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Aim: In the present study, the effect of donepezil hydrochloride was studied on the transgenic Drosophila expressing human amyloid beta-42 in the neurons. Methods: Donepezil hydrochloride at final concentration of 0.1, 1 and 10 mM was mixed in the diet and the flies expressing human amyloid beta-42 under Upstream Activation Sequence control (Alzheimer Disease [AD] flies) were allowed to feed on it for 30 days. Results: The AD flies exposed to various doses of Donepezil hydrochloride showed a dose dependent significant delay in the loss of climbing ability, increase in activity, reduction in the oxidative stress and apoptotic markers. A significant improvement was also observed in cognitive parameters. A dose dependent significant reduction in the activity of acetylcholinesterase was also observed. The docking studies suggest the positive interaction between donepezil, amyloid beta-42 and acetylcholinesterase. The results obtained from immunohistochemistry also showed a dose dependent significant reduction in the amyloid beta-42 aggregates. Conclusion: The results suggest that donepezil hydrochloride is potent enough to reduce the AD symptoms being mimicked in transgenic flies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Small vessel cerebrovascular disease (SVCVD) accounts for 35% to 67% of vascular dementias, and may be overlooked by healthcare providers due to its insidious onset. SVCVD involves chronic cerebral ischemia and hypoperfusion, endothelial dysfunction, blood-brain barrier disruption, and interstitial fluid reflux. The purpose of this study was to investigate the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with donepezil hydrochloride compared to donepezil alone in the treatment of mild-to-moderate cognitive impairment in patients with SVCVD. Material and methods: A cohort of 115 individuals with mild-to-moderate cognitive impairment due to SVCVD was purposefully selected and randomized into two groups: a test group and a control group. The test group received a combination of repetitive transcranial magnetic stimulation (rTMS) and oral donepezil hydrochloride (10 mg/day), while the control group received oral donepezil alone (10 mg/day). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were evaluated in both groups prior to and following the interventions. Results: Following 6 weeks of treatment, both groups demonstrated enhancement in cognitive function. However, a statistically significant difference was observed between the test group and the control group (p <.05 on both the MMSE and the MOCA), favoring the test group. Conclusions: Compared to donepezil alone, the combination of repetitive transcranial magnetic stimulation (rTMS) and donepezil has a significantly greater effect on enhancing cognitive function among individuals experiencing mild-to-moderate cognitive impairment resulting from SVCVD. [ABSTRACT FROM AUTHOR]

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-TiO2 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.

Alzheimer's disease is the most serious neurodegenerative disorder characterized by cognitive and memorial defects alongside deterioration in behavioral, thinking and social skills. Donepezil hydrochloride (DPZ) is one of the current two FDA-approved cholinesterase inhibitors used for the management of Alzheimer's disease. The current study aimed to formulate hyaluronic acid-coated transfersomes containing DPZ (DPZ-HA-TFS) for brain delivery through the intranasal pathway to surpass its oral-correlated GIT side effects. DPZ-HA-TFS were produced using a thin film hydration method and optimized with a 24 factorial design. The influence of formulation parameters on vesicle diameter, entrapment, cumulative release after 8 h, and ex vivo nasal diffusion after 24 h was studied. The optimal formulation was then evaluated for morphology, stability, histopathology and in vivo biodistribution studies. The optimized DPZ-HA-TFS formulation elicited an acceptable vesicle size (227.5 nm) with 75.83% entrapment efficiency, 37.94% cumulative release after 8 h, 547.49 µg/cm2 permeated through nasal mucosa after 24 h and adequate stability. Histopathological analysis revealed that the formulated DPZ-HA-TFS was nontoxic and tolerable for intranasal delivery. Intranasally administered DPZ-HA-TFS manifested significantly superior values for drug targeting index (5.08), drug targeting efficiency (508.25%) and direct nose-to-brain transport percentage (80.32%). DPZ-HA-TFS might be deemed as a promising intranasal nano-cargo for DPZ cerebral delivery to tackle Alzheimer's disease safely, steadily and in a non-invasive long-term pattern. [ABSTRACT FROM AUTHOR]

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]

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]

Post-Coronavirus Disease (COVID-19) condition, known as "post-COVID syndrome," is associated with a range of complications persisting even after recovery. Among these complications, cognitive dysfunction, including memory impairment, has been relatively common observed, impacting executive function and quality of life. To date, no approved treatment exists for this specific complication. Therefore, the present clinical trial aimed to investigate the impact of Donepezil Hydrochloride on post-COVID memory impairment. A randomized, controlled trial (Approval ID: IRCT20210816052203N1) was conducted, enrolling 25 patients with post-COVID memory impairment. Participants with a history of hospitalization were randomly assigned to either the drug group (n = 10) or the control group (n = 15). Memory indices were assessed at baseline, one month, and three months later using the Wechsler Memory Scale-Revised test. SPSS software and appropriate statistical tests were employed for data analysis. The statistical analysis revealed no significant difference in WMS-R subtest and index scores between the drug and control groups at the 4-week and 12-week follow-up periods. However, within the drug group, there was a notable increase in the visual reproduction I and verbal paired associates II subtests during the specified time intervals. While donepezil 5 mg did not exhibit a significant overall increase in memory scales compared to the control group over time, our findings suggest that this medication may exert a positive effect on specific memory subtests. Further research and exploration are warranted to better understand the potential benefits of donepezil in managing post-COVID-related memory impairment. The study was approved by the Research Ethics Committee of Aja University of Medical Sciences (Approval ID: IR.AJAUMS.REC.1400.125) and registered in the Iranian Registry of Clinical Trials (IRCT) (Approval ID: IRCT20210816052203N1). [ABSTRACT FROM AUTHOR]

Movement disorders associated with donepezil have been only rarely reported. Herein, we describe an older woman who developed myoclonus secondary to donepezil. A 61-year-old female presented with brief involuntary twitching. The patient reported that she consulted a general practitioner about 1 month before due to memory complaints. A diagnosis of mild cognitive impairment was made. Donepezil was started. After 4 weeks, she presented to our emergency department due to significant twitching. Multifocal myoclonus was observed. These movements occurred during rest and voluntary movement. Laboratory exams and cerebrospinal fluid analysis were normal. A cranial computed tomography and brain magnetic resonance imaging were unremarkable. Electroencephalography did not show epileptic activity. Electromyography revealed burst durations varying between 50 and 100 ms. Diazepam intravenous was started, which improved her abnormal movement within 1 hour. On the next day, she developed the same clinical symptoms of presentation. Donepezil was discontinued, and clonazepam was started. The patient had a complete recovery from her myoclonus. To the authors' knowledge, there are six reports of myoclonus secondary to donepezil/galantamine. There is no report of rivastigmine-induced myoclonus. The most frequent presentation was multifocal myoclonus. The management was the discontinuation of the acetylcholinesterase inhibitor. All the individuals recovered within 3 weeks. [ABSTRACT FROM AUTHOR]

Based on published information, the occurrence and development of Alzheimer's disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to develop nanostructured lipid carriers of donepezil hydrochloride (DNZ HCl) for effective management of Alzheimer's disease (AD). Intranasal administration of DNZ NLC containing Nigella sativa (NS) oil as a liquid lipid may significantly improve nasal penetration and deliver the drug directly to the brain avoiding blood brain barrier (BBB). High pressure homogenization was used to prepare nanostructured lipid carriers (NLCs), followed by ultrasonication. Glyceryl monostearate (GMS), Tween 80, and Poloxamer 407 were used as solid lipid, surfactant and co-surfactant respectively, whereas, Nigella sativa oil was used as a liquid lipid. The particle size, polydispersity index and zeta potential were found to be 107.4 ± 2.64 nm, 0.25 ± 0.04 and −41.7 mV. The entrapment efficiency and drug content were found to be 70.20% and 89.05% respectively. After intranasal administration of Donepezil hydrochloride (DNZ HCl) loaded NLC's, the maximum concentrations (Cmax) of 4.597 µg/mL in brain and 2.2583 µg/mL in blood was achieved after 1 h (Tmax). The formulated DNZ HCl loaded NLCs significantly improved nasal penetration and enhanced drug distribution in brain resulting in a potentially effective intranasal drug delivery system for the effective management of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments (N,N′-dialkyl-N,N′-bis(2-(ethylcarbamoyloxy)ethyl)-N,N′-dimethyldodecan-1,6-diammonium dibromide, n-12-n(Et), where n = 10, 12, 14) were comprehensively described. The critical micelle concentrations of gemini surfactants were obtained using tensiometry, conductometry, spectrophotometry, and fluorimetry. The thermodynamic parameters of adsorption and micellization, i.e., maximum surface excess (Гmax), the surface area per surfactant molecule (Amin), degree of counterion binding (β), and Gibbs free energy of micellization (∆Gmic), were calculated. Functional activity of the surfactants, including the solubilizing capacity toward Orange OT and indomethacin, incorporation into the lipid bilayer, minimum inhibitory concentration, and minimum bactericidal and fungicidal concentrations, was determined. Synthesized gemini surfactants were further used for the modification of liposomes dual-loaded with α-tocopherol and donepezil hydrochloride for intranasal treatment of Alzheimer's disease. The obtained liposomes have high stability (more than 5 months), a significant positive charge (approximately + 40 mV), and a high degree of encapsulation efficiency toward rhodamine B, α-tocopherol, and donepezil hydrochloride. Korsmeyer-Peppas, Higuchi, and first-order kinetic models were used to process the in vitro release curves of donepezil hydrochloride. Intranasal administration of liposomes loaded with α-tocopherol and donepezil hydrochloride for 21 days prevented memory impairment and decreased the number of Aβ plaques by 37.6%, 40.5%, and 72.6% in the entorhinal cortex, DG, and CA1 areas of the hippocampus of the brain of transgenic mice with Alzheimer's disease model (APP/PS1) compared with untreated animals. [ABSTRACT FROM AUTHOR]

Movement disorders associated with donepezil have been only rarely reported. Herein, we describe an older woman who developed myoclonus secondary to donepezil. A 61-year-old female presented with brief involuntary twitching. The patient reported that she consulted a general practitioner about 1 month before due to memory complaints. A diagnosis of mild cognitive impairment was made. Donepezil was started. After 4 weeks, she presented to our emergency department due to significant twitching. Multifocal myoclonus was observed. These movements occurred during rest and voluntary movement. Laboratory exams and cerebrospinal fluid analysis were normal. A cranial computed tomography and brain magnetic resonance imaging were unremarkable. Electroencephalography did not show epileptic activity. Electromyography revealed burst durations varying between 50 and 100 ms. Diazepam intravenous was started, which improved her abnormal movement within 1 hour. On the next day, she developed the same clinical symptoms of presentation. Donepezil was discontinued, and clonazepam was started. The patient had a complete recovery from her myoclonus. To the authors’ knowledge, there are six reports of myoclonus secondary to donepezil/galantamine. There is no report of rivastigmine-induced myoclonus. The most frequent presentation was multifocal myoclonus. The management was the discontinuation of the acetylcholinesterase inhibitor. All the individuals recovered within 3 weeks.

Liposomes modified with tetradecyltriphenylphosphonium bromide with dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal administration. Physicochemical characteristics of cationic liposomes such as the hydrodynamic diameter, zeta potential, and polydispersity index were within the range from 105 to 115 nm, from +10 to +23 mV, and from 0.1 to 0.2, respectively. In vitro release curves of donepezil hydrochloride were analyzed using the Korsmeyer–Peppas, Higuchi, First-Order, and Zero-Order kinetic models. Nanocontainers modified with cationic surfactant statistically better penetrate into the mitochondria of rat motoneurons. Imaging of rat brain slices revealed the penetration of nanocarriers into the brain. Experiments on transgenic mice with an Alzheimer's disease model (APP/PS1) demonstrated that the intranasal administration of liposomes within 21 days resulted in enhanced learning abilities and a reduction in the formation rate of Aβ plaques in the entorhinal cortex and hippocampus of the brain. [ABSTRACT FROM AUTHOR]

Objective: To conduct a meta-analysis of the effectiveness and safety of ginkgo biloba preparations combined with donepezil hydrochloride vs. donepezil for the treatment of Alzheimer's disease (AD). Methods: Three English databases (Cochrane Library, PubMed, EMBASE), and four Chinese databases [the China National Knowledge Infrastructure (CKNI), the Chinese Biomedical Literature database (CBM), the Chongqing VIP database, and WANFANG DATA)] were manually searched for literature published from the respective dates of inception of the databases to December 2022. The randomized controlled trials (RCTs) of ginkgo biloba preparations with donepezil hydrochloride vs. donepezil for the treatment of AD were included. Relevant literature was screened, and the data in the included studies were extracted for quality assessment according to the Risk of bias tool. The RevMan 5.3 software was used for meta-analysis. Results: A total of 1,642 participants were enrolled in the 18 RCTs. Of these, 842 were in the experimental group (ginkgo biloba preparations combined with donepezil hydrochloride) and 800 were in the control group (donepezil). The overall methodological quality of the included RCTs is poor due to the high risks of blindness and allocation concealment. The meta-analysis results showed statistically significant differences in several outcomes including Risk Ratio (RR) in change for clinical effectiveness rate (1.23, 95% CI 1.13, 1.34, P < 0.00001), mean difference (MD) in change for Mini-Mental State Examination score (3.02, 95% CI 2.14, 3.89, P < 0.00001), Activity of Daily Living Scale score (-4.56, 95% CI -5.09, -4.03, P < 0.00001), Hasegawa Dementia Scale score (2.04, 95% CI 1.74, 2.34, P < 0.00001), Montreal Cognitive Assessment score (2.38, 95% CI 0.72, 4.06, P = 0.005), between the experimental and control groups. But there is no statistically significant difference in change for adverse reaction (0.91, 95% CI 0.58, 1.42, P = 0.69). Conclusion: Ginkgo biloba preparations plus donepezil can improve clinical effectiveness rate and vocabulary memory outcomes. However, more relevant high-quality RCTs are needed in the future to validate these results. [ABSTRACT FROM AUTHOR]

Nowadays, innovative and more effective drug dosage forms continue to be researched and developed compared to traditional drug dosage forms. The importance of orally disintegrating films (ODFs) in current studies and advancements cannot be overstated. This study aims to create the optimum ODF formulations using pullulan and lycoat with donepezil hydrochloride (donepezil HCl). Plasticizers such as polyethylene glycol 400 (PEG-400) and glycerine were used to form flexible films. In the characterization studies of the films produced by the solvent casting technique: determination of morphology, determination of folding, determination of disintegration time, determination of thickness, determination of swelling, determination of pH, determination of mass uniformity, determination of In vitro release, and determination of content uniformity studies were carried out. According to the results obtained, the nonbrittle, smooth-surfaced films were disintegrated in the mouth in an average of 35 seconds. Since the 10th minute, more than 85% of the active pharmaceutical ingredient (API) has been revealed. These values suggested that the pullulan polymer showed better film-forming capacity when used with lycoat polymer. Ultraviolet (UV)-visible spectrum studies were carried out to validate donepezil HCl. Thanks to the ODFs containing donepezil HCl, an effective and safe, innovative clinical use has been achieved in the treatment of diseases such as dementia and Alzheimer, which are characterized by a decrease in daily life activities and atrophy in cognitive abilities. [ABSTRACT FROM AUTHOR]

Purpose: The main aim of the present study was to formulate Donepezil Hydrochloride (DH)–loaded ethosomal intranasal gel to increase the transport of the drug through the blood–brain barrier (BBB), thus decreasing plasma fluctuation and also decreasing the oral side effects associated with the drug. Methods: DH-loaded ethosomes were prepared by ethanol injection method. Nine ethosomal formulations were prepared containing three different concentrations of Phospholipon 90G and ethanol in combination and were evaluated for vesicle size, %entrapment efficiency, and drug content. The optimized ethosomal formulation was incorporated into the gelling base containing Poloxamer 407 (18%) and Poloxamer 188 (6%) as thermosensitive polymers and Carbopol 934 (0.1–0.5%) as mucoadhesive polymer. The prepared gels were further evaluated for gelation temperature, gelation time, drug content, mucoadhesive strength, viscosity, in vitro drug release, and ex vivo drug permeation study through the sheep nasal mucosa. Results: The optimized ethosomal formulation F4 showed a vesicle size of 110.06 ± 1.910 and a % entrapment efficiency of 70.02 ± 0.353. The mucoadhesive strength and gelation temperature were found to be 3332 ± 4.314 and 31.7 ± 0.033 in the case of optimized gel formulation. The in vitro and ex vivo drug permeation from the optimized gel formulation was almost 100% after a period of 24 h. Conclusion: Formulated DH-loaded ethosomal intranasal gel could serve as the better alternative for the brain targeting via the intranasal route. [ABSTRACT FROM AUTHOR]

PURPOSE : We investigated the efficacy and safety of donepezil hydrochloride (DH), an acetylcholinesterase inhibitor, for dysuria and defecation disorders in patients with Down syndrome. 　METHODS : We retrospectively reviewed 8 patients with Down syndrome who were treated with DH and who presented to our urology hospital for dysuria and defecation disorders between January 2010 and December 2017.　Six of the patients (male, n=2 ; female, n=4 ; age, 11-23 years) had been treated with DH for 3 months, and their lower urinary tract function and Bristol Stool Form Scale before and after the administration of DH were analyzed.　At the same time, safety was examined. 　RESULTS : The median residual urine volume before the administration of DH was 48.9 ml (IQR 15.0 ‒ 179.5), and after it was 3.5 ml (IQR 0 ‒ 20.15), which was significantly decreased (p = 0.043).　The median maximum urinary flow rate was 11.0 ml/s (IQR 6.1 ‒ 17.2) before treatment, and 14.2 ml/s (IQR 10.2 ‒ 19.4) after treatment, which was significantly improved (p = 0.031).　The urinary flow patterns before treatment were Interrupted type and Staccato type, while after treatment three of their patterns were close to Bell type and were improved.　The number of urinations per day significantly increased from 3.5 times (IQR 2.5 - 4.0) before treatment to 4 times (IQR 4.0 ‒ 5.5) after treatment (p = 0.031).　The Bristol Stool Form Scale before treatment was Type 1-2 in four patients, all of whom showed an improvement to Type 3-4 after treatment. No severe adverse events were observed due to DH. 　CONCLUSION : Treatment with DH was confirmed to be both effective and safe for Down syndrome patients with who were suffering from dysuria and defecation disorders. [ABSTRACT FROM AUTHOR]

Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is not clear in the literature. BCS is one of the accepted criteria used to grant biowaiver (waiver of in vivo bioequivalence studies) of new drug products. So, the purpose of this work was to elucidate the BCS classification of DH and to raise the discussion about the possibility of biowaiver for new medicines containing it. The polymorphic form was previously identified as form III of DH. The drug showed high solubility in the entire pH range evaluated (1.2 to 6.8, at 37 °C) with a pH-dependent solubility profile. The effective permeability (P eff) values obtained with different DH concentrations, using in situ closed-loop perfusion model were statistically similar (p > 0.05), even when compared to high permeability control used (ketoprofen), demonstrating that DH has high permeability which, associated with its high solubility, allows to classify DH as BCS class 1. Relevant data to evaluate for granting a biowaiver for new medicines were also reviewed from the literature. Based on information reunited new immediate-release drug products containing DH should be eligible for BCS-based biowaiver. [Display omitted] [ABSTRACT FROM AUTHOR]

Based on published information, the occurrence and development of Alzheimer’s disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology.

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer's disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor's concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model. [ABSTRACT FROM AUTHOR]

Nanofibers (NFs) offer an alternative option for the treatment of Alzheimer's disease (AD) by addressing unmet clinical problems. In this study, anti‐AD drugs, donepezil (DO) and curcumin (CUR), are loaded in polylactic acid/polycaprolactone NFs. The effect of fiber diameter on drug release behavior is mainly observed, and the successful loading of DO and CUR to NFs is demonstrated. The tensile strength of DO/CUR‐loaded NFs (DNFs) with lower fiber diameter is found to be higher. The working temperature is increased by the decrease of glass transition temperature and increase of the melting temperature after loading drugs. Furthermore, the increase in the percentage of swelling and decrease in the degradation rate for NFs are observed due to the increase of fiber diameter. Encapsulation efficiency and burst release percentages for DNFs are augmented by the increase of fiber diameter. Nevertheless, DNFs exhibit a sustained drug release manner over 2 weeks. NFs do not demonstrate a toxic effect on L929 (mouse fibroblast) cells, and additionally, they promote cell proliferation. Considering all these results, it is proven that the fiber diameter affects all characteristic features of NFs, and DNFs lead to a new and promising drug delivery system for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Accumulation of amyloid-β (Aß) plaques, primarily in the hippocampus, leads to neuronal death and Alzheimer disease. Exercise and medications can prevent and treat neuronal diseases. This study aimed to determine the effects of aerobic training and donepezil, a medication used in Alzheimer disease, on the improvement of learning and memory deficits in Aß-injected male rats. Objectives: This study aimed to determine the effects of aerobic training and donepezil, a medication used in Alzheimer disease, on the improvement of learning and memory deficits in Aß-injected male rats. Methods: Male Rats were injected with an Aβ solution into their CA1 hippocampal region. After 20 days, the rats were treated with donepezil hydrochloride at doses of 2 mg/kg/d by gavage and following treadmill exercise for 4 weeks. Then, after 24 h, they performed the Morris water maze test for five days. Additionally, we studied the molecular factors involved in neuronal plasticity, such as Ca2+/cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) on day 33. The animals were also evaluated histologically to determine the deposition of Aβ in the brain tissue. Results: Behavioral analysis showed that in the probe test, the latency to the platform zone significantly increased in the training group (F1,20=6.815; P0.05). Molecular analysis showed that CREB gene expression improved in the training group (F1,8=9893.539; P0.05). BDNF gene expression improved in the training group (F1,8=25.077; P

Donepezil hydrochloride thermosensitive in situ gel for nasal delivery was prepared by using Poloxamer 407 and Poloxamer 188 as thermoreversible polymers, hydroxypropyl-β-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 in vitro erosion and in vitro release tests exhibited obvious drug sustained release behavior. Meantime, main pharmacokinetic parameters such as tmax, cmax and AUC in plasma as well as in brain were significantly different between the nasal gel formulation and intragastric drug solution in rats (p < 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.

A 76-year-old woman with a 2-year history of Parkinson's disease presented with dropped head, which had developed rapidly after she had been prescribed donepezil hydrochloride (DNP) at 3 ‍mg/day. After one month of medication, the extent of the head drop reached 90°. Examination revealed hypertrophy of the left sternocleidomastoid muscle, but no weakness of the extensor muscles in the cervical region. Surface electromyography demonstrated co-‍contraction of the sternocleidomastoid and splenius capitus muscles during head flexion and extension. DNP was withdrawn, resulting in immediate amelioration of the head drop, and complete resolution was achieved after two months. Although head drop is often seen in patients with Parkinson's disease, few previous reports have documented DNP as a causative factor. If patients with Parkinson's disease develop head drop, it is important to investigate any history of DNP medication.

To investigate the effect of donepezil hydrochloride combined with comprehensive rehabilitation training on cognitive function, event-related potential and serum brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) in patients with senile dementia. 120 patients with senile dementia who were treated in our hospital from March 2017 to March 2020 were selected, they were divided into control group (n=60, donepezil hydrochloride treatment) and combination group (n=60, donepezil hydrochloride combined with comprehensive rehabilitation training treatment) according to random number table method. The efficacy, cognitive function scores, event-related potential and serum BDNF, IGF-1 before and 3 months after treatment, and the occurrence of adverse reactions during treatment of the two groups were compared. The total effective rate of the combination group was 91.67%, which was higher than 72.92% of the control group (P<0.05). The scores of activities of daily living (ADL) assessment scale, clinical dementia rating (CDR) in both groups decreased, and the combination group was lower than the control group (P<0.05), the scores of Mini Mental State Scale (MMSE) increased,, and the combination group was higher than that of the control group (P<0.05). N1 latency and P2 latency shortened, P3 amplitude increased in the two groups at 3 months after treatment, and the P2 latency in the combination group was shorter than that in control group at 3 months after treatment, P3 amplitude was higher than that in control group (P<0.05), there was no significant difference in N1 latency between the two groups at 3 months after treatment (P>0.05). The level of BDNF in the combination group at 3 months after treatment was significantly higher than that in control group (P<0.05), there was no significant difference in IGF-1 level of the two groups at 3 months after treatment (P>0.05). There was no statistical difference in the incidence of adverse reactions between control group and combination group (P>0.05). Combined with comprehensive rehabilitation training on the basis of donepezil hydrochloride, the cognitive function of patients with senile dementia can be significantly improved. At the same time, it can also adjust the event-related potential and the levels of serum BDNF and IGF-1. [ABSTRACT FROM AUTHOR]

The crystal structure of donepezil hydrochloride, form III, has been solved with FOX using laboratory powder diffraction data previously submitted to and published in the Powder Diffraction File. Rietveld refinement with GSAS yielded monoclinic lattice parameters of a = 14.3662(9) Å, b = 11.8384(6) Å, c = 13.5572(7) Å, and β = 107.7560(26)° (C24H30ClNO3, Z = 4, space group P21/c). The Rietveld-refined structure was compared to a density functional theory (DFT)-optimized structure, and the structures exhibit excellent agreement. Layers of donepezil molecules parallel to the (101) planes are maintained by columns of chloride anions along the b-axis, where each chloride anion hydrogen bonds to three donepezil molecules each. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the efficacy of donepezil hydrochloride in the treatment of elderly patients with Alzheimer’ s disease and its effects on mini mental status examination (MMSE) score and other indicators. METHODS: Totally 110 elderly patients with Alzheimer’s disease admitted into Baoding First Central Hospital from Jan. 2018 to Jun. 2020 were extracted to be divided into the study group and the control group via the random number table, with 50 cases in each group. The control group received conventional treatment, and on this basis, the study group was given donepezil hydrochloride. The treatment efficacy and adverse drug events of two groups were observed. The MMSE score, activities of daily living ( ADL) score and pathological behavior scale-Alzheimer’ s disease (BEHAVE-AD), oxidative stress and other related serum indicators of two groups were compared before and after treatment. RESULTS: Compared with 70. 00%(35/50) in the control group, the total effective rate in the study group was significantly higher, totally 90. 00%(45/50), the difference was statistically significant (P <0. 05). Compared with before treatment, MMSE score, ADL score and BEHAVE-AD score of two groups changed significantly after treatment. Compared with the control group, MMSE score and ADL score in the study group increased significantly, while BEHAVED-AD score decreased significantly, the differences were statistically significant (P<0. 05). Compared with before treatment, the levels of SOD, MDA, DA and NGF of two groups were improved significantly; compared with the control group, the levels of SOD, DA and NGF in the study group increased significantly, while the level of MDA decreased significantly, with statistically significant difference (P<0. 05). The incidence of adverse drug events in the study group and the control group was respectively 12. 00% (6/50) and 8. 00%(4/50), with no statistically significant difference between two groups (P>0. 05). CONCLUSIONS: For elderly patients with Alzheimer’s disease, the efficacy of donepezil hydrochloride combined with conventional treatment if significant with higher safety, which can effectively improve the cognitive function, life ability, mental and behavioral symptoms of patients, with high clinical application value. [ABSTRACT FROM AUTHOR]

Chenhao Zhang,1 Yanjing Zang,2 Qin Song,3 Hongxuan Li,1 Lei Hu,1 Weidong Zhao,3 Shanshan Feng,1 Fang Gu,4 FengLi Zhao,1 Chunliang Zhang11Department of Neurology, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 2Department of Geriatric, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 3Second Neurology Department, The Second Hospital of Baoding City, Baoding, Hebei, 071051, People’s Republic of China; 4Fifth Department of Internal Medicine, Baoding Children’s Hospital, Baoding, Hebei 071051, People’s Republic of ChinaObjective: To explore the efficacy and safety of “cocktail therapy” in Parkinson’s disease with dementia (PDD).Patients and methods: Sixty patients with PDD were randomly assigned to the test group (n=30) and a control group (n=30). The control group received 10 mg of donepezil hydrochloride tablets orally, once a day. The test group was treated with a “cocktail therapy”, which consisted of 10 mg of donepezil hydrochloride tablets taken orally, once a day; 200 mg of dl-3n-butylphthalide soft capsules taken orally, 15 mins before each meal, three times daily; 800 mg of oxiracetam capsules taken orally, three times daily; and 80 mg of Ginkgo biloba extract tablets taken orally, three times daily. Treatment was administered for six months. The Montreal cognitive assessment scale (MoCA), Blessed-Roth dementia scale, and Clinical Dementia Rating Scale sum of boxes (CDR-SB) were used before treatment and on the third and sixth month after treatment. Adverse events were also monitored.Results: There were no statistical differences in MoCA, CDR-SB, or Blessed-Roth dementia scale scores between the two groups before treatment. MoCA scores of the test group at six months were significantly higher than those before the treatment and at three months, while both the Blessed-Roth and CDR-SB scores were significantly lower than those before treatment and at three months (p0.05) between the test group (16.67%) and the control group (13.33%) in the rate of abnormal liver function after treatment.Conclusion: Treatment with “cocktail therapy” was safe and improved the conditions of patients with PDD, as well as the quality of life of the patients.Keywords: cocktail therapy, Parkinson’s disease with dementia, efficacy, donepezil hydrochloride, cocktail therapy

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (

Objective: To study the therapeutic effectiveness of donepezil hydrochloride (DPZ) in combination with butylphthalide (BP) for the treatment of post-stroke cognitive impairment (PSCI)., Methods: In this retrospective study, the clinical data of 125 PSCI patients treated at the First Affiliated Hospital of Harbin Medical University from December 2019 to December 2023 were collected and analyzed. The patients were grouped into a joint group (n=75, receiving DPZ + BP) and a control group (n=50, receiving DPZ alone) according to their treatment regimen. Inter-group comparisons were then carried out from the perspectives of therapeutic effectiveness, safety (constipation, abdominal distension and pain, and gastrointestinal reactions), cognitive function (Montreal Cognitive Assessment Scale [MoCA], Chinese Stroke Scale [CSS]), Activities of Daily Living Scale (ADL), and serum biochemical indexes (neuron-specific enolase [NSE], high-sensitivity C-reactive protein [hs-CRP], nitric oxide [NO], and malondialdehyde [MDA]). In addition, a univariate analysis was carried out to identify factors affecting therapeutic effectiveness in PSCI patients., Results: The joint group showed significantly better therapeutic effectiveness compared to the control group (P<0.05). There was a significant correlation between the type of stroke, treatment method, and therapeutic effectiveness in PSCI patients (P<0.05). There was no significant difference in the total incidence of adverse reactions (P>0.05). After the treatment, compared to the control group, the joint group demonstrated significant improvements in MoCA and ADL scores (all P<0.05) and reductions in CSS scores and levels of NSE, hs-CRP, NO, and MDA (all P<0.05)., Conclusions: DPZ in combination with BP is highly effective for the treatment of PSCI. It positively affects cognitive function and ADL, alleviates neurological deficits, and reduces abnormal serum biochemical indices without increasing the risk of adverse reaction., Competing Interests: None., (AJTR Copyright © 2024.)

Background and Objective: Dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are the earliest pathological events in the pathogenesis of alzheimer disease (AD). This study was done to evaluate the effect of donepezil hydrochloride on reference and working memory caused by mutual electrical lesion of the nucleus basalis magnocellularis (NBM) in animal model of AD. Methods: In this experimental study, 56 adult male Wistar rats were allocated into 8 group (n=7) including: control (intact), NBM lesion group, which received electrically- induced lesion (0.5 m A, 3s) in NBM, Sham group (the electrode was impaled in to the NBM with no lesion), donepezil groups (lesion + 0.1, 1, 5, 10 mg/kg/bw of donepezil hydrochloride) and vehicle group (NBM lesion+ saline). Acquisition and retention testing were done by using an eight-radial arm maze, in which, the patterns of arm entries in each group was recorded for calculating correct choice, working memory errors, reference memory error and latency. Results: The spatial learning of animals in the lesion of NBM group significantly reduced in compared to controls (P

Donepezil hydrochloride is one of the most prescribed anti-Alzheimer's drugs, despite being available for more than two decades, chromatographic methods for the quantification of the drug in biorelevant media that mimics pH physiological conditions in vivo (pH 1.2, 4.5, and 6.8) are not available in the literature. These media are used in the dissolution test, an important tool, for registration and quality control of medicines. Considering the need for methods with this purpose, this work aimed to develop and validate a sustainable UPLC-UV method for quantification of donepezil hydrochloride in tablets, specifically on assay and dissolution profile, with reduced environmental impacts. The proposed method has a run time of 2 min and requires for each run, only 0.8 mL of solvents, providing excellent green analysis. The method proved to be selective, linear, precise, accurate, robust in the range of 2–14 µg/mL. Three products (reference, similar, and generic) were analyzed and showed very rapid dissolution. The average content varied from 100.2 ± 0.6% to 109.5 ± 2.1%. Using dissolution efficiency (DE), the drug release profiles were compared in different biorelevant media. [ABSTRACT FROM AUTHOR]

Objectives: The aim of present study was the formulation of donepezil hydrochloride loaded polymeric mucoadhesive microspheres for delivery via nasal route to increase the residence time and absorption of drug from the nasal mucosa. Methodologies: The microspheres were formulated by conventional spray drying technique by using gellan gum as a mucoadhesive polymer. A 3² full factorial design was utilized with polymer concentration (X1) and liquid feed flow rate (X2) as independent variables in formulation of the microspheres and their effect was studied on entrapment efficiency, particle size and drug loading. Results: The results specified that the X1-X2 interaction had significant effect on drug loading while X2 alone effect on entrapment efficiency and particle size. The optimized microspheres were further evaluated for drug release kinetic study, histological examination, ex vivo permeation study and stability study. Conclusion: It was concluded that the gellan gum containing microspheres of donepezil hydrochloride with mucoadhesive property are suitable for nasal delivery. [ABSTRACT FROM AUTHOR]

The present study aimed to examine the effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease (AD). For this purpose, a total of 126 patients with AD admitted to Luoyang Central Hospital from January, 2018 to December, 2018 were enrolled. Patients were divided into different groups according to the treatment they selected. Patients treated with single-agent donepezil were separated into a monotherapy group (n=56), and patients receiving donepezil plus rivastigmine were placed in the combination group (n=70). Before and after treatment, the cognitive functions, mental behavior and quality of life of the patients in the two groups were respectively evaluated by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Blessed-Roth Dementia Scale (BRDS) and the QOL-AD. In addition, the serum bradykinin level was detected by enzyme-linked immunosorbent assay. Following treatment, the MMSE score, BRDS, ADAS-Cog and QOL-AD scores were improved compared with those before treatment (P<0.05). However, following treatment, the 4 scores in the combination group were significantly higher than those in the monotherapy group (P<0.05). No significant differences were observed in the incidence of adverse reactions between the 2 groups (P>0.05). Following treatment, the bradykinin level in both groups was significantly decreased (P<0.05), although the decrease in the combination group was more significant than that in the monotherapy group (P<0.05). On the whole, the findings of the present study indicate that rivastigmine hydrogen tartrate used in combination with donepezil hydrochloride relieves the symptoms and improves the quality of life of patients with AD more effectively, which may be related to the reduction of the bradykinin level in these patients. [ABSTRACT FROM AUTHOR]

Objective To compare the effects of donepezil hydrochloride in the treatment of single cognitive domain impairment and multiple cognitive domain impairment of Parkinson's disease with mild cognitive impairment (PD-MCI) Methods Sixty patients with PD-MCI were divided into the single cognitive domain impairment group (PD-MCI-SD group, 29 patients) and multiple cognitive domain impairment group (PD-MCI-MD group, 31 patients) according to the screening criteria. Patients in both groups received donepezil hydrochloride. Before and 12 weeks after treatment, Mini一 Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Digit Span Backward Test (DSB-T), Trail Making Test B (TMT-B), Boston Naming Test (BNT), Auditory Verbal Learning Test (A VLT), and Clock Copying Test (CCT) were used to assess cognitive function, the serum uric acid and plasma homocysteine (HCY) were measured by the automatic biochemical analyzer. Results The MMSE and DSB-T scores of both groups increased at 12 weeks after treatment as compared with those before treatment (both P <0. 05), and the PD-MCI-MD group had higher MMSE and DSB-T scores than the PD-MCI-SD group (both P <0. 05) ; PD-MCI-MD group had lower TMT-B score at 12 weeks than that before treatment (P <0. 05), and the TMT-B score was lower than that of the PD-MCI-SD group at 12 weeks after treatment (P < 0. 05). The plasma HCY level in the PD-MCI-MD group at 12 weeks after treatment was lower than that before treatment (P <0. 05), and the plasma HCY level was lower than that in the PD-MCI-SD group at 12 weeks after treatment (P <0.05).Conclusion After donepezil hydrochloride treatment, PD-MCI-MD patients had better improvement in the overall cognitive function, attention, and executive function than PD-MCI-SD patients, and PD-MCI-MD patients had lower plasma HCY level. [ABSTRACT FROM AUTHOR]

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

Background: Alzheimer's Disease (AD) is a long-term brain disorder that worsens over time. A cholinesterase inhibitor called Donepezil HCl (DNZ) is used to treat and control AD. Due to its failure to reach the appropriate concentration in the brain cells, its efficacy upon oral administration is limited, and thus investigation of alternative administration route is necessary., Objective: The objective of this study was to develop donepezil HCl-loaded Nanostructured Lipid Carriers (NLCs) that can bypass the blood-brain barrier and thus be directly delivered to the brain through the nasal route. This method improves availability at the site of action, reduces the negative effects of oral medication, and ensures an expedited commencement of action., Method: High-pressure homogenization and ultrasonication were used to formulate NLCs. Glyceryl Monostearate (GMS) as a solid lipid, Tween 80 as a surfactant, and Poloxamer 407 as a co-- surfactant were used. In this study, argan oil was employed as a liquid lipid as well as a penetration enhancer., Results: The chosen NLCs displayed a particle size of 137.34 ± 0.79 nm, a PDI of 0.365 ± 0.03, and a zeta potential of -10.4 mV. The selected formulation showed an entrapment efficiency of 84.05 ± 1.30% and a drug content of 77.02 ± 0.23%. The concentration of the drug in the brain after intravenous and intranasal administration of DNZ NLCs at 1 h was found to be 0.490 ± 0.007 and 4.287 ± 0.115, respectively. Thus, the concentration of DNZ achieved in the brain after intranasal administration of DNZ NLCs was approximately 9 times more than the concentration when administered by intravenous route., Conclusion: The DNZ-loaded NLCs, when administered via nasal route, showed markedly improved drug availability in the brain, suggesting an efficient drug delivery strategy to treat Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The objective of this research was to optimize the tasted-masked microparticles for orally disintegrating tablets containing donepezil hydrochloride using quality risk assessment and design of experiment approaches. The double emulsion solvent evaporation technique using aminoalkyl methacrylate copolymer (AMC) was used to prepare taste-masked microparticles. Factors affecting the quality of the taste-masked microparticles were analyzed using an Ishikawa diagram. A risk-ranking approach was used to rank the formulation and process risks. Furthermore, the effect of AMC quantity, stirring time, and volume of outer water phase on various responses, such as particle size, the amount of drug dissolved at 5 min (Q5) in simulated saliva fluid, and mean dissolution time (MDT) in simulated gastric fluid, was investigated using the Box-Behnken design. The optimized microparticles were then used to prepare orally disintegrating tablets (ODTs) and evaluated by in vitro and in vivo testing. The results demonstrated that particle size was influenced by the AMC amount and stirring time. Q5 was significantly affected by the amount of AMC and the volume of the outer water phase. On the other hand, these two factors had a positive effect on MDT. The optimized microparticles had a particle size of 174.45 ± 18.19 µm, Q5 of 5.04%, and MDT of 5.97 min. The ODTs with taste-masked microparticles showed acceptable in vitro dissolution with an MDT of 5 min. According to the results of a panel of six human volunteers, they greatly improved palatability.

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888.

Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days), or combined with acupuncture at Shenting (DU24), Tianzhu (BL10), Sishencong (Extra), Yintang (Extra), Renzhong (DU26), Neiguan (PC6), Shenmen (HT7), Fengchi (GB20), Wangu (GB12) and Baihui (DU20) (once a day for 56 days). Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia.

Kaori Kurata,1 Eitarou Taniai,2 Kanae Nishimura,3 Kenji Fujita,3 Akira Dobashi1 1Education and Research Institute of Information Science, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; 2Informational Headquarters, Yakuju Corporation, Minato-ku, Tokyo, Japan; 3General Incorporated Foundation Social University, Minato-ku, Tokyo, Japan Purpose: We investigated prescriptions regarding the combined use of donepezil hydrochloride (DPZ) and anticholinergics for elderly outpatients in Japan to determine the impact that combination therapy has on decreasing their cognitive functions. Methods: Using electronic medication records from 142 community pharmacies, outpatients older than 40 years of age taking DPZ, with or without other prescription medicines, were assessed over 6 years, beginning in 2007. We estimated the number of medicines administered along with DPZ, the number of anticholinergics administered along with DPZ, and the medicines' anticholinergic cognitive burden (ACB) scale cumulative score based on data from the top four pharmacies that filled the highest number of prescriptions for DPZ for outpatients with dementia in 2010. Data were gathered from records of 431 patients; only three patients were younger than 60 years. Results: There was a 1.94-fold increase in the number of prescriptions including DPZ over 6 years. The proportion of patients to whom other medicines were administered along with DPZ was 65.6% (n=283) and the proportion of those taking at least one anticholinergic agent was 24.1% (n=104). The mean number of medicines among subjects taking at least one anticholinergic was 5.7, and the mean cumulative ACB score for anticholinergics contained in these medicines was 2.6. Among 104 patients to whom the anticholinergics were administered along with DPZ, two outpatients taking urologic medicines such as oxybutynin hydrochloride or tolterodine tartrate were found. Conclusion: Our findings suggest that it is necessary to pay attention to a decline in cognitive function when prescribing multiple medicines, especially to elderly patients who have already been prescribed DPZ. Keywords: dementia, donepezil hydrochloride, anticholinergic medicines, outpatients' medication, prescription survey, prescription cascade

This study was designed to explore the combined effect of donepezil hydrochloride and aerobic exercise training on learning and memory and to check its mechanism of action in an Alzheimer's disease (AD). Thirty rats were randomly divided into normal control group, model group and donepezil hydrochloride combined with aerobic exercise training group (n=10). Amyloid β-protein (Aβ1-40) was injected into rats to establish an elderly AD model. After 4 weeks of administration, changes in the spatial learning and memory of rats were tested in the Morris water maze. Choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) in the hippocampus and cerebral cortex were measured by colorimetry. Compared with the normal control group, rats in the model group took more time to find the platform (P<0.001) and showed a longer swimming path (P<0.001). Rats in the intervention group took less time to find the platform (P<0.001) and showed a shorter swimming path (P<0.001) in comparison to the model group. Similarly, rats in the model group showed decreased ChAT activity (P<0.001) and increased AchE activity (P<0.001) in the hippocampus and cortex as compare to the normal control group. Compared with the model group, rats in the intervention group showed increased ChAT activity (P<0.001) and decreased AchE activity (P<0.001) in the hippocampus and cortex. The study concluded that Donepezil hydrochloride combined with aerobic exercise training improved the learning and memory function of rats with AD. The mechanism was also related to improved morphological structure of hippocampal neurons, reduced loss of neuronal cells, increased ChAT content and decreased AchE content. [ABSTRACT FROM AUTHOR]

A green, simple and cost effective chemometric UV–Vis spectrophotometric method has been developed and validated for correcting interferences that arise during conducting biowaiver studies. Chemometric manipulation has been done for enhancing the results of direct absorbance, resulting from very low concentrations (high incidence of background noise interference) of earlier points in the dissolution timing in case of dissolution profile using first and second derivative (D1 & D2) methods and their corresponding Fourier function convoluted methods (D1/FF& D2/FF). The method applied for biowaiver study of Donepezil Hydrochloride (DH) as a representative model was done by comparing two different dosage forms containing 5 mg DH per tablet as an application of a developed chemometric method for correcting interferences as well as for the assay and dissolution testing in its tablet dosage form. The results showed that first derivative technique can be used for enhancement of the data in case of low concentration range of DH (1–8 μg mL −1 ) in the three different pH dissolution media which were used to estimate the low drug concentrations dissolved at the early points in the biowaiver study. Furthermore, the results showed similarity in phosphate buffer pH 6.8 and dissimilarity in the other 2 pH media. The method was validated according to ICH guidelines and USP monograph for both assays (HCl of pH 1.2) and dissolution study in 3 pH media (HCl of pH 1.2, acetate buffer of pH 4.5 and phosphate buffer of pH 6.8). Finally, the assessment of the method greenness was done using two different assessment techniques: National Environmental Method Index label and Eco scale methods. Both techniques ascertained the greenness of the proposed method. [ABSTRACT FROM AUTHOR]

The ultimate aim of the present study was to develop sustained release (SR) tablets of Donepezil Hydrochloride by employing natural polymers (Guar gum and Xanthan gum) as the matrix material in different proportion by wet granulation method. Initially drug-excipients compatibility studies were carried out using FTIR and DSC which showed no interaction between drug and excipients. Granules of prepared batches were evaluated for bulk density, tapped density, carr's index, hausner's ratio, angle of repose. Tablets were evaluated for various physicochemical parameters like hardness, thickness, friability, weight variation test, drug content and in vitro drug release. All the formulation showed compliance with pharmacopoeial standards. 32 full factorial design was applied in which Guar gum (X1) and Xanthan gum (X2) were taken as independent factor and %CDR at 2hr (Y1) and at 12hr (Y2) were taken as response. In-vitro drug release study revealed that as the amount of polymers increased, % CDR decreased. Contour plots as well as response surface plots were constructed to show the effect of X1 and X2 on %CDR and predicted at the concentration of independent variables X1(40mg) and X2(40mg) for maximized response. The kinetic release treatment showed that korsmeyer peppas equation has shown of r2 0.9517 which was close to one indicating that the dissolution profile fits in Korsmeyer-Peppas model and the mechanism of drug release from these tablets was by non-fickian diffusion mechanism. The optimized batch was kept for stability study at 40 ± 2oC/ 75 ± 5 % RH for a period of 1 month according to ICH guidelines and found to be stable after 1 month of study. [ABSTRACT FROM AUTHOR]