The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18–55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg + donepezil 5 mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1–13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n = 14) significantly reduced the area of allodynia vs placebo (n = 14; −12.83 cm²; 95% confidence interval [CI] −23.14 to −2.53; P = 0.015) with supportive results for hyperalgesia (−14.04 cm²; 95% CI −28.49–0.41; P = 0.057), validating the electrical hyperalgesia model. Gabapentin + donepezil (n = 30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n = 30; −11.73 cm²; 95% CI −21.04 to −2.42; P = 0.014), with supportive results for allodynia (−6.62 cm²; 95% CI −13.29–0.04; P = 0.052). The adverse event profile for gabapentin + donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin.     

盐酸美金刚联合多奈哌齐治疗中、重度阿尔茨海默病的临床研究

目的：探讨盐酸美金刚联合多奈哌齐治疗中、重度阿尔茨海默病（AD）的临床疗效及安全性。方法将86例AD 患者随机分为盐酸美金刚联合多奈哌齐组（实验组）和多奈哌齐组（对照组）,在治疗前、治疗后24周末分别利用简易智能状态检查（MMSE）评分量表、AD评估量表-认知部分（ADAS-cog）、日常生活能力（ADL）量表和神经精神症状问卷（NPI）评估。结果实验组和对照组在治疗前后ADAS-cog、ADL和NPI及MMSE差异均有统计学意义（P〈0．01）,实验组的NPI评分变化高于对照组（P〈0．05）。两组不良反应事件发生率差异无统计学意义（P〉0．05）。结论实验组和对照组对AD认知功能均有改善,但前者对NPI的改善更明显,两组治疗均具有良好的安全性。     

盐酸多奈哌齐对血管性痴呆大鼠海马CA1区caspase-3的表达及神经细胞凋亡的影响

目的观察盐酸多奈哌齐对血管性痴呆（VD）大鼠海马CA1区神经细胞凋亡及凋亡因子caspase-3表达变化的影响,探讨其可能的保护机制。方法应用双侧颈总动脉结扎法建立血管性痴呆大鼠动物模型,48只雄性SD大鼠随机分为：对照组（n=16）、实验组（n=16）和盐酸多奈哌齐干预组（n=16）。通过Morris水迷宫实验观察认知行为学改变,免疫组化法及原位凋亡（TUNEL）法检测大鼠海马CA1区caspase-3的表达及凋亡细胞。结果水迷宫实验发现与对照组相比,实验组和干预组大鼠逃避潜伏期延长,但干预组与实验组相比明显缩短（P〈0．01）;实验组和干预组caspase-3阳性细胞表达及凋亡细胞数量均较对照组明显增高（P〈0．01）,但二者在干预组的表达较实验组明显降低（P〈0．01）。结论盐酸多奈哌齐可以改善VD大鼠的行为学症状,抑制大鼠脑组织caspase-3的表达并减少凋亡发生。     

多奈哌齐联合语言训练对脑卒中后失语症的康复疗效

目的观察多奈哌齐联合语言训练对脑卒中后失语症的康复疗效。方法脑卒中后失语症患者52例,随机分为多奈哌齐联合语言训练组和单纯语言训练组,治疗前后采用改良波士顿诊断失语症检查法评价患者语言功能。结果多奈哌齐联合语言训练组较对照组治疗有效率明显提高(p<0.05)。结论多奈哌齐联合语言训练能更有效的提高脑卒中后失语症患者的语言交流能力,是一种安全有效的治疗方法。     

多奈哌齐的心血管治疗作用研究进展

阿尔茨海默病（AD）为痴呆的主要类型,中枢神经系统胆碱能神经元的减少是其重要的发病机制之一。多奈哌齐作为一种高选择性、可逆性的胆碱酯酶抑制剂,能够通过对胆碱酯酶的抑制提高大脑皮质中的胆碱水平,从而改善患者的认知功能,是当前临床上治疗痴呆的一线药物之一,已有大量的临床研究证实其临床应用的有效性及安全性。许多痴呆患者同时合并心血管疾病,近期有研究表明多奈哌齐对心血管系统疾病亦有治疗作用。本文旨在对多奈哌齐目前的临床使用及心血管系统作用进行综述,并探讨其作用机制,比较其与加兰他敏和利斯的明的心血管作用效果,以指导多奈哌齐在临床中的进一步运用。     

多奈哌齐联合醒智散治疗阿尔茨海默病的疗效分析

目的探讨多奈哌齐联合醒智散治疗阿尔茨海默病的疗效。方法 100例阿尔茨海默病患者,随机分为研究组和对照组,每组50例。两组患者均采用多奈哌齐治疗,研究组患者在此基础上联合醒智散治疗。比较两组治疗前后血清炎症因子水平、简易精神状态评价量表(MMSE)评分及临床疗效、治疗期间不良反应发生情况。结果治疗后,研究组患者白细胞介素-1β(IL-1β)为(0.23±0.07)ng/L、白细胞介素-6(IL-6)为(60.34±7.42)ng/L及肿瘤坏死因子-α(TNF-α)水平为(1360.83±490.28)ng/L,均低于对照组的(0.46±0.11)、(105.36±73.52)、(1860.53±430.87)ng/L,差异具有统计学意义(P<0.05)。治疗后,研究组患者MMSE评分(22.83±2.08)分高于对照组的(19.05±1.67)分,差异具有统计学意义(P<0.05)。研究组患者治疗总有效率为80%高于对照组的62%,差异具有统计学意义(P<0.05)。研究组患者治疗期间不良反应发生率为4%,对照组患者治疗期间不良反应发生率为6%,两组比较差异无统计学意义(P>0.05)。结论多奈哌齐联合醒智散治疗阿尔茨海默病具有较好的疗效,同时药物服用期间安全性好,对降低血清炎症因子水平有积极作用。     

Zur Nootropikabewertung für die Praxis

Zusammenfassung Die Behandlung von Demenzkranken mit „Nootropika” wird h?ufig als umstritten dargestellt. Hier wird geprüft, was bei Abw?gung von Wirkungen und Nebenwirkungen sowie von Kosten und Nutzen im Vergleich mit nichtmedikament?sen Behandlungsma?nahmen für oder gegen den Einsatz von Nootropika in der Praxis spricht. Eine Zusammenfassung der zu diesen Bewertungskriterien ver?ffentlichten Literatur best?tigt den Nootropika Wirksamkeit im Sinne einer anf?nglichen Symptomverbesserung und eines protrahierten Verlaufs mit bei den meisten Substanzen nur geringen Nebenwirkungen bei dementiellen Erkrankungen. Es fehlt an Vergleichsuntersuchungen zwischen den Substanzen insbesondere zu Umfang und Ausma? der Wirkung ebenso wie zur prophylaktischen Wirksamkeit. Die gesamtgesellschaftliche Kostensituation stellt sich unter Nootropikabehandlung u.a. durch verz?gerte Inanspruchnahme von Heimpl?tzen günstiger dar. Die Analyse spricht für den Nootropikaeinsatz. Die vorliegenden Untersuchungen weisen darauf hin, da? günstigere Effekte unter einer Kombination von nootroper Medikation mit Training und Umfeldstrukturierung zu erwarten sind. Aus den Ergebnissen wird ein Vorschlag für den rationalen Einsatz von Nootropika abgeleitet.      

多奈哌齐服药时间对阿尔茨海默病患者睡眠质量的影响

目的:观察多奈哌齐不同服药时间对阿尔茨海默病患者睡眠质量的影响,为该药的临床应用提供指导。方法:将2013年4月至2015年6月于我院就诊的150例伴有睡眠障碍的阿尔茨海默病患者作为研究对象,随机分为3组,每组各50例,A组服用加兰他敏,B组晚间服多奈哌齐,C组早晨服多奈哌齐。治疗8周后检测匹兹堡睡眠质量指数(Pittsburgh sleep quality index,PSQI)、Epworth日间嗜睡量表指数。结果:经过治疗后,C组PSQI指数与A组、B组比较差异有统计学意义(t=12.14,32.50;P0.05);C组Epworth指数与A组、B组比较差异有统计学意义(t=5.59,16.22;P0.05),B组治疗前后PSQI指数、Epworth指数无差异(t=0.14,0.47;P0.05)。结论:在早晨服用多奈哌齐可以更好改善阿尔茨海默病患者的睡眠状态。     

阿尔茨海默病的康复治疗

目的　探讨康复治疗对阿尔茨海默病 (AD)患者的有效性。方法　将 63例轻、中度AD患者分成 2组进行为期 8周的临床治疗 ,即康复组 (2 9例 )进行康复治疗 ,药物组 (3 4例 )应用盐酸多奈哌齐进行药物治疗。应用简易智能精神状态检查量表 (MMSE)、AD评定量表 (ADAS)及Blessed Roth痴呆量表判定疗效。结果　康复组患者的日常生活自理能力改善 (P <0 .0 5) ;药物组的认知功能 :MMSE较治疗前提高 3 .9分 (P <0 .0 5) ,ADAS认知部分 (ADAS cog)改善 4.8分 (P <0 .0 5) ,日常生活自理能力无明显变化 ,其中 2例(5.88% )出现轻度副作用 ;2组经治疗后的MMSE、ADAS认知部分和Blessed Roth评分进行比较 ,差异均有显著性意义 (P <0 .0 5)。结论　康复治疗能改善AD患者的日常生活自理能力 ;盐酸多奈哌齐可改善AD患者的认知功能 ,减轻痴呆的病情 ;整个治疗过程安全性好 ;康复干预应采取综合措施     

Fluoxetine,not donepezil,reverses anhedonia,cognitive dysfunctions and hippocampal proteome changes during repeated social defeat exposure

While anhedonia is considered a core symptom of major depressive disorder (MDD), less attention has been paid to cognitive dysfunctions. We evaluated the behavioural and molecular effects of a selective serotonin re-uptake inhibitor (SSRI, fluoxetine) and an acetylcholinesterase inhibitor (AChEI, donepezil) on emotional-cognitive endophenotypes of depression and the hippocampal proteome. A chronic social defeat (SD) procedure was followed up by “reminder” sessions of direct and indirect SD. Anhedonia-related behaviour was assessed longitudinally by intracranial self-stimulation (ICSS). Cognitive dysfunction was analysed by an object recognition test (ORT) and extinction of fear memory. Tandem mass spectrometry (MS^E) and protein-protein-interaction (PPI) network modelling were used to characterise the underlying biological processes of SD and SSRI/AChEI treatment. Independent selected reaction monitoring (SRM) was conducted for molecular validation. Repeated SD resulted in a stable increase of anhedonia-like behaviour as measured by ICSS. Fluoxetine treatment reversed this phenotype, whereas donepezil showed no effect. Fluoxetine improved recognition memory and inhibitory learning in a stressor-related context, whereas donepezil only improved fear extinction. MS^E and PPI network analysis highlighted functional SD stress-related hippocampal proteome changes including reduced glutamatergic neurotransmission and learning processes, which were reversed by fluoxetine, but not by donepezil. SRM validation of molecular key players involved in these pathways confirmed the hypothesis that fluoxetine acts via increased AMPA receptor signalling and Ca²⁺-mediated neuroplasticity in the amelioration of stress-impaired reward processing and memory consolidation. Our study highlights molecular mediators of SD stress reversed by SSRI treatment, identifying potential viable future targets to improve cognitive dysfunctions in MDD patients.