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The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

In recent years, nanoparticle (NP) systems have demonstrated significant promise in pharmaceutical applications. This study focused on the development of donepezil hydrochloride-loaded PLGA-NPs, prepared using the ‘Double Emulsion Solvent Evaporation’ method. The impact of varying concentrations of polyvinyl alcohol-(PVA) in the aqueous phase and sonication time on NP characteristics was comprehensively examined. Results showed that increasing PVA concentration and sonication time resulted in a reduction in NP size, with an optimal formulation (I-DNP) achieving a particle size of 136.37 nm ± 0.93 and a PDI of 0.122 ± 0.011, indicating uniformity. The zeta potential was measured at − 24.17mV ± 1.21, confirming the electrostatic stability of the formulation, essential for long-term stability. Trehalose was incorporated to enhance stability, and gastrointestinal stability testing revealed that I-DNP degraded faster in acidic environments. The encapsulation efficiency reached 69.22 ± 4.84%, suggesting effective drug loading, and release studies exhibited a sustained release profile, with a Fickian and non-Fickian release mechanism. DSC, FT-IR, and 1 H-NMR analyses confirmed the encapsulation and structural integrity of the formulation. In biological activity studies, I-DNP exhibited potent anti-AChE and anti-BuChE activities, with Chorioallantoic Membrane (CAM) assays showing significant inhibition of angiogenesis. These findings highlight the potential of I-DNP as a promising therapeutic strategy for Alzheimer’s disease, demonstrating its ability to enhance drug stability, controlled release, and potential blood-brain barrier (BBB) penetration. Future studies will focus on long-term stability testing and in vivo Alzheimer’s models to further validate its clinical applicability. This research contributes to the advancement of nanoparticle-based drug delivery systems for neurodegenerative diseases, paving the way for innovative therapeutic approaches.

This study aims to prepare, characterize and evaluate the pharmacokinetics of liposomal donepezil HCl (LDH) dispersed into thiolated chitosan hydrogel (TCH) in rabbits. Various hydrogels including TCH were prepared, and after characterization, TCH was selected for subsequent evaluations, due to the promising results. TCH was then incorporated with LDH prepared by reverse phase evaporation method. The hydrogel was characterized using scanning electron microscope, dialysis membrane technique, and ultra-performance liquid chromatography methods. The optimized resultant was then evaluated in terms of pharmacokinetics in an in vivo environment. The mean size of LDH and drug entrapment efficiency were 438.7 ± 28.3 nm and 62.5% ± 0.6, respectively. The controlled drug release pattern results showed that the half-life of the loaded drug was approximately 3.5 h. Liposomal hydrogel and free liposomes were more stable at 4 °C compared to those in 20 °C. The pharmacokinetics study in the rabbit showed that the optimized hydrogel increased the mean peak drug concentration and area under the curve by 46% and 39%, respectively, through nasal route compared to the oral tablets of DH. Moreover, intranasal delivery of DH through liposomal hydrogel increased the mean brain content of the drug by 107% compared to the oral DH tablets. The results suggested that liposomes dispersed into TCH is a promising device for the nasal delivery of DH and can be considered for the treatment of Alzheimer’s disease.

The development of advanced drug delivery systems is essential for improving therapeutic efficacy, particularly in the treatment of neurodegenerative disorders such as Alzheimer’s disease. This study investigates zinc-modified mordenite zeolite (MR-ZN) as a novel platform for the controlled delivery of donepezil (DPZ), a cholinesterase inhibitor. Natural mordenite was modified with zinc, enhancing its surface area from 62.1 to 85.4 m2/g and improving its adsorption properties. Donepezil was successfully loaded at two doses (10 mg and 23 mg), achieving high loading efficiencies of 95% and 94%, respectively. Adsorption kinetics followed a pseudo-second-order model (R2 > 0.99), indicating that chemisorption predominates through coordination between DPZ functional groups and Zn2+ sites, while complementary physisorption via hydrogen bonding and van der Waals interactions also contributes to molecular stabilization within the zeolite framework. In vitro release studies under simulated gastrointestinal conditions demonstrated sustained and pH-responsive release profile with 80% and 82% of donepezil released after 24 h for 10 mg and 23 mg formulations, respectively. Density Functional Theory (DFT) calculations revealed favorable adsorption energy (−26.4 kJ/mol), while Bader and Electron Localization Function (ELF) analyses confirmed hydrogen bonding and electrostatic interactions without compromising the zeolite framework. These findings validate MR-ZN as structurally stable, efficient, cost-effective and biocompatible matrix for oral drug delivery. The combination of experimental data and theoretical modeling supports its potential to improve bioavailability and therapeutic performance in neurodegenerative treatment.

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer’s disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer’s disease treatment.

Donepezil hydrochloride thermosensitive gel for nasal delivery was prepared by using Poloxamer 407 and Poloxamer 188 as thermoreversible polymers, hydroxypropyl- -cyclodextrin and ethylparaben as permeation enhancer and preservative, respectively. The gelation temperature and time, pH value of the gel formulation were found to meet the requirements for nasal administration. The erosion and release tests exhibited obvious drug sustained release behavior. Meantime, main pharmacokinetic parameters such as , and in plasma as well as in brain were significantly different between the nasal gel formulation and intragastric drug solution in rats ( < 0.01). The relative bioavailability and drug targeting efficiency of the gel formulation were calculated to be 385.6 and 151.2 %, respectively. Thus, the drug gel formulation might be a potential new delivery system for treatment of Alzheimer’s disease due to its higher bioavailability and better distribution to brain when compared to oral route.

Among neurodegenerative disorders, Alzheimer's disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank and MD simulation. In addition, it is observed that the π- π stacking with the residues of Trp86, Tyr337, Tyr341, Tyr124 and Trp286 may be required for strong ligand binding. Moreover, ADME/T analysis suggests that modified derivatives are less toxic and have improved pharmacokinetic properties than those of the parent drug. These results further confirm the ability of metal-directed drugs to bind simultaneously to the active sites of AChE and support them as potential candidates for the future treatment of Alzheimer's disease.

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Fatigue is the most commonly reported symptom of post-COVID-19 condition (also known as long COVID) and impairs various functions. One of the underlying mechanisms may be intracerebral inflammation due to decreases in acetylcholine levels. To examine the effects of donepezil hydrochloride, an acetylcholinesterase inhibitor, on post-COVID-19 fatigue and psychological symptoms. A multicenter, double-blind randomized clinical trial was performed in Japan. Between December 14, 2022, and March 31, 2024, adult patients within 52 weeks of the onset of COVID-19 and with a global binary fatigue score of 4 or greater on the Chalder Fatigue Scale were randomized into a donepezil or a placebo group. The intervention was conducted during a 3-week period, with donepezil hydrochloride being administered at a dosage of 3 mg/d for the first week and then 5 mg/d for 2 weeks. The primary outcome was a change in the Chalder Fatigue Scale score and the absolute score 3 weeks after the initiation of treatment. Other outcomes at 3 and 8 weeks, such as psychological symptoms and quality of life, were evaluated as secondary outcomes. A total of 120 eligible patients were enrolled and 10 withdrew or were lost to follow-up; therefore, 110 patients (55 in each group) were included in the efficacy analysis (64 [58%] female; mean [SD] age, 43 [12] years). No significant differences were observed in baseline characteristics between the 2 groups. The baseline-adjusted estimating treatment effect of donepezil, measured as the mean difference on Chalder Fatigue Scale scores at 3 weeks, was 0.34 (95% CI, -2.23 to 2.91), showing no significant effect of the intervention (P = .79). Scores for the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, EuroQol 5-Dimension 5-Level Version, Patient Health Questionnaire, and Daily Health Status at 3 and 8 weeks were similar. No serious adverse events occurred in either group. In this randomized clinical trial of donepezil to treat post-COVID-19 condition, the efficacy for fatigue and psychological symptoms was not confirmed in a general population. The development of effective therapeutics for post-COVID-19 symptoms is needed, and more clinical trials should be conducted in the future. Japan Registry of Clinical Trials Identifier: jRCT 2031220510.