Donepezil Research Articles

Optimized Taste-Masked Microparticles for Orally Disintegrating Tablets as a Promising Dosage Form for Alzheimer's Disease Patients.

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.

Crystal structure of donepezil hydrochloride form III, C24H29NO3⋅HCl

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.

Donepezil hydrochloride as a novel inducer for osteogenic differentiation of mesenchymal stem cells on PLLA scaffolds in vitro.

Over the past decades, bone defects caused by illness or trauma have been the most common traumatic injuries in humans and treatment of orthopedic infections has always been a serious challenge to experts in the world. In this project, poly L-lactic acid (PLLA) nanofibrous scaffolds were synthesized as a nontoxic, eco-friendly, and cost-effective scaffold by the electrospinning technique. Then, the impact of PLLA on the cell proliferation and osteogenic differentiation of human mesenchymal stem cells (hMSCs) was assayed in the presence and absence of donepezil hydrochloride (DH) which was prescribed in patients with Alzheimer's disease. Also, hMSCs were seeded on PLLA scaffold in the presence (PLLA-DH) and absence of 1μg mL-1 of DH under osteogenic induction media. Osteogenic differentiation of hMSCs was assessed by specific bone-related tests including alkaline phosphatase (ALP) activity, Alizarin red and von Kossa staining, calcium content assay. Also, Osteocalcin and osteopontin were evaluated as osteogenic proteins as well as ALP, osteonectin, osteocalcin, collagen type I (Col-I) and Runx2 as osteogenic genes via immunocytochemistry (ICC) and Real-time PCR analyses. The obtained data showed the higher ALP enzyme activity and biomineralization, more intensity during von Kossa staining as well as the increase in the expression rate of osteogenic related gene and protein markers in differentiated hMSCs on PLLA-DH. In conclusion, the present study revealed that the combination of PLLA scaffold with DH provides a scope to develop a suitable matrix in bone tissue engineering applications.

Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy.

Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer's disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.

Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression.

This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.

Bushen-Huatan-Yizhi formula reduces spatial learning and memory challenges through inhibition of the GSK-3β/CREB pathway in AD-like model rats

BackgroundThere is an increase in cases of Alzheimer's disease (AD) stemming from a globally ageing population demographic. Although substantial research efforts were performed for the scope of prophylaxis and therapeutic measure development against AD, based on its pathogenesis, most were unsuccessful. Bushen-Huatan-Yizhi formula (BSHTYZ) is extensively implemented to manage dementia. However, few studies have been carried out to understand how BSHTYZ enhances recovery of spatial learning and memory and how it modulates relevant molecular interplays in order to achieve this. PurposeTo investigate neuroprotective function, ameliorating learning/memory capacity of BSHTYZ via GSK-3β / CREB signaling pathway in rat AD models influenced through Aβ1-42. MethodsA total of 60 male SD rats (3 months old) were randomized into six groups and treated with 2.6 μg/μl Aβ1-42 (5 μl) into the lateral ventricle, though the control group (Con) was administered an equivalent volume of vehicle. Consequently, the rat cohorts were administered either BSHTYZ or donepezil hydrochloride or normal saline, by intragastric administration, for four weeks. Spatial learning / memory were detected through the Morris water maze, and possible mechanisms detected by histomorphological examination and Western blot in the rat AD models induced by Aβ1-42. ResultsSpatial learning/memory issues were monitored after Aβ1-42 infusion in rats. Simultaneously, neuron loss in cornuammonis1 (CA1) / dentate gyrus (DG) within hippocampus region were identified, together with enhanced black granule staining within the hippocampus and hyperphosphorylated tau within Ser202 and Ser396 sites. It was also elucidated that Aβ1-42 had the capacity to up-regulate glycogen synthase kinase-3β (GSK-3β) and down-regulate cAMP response element binding protein (CREB). BSHTYZ was found to reverse such molecular interplays. ConclusionThe study suggested BSHTYZ could possibly provide neuroprotective role against learning / memory impairment, which provided a potential therapeutic tool delaying the progression of AD molecular interplays that includes the GSK-3β / CREB signaling pathway.

Comparison of malondialdehyde levels and superoxide dismutase activity in resveratrol and resveratrol/donepezil combination treatment groups in Alzheimer\u2019s disease induced rat model

The aim of this study was to determine the malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in colchicine induced Alzheimer’s disease (AD), resveratrol (RS) treated and RS + donepezil (DPZ) treated rat models. The objective was to compare the MDA level and SOD activity among these rat models. The present study included 3 months old male albino Wistar rats, which were in-house bred and weighting about 220–250 g. The rats were divided into nine subgroups which included control, sham, AD induced, RS treated and DPZ treated groups in different doses and combinations. The lipid peroxidation product for MDA in the brain homogenate was measured by estimating the levels of thiobarbituric acid reactive substance. Estimation of SOD was done by the method of autoxidation of pyrogallol by Marklund and Marklund. There was a marked increase in the MDA levels in AD induced group in comparison to the control group (p < 0.05). The SOD activity was higher in the RS 10 and RS 20 treated groups in contrast to the AD group (p < 0.05). In DPZ + RS group, there was a substantial increase in the SOD activity (p < 0.05). It is also observed that the RS 20 treatment group showed higher SOD activity than the RS 10 group (p < 0.05). This study showed that, AD induced group had elevated levels of MDA, which indicates the poor oxidative stress–defence mechanism. The RS 10 and RS 20 groups showed higher SOD activity in comparison to the AD group, which indicated the improved oxidative stress–defence mechanism. The RS + DPZ group showed higher SOD activity, indicating a synergistic effect of DPZ and RS.

Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin

The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer’s disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 ± 12.8 µm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G′), loss modulus (G″), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the Cmax value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUClast value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer’s disease.

An Update on the Routes for the Delivery of Donepezil.

Dementia is a significant public health problem in the 21st century. Alzheimer's disease (AD) is an essential factor in dementia. Currently, the drugs used for the treatment of AD are mainly acetylcholine inhibitors (AChEIs). As an AChEI, donepezil (DP) can improve patients' cognitive ability with low side effects and has been accepted by most patients and doctors. For AD patients, the dosage regimen is also crucial due to aging and diseases. Although there are DP oral tablets on the market, there are still many problems to be solved. At present, more and more research is conducted to optimize the route of administration of DP to improve the self-administration of patients. The research fields of DP administration include oral administration, injection administration, intranasal administration, and transdermal administration. This Review is to present the development of different DP administrations and evaluates the advantages and limitations of those works, hoping to optimize the DP dosage regimen for AD patients.

Modification and characterization of an innovative polyvinyl alcohol-45S5 bioactive glass nanocomposite scaffold containing Donepezil hydrochloride for bone tissue engineering applications

The bone tissue engineering field is in desperate need of a suitable scaffold. We synthesized a polyvinyl alcohol (PVA) based scaffold and modified it by adding bioglass (BG) and Donepezil hydrochloride (DPH) to offset the lack of bioactivity and promote bone induction. XRD and FTIR analysis corroborated the successful chemical bonding of the compounds within the scaffold. Incorporating DPH leads to accelerated degradation and enhanced swelling of the composite. MTT and Acridine orange manifested increased adherence, viability, growth and proliferation of PVA/BG/DPH. Further, following osteogenic induction, PVA/BG/DPH directed hMSCs to synergistically boost the level of calcium biomineralization and alkaline phosphatase (ALP) activity.

Effect of electroacupuncture on learning-memory ability and expression of IL-1β, IL-6 and TNF-α in hippocampus and spleen in mice with Alzheimer's disease

To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1β, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1β, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.

Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation.

Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC50 value of 5.07 µM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents (Figure 1(Fig. 1)).

Preparation of Photopolymerizable HEMA/PEG-DA Based Hydrogels Filled with Low Concentrations of Nanoparticle Titanium Dioxide for Release Of Donepezil HCl

: 2-hydroxyl ethyl methacrylate/poly(ethylene glycol) diacrylate (HEMA/PEG-DA) based hydrogels are attractive drug carriers due to their appealing properties such as biodegradability and sustained release. The scope of this study was to investigate the swelling and release behaviors of HEMA/PEG-DA-based hydrogels filled with low concentrations of nanoparticle titanium dioxide (TiO2). Hydrogels have been synthesized successfully by photopolymerization. 2,2-Dimethoxy-2-Phenyl-Acetophenone (Irgacure 651), 1-Hydroxycyclohexyl Phenyl Ketone (Irgacure 184) and 2-Hydroxy-4'-(2-Hydroxyethoxy)-2 Methylpropiophenone (Irgacure 2959) were selected for photopolymerization. Fourier Transform Infrared Spectroscopy (FT-IR) had been used in confirming the functional group of hydrogels. A digital microscope and Scanning Electron Microscope (SEM) were used for characterizing synthesized hydrogels. This study revealed that the content of hydrogels, the kind of photo-initiators and pH have a significant effect on the swelling and releasing of Donepezil Hydrochloride (active pharmaceutical ingredient (API) for Alzheimer disease) behaviours.

The effect and pharmacology of Yizhi Sheng Hui decoction on Alzheimer's disease.

Alzheimer's disease (AD) has gradually increased as society has aged and is now a serious social problem. In the clinical treatment of AD, patients show improvement in cognitive function after treatment with the traditional Chinese medicine compound, Yizhi Sheng Hui (YZSH) decoction. This study systematically investigates the effect and pharmacology of the YZSH decoction on AD. In this study, 24 SAMP8 AD model mice were randomly divided into three groups: an untreated control group, a group treated with the YZSH decoction, and a positive control group treated with donepezil hydrochloride. Eight SAMR1 mice were placed in the normal control group. A Morris water maze test and a step-down test were conducted at 8 and 13 weeks after continuous intragastric administration of the two drugs. After 13 weeks of administration, the hippocampal expression of Aβ1-42 and tau protein were measured. There was no change in the latent period duration and the number of platform crossings in each group after 8 weeks of administration, but after 13 weeks of administration, the latent period of the treatment group and the positive control group were significantly shorter than the untreated control group. Initially, the SAMP8 mice showed a lower spatial exploration ability than the SAMR1 mice. However, after 13 weeks of administration, the treatment group and the control group exhibited a better exploration ability. Compared with the SAMR1 mice, the on-stage evasion time and step-down errors significantly increased in the untreated group. Compared with the untreated group, mice in the treatment group and the positive control group showed a shorter latent period after 8 weeks of administration, and the on-stage evasion time for both groups was significantly reduced after 13 weeks of administration. The treatment group showed fewer instances of electric shock. Hippocampal expression of Aβ1-42 was high in the untreated group, was much lower in the positive control group, and no Aβ1-42 expression was observed in the treatment group. The YZSH decoction improved the learning and memory of mice with AD, related to the inhibition of Aβ1-42 expression.

Effective factors on iontophoretic transdermal delivery of memantine and donepezil as model drugs

The purpose of this study is to compare in vitro and in vivo release characteristics of memantine hydrochloride and donepezil hydrochloride in monolayer films those prepared by the solvent evaporation method. Eudragit EPO (EPO), hydroxypropyl methylcellulose (HPMC), and ethylcellulose (EC) were used as polymer matrix; polyethylene glycol (PEG) was used as a plasticizer, and glycerol (Gl) was used to give balanced monolayer film moisture content. The same matrix were used to load the same concentrations of the model drugs to compare their characteristic release properties and to minimalize the effect of formulation that may affect their specific release properties. Drug-loaded monolayer films were surrounded with cellophane membranes as a barrier on in vitro release studies. The in vivo studies were performed on the shaved (hairless) dorsal region of Wistar albino rats. Anodal iontophoresis was applied as a physical penetration enhancement method for a constant time of 1 h. Linear regression applied to calculate the correlation between the in vivo and in vitro results.Anodal iontophoresis were applied on drug-loaded monolayer films. Iontophoretic results were compared with passive diffusion results of drug-loaded monolayer films. Anodal iontophoresis studies were performed by applying two different current intensities to both lower and higher concentration drug-loaded monolayer films to evaluate the effect of concentration and intensity on the transported drug quantities.The transported average memantine hydrochloride (MEM) and donepezil hydrochloride (DON) concentrations after 24 h passive diffusion study were found as 166.13 ng/mL and, 73.56 ng/mL, respectively. These concentrations were increased to 10.59 μg/mL and, 636.81 ng/mL, respectively after 1 h 0.5 mA/cm2 anodal iontophoretic pre-treatment.The obtained results support the phenomenon; transported drug quantities through the skin from the selected matrix increased according to the concentration of the drug and, the current intensity that applied on iontophoretic pre-treatment. It was observed that the difference between the transported quantities of two drugs depends on mainly to the physicochemical properties of the drugs. Iontophoretic pre-treatment found more effective on transported quantities of memantine hydrochloride through the skin. This supports that the selected matrix and penetration enhancer is sufficient for memantine hydrochloride but not for donepezil hydrochloride. This suggests that the transported donepezil hydrochloride quantities through the skin may increase by the selection of suitable penetration enhancers or combination thereof in a suitable matrix.

Optimization and Evaluation of In situ Nasal Gel of Donepezil Hydrochloride

Introduction: The nasal route has been explored as a route of administration, due to the benefits it offers. The formulation in the form of in situ gel has been utilized for the local and systemic effect. This type of formulation first exists in sol form, but once they are administered, it undergoes gelation to form gel, and this approach can be used for successful drug delivery system. Methods: Thus, in the present study, formulation of in situ gel for nasal administration for donepezil hydrochloride (HCL), by the use of 32 factorial designs, to improve its nasal bioavailability, was developed by increasing its nasal retention time and arrive at an optimized formulation. The formulation was developed by the use of cold method, by incorporation of thermoreversible polymer poloxamer 407 and mucoadhesive agent tragacanth. The in situ gel was later evaluated for different parameters such as pH, gelation time gelation temperature, gel strength, drug content, mucoadhesion, viscosity, in vitro drug diffusion, and stability. Results: Based on results obtained, F5 formulation was found to be optimum. The concentration of 22.5% Poloxamer 407 with 0.07% tragacanth showed promising nasal drug delivery system for donepezil HCl, with enhanced residence time due to increase in viscosity and mucoadhesion characteristics. Conclusion: The use of in situ gel formulation thus can effectively and safely improve the nasal residence time and absorption of donepezil HCl.

Novel fumarate derivatives; synthesis and investigation of acetylcholinesterase inhibitor properties

In this study, new fumarate compounds (I-IV) containing some natural phenols (eugenol, guaiacol, isoeugenol and vanillin) were synthesized and characterized. The single crystal X-ray diffraction technique was used to determine the crystal structures of all compounds. All compounds were evaluated as acetylcholinesterase (AChE) inhibitory, especially compound IV (IC50 =5.25±0.51 µg/mL), can be identified as a promising anti-acetylcholinesterase agent due to its good inhibitory effect, when compared with donepezil hydrochloride (IC50 =16.02±0.66 µg/mL) as used standard acetylcholinesterase inhibitory agent.

ACETATE AMELIORATES GLUCOSE DYSREGULATION AND NEUROBEHAVIOURAL DEFICIT IN DEXAMETHASONE PLUS SCOPOLAMINE-TREATED MICE: GUT-HEART-BRAIN CROSSTALK

Objective: Cardiometabolic disorders have been shown to be associated with the etiology of neurodegenerative diseases but the mechanisms are elusive. There is increasing evidence that the gut microbiota-derived short-chain fatty acids (SCFAs) plays key role in mediating the beneficial effects of the gut microbiome in maintenance of host health. This study was designed to investigate whether SCFA, acetate, would mitigate dexamethasone plus scopolamine-induced dysmetabolism and cognitive decline. Design and method: Male mice (n = 6/group) received (p.o.) vehicle, dexamethasone with scopolamine (DEX; 0.2 mg/kg + SC; 3.0 mg/kg), DEX+SC with sodium acetate (ACE; 200 mg/kg) and DEX+SC with donepezil hydrochloride (DP; 1.0 mg/kg) for 7 days. Morris water maze was used to examine spatial learning and memory while Y-maze was used to determine working and cognitive memory respectively. Oral glucose tolerance test was carried. Results: Degenerative changes such as weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments were noticed in DEX+SC-treated mice compared to control. Furthermore, DEX+SC treatment led to impaired glucose tolerance, elevated 1-hour postload glucose response and increased triglyceride-glucose index. Likewise oxidative impairment was indicated by depleted plasma, cardiac and brain glutathione reductase, nitric oxide and elevated lipid peroxidation (malondialdehyde). Cholinergic deficits characterized by increased neural acetylcholinestrase (AChE) expression and elevated uric acid, lactate dehydrogenase, lactate the plasma, cardiac and neural tissues of the DEX+SC-treated mice further implied cardiac dysfunction alongside the degenerative changes. Consequently, proteolysis was evident by observed diminshed Nissl profiles in axons and dendrites of neurons which correspond to apoptotic changes observed in H&amp;E staining of prefrontal cortex and hippocampal sections. Conclusions: Interestingly, ACE treatment ameliorated the DEX+SC-induced behavioural deficits and cardiometabolic dysfunctions in mice. The effects of ACE treatment were comparable to the DP in DEX+SC-treated rats. Hence, ACE prevents neural and cardiac oxidative damage, behavioural deficits and glucose deregulation. Furthermore, ACE could be a potential AChE inhibitor. These findings suggest that the gut microbiota-derived SCFA, acetate, would be a cost effective therapeutic target for inhibition of neuro-cardiac degenerative processes and behavioural deficits through the gut-heart-brain crosstalk

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology.

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.

Dengzhan shengmai capsule combined with donepezil hydrochloride in the treatment of Alzheimer's disease: preliminary findings, randomized and controlled clinical trial.

To observe the effects of Dengzhan Shengmai capsule combined with donepezil hydrochloride on cognitive function, daily living ability, and safety in patients with Alzheimer's disease. A total of 294 patients with Alzheimer's disease were randomly divided into a treatment group and a control group, 147 cases each group. The control group was given oral donepezil hydrochloride 5 mg once a day, and the treatment group was given oral Dengzhan Shengmai capsule 0.36 g three times a day, based on the control group. At 3 and 6 months of treatment, the ADAS-cog score of the treatment group was 48.69±6.23 and 44.24±5.53; for the control group, 45.48±5.94 and 41.57±5.10. The difference between the two groups is statistically significant (p<0.05). At 3 and 6 months of treatment, the NO level in the treatment group was (46.28±6.68) umol/l, (43.55±7.92) umol/l, and the control group was (42.95±7.92) umol/l, (38.89±5.93) umol/l. The differences between both groups were statistically significant (p<0.05). At 3 and 6 months of treatment, ET levels in the treatment group were (156.08±17.39) ng/l, (144.91±17.60) ng/l, and the control group was (150.48±22.94) ng/l, (135.04±10.08) ng/l. Correlation analysis showed that ADAS-cog score was negatively correlated with NO and ET (p<0.001). Dengzhan Shengmai capsule combined with donepezil hydrochloride can improve cognitive function and the living capacity of patients with Alzheimer's disease, reduce the production of neurotoxic substances NO and ET, and provide higher safety.