioisosteres of the piperidine ring in donepezil have high binding affinity towards acetylcholine esterase. These results need to be confirmed by synthesis of the donepezil analogues designed in the study and in vitro activity measurements. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (ad) is a neurological condition that worsens over time and is characterized by the buildup of amyloid (Aβ) plaques in the brain parenchyma. Neuroprotection and cholinesterase inhibition have been the two primary techniques used in the creation of medications to date. In ad , a novel sort of programmed cell death known as ferroptosis takes place along with iron buildup, lipid peroxidation, and glutathione deficiency. The objective of the current investigation was to examine the neuroprotective and anti-ferroptotic role of nanocurcumin and Donepezil against model of aluminum chloride AlCl3 and D-galactose induced ad. The experiment was performed on 70 rats divided into (G1: control, G2: NCMN, G3: Donepezil, G4: ad -model, G5: Donepezil co-treatment, G6: NCMN co-treatment and G7: NCMN+Donepezil co-treatment). Hematological parameters and biochemical investigations as oxidative stress, liver function, kidney function, iron profile and plasma fibrinogen were evaluated. Treatment with Nanocurcumin alone or in combination with Donepezil improved oxidative stress, liver functions, and kidney functions, improve iron profile and decreased plasma fibrinogen. [ABSTRACT FROM AUTHOR]

Background: Trials of cholinergic and glutamatergic agents have improved cognition and memory for the geriatric schizophrenic population. Donepezil is an acetylcholinesterase inhibitor that improves cognition by preventing postsynaptic degradation of hippocampal acetylcholine in patients with mild-to-moderate dementia. Donepezil has been attributed to some adverse effects, especially gastrointestinal symptoms. However, cardiovascular adverse effects are not common as there remains a dearth of literature regarding donepezil-induced bradycardia. Case report: Hence, we present the case of a 70-year-old Hispanic female with past psychiatry history of schizophrenia who developed bradycardia and syncope following the commencement of low-dose donepezil in the inpatient unit and subsequent resolution with cessation. She had no prior cardiovascular symptoms or diagnosis. Discussion: Considering there is no baseline cardiac monitoring requirement guideline for patients on Donepezil treatment, pre-assessment electrocardiogram is advised before the commencement of acetylcholinesterase inhibitors. Finally, routine monitoring of vital signs for at least the first 72 hours following the start of donepezil might be good proactive practice for all psychiatrists. Extending this practice to inpatient and outpatient service settings will be worthwhile. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common form of progressive dementia in the elderly, is a chronic neurological disorder that decreases cognitive ability. Although the underlying cause of AD is yet unknown, oxidative stress and brain acetylcholine shortage are the key pathogenic causes. Results: The current study shows that these derivatives have the potential to improve memory in mice by inhibiting scopolamine-induced acetylcholinesterase activity, oxidative and nitrosative stress, and improving locomotor activity and muscle grip strength in the rota rod test. When compared to the illness control, the memory-enhancing potential of novel N-benzyl pyridine-2-one derivatives was highly significant (P < 0.0001). Conclusions: The observed memory ameliorating effect of novel N-benzyl pyridine-2-one makes them as a a good choice for treatment of individuals with cognitive impairment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia and a significant concern to global public health due to the prevalence of aging populations. Donepezil is one of only a few medications approved for use as an anti-AD agent but all have adverse side effects. Reducing the dosage of AD drugs with plant extracts (phytotherapy) while maintaining efficacy is one strategy to minimize adverse side effects. We previously reported the anti-AD properties of an edible fern, Diplazium esculentum (Retz.) Sw. (DE), which inhibited key enzymes involved in AD pathogenesis including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase 1 (BACE-1). This study aimed to determine whether DE exhibited a synergistic effect with donepezil. The enzyme inhibitory assay showed that DE extract and its bioactive compounds, kaempferol, and quercetin, slightly impeded AChE inhibition with donepezil, while DE extract and quercetin showed synergistic or additive effects with donepezil against BChE and BACE-1, respectively. DE extract combined with donepezil also improved eye phenotypes in a Drosophila model of AD by preventing ommatidia atrophia and bristle breakages. Furthermore, the DE extract exhibited no genotoxic activities, as determined by the Ames test. Our data revealed that DE extract showed promise when combined with donepezil during AD treatment by targeting BChE and BACE-1. [ABSTRACT FROM AUTHOR]

This comprehensive review focuses on the synthesis and derivatives of donepezil, a pivotal Alzheimer's disease (AD) medication introduced in 1997. As a selective acetylcholinesterase inhibitor with 100% oral bioavailability and a 70-h half-life, donepezil's success in neurodegenerative disorder management has spurred extensive research into its synthesis and structural modifications. The review examines diverse synthetic approaches, evaluating their efficiency, cost, toxicity, and scalability. Methods range from traditional hazardous chemicals to eco-friendly strategies. Structural modifications and their impact on biological activities are explored, emphasizing their role in developing therapeutic agents for neurodegenerative diseases. The versatility of donepezil in drug design is demonstrated through discussions on analogues and hybrids, including those with lipoic and ferulic acid. Given projections of increased AD cases, the synthesis and modification of drugs like donepezil gain paramount importance. This review consolidates information for medicinal chemists, offering insights to guide the development of efficient compounds for neurodegenerative disorder management. [ABSTRACT FROM AUTHOR]

IntroductionThe KCNQ2/KCNQ3 genes encode the voltage-gated K channel underlying the neuronal M-current, regulating neuronal excitability. Loss-of-function (LoF) variants cause neonatal epilepsy, treatable with the M-current-opener retigabine, which is no longer marketed due to side effects. Gain-of-function (GoF) variants cause developmental encephalopathy and autism that could be amenable to M-current, but such therapies are not clinically available. In this translational project, we investigated whether donepezil, a cholinergic drug used in Alzheimer’s, suppresses M currents in vitro and improves cognitive symptoms in patients with GoF variants.Methods(1) The effect of 1 μM donepezil on the amplitude of the M-current was measured in excitatory and inhibitory neurons of mouse primary cultured hippocampal cells. M-current was measured using the standard deactivation protocol (holding at 0 mV and deactivation at −60 mV) in the voltage-clamp configuration of the whole-cell patch clamp technique. The impact of donepezil was also examined on the spontaneous firing activity of hippocampal neurons in the current-clamp configuration. (2) Four children with autism, aged 2.5–8 years, with the following GoF variants were enrolled: KCNQ2 (p. Arg144Gln) and KCNQ 3 (p.Arg227Gln, p.Arg230Cys). Patients were treated off-label with donepezil 2.5–5 mg/d for 12 months and assessed with: clinical Global Impression of Change (CGI-c), Childhood Autism Rating Scale 2 (CARS-2), Adaptive Behavior Assessment System-II (ABAS-II), and Child Development Inventory (CDI).Results(1) Application of donepezil for at least 6 min produced a significant inhibition of the M-current with an IC50 of 0.4 μM. At 1 μM, donepezil reduced by 67% the M-current density of excitatory neurons (2.4 ± 0.46 vs. 0.89 ± 0.15 pA/pF, p 0.05). Donepezil (1 μM) potently increased by 2.6-fold the spontaneous firing frequency, which was prevented by the muscarinic receptor antagonist atropine (10 μM). (2) The CARS-2 decreased by 3.8 ± 4.9 points (p > 0.05), but in two patients with KCNQ3 variants, the improvement was over the 4.5 clinically relevant threshold. The global clinical change was also clinically significant in these patients (CGI-c = 1). The CDI increased by 65% (p

ObjectiveThe purpose of this study was to compare donepezil at 5 mg and 10 mg/day against a placebo to systematically evaluate its effectiveness in improving cognitive function among patients suffering from dementia at any stage.MethodFor this systematic review and meta-analysis, we looked up Medline, Scopus, Embase, Web of Science, and The Cochrane Library for articles on the efficacy of donepezil in dementia published in the past 20 years and summarized the placebo and intervention data. Initially, a total of 2,272 articles were extracted using our search query and after the inclusion and exclusion criteria set for extraction of data, 18 studies were included in this review using PRISMA flowchart. The ADAS-cog and MMSE assessment scales were used for measuring the outcomes using IBM SPSS 29.0 for the meta-analysis.ResultThe meta-analysis comprised a total of 18 RCTs (randomized controlled trials) that were randomized to receive either donepezil 5 mg/day (n = 1,556), 10 mg/day (n = 2050) or placebo (n = 2,342). Meta-analysis concerning efficacy showed that donepezil at 10 mg/day significantly improved the MMSE score (g: 2.27, 95%CI: 1.25–3.29) but could not substantially reduce the ADAS-cog. At 5 mg/day donepezil, an overall slight improvement in MMSE score (Hedges’ g: 2.09, 95%CI: 0.88–3.30) was observed.ConclusionBoth donepezil 5 mg/day and 10 mg/day doses demonstrated improved cognitive functions for patients with dementia, however results indicated that the 10 mg/day dose was more efficacious.

Abstract Background Donepezil, an acetylcholinesterase inhibitor commonly used to treat Alzheimer's disease (AD), is generally well tolerated. There have been no previous reports on donepezil‐induced obsessive–compulsive disorder (OCD). Case Presentation The patient, a retired man in his 70s diagnosed with AD, displayed OCD symptoms following donepezil initiation, exacerbating post‐stroke—specifically, a cerebral infarction in the right posterior limb of the internal capsule. Remarkably, the symptoms abated upon discontinuation of donepezil. Conclusion Caution should be exercised when using donepezil in patients with a history of stroke.

Alzheimer’s disease (AD) is a neurodegenerative disorder. Although the first case of Alzheimer’s disease was recorded over a century ago, the etiology of the disease remains unknown. There are several hypotheses regarding the process of neurodegeneration, however, it is impossible to provide a specific cause of Alzheimer’s disease in humans, due to the lack of in vivo models. Only a few specific changes in the body occurring in the course of this disease have been described so far, and no effective drugs have been developed to stop its progression. The effect of the currently used drugs is limited only to improving the cognitive functions and general patients’ well-being. Four medicinal substances have been approved for the treatment of Alzheimer's disease so far, namely, donepezil, rivastigmine, galantamine, and memantine. In this article, a brief description of marketed drugs used for the treatment of Alzheimer's disease is presented as well as selected substances in phase III clinical trials. Moreover, a strategy of multifunctional ligands along with a description of the activity of selected compounds containing in their structure a moiety of one of the drugs used in the treatment of Alzheimer’s disease, namely, donepezil, rivastigmine, or galantamine, is presented in the paper. Selected compounds synthesized over the last five years are described. Taking into account the multifactorial nature of Alzheimer's disease, the multifunctional ligands strategy directed at more than one biological target is used by many research groups. A large group of multi-target ligands is based on derivatives containing in their structure a moiety of selected acetylcholinesterase inhibitors. These moieties are combined with various types of compounds with known biological activity. As a result, derivatives with multi-target effects are obtained, mainly cholinesterase inhibitory properties and inhibition of the β-amyloid aggregation process, as well as antioxidant and neuroprotective effects.

Abstract Background To assess the effectiveness, safety, and tolerability of anti-Alzheimer agents (memantine, galantamine, rivastigmine, and donepezil) in controlling ADHD symptoms in children, adolescents, and adults. Methods Following the PRISMA guideline, clinical trials assessing the potency of anti-Alzheimer medications in managing ADHD symptoms were imported from PubMed, Web of Science, and Scopus (until February 2023). Screening stages were conducted by two independent researchers. Two independent researchers also extracted data from clinical trials reporting the outcomes as the reduction in scores of ADHD questionnaires. The risk of bias within the included studies was assessed using the Cochrane Collaboration tool, while the certainty of outcomes was evaluated based on the GRADE criteria. Results Of the initial 1597 studies, 11 studies were included. No studies were available for rivastigmine, and only a single study was conducted for galantamine. The results of the other two medications had a slight inconsistency. While both memantine and donepezil were reported to be effective in several studies, they were reported to be ineffective in some other studies. Side effects were mostly reduced appetite and headache. The tolerability of memantine, donepezil, and galantamine was all convincing. Conclusions While galantamine did not demonstrate a promising efficacy in ADHD, memantine and donepezil showed effectiveness. However, future studies are needed to confirm their efficacy in ADHD since there was some inconsistency.

Rummenigge Oliveira Silva,1 Hermine Counil,1 Jean-Michel Rabanel,2 Mohamed Haddad,1 Charlotte Zaouter,1 Mohamed Raâfet Ben Khedher,1,3 Shunmoogum A Patten,1 Charles Ramassamy1 1Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Québec, Canada; 2Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada; 3Higher Institute of Biotechnology of Beja, University of Jendouba, Beja, TunisiaCorrespondence: Charles Ramassamy, INRS, Centre Armand-Frappier Santé Biotechnologie, 531 Boul des Prairies, Laval, QC, H7V 1B7, Canada, Tel +450-687 50 10, Email charles.ramassamy@inrs.caIntroduction: Drug delivery across the blood-brain barrier (BBB) is challenging and therefore severely restricts neurodegenerative diseases therapy such as Alzheimer’s disease (AD). Donepezil (DNZ) is an acetylcholinesterase (AChE) inhibitor largely prescribed to AD patients, but its use is limited due to peripheral adverse events. Nanodelivery strategies with the polymer Poly (lactic acid)-poly(ethylene glycol)-based nanoparticles (NPs-PLA-PEG) and the extracellular vesicles (EVs) were developed with the aim to improve the ability of DNZ to cross the BBB, its brain targeting and efficacy.Methods: EVs were isolated from human plasma and PLA-PEG NPs were synthesized by nanoprecipitation. The toxicity, brain targeting capacity and cholinergic activities of the formulations were evaluated both in vitro and in vivo.Results: EVs and NPs-PLA-PEG were designed to be similar in size and charge, efficiently encapsulated DNZ and allowed sustained drug release. In vitro study showed that both formulations EVs-DNZ and NPs-PLA-PEG-DNZ were highly internalized by the endothelial cells bEnd.3. These cells cultured on the Transwell® model were used to analyze the transcytosis of both formulations after validation of the presence of tight junctions, the transendothelial electrical resistance (TEER) values and the permeability of the Dextran-FITC. In vivo study showed that both formulations were not toxic to zebrafish larvae (Danio rerio). However, hyperactivity was evidenced in the NPs-PLA-PEG-DNZ and free DNZ groups but not the EVs-DNZ formulations. Biodistribution analysis in zebrafish larvae showed that EVs were present in the brain parenchyma, while NPs-PLA-PEG remained mainly in the bloodstream.Conclusion: The EVs-DNZ formulation was more efficient to inhibit the AChE enzyme activity in the zebrafish larvae head. Thus, the bioinspired delivery system (EVs) is a promising alternative strategy for brain-targeted delivery by substantially improving the activity of DNZ for the treatment of AD. Keywords: Alzheimer’s disease, donepezil, extracellular vesicular, PLA-PEG, bEnd.3 cells, zebrafish

Objective: To evaluate the efficacy and safety of Chinese herbal medicines (CHMs) combined with chemical drugs for the treatment of Alzheimer's disease (AD). Materials and Methods: Databases were searched to retrieve randomized controlled trials (RCTs) of CHMs combined with tacrine, galantamine, rivastigmine, donepezil, or memantine, following strict inclusion and exclusion criteria. Only research papers published in English, Chinese, and Japanese were considered. The primary outcome was the mini-mental state examination (MMSE) score and the secondary outcomes were AD assessment scale cognitive subscale (ADAS-Cog) score and safety evaluation. Meta-analysis was carried out using RevMan 5.3 and subgroup analysis was conducted to identify the sources of heterogeneity. Results: A total of 15 RCTs with 1386 participants were included in this study. Only donepezil was used in the retrieved literature. Meta-analyses showed that the combination of CHMs with donepezil led to significant improvement in the MMSE score (Z = 9.45; P < 0.00001; weighted mean difference [WMD] =2.68, 95% confidence interval [CI]: 2.12–3.24) and a significant decrease in the ADAS-Cog score (Z = 5.53; P < 0.00001; WMD = −3.79; 95% CI: −5.13–−2.44). Safety evaluation demonstrated that these combination treatments relieved adverse events such as insomnia (risk ratio [RR] =0.20, 95% CI: 0.06–0.68; P = 0.01) and hive (RR = 0.10; 95% CI: 0.01–0.73; P = 0.02). Conclusions: The combination of CHMs with a chemical drug like donepezil led to significant improvements in patient cognition as well as a better safety profile when compared to the application of a chemical drug alone.

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients. Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury, but relatively less is known about the effect in pediatric populations. The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibitors as a potential adjuvant treatment for neurocognitive decline in pediatric patients with traumatic brain injury. Investigators queried PubMed to identify literature published from database inception through June 2023 describing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions. Based on preselected search criteria, 340 unique papers were selected for title and abstract screening. Thirty-two records were reviewed in full after eliminating preclinical studies and papers outside the scope of the project. In adult traumatic brain injury, we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tolerated and shows both objective and patient-reported efficacy for reducing cognitive impairment. In children, 3 papers report on 5 children recovering from traumatic brain injury, showing limited efficacy. An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group. Given its promise for efficacy in adults with traumatic brain injury and tolerability in pediatric patients, we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

BackgroundDyadic 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.MethodsUsing 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.ResultsAmong 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.DiscussionIncreasing participation among nonspousal dyads may facilitate more inclusive and representative MCI trial samples.

Background: To assess the effectiveness, safety, and tolerability of anti-Alzheimer agents (memantine, galantamine, rivastigmine, and donepezil) in controlling ADHD symptoms in children, adolescents, and adults. Methods: Following the PRISMA guideline, clinical trials assessing the potency of anti-Alzheimer medications in managing ADHD symptoms were imported from PubMed, Web of Science, and Scopus (until February 2023). Screening stages were conducted by two independent researchers. Two independent researchers also extracted data from clinical trials reporting the outcomes as the reduction in scores of ADHD questionnaires. The risk of bias within the included studies was assessed using the Cochrane Collaboration tool, while the certainty of outcomes was evaluated based on the GRADE criteria. Results: Of the initial 1597 studies, 11 studies were included. No studies were available for rivastigmine, and only a single study was conducted for galantamine. The results of the other two medications had a slight inconsistency. While both memantine and donepezil were reported to be effective in several studies, they were reported to be ineffective in some other studies. Side effects were mostly reduced appetite and headache. The tolerability of memantine, donepezil, and galantamine was all convincing. Conclusions: While galantamine did not demonstrate a promising efficacy in ADHD, memantine and donepezil showed effectiveness. However, future studies are needed to confirm their efficacy in ADHD since there was some inconsistency. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United States Food and Drug Administration (FDA). Three (donepezil, rivastigmine, and galantamine) out of these four drugs are anticholinesterase inhibitors, while the fourth one memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Currently, two immunotherapy drugs that target amyloid protein (donanemab and lecanemab) are being considered for the treatment of Alzheimer's disease at an early stage. All these drug molecules are still not the complete answer to the treatment of Alzheimer's disease. A recent report from the Office of National Statistics showed that AD is the leading cause of death in 2022. Therefore, there is an urgency to develop more drugs that can treat AD. Based on this urgency, we aim to investigate how bioactive and already approved drugs could be repurposed for inhibiting the anticholinesterase enzyme using computational studies. To achieve this, the data science tool—Python coding was compiled on Jupyter Notebook to mine bioactive compounds from the ChEMBL database. The most bioactive compounds obtained were further investigated using Molecular Operating Environment (MOE) software to carry out molecular docking and ligand analysis, and this was followed by molecular dynamics simulation production at 35 ns using GROMACS 2022.4 on Archer 2 machine. The molecular dynamic analysis was carried out using HeroMDanalysis software. Data mining of the ChEMBL database was carried out for lipase inhibitors, and this gave CHEMBL-ID 1240685, a peptide molecule, the most active compound at the time of data mining. Further literature studies gave Zoladex an FDA-approved drug for the treatment of breast cancer as another compound of interest. The in silico studies were carried out against the anticholinesterase enzyme using two FDA-approved drugs donepezil and galantamine as a template for comparing the in silico activities of the repurposed drugs. A very useful receptor for this study was PDB-1DX6, a cocrystallized galantamine inhibitor of acetylcholinesterase enzyme. The molecular docking analysis (using ligand interactions) and molecular dynamic analysis (root mean square deviation (RMSD) and root mean square fluctuation (RMSF)) showed that the two peptide molecules CHEMBL-1240685 and Zoladex gave the best binding energy and stability when compared to the FDA-approved drugs (donepezil and galantamine). Finally, further literature studies revealed that Zoladex affects memory reduction; therefore, it was dropped as a possible repurposed drug. Our research showed that CHEMBL-1240685 is a potential compound that could be investigated for the inhibition of anticholinesterase enzyme and might be another drug molecule that could be used to treat Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common age‐related neurodegenerative brain disorder characterized by the impairment in memory and other cognitive functions. Although there is currently no successful pharmacotherapy for AD, researchers are continuously exploring the various pathogenesis of AD to develop potential therapeutic drugs. Of the multiple hypotheses for AD, the cholinergic and amyloid‐β (Aβ) hypothesis are the main targeting hypothesis for AD. Some researchers proposed that the symptoms involved in AD (loss of memory, cognitive impairment, and amnesia) are the main event linked to the cholinergic neurotransmitter (acetylcholine). Therefore, the development of AChE inhibitors to increase the level of ACh in the synaptic cleft can improve learning and memory in AD patients. Huprine X is a synthetic ChE inhibitor developed by the hybridization of Huperzine A and the synthetic drug tacrine. This review focuses on the last 10 year's literature search on huprine and its analogues for the treatment of AD. We expect that this review can be helpful for medicinal chemists, and neuro‐chemists to provide new ideas for the development of new drugs therapy for AD. [ABSTRACT FROM AUTHOR]