Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations:a scoping review

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

Effect of cerebralcare granule®combined with donepezil on Alzheimer’s disease

Background:The current prevalence of Alzheimer’s disease(AD)in the elderly has risen from 1%at 65 to 40%to 50%at 95,and the overall proportion is rising.Emerging evidence suggests that ros-driven oxidative stress is a crucial mediator of the aging process.Thus,in recent years,oxidative damage and inflammation have become targets for exploring pharmacological strategies for treating age-related diseases.Methods:In C57BL/6J mice,to determine whether the mechanism of action of cerebralcare granule®(CG)combined with donepezil(Don)treatment is better than dementia alone,we constructed a mouse model and treated it with CG in combination with Don.Results:A combination of Don and CG significantly reduces the damage caused by lipid peroxidation in the hippocampus of AD mice,reduces oxidative damage,and reduces inflammation,increases the activity of antioxidant enzymes,which is finally manifested as the improvement effect on the learning and memory impairment of AD mice.Conclusion:CG combined with Don has a better effect on improving cognitive and behavioral deficits caused by D-galactose in AD mice than Don alone.The mechanism may be related to reducing inflammation via the NF-κB pathway,resisting oxidative damage and increasing acetylcholine levels.

Donepezil对大鼠海马及新皮层锥体神经元延迟整流样钾电流的影响

目的 探讨donepezil对大鼠海马和新皮层锥体神经元具有延迟整流样特性钾电流 (IK)的影响。方法用膜片钳全细胞记录法。结果 Donepezil在微摩尔水平即可抑制IK,并呈剂量依赖性和电压依赖性 ,且可使IK 的稳态激活曲线向超级化的方向移动。结论 低浓度donepezil即可抑制大鼠海马和新皮层锥体神经元电压激活的IK,此作用可能与其抑制胆碱酯酶活性协同 。

A donepezil/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption

The aim of this study was to develop a palatable donepezil(DP) orodispersible film(ODF)to facilitate the swallowing process and investigate the effect of cyclodextrin on tastemasking based on dynamic process and in vivo drug absorption. Complexation of DP with hydroxypropyl-β-cyclodextrin(HP-β-CD) was applied to mask the bitter taste then the prepared complexes were incorporated into ODF using solvent casting method. The tastemasking efficiency was evaluated by e-tongue; meanwhile the pharmacokinetic behavior of DP/HP-β-CD ODF was investigated by in vivo study. Results showed the optimized film was more palatable than donepezil hydrochloride(DH) film and was bioequivalent with DH. The molecular mechanism was revealed by phase solubility study, Fourier-transform infrared spectrometer(FT-IR), Differential scanning calorimeter(DSC), X-ray diffraction(XRD) and molecular modeling. Taste-masking was attributed to the formation of DP/HP-β-CD which was due to moderate interaction between DP and HP-β-CD. The stability of DP/HP-β-CD was decreased because of the acid environment in stomach, which facilitated the absorption of DP. These results extended our understanding about the application of cyclodextrin complexation and provided guidance for the design of ODF especially for drugs with disgusting taste.

Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride：P300 event related potential

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.

Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Efficacy and safety of traditional Chinese medicine kidney-nourishing formula for Alzheimer's disease in comparison with donepezil:a systematic review and meta-analysis

Objective:Finding an effective therapy against Alzheimer’s disease(AD)has been associate increasingly pressing issue and traditional Chinese medicine(TCM)is widespread in the prevention and treatment of AD in China.The aim of this study was to judge the efficaciousness and safety of TCM kidney-nourishing(the changes of pathological state of kidney deficiency by means of TCM treatment and so on)formula(TKNF)for AD in comparison with donepezil.Methods:The retrieval period of seven databases was from the establishment of each database to April 2019.Two authors independently identified randomized controlled trials(RCTs),fetched data and assessed bias risk.Comprehensive analysis process was conducted with review manager for eligible and appropriate RCTs.Results:A complete of 981 AD patients from 13 studies were enclosed.Meta-analysis of RCTs showed that there was no significant difference in the improvement of Alzheimer's disease assessment scale-cognitive subscale score between 2 groups in short term,but the effect of long-term treatment may exceed donepezil;there was a significant difference in the improvement of activities of daily living score between 2 groups;there was a significant difference in TCM curative efficacy between 2 groups with long-term treatment.There was no significant difference in the incidence of adverse events between 2 groups.The quality of the evidence was high or moderate.Conclusion:Compared with donepezil,TKNF was an effective drug for AD patients and the clinical application of TKNF was safe.TKNF's long-term benefits need more evidence to verify.

Preparation and in vitro Release of Donepezil Hydrochloride Microspheres

[Objectives]To prepare donepezil hydrochloride microspheres and evaluate their quality.[Methods]The donepezil hydrochloride microspheres were prepared by emulsification-solvent evaporation method.The morphology was observed by scanning electron microscopy and the particle size distribution was determined by Laser Diffraction Method.The encapsulation efficiency,drug loading capacity,and in vitro release were determined by HPLC.[Results]The prepared donepezil hydrochloride microspheres were spherical with the average particle diameter of 15.927 μm.The drug loading capacity was 35.62%.The encapsulation efficiency was 90.32%.The drug release in vitro lasted for14 d.The release curve accorded with the first-order kinetic equation.[Conclusions]The prepared donepezil hydrochloride microspheres performed good sustained release effect in vitro,and it was expected to be used for research on Parkinson's disease.

Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice

Olfactory bulbectomy (OBX) causes cognitive dysfunction by degeneration of cholinergic neurons in the medial septum. Here, we define an involvement of nicotinic acetylcholine receptor (nAChR) in neuroprotective effect of donepezil in the septum neurons of OBX mice. Neuroprotective effects on the medial septal cholinergic neurons were assessed after chronic donepezil administration in OBX mice. We also measured Akt and ERK phosphorylation to define the neuroprotective mechanism of donepezil. We found that treatment with donepezil (1 - 3 mg/kg) for 15 consecutive days completely rescued cholinergic neurons in the OBX mice with concomitant improved memory. Reduction of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were restored by chronic donepezil administration (1 - 3 mg/kg) in OBX mouse medial septum. Both phosphorylated Akt and ERK immunoreactivities were localized in cell bodies of choline acetyltransferase (ChAT)-positive cholinergic cells in the medial septum. Enhancement of Akt and ERK phosphorylation seen following donepezil administration was totally blocked by pre-administration of mecamylamine (10 μM), a nicotinic acetylcholine receptor antagonist. Donepezil increases phosphorylation of Akt and ERK via nAChR stimulation in the medial septum cholinergic neurons. The Akt and ERK stimulation by donepezil is associated with its ability of neuroprotection in the medial septum and memory improvement.

Donepezil-related inadequate neuromuscular blockade during laparoscopic surgery: A case report

BACKGROUND Donepezil is an acetylcholinesterase inhibitor used to improve cognition and delay disease progression in dementia patients by increasing acetylcholine levels.This drug may potentially interact with neuromuscular blocking agents(NMBAs)that act on muscular acetylcholine receptors during general anesthesia.Herein,we present a case of inadequate neuromuscular blockade with rocuronium,a nondepolarizing NMBA,in a dementia patient who had taken donepezil.CASE SUMMARY A 71-year-old man was scheduled for laparoscopic gastrectomy.He had been taking donepezil 5 mg for dementia.General anesthesia was induced with propofol and remifentanil.The depth of neuromuscular blockade was monitored by train-of-four(TOF)stimulation.After the administration of rocuronium,the TOF ratio decreased at an unusually slow rate,and a TOF count of 0 was detected 7 min later.After intubation,a TOF count of 1 was detected within 1 min,and a TOF ratio of 12%was detected within 2 min.The TOF count remained at 4 even with an additional bolus and continuous infusion of rocuronium,suggesting resistance to this NMBA.Instead of propofol,an inhalation anesthetic was administered alongside another NMBA(cisatracurium).Then,the quality of neuromuscular blockade improved,and the TOF count remained at 0-1 for the next 70 min.No further problems were encountered with respect to surgery or anesthesia.CONCLUSION Donepezil may be responsible for inadequate neuromuscular blockade during anesthesia,especially when total intravenous anesthesia is used.

Meta-analysis of efficacy and safety of Donepezil in treating cognitive decline of Parkinson's disease

Objective:To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease(PD).Methods:Nine literature databases in domestic and abroad were searched by computer,and the search deadline was November 2,2020.The randomized controlled trials(RCT)using donepezil to treat the cognitive decline in patients with PD were screened.The MMSE(Mini-Mental State Exam)scores,MoCA(Montreal Cognitive Assessment)scores and adverse events of the included RCTs were extracted.Meta-analysis was implemented with RevMan 5.3 software,and the subgroup analyses were conducted to evaluate the effects of mean age and mean course of disease on the MMSE scores.Results:14 RCTs with 1263 patients were selected,including 646 cases in the experimental group and 617 cases in the control group.There were 1209 effective patients who completed MMSE score,including 612 in the experimental group and 597 in the control group.Meta-analysis results showed that MMSE scores in the experimental group were higher than that in the control group after using donepezil intervention,and the difference was statistically significant[SMD=0.55,95%CI(0.24,0.87),P=0.0006].It was also found that the MoCA scores of experimental group were higher than that of control group after using donepezil intervention,and the difference was statistically significant[SMD=1.25,95%CI(0.79,1.72),P<0.00001].Subgroup analysis showed that donepezil improved MMSE scores in different subgroups,and the difference between each group was statistically significant.There was no heterogeneity in the subgroup of mean age lower than 65 years,and the heterogeneity existed between the subgroup of mean course of disease lower than 3 years and the subgroup of mean course of disease larger than or equal to 3 years.For adverse events,the incidence of adverse events in the experimental group was 22.18%.There was no heterogeneity between the included studies(I2=0%),and the difference was not statistically significant[RR=1.18,95%CI(0.95,1.47),P=0.14].Conclusion:The results of meta-analysis showed that donepezil can improve the cognitive decline in patients with Parkinson's disease significantly,and it has good safety.

The efficacy and safety of donepezil plus ginkgo biloba for Alzheimer's disease: a systematic review and meta-analysis

Background:To evaluate the efficacy and safety of donepezil and ginkgo biloba for Alzheimer5s disease.Methods:A systematic literature retrieval was carried out for eligible studies in PubMed,Embase,Cochrane Library,Web of Science,China National Knowledge Infrastructure,Wanfang and China Science and Technology Journal Database from the establishment of database to 1 February 2020.Nine randomized controlled trials were included in our study in the Review Manager 5.3.Results:Our meta-analysis found that compared with donepezil alone,ginkgo biloba and donepezil could improve clinical efficacy and enhance cognitive function measured by the mini-mental state examination score.No significant difference in the total adverse reaction,the digestive symptoms and the neurological symptoms between two groups was observed.Conclusion:The combination of donepezil plus ginkgo biloba could provide more benefits for Alzheimer 5s disease patients than donepezil alone.

Effcacy and pharmacogenomics of donepezil

With the aging of society, dementia has become a more and more serious social problem. Alzhei-mer’s disease （AD） is a major cause of dementia, and there is no drug to reverse the disease progression. Donepezil is the main drug currently in symptomatic treatment. How-ever,the effcacy of donepezil was moderate, with the patient variably responding to the treatment with donepe-zil. The commonest adverse events in the treatment were nausea,vomiting,and diarrhea; QT prolongation rarely occurred. Many patients gave up treatment because of adverseevents orlack of effcacy. Pharmacogenomicsis developed on the basis of pharmacogenetics, by studying the polymorphisms in genes involved in drug metabolicenzymes, transporter and drug receptor, to guide individ-ualized treatment. In terms of the pharmacogenomics on the effcacyof onepezil, there is no clear conclusion ex-cept CYP2D6 genotype affecting drug clearance.

Effects of donepezil combined with folic acid and vitamin B12 on serum levels of inflammatory factors, HCY, NSE and neurotransmitters in elderly patients with Alzheimer's disease complicated with hyperhomocysteinemia

Objective: To investigate the effects of donepezil combined with folic acid and vitamin B12 on the levels of serum inflammatory factors, Hcy, NSE and neurotransmitters in elderly patients with Alzheimer's disease (AD) complicated with hyperhomocysteinemia. Methods: A total of 98 elderly patients with AD complicated with hyperhomocysteinemia were randomly divided into control group (n=48) and observation group (n=50) according to the random data table method. Patients in the control group were treated with donepezil. On this basis, the patients in the observation group were treated with folic acid and vitamin B12, all patients were treated for 3 months. Before and after treatment, the levels of serum inflammatory factors (TNF-α, IL-6 and hs-CRP), Hcy, NSE and brain neurotransmitter (5-HT, NE and DA) were compared between the two groups. Results: Before treatment, the levels of TNF-α, IL-6, hs-CRP, Hcy, NSE, 5-HT, NE and DA of the control group and the observation group were not statistically significant. Compared with the group before treatment, the levels of TNF-α, IL-6, hs-CRP, Hcy and NSE in the two groups were significantly lower, and the level of the observation group was significantly lower than those of the control group, the difference was statistically significant;Compared with the group before treatment, the levels of 5-HT, NE and DA in the two groups were significantly increased, and the observation group was significantly higher than that of the control group, the difference was statistically significant. Conclusion: Donepezil combined folic acid and vitamin B12 in treatment of AD with hyperhomocysteinemia, which can effectively reduce the body's inflammatory response, reduced Hcy and NSE levels, elevated levels of brain neurotransmitters, has important clinical significance.

盐酸多奈哌齐联合孙氏经颅重复针刺法治疗阿尔茨海默病的效果

目的 观察盐酸多奈哌齐联合孙氏经颅重复针刺法治疗阿尔茨海默病(AD)的临床效果。方法 选取2022年9月至2023年9月黑龙江中医药大学附属第二医院哈南分院针灸门诊收治的90例AD患者,按照随机数字表法将其分为观察组、对照A组、对照B组,各30例。对照A组给予口服盐酸多奈哌齐治疗,对照B组行孙氏经颅重复针刺法治疗,观察组为盐酸多奈哌齐联合孙氏经颅重复针刺法治疗,均治疗8周。评价其临床疗效。比较三组治疗前及治疗后4、8周简易智力状态检查量表(MMSE)、阿尔茨海默病认知评估量表(ADAS-cog)和日常生活活动能力量表(ADL)评分及血清同型半胱氨酸(Hcy)水平。结果 观察组临床疗效优于对照A组及对照B组,差异有统计学意义(P<0.05)。三组治疗后4、8周MMSE评分高于治疗前,ADAS-cog、ADL评分和血清Hcy水平低于治疗前,差异有统计学意义(P<0.05);三组治疗后8周MMSE评分高于治疗后4周,ADAS-cog、ADL评分和血清Hcy水平低于治疗后4周,差异有统计学意义(P<0.05)。治疗后8周,观察组MMSE评分高于对照A组和对照B组,ADAS-cog、ADL评分和血清Hcy水平低于对照A组和对照B组,差异有统计学意义(P<0.05)。结论盐酸多奈哌齐联合孙氏经颅重复针刺法可改善轻中度AD患者的认知功能及行为能力,降低血清Hcy水平,且效果优于单纯口服多奈哌齐和孙氏经颅重复针刺法,值得临床推广。

多奈哌齐联合美多芭对帕金森病大鼠神经细胞凋亡及认知功能的影响

目的:探究多奈哌齐联合美多芭对帕金森病(PD)大鼠神经细胞凋亡及认知功能的影响及其可能的作用机制。方法:造模成功的PD大鼠分为模型组(生理盐水)、美多芭组(11.0 mg/kg美多芭)、多奈哌齐组(0.6 mg/kg盐酸多奈哌齐)、多奈哌齐+美多芭组(11.0 mg/kg美多芭+0.6 mg/kg盐酸多奈哌齐),另取12只大鼠作为假手术组(生理盐水)。评估各组大鼠运动功能、认知功能;免疫组化检测酪氨酸羟化酶(TH)阳性表达;Western blot检测TH蛋白、细胞凋亡相关蛋白(cleaved caspase-3、Bax、Bcl-2)及PI3K/AKT通路相关蛋白表达水平;TUNEL染色检测细胞凋亡率;商品化试剂盒检测氧化应激指标(MDA、SOD、GSH-Px)和炎症因子(IL-6、IL-18、TNF-α)水平。结果:与假手术组比较,模型组大鼠旋转圈数增加,掉落潜伏期缩短,自发交替行为(SAB)正确率降低,逃避潜伏期延长,跨越原平台次数减少,脑黑质TH阳性表达、TH和Bcl-2蛋白表达水平、SOD和GSH-Px活性及p-PI3K/PI3K、p-AKT/AKT降低,脑黑质神经细胞凋亡率、cleaved caspase-3和Bax蛋白表达水平、MDA含量及IL-6、IL-18、TNF-α水平升高(P<0.05);而美多芭、多奈哌齐及多奈哌齐+美多芭均能够减少PD大鼠的旋转圈数,延长掉落潜伏期,升高SAB正确率,缩短逃避潜伏期,增加跨越原平台次数,升高脑黑质TH阳性表达、TH和Bcl-2蛋白表达水平、SOD和GSH-Px活性及p-PI3K/PI3K、p-AKT/AKT,降低脑黑质神经细胞凋亡率、cleaved caspase-3和Bax蛋白表达水平、MDA含量及IL-6、IL-18、TNF-α水平(P<0.05),且多奈哌齐+美多芭组的作用效果显著优于美多芭组、多奈哌齐组(P<0.05)。结论:多奈哌齐联合美多芭可降低PD大鼠氧化应激和炎症反应,提高认知功能,可能通过激活PI3K/AKT通路实现。

丁苯酞联合盐酸多奈哌齐对血管性痴呆患者认知功能及血清黑色素瘤凋亡抑制蛋和或肾凋亡抑制蛋白与β转化生长因子的影响

目的探讨丁苯酞联合盐酸多奈哌齐治疗血管性痴呆的临床疗效。方法选取2018年1月至2020年1月山东省荣军总医院收治的93例血管性痴呆患者作为研究对象,按照随机数字表法分为参比组(n=45)与研究组(n=48)。参比组在常规基础治疗上给予盐酸多奈哌齐片治疗,研究组在参比组的基础上给予丁苯酞软胶囊治疗。比较两组血液指标、病情发展进程、认知功能、日常生活能力。结果治疗6个月后,研究组血浆转化生长因子β(TGF-β)、胰岛素样生长因子-1(IGF-1)、血清抗凋亡因子(Livin)、血管内皮生长因子(VEGF)水平及长谷川痴呆量表(HDS)、简易智力状态检查量表(MMES)、日常生活能力量表(ADL)评分均高于参比组,血浆细胞间黏附分子-1(IGAM-1)、血清干扰素-γ(IFN-γ)水平均低于参比组,差异有统计学意义(P<0.05)。结论丁苯酞联合盐酸多奈哌齐治疗血管性痴呆效果显著,可缓解患者病情发展进程,降低血管炎症反应,保护脑组织细胞功能,提高患者认知功能及生活自理能力。