Investigation on formulation parameters of donepezil HCl loaded solid lipid nanoparticles

Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer's disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer's treatment with reduced side effects and doses for patients

Clinical study of acupuncture combined with medication for the elderly with Alzheimer disease / 针灸推拿医学（英文版）

Objective: To observe the impact of mind-regulating acupuncture plus donepezil on the cognitive ability, mean cerebral blood flow velocity, event-related potential P300, and activities of daily living (ADL) in the aged patients with Alzheimer disease (AD).Methods: Sixty senile AD patients were divided into a treatment group and a control group following the envelope method for random allocation, with 30 cases in each group. Based on the conventional treatment of the internal medicine, the control group received oral donepezil, and the treatment group received oral donepezil plus mind-regulating acupuncture. After 4-week treatment, the two groups were evaluated by the mini-mental state examination (MMSE), Alzheimer disease assessment scale-cognitive part (ADAS-Cog), and ADL; changes in P300 and the mean cerebral blood flow velocity were also observed.Results: Before treatment, there were no significant differences in the scores of MMSE, ADAS-Cog, or ADL between the two groups (P>0.05). The MMSE score increased after treatment in both groups and was notably higher in the treatment group than in the control group, showing intra-group and inter-group statistical significance (P<0.05). After treatment, the ADAS-Cog and ADL scores dropped in both groups and were markedly lower in the treatment group than in the control group, also showing intra-group and inter-group statistical significance (P<0.05). Compared with the same group before treatment, the latency of P300 was shortened and the amplitude was extended in both groups, all with statistical significance (P<0.05); the latency was shorter and the amplitude was larger in the treatment group than in the control group after treatment, presenting significant between-group differences (P<0.05). The mean blood flow velocity accelerated after the intervention in both groups, and the differences were statistically significant (P<0.05); the improvement in the treatment group was more notable than that in the control group (P<0.05).Conclusion: Mind-regulating acupuncture plus donepezil can regulate the latency and amplitude of P300, increase cerebral blood flow, and improve the learning and memory abilities of AD patients.

Clinical efficacy and safety of Butylphthalide combined with Donepezil in the treatment of vascular dementia / 中华老年医学杂志

Objective:To investigate the clinical efficacy and safety of Butylphthalide combined with Donepezil in the treatment of vascular dementia.Methods:A total of 214 patients with vascular dementia admitted to our hospital from December 2018 to December 2020 were divided into control(n=107)treated with Donepezil tablets, and study group(n=107)treated with Butylphthalide capsule plus Donepezil tablets in a multicenter single-blind randomized control trial.Clinical efficacy, dementia degree, cognitive function, behavioral ability, homocysteine(Hcy), brain-derived neurotrophic factor(BDNF), glial fibrillary acidic protein(GFAP)and neuron-specific enolatase(NSE)expression were compared between the two groups before versus after 24 weeks of treatment.And their safety was also evaluated.Results:The total effective rate was statistically significantly higher in study group than in the control group(93.46% and 80.37%, χ2=8.054, P<0.05). The scores of Hasegawa Dementia Scale(HDS), mini mental state examination scale(MMSE)and blessed Behavior Scale(BBS)in the treatment group before treatment were(17.2±2.4)points, (19.0±2.2)points and(25.1±1.8)points respectively; After 24 weeks of treatment, the scores in the treatment group were(27.4±2.8)points, (26.8±1.9)points and(14.2±2.7)points respectively; Before treatment, the scores in control group were(17.4±2.0)points, (18.6±2.1)points and(25.4±1.7)points respectively; After 24 weeks of treatment, the scores in control group were(21.8±3.3)points, (22.3±1.6)points and(19.5±2.3)points respectively.Hcy, BDNF, GFAP and NSE in the treatment group before treatment were(34.5±4.3)μmol/L、(3.5±0.4)μg/L、(13.2±0.8)μg/L and(18.9±1.7)μg/L; After 24 weeks of treatment, the scores in treatment group were(15.9±2.9)μg/L respectively μmol/L、(5.3±0.3)μg/L、(9.7±0.6)μg/L and(18.9±1.7)μg/L; Before treatment, the scores in control group were(35.3±4.4)μmol/L、(3.4±0.4)μg/L、(13.1±0.9)μg/L and(19.2±1.3)μg/L; After 24 weeks of treatment, the scores in control group was(23.3±4.9)μmol/L、(4.5±0.4)μg/L、(10.8±0.7)μg/L and(14.3±2.1)μg/L respectively.Before treatment, there was no significant difference in the expression of HDS scale, MMSE score, BBS score, Hcy, BDNF, GFAP and NSE between the two groups of patients with vascular dementia( t=0.662, 1.360, 1.253, 1.345, 1.829, 0.859, 1.450, all P>0.05); After treatment 24 weeks, the ADAS-Cog score, BBS score, Hcy, GFAP and NSE expressions of the two groups of vascular dementia patients were lower than that before treatment, while the HDS scale score, MMSE score and BDNF expression were higher than that before treatment(in treatment group: t=34.746, 31.273, 36.204, 36.289, 28.610, 27.256, 37.239; in control group: t=21.339, 18.849, 20.866, 20.522, 11.795, 14.497, 20.115, all P<0.05), the differences were statistically significant; After treatment for 24 weeks, the BBS score, Hcy, GFAP and NSE expression in the treatment group were lower than in control group, while the HDS scale score, MMSE score and BDNF expression were higher than in control group( t=15.457, 11.623, 16.551, 12.342, 13.385, 18.740, 11.547, all P<0.05), the differences were statistically significant.In the control group, there were 2 cases of mild gastrointestinal reaction and 3 cases of dizziness, with the incidence of 4.67%; Slight gastrointestinal reaction occurred in 4 cases and dizziness in 5 cases in the treatment group, with an incidence of 8.41%.There was no significant difference in the incidence of adverse reactions between the two groups( χ2=1.223, P>0.05). Conclusions:Butylphthalide soft capsules combined with Donepezil hydrochloride tablets have significant clinical effects on patients with vascular dementia, effectively reduce the degree of dementia, and improve the cognitive function and behavioral ability of patients, with good security.Therefore, it is worthy of clinical promotion.

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

SUMMARY OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Efficacy and safety of hydrochloridememantine or donepezil combined with risperidone in treatment of Alzheimer′s disease patients with behavioral and psychological symptoms / 中华全科医师杂志

One hundred Alzheimer′s disease (AD) patients with behavioral and psychological symptoms of dementia (BPSD) treated with donepezil+risperidone group ( n=50, group 1) or hydrochloride memantine+risperidone group ( n=50, group 2) in geriatric departments of Hangzhou Seventh People′s Hospital were enrolled in the study. Montreal cognitive assessment scale (MoCA), positive and negative syndrome scale (PANSS), treatment emergent symptom scale (TESS) were applied for evaluation; and blood routine examination, blood biochemistry, eletrocardiogram were performed in two groups before and after treatment. After treatment, MoCA score in group 2 (16.10±3.90) was significantly higher than that in group 1 (18.14±3.71)( t=-3.99, P<0.01), and PANSS score in group 2 (86.66±6.62) was significantly lower than that in group 1 (109.50±11.51; t=12.67, P<0.01). The incidence rates of dry mouth (16%,8/50), extrapyramidal side effects (10%,5/50) and the total score of TESS (3.92±2.02) in group 2 were markedly lower than those of group 1 [44%(22/50), 36%(18/50), (12.49±1.45);χ 2=9.33,9.54, t=17.90,all P<0.01]. Meanwhile, group 2 had significantly lower influences on the levels of blood lipids and fasting blood glucose (all P<0.01). The risperidone dose used in group 2 was significantly lower than that in group 1 [(2.06±0.50) vs. (3.85±0.89)mg, t=14.40, P=0.04].The results suggest that hydrochloridememantine combined with risperidone is more effective with less side effects compared to donepezil combined with risperidone for AD patients with BPSD.

Comparison of Clinical Efficacy of Donepezil Monotherapy versus Donepezil Combined with Memoriam in the Treatment of Moderate and Severe Alzheimer ’s Disease / 中国药房

OBJECTIVE：To investiga te the clinical efficacy and safety of donepezil monotherapy versus donepezil combined with memoriam in the treatment of Alzheimer ’s disease （AD）. METHODS ：Totally 100 patients with moderate and severe AD who received medical care in Sichuan Academy of Medical Sciences & Sichuan Provincial People ’s Hospital （East Hospital ）from March 2018 to March 2020 were enrolled as study subjects ，and then were divided into control group and treatment group randomly. Control group was given donepezil monotherapy treatment （initial dose of 5 mg/d，before bedtime ；after 4 weeks，the dose was changed to 10 mg/d before bedtime ；the total medication time was 6 months）. Treatment group was treated with memantine（initial dose was 5 mg/d，the dose of those without adverse reactions was increased by 5 mg until 20 mg/d，for 6 months）on the basis of the control group ，with 50 patients in each group. Montreal cognitive assessment scale （MoCA）score， MMSE score ，ADL score ，treatment response rate and the occurrence of ADR were compared between 2 groups before and after treatment. RESULTS ：Compared with same group before treatment ，MoCA score ，MMSE score and ADL score of the two groups were significantly improved after treatment （P＜0.05）. After treatment ，compared with control group ，MoCA score ，MMSE score ， ADL score and total response rate in the treatment group were significantly increased （P＜0.05），while the incidence of ADR was decreased significantly （P＜0.05）. CONCLUSIONS ：Donepezil combined with memantine has better clinical efficacy than donepezil monotherapy in the treatment of moderate and severe AD ，and is helpful to improve the neurological function of AD patients，with good safety.

Rapid Health Technology Assessment of Donepezil in the Treatment of Alzheimer ’s Disease / 中国药房

OBJECTIVE：To evaluate the efficacy ，safety and econom y of donepezil in the treatment of Alzheimer ’s disease （AD），so as to provide evidence-based evidence for clinical rational drug use. METHODS ：Retrieved from PubMed ，Embase，the Cochrane Library ，CNKI，Wanfang database ，CBM and health technology assessment （HTA）organization websites ，systematic review/Meta-analysis，economic evaluation and HTA reports about donepezil in the treatment of AD were collected during the inception to Feb. 2021. Data extraction and quality evaluation were carried out for the literature that met the inclusion and exclusion criteria，and the research results were summarized and analyzed qualitatively. RESULTS ：A total of 26 studies were included ， including 15 systematic reviews/Meta-analysis ，and 11 economic studies ；HTA reports were not included. The results showed that in terms of effectiveness ，compared with placebo ，donepezil could significantly improve the cognitive function ，activity of daily life，mental behavior and overall function of AD patients （P＜0.05）；compared with rivastigmine ，donepezil could significantly improve cognitive function of AD patients （P＜0.05）；compared with galantamine ，donepezil could significantly improve cognitive function and overall function （P＜0.05），but there was no statistical significance in terms of improving mental behavioral symptoms（P＞0.05）；there was no statistical significance between donepezil and memantine in improving cognitive function ， psychobehavioral symptoms and activities of daily living in AD patients （P＞0.05），but donepezil was weaker than memantine in overall functional （P＜0.05）. In terms of safety ，there was no significant difference in the tolerance and mortality in patients using donepezil and placebo （P＞0.05）；donepezil was better tolerated than rivastigmine and galantamine （P＜0.05）；there was no significant difference in the incidence of ADR for donepezil compared with placebo ， metamine and other non-placebo mail：15201008872@163.com controlled drugs （P＞0.05）. Economic studies showed that # compared with rivastigmine ，placebo and no AD-related drug treatment，donepezil could prolong quality adjusted life years （QALY）and saved medical costs ，which was more cost-effective. Compared with conventional treatment for basic disease and memantine，although donepezil could prolong QALY ，whether it had economic advantages still needed to confirmed in combination with national or regional health resource conditions. CONCLUSIONS ：Donepezil is ralatively effective ，safe and economical in the treatment of AD.

Formulation and in vitro Characterization of Donepezil-loaded Chitosan Nanoparticles

Millions of people are affected globally by alzheimer’sdisease and it is regarded as a dangerous progressive medical and socio-economic burden. The drug delivery to brain is hindered due to the presence of blood brain barrier. Nanoparticle mediated drug delivery is a promising approach in this regard. Chitosan is a hydrophilic polysaccharide polymer of N-acetylglycosamine and glucosamine. Owing to its biodegradability, nontoxicity and biocompatibility it is regarded as a safe excipient. The aim of the study was to fabricate donepezil-loaded sustained release chitosan nanoparticles as a simple way to deliver nano-drugs to the brain. The nanoparticles were fabricated using ionic gelation method using different concentrations of Sodium tripolyphosphate (TPP) and chitosan. The fabricated nanoparticles were assessedfor particle size, zeta potential, encapsulation efficiency and in vitrodrug release. The effect of sonication time on the particle size of nanoparticles was also studied. The nanoparticles exhibited mean particle size (between 135-1487nm) and zeta potential (between +3.9-+38mV) depending on chitosan and TPP concentration used. The rise in the sonication time from 25 to 125 sec exhibited a decrease in particle size. The encapsulation efficiency was found to be in the range of 39.1-74.4%. Sustained and slow release of donepezil at a constant rate was exhibited from nanoparticles. The nanoparticles show potential to deliver donepezil to brain with enhanced encapsulation efficiency

Evaluation of the effects of donepezil in psychotic disorders using Swiss albino mice

Background: Schizophrenia as a psychotic disorder is currently treated by various antipsychotic drugs. A large group of patients still remain resistant to the treatment and present in the form of residual cognitive deficits. Donepezil has been advocated at various conferences and seminars for using it in schizophrenia patients. Donepezil is currently approved drug for Alzheimer's disease to improve cognition. Hence, we have tried to assess its role for psychotic models induced by methylphenidate in mice.Methods: Methylphenidate 5 mg/kg was given by intraperitoneal (i.p) route to induce psychosis in Swiss albino mice (n=6). Donepezil was given alone in a dose of 1 mg/kg and in combination with low dose haloperidol 0.1 mg/kg and groups were compared with haloperidol 0.2 mg/kg. Activity of donepezil was also assessed on the haloperidol induced catalepsy test. Statistical analysis was done with ANOVA followed by Bonferroni抯 test.Results: Methylphenidate successfully induced characteristic stereotypy behaviour in mice similar to amphetamine. Both donepezil 1 mg/kg and haloperidol 0.2 mg/kg showed significant reduction in stereotypy behaviour and there was no statistically significant difference between the two (p<0.05). Effects with donepezil were only slightly inferior to standard while it抯 combination (1 mg/kg with haloperidol 0.1 mg/kg) showed comparable results with the standard haloperidol. Donepezil had only marginally enhanced potential to induce catatonia which was statistically insignificant (p>0.05).Conclusions: Methylphenidate can be used successfully to induce psychosis in animals and donepezil may be a promising and potentially useful drug as add on therapy to routine antipsychotics.

Effect of Donepezil and Vitamin B12Supplement on Serum Thyroid Profile in Alzheimer’s Disease

Aims: The aim of this study was to investigate thyroid status in Alzheimer’s Disease (AD) patients and its response to donepezil and vitamin B12supplement therapy for 6 months.Design:Case-Control Observational study.Place and Duration:Department of Biochemistry, GGMC & Sir J. J. Group of Hospitals, Mumbai, India between March 2017 and July 2019.Methodology:Case-Control study comprised of 71 AD patients and 70 healthy controls above 60 years of age. Blood serum samples were analyzed forthyroid hormones levels by the chemiluminescence method. AD patients weretreated with donepezil (5mg/day) and vitamin B12supplement (1.5mg/day) and thyroid profile was observed at intervals of 3 and 6 months. Statistical evaluationwas done by using IMB SPSS statistics version 25.Results:Serum levels of thyroid hormones were low in euthyroidAD patients when compared with controls at the baseline level [T3 (120.64 ± 20.64 vs127.8 ± 17.29), T4 (7.71 ± 2.34 vs 7.54 ± 1.85), FT3 (1.2 ± 0.13 vs 2.26 ± 0.63) and FT4 (0.79 ± 0.08 vs 1.29 ± 0.27)]except TSH which was increased in AD [TSH (2.71 ± 1.19 vs 2.34 ± 0.65)]. During follow-ups at 3 and 6 months, there was a slight decrease in TSH levels in response to the therapy.Conclusion: The AD patients were euthyroid with low T3, FT3 and FT4 serum levels and high TSH serum levels. Thyroid hormones might play a role as markers for disease progression. Donepezil and vitamin B12therapy could not benefit restorethe normal thyroid functioning in a period of 6 months. Further longitudinal research with larger cohort might help in elucidating thyroid dysfunction in AD and develop novel therapeutic strategies.

Micro and nanocrystalline cellulose based oral dispersible film; preparation and evaluation of in vitro/in vivo rapid release studies for donepezil

Oral fast-dispersible film was prepared by utlizing donepezil hydrochloride (drug) and various cellulose derivatives such as hydroxypropyl methyl cellulose (hypermellose) (HPMC), microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC) to treat Alzheimer's disease. NCC was synthesized by ultra-sonication method using MCC and this was converted to thinfilm formulation (NCC-F) using solvent casting technique. The interaction between the polymer and the drug was investigated by spectral analysis such as UV, FTIR, and 1H- NMR. FTIR confirmed that the compatibility of drug and polymer in ODF formulation. NCC-F has shown an average surface roughness of 77.04 nm from AFM and the average particle size of 300 nm from SEM analysis. Nano sized particle of NCC-F leads faster in vitro dissolution rate (94.53%) when compared with MCC-F and F3 formulation. Animal model (in vivo) studies of NCC-F formulation has reached peak plasma concentration (Cmax) up to 19.018 ng/mL in the span of (tmax) 4 h with greater relative bioavailability of 143.1%. These results suggested that high surface roughness with nanosized NCC-F formulation attained extended drug availability up to (t1/2) 70 h.

Effect of electroacupuncture combined with Donepezil on learning-memory ability and expression of hippocampal β-amyloid clearance-related genes in SAMP8 mice / 针刺研究

OBJECTIVE: To investigate the effect of electroacupuncture (EA) combined with Donepezil on learning-memory ability and gene expression of β-amyloid (Aβ) clearance-related factors in the hippocampus in senescence-accelerated mouse prone 8 (SAMP8) mice, so as to explore their synthetic effect in improving dementia of Alzheimer's disease (AD)．. METHODS: Male SAMP8 mice (30-week-old) were randomly divided into model, medication and EA＋medication groups (n＝6 mice in each group), and other 6 senescence-resistant 1 (SAMR1) mice were used as the control group. Mice of the medication and EA＋medication group received gavage of Donepezil (1.3 mg•kg－1•d－1) once daily for 4 weeks. EA (2 Hz, 1 mA) was applied to "Baihui"(GV20) and "Yintang" (EX-HN3) for 15 min, once daily, 6 days a week for 4 weeks for rats in the EA＋medication group. The Morris water maze (MWM) task (including place navigation tests and space exploration trials) was used to assess the mouse's learning-memory ability. Histopathological changes of hippocampus tissue were observed by H．E. staining. The expression levels of matrix metalloprotein 9 (MMP-9), low density lipoprotein receptor-related protein-1 (LRP-1), P-glycoprotein (Pgp, an important drug transporter responsible for multidrug resistance), Claudin-5 (a component of tight junction strands that serves as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets of blood-brain barrier, BBB) and Aβ mRNAs of the hippocampus tissue were detected by quantitative real-time PCR. RESULTS: Compared with the control group, the average escape latency of place navigation tests, and the expression levels of MMP-9 and Aβ mRNAs were significantly increased (P<0.01), and the number of platform quadrant-crossing times of space exploration trials, and the expression levels of LRP-1, Pgp and Claudin-5 mRNAs considerably decreased in the model group (P<0.01). After the intervention, the learning-memory ability was significantly improved in the medication and EA＋medication groups (P<0.01，P<0.05), the expression levels of Aβ mRNAs in the medication and EA＋medication groups and MMP-9 mRNA in the EA＋medication group were obviously down-regulated (P<0.01), and those of LRP-1 and Pgp mRNAs in the medication and EA＋medication groups and Claudin-5 mRNA in the EA＋medication group were remarkably up-regulated (P<0.05, P<0.01). The therapeutic effect of EA＋medication was apparently superior to that of simple medication in shortening the escape latency (P<0.05，P<0.01) and in down-regulating the expression of MMP-9 and Aβ mRNAs(P<0.01), and in increasing the number of platform quadrant-crossing times(P<0.01), and expression levels of LRP-1, Pgp and Claudin-5 mRNAs (P<0.01). H．E. staining showed scatted and loose arrangement of neurons in the hippocampus, with reduction of number of cell layers and unclear nucleoli, which was relatively milder in the medication and EA＋medication groups. CONCLUSION: EA can enhance the effect of Donepezil in improving learning-memory ability in AD mice possibly by regulating expression of MMP-9, LRP-1, Pgp and Claudin-5 mRNAs and strengthening the effect of Donepezil in transporting Aβ via BBB.

Repeated transcranial magnetic stimulation combined with Donepezil can improve the cognition of cognitively impaired stroke survivors / 中华物理医学与康复杂志

Objective@#To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) combined with donepezil on the cognition of persons with post-stroke cognitive impairment (PSCI) and their ability to perform activities of daily living (ADL).@*Methods@#A total of 106 PSCI patients were randomly divided into an observation group and a control group using a random number table. Those in the observation group received 10Hz rTMS (5 seconds on and 25 seconds off for 20 minutes daily) and donepezil daily, 5 days per week for 4 weeks, while those in the control group were provided with donepezil but only sham rTMS on the same schedule. Before and after 4 weeks of treatment, the Montreal cognitive assessment scale (MoCA), the Rivermead behavior memory test (RBMT) and the modified Barthel index (MBI) were used to evaluate the subjects′ cognitive functioning, memory capacity and ADL ability. The latency and amplitude of auditory event-related potential P300 were also assessed using a myoelectric evoked potential apparatus.@*Results@#After the treatment, improvement was observed in all the measurements of both groups. After the treatment, the average MoCA, RBMT and MBI scores, as well as the latency and amplitude of P300 in the observation group were all significantly better than among the control group.@*Conclusions@#rTMS can supplement donepezil′s ability to improve the cognition and ADL ability of persons with PSCI. Such therapy is worthy of clinical promotion and application.

Method Development And Validation Of Donepezil Hydrochloride By Using Uv Spectrophotometric Method

Abstract: Simple, specific, accurate and cost economic UV spectrophotometric methods weredeveloped and validated for determination of Donepezil Hydrochloride. Instead of usingorganic solvents, mixture of Acetonitrile and water was used during method development andvalidation. Donepezil hydrochloride standard solution was scanned in the UV range (400-200nm) in a 1cm quartz cell in a double beam UV spectrophotometer. The standard solution ofDonepezil Hydrochloride showed maximum absorption at wavelength 231 nm. The methodobeys Beer’s law in the concentration range from 4-20µg/ml. The correlation coefficient wasfound to be 0.9983and regression of the curve was found Y=0.0376x+0.0185 with excellentrecovery 99.66-100.83%. Limit of detection and limit of quantification were found to be0.197µg/ml and 0.6µg/ml respectively. The ruggedness and robustness were performed. Themethod was validated for several parameters like accuracy, precision as per ICH guidelines.Statistical analysis proved that the methods are repeatable and specific for determination ofthe drug. These methods can be adopted in the routine assay analysis of DonepezilHydrochloride in API and pharmaceutical dosage form.

Progress of multi-target directed drugs based on tacrine and donepezil in alzheimer′s disease / 中国药学杂志

Alzheimer′s disease (AD) is a progressive multifactorial neurodegenerative disorder in elder people. Currently, the pathogenesis of AD is unclear, and it is presently incurable. In view of the complex network pathological features of AD, a single small molecule compound that can act simultaneously with multiple targets, called multi-target directed ligands (MTDLs), is considered to be an effective therapeutic strategy at present. Here, we review highlights recent MTDLs approach based cholinesterase inhibitors, antioxidant, metal chelator and neuroprotectant in the novel drug candidate prototypes for the treatment of AD.

The effectiveness and tolerability of the high dose Donepezil at 23 mg tablet per day for Alzheimer’s disease: A meta-analysis of randomized controlled trials

Objective@#To assess the effectiveness and tolerability of the 23 mg tablet donepezil in patients with Alzheimer’s disease (AD) using meta-analysis of randomized controlled trials.@*Methods@#Major healthcare databases were searched from May to September 2016. Evaluation of relevant trials, assessment of risk of bias, collection and analyses of data were performed.@*Results@#A total of 1,774 adult participants with AD were pooled from the two trials included. Pooled data showed that after 24 weeks of treatment, no significant difference was noted between Donepezil 23 mg/day and Donepezil 10 mg/day in terms of cognitive function (1.06 SIB points [-0.13, 2.26]; 1704 participants) and in terms of global clinical assessment (-0.02 CIBIC+ points [-0.13, 0.09]; 1705 participants). The participants who took the higher dose were at higher risk to experience “any adverse event” than those who received the lower dose (1.17 RR [1.09, 1.26]; 1785 participants).@*Conclusion@#Current evidences do not support the routine use of Donepezil 23 mg tablet for the improvement of cognitive function and global clinical status of patients with AD. The higher dose is also marked with an increased incidence of adverse events compared to the lower dose.

Monitoring of drug treatment and psychosocial intervention with SPECT in Alzheimer patients: implications for neurologically appropriate psychosocial interventions. An observational study. The Osaki-Tajiri Project / Monitoramento do tratamento medicamentoso e intervenção psicossocial com SPECT em pacientes com Alzheimer: implicações para intervenções psicossociais neurologicamente apropriadas. um estudo observacional. o Projeto Osaki-Tajiri

ABSTRACT We previously examined cerebral blood flow (CBF) with single-photon emission computed tomography (SPECT) in Alzheimer's disease (AD) with reference to drug treatment (donepezil) and psychosocial intervention. Objective: The aim is to provide "brain-based" evidence for psychosocial interventions using SPECT. Methods: The participants were 27 consecutive outpatients with AD who received the drug and psychosocial intervention, and SPECT three times (baseline, pre-/post-intervention) at 6 month-intervals. The significance level of changes in CBF (Z score) and the extent of significantly changed areas, calculated with the eZIS system, were used as monitoring parameters. The participants were classified into three groups: improve (post-intervention CBF increased), worsening (progressive decline), and no change. Results: Six, 8, and 13 patients were classified as improve, worsening, and no change, respectively. All subjects in the improve group showed improvement in cognitive test scores for the MMSE and/or the CGI scores associated with the brain area with a CBF increase (right parietal lobe), suggesting appropriate psychosocial intervention (visuospatial intervention). Conclusion: These results suggest that monitoring of CBF with the eZIS system may be clinically applicable for monitoring of drug treatment and psychosocial intervention in AD patients.

RESUMO Nós examinamos previamente o fluxo sanguíneo cerebral (FSC) com tomografia computadorizada de emissão de fóton único (SPECT) na doença de Alzheimer (DA) com referência ao tratamento medicamentoso (donepezila) e intervenção psicossocial. Objetivo: Fornecer evidências "baseadas no cérebro" para intervenções psicossociais usando o SPECT. Métodos: Os participantes foram 27 pacientes ambulatoriais consecutivos com DA que receberam a droga e intervenção psicossocial, e SPECT por três vezes (basal, pré/pós-intervenção) em intervalos de seis meses. O nível de significância das mudanças no FSC (escore Z) e a extensão das áreas significativamente alteradas calculadas com o sistema eZIS foram utilizados como parâmetros de monitoramento. Os participantes foram classificados em três grupos: melhora (FSC pós-intervenção aumentada), piora (declínio progressivo) e nenhuma mudança. Resultados: Seis, oito e 13 pacientes foram classificados como melhora, piora e sem alteração, respectivamente. Todos no grupo melhora mostraram aumento dos escores no MEEM e/ou nos escores do CGI associados à área do cérebro com aumento do FSC (lobo parietal direito), sugerindo intervenção psicossocial apropriada (intervenção visoespacial). Conclusão: Estes resultados sugerem que o monitoramento do FSC com o sistema eZIS pode ser clinicamente aplicável para o monitoramento do tratamento medicamentoso e intervenção psicossocial em pacientes com DA.

Chinese Medicine for Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Trials / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the effificacy of oral Chinese medicine (CM) in comparison with donepezil, a cholinesterase inhibitor (ChEI), for the treatment of Alzheimer's disease (AD).</p><p><b>METHODS</b>Randomized controlled trials (RCTs) have been searched, and the effect of CM compared with donepezil in AD has been investigated. An electronic search of MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBMdisc), and China National Knowledge Infrastructure (CNKI) to identify articles in English and Chinese from the inception of the database until October 18, 2015. A modifified Jadad score (7-points) to judge the methodological quality of studies, comprehensive meta-analysis was performed with Cochrane Collaboration Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confifidence interval (CI), while continuous variables were analyzed by using mean differences (MD) with 95% CI for effect size.</p><p><b>RESULTS</b>Six studies involving 596 AD patients through Jadad assessment with low bias were included in the meta-analysis. No signifificant difference was observed in cognitive improvement and daily abilities of patients using the Mini Mental State Examination (MMSE) (MD: 0.69, 95% CI:-0.17 to 1.56) and Activities of Daily Living (ADL) scale (MD: 0.94, 95% CI:-1.54 to 3.43). There were no signifificant differences in status of illness or MD for mild-moderate AD patients at 24 weeks (MD: 0.62, 95% CI:-2.99 to 4.23) and 48 weeks (MD:-0.73, 95% CI:-5.02 to 3.56). Severe AD patients were also assessed at 24 weeks (MD: 3.13, 95% CI:-6.92 to 13.18) and 48 weeks (MD: 4.23, 95% CI:-6.38 to 14.84). Furthermore, compared with donepezil, Xin (Heart)-regulating CM and Shen (Kidney)-tonifying groups were observed (MD:-1.50, 95% CI:-3.08 to 0.08; MD:-1.92, 95% CI:-3.50 to-0.33; respectively). CM had fewer side effects in AD patients.</p><p><b>CONCLUSION</b>Compared with donepezil, oral CM showed no signifificant difference in effectiveness in AD patients, and more evidence is needed to verify the fifindings.</p>

The efficacy and safety evaluation of donepezil combined with memantine for the treatment of Alzheimer′s disease / 药学实践杂志

Objective To evaluate the efficacy and safety of donepezil combined with memantine in the treatment of Alzheimer′s disease and provide a guidance for the proper clinical use of those medications.Methods The literatures published from 2014 to 2016 in CNKI/VIP/WanFang Med-online/CBM and other databases were collected.Screening and quality evalua-tion were carried out with include and exclude standard.The software RevMan 5.3 was used for data analysis.Results Eight-een studies included are randomized controlled trials with 900 cases in study group and 896 cases in control group.The com-bined results showed that MMSE,NPI and BEHAVE-AD of the combination therapy were superior to those of monotherapy group.There is no significant difference in ADL and ADAS-Cog.Conclusion The combination therapy was better than mono-therapy both in mental state and pathological behavior.The clinical application of those medications should be based on the spe-cific conditions of individual patient.

Determination of donepezil in human plasma using ultra performance liquid chromatography-tandem mass spectrometry

An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of donepezil in human plasma. Donepezil and donepezil-D4 were extracted from human plasma by liquid-liquid extraction using a mixture of hexane and ethyl acetate (70:30 v/v). The extracted samples were analyzed using a Thermo Hypersil Gold C18 column with 5% acetic acid in 20 mM ammonium acetate buffer (pH 3.3) and 100% acetonitrile as a mobile phase with the 60:40 (v:v) isocratic method, at a flow rate of 0.3 mL/min. The injection volume was 3 µL, and the total run time was 3 min. Inter- and intra-batch accuracies ranged from 98.0% to 110.0%, and the precision was below 8%. The developed method was successfully applied to the quantification of donepezil in human plasma. The mean (standard deviation) maximum concentration and the median (range) time to maximum concentration were 8.6 (2.0) ng/mL and 2.0 h (1.0~5.0 h), respectively, in healthy Koreans after oral administration of 5 mg donepezil.