复方海蛇胶囊及盐酸多奈哌齐联合治疗血管性痴呆的临床研究

目的研究复方海蛇胶囊（Reinhartdt and Sea Cumber Capsule,RSC）及盐酸多奈哌齐联合治疗血管性痴呆（vascular dementia,VD）的临床疗效、安全性及其对VD患者甲状腺功能轴的影响。方法63例患者随机分为RSC治疗组、盐酸多奈哌齐治疗组、联合（RSC加盐酸多奈哌齐）治疗组治疗,以MMSE、ADAS-Cog和ADL分数评定疗效,每组患者分别在治疗前、治疗3个月及6个月用放免法测定甲状腺素水平（TSH,FT3,FT4,TT3,TT4）。结果3组在治疗3、6个月,MMSE评分升高,ADAS-Cog、ADL评分降低,较治疗前有显著性差异（P〈0.05,P〈0．01）;盐酸多奈哌齐组治疗6个月MMSE、ADAS-Cog、ADL评分较同期RSC组有统计学差异（P〈0．05）;联合治疗组治疗3、6个月MMSE、ADAS-Cog、ADL评分较同期RSC组、盐酸多奈哌齐组有显著性差异（P〈0.01）;联合治疗组FT3、FT4水平在治疗3个月较治疗前升高,无统计学差异（P〉0．05）;FT3、FT4水平在治疗6个月,较治疗前有显著性差异（P〈0．01）;TSH、TT3、TT4水平治疗前后差异无显著性（P〉0．05）。盐酸多奈哌齐组FT3、FT4水平在治疗6个月后较治疗前水平升高,但无统计学差异（P〉0．05）;TSH、TT3、TT4水平治疗前后无显著差异（P〉0．05）。RSC组甲状腺素水平治疗前后无显著差异（P〉0．05）。3组患者未发现明显不良反应。结论RSC加盐酸多奈哌齐联合治疗VD安全、有效,无明显不良反应,作用优于单一药物组。联合治疗组作用优于单一药物组可能是通过影响VD患者甲状腺激素代谢、调节甲状腺激素水平,从而进一步改善认知功能。     

安理申治疗阿尔茨海默病的临床研究

目的：观察安理申治疗轻、中度阿尔茨海默病（AD）的临床疗效和安全性。方法：72例轻、中度AD患者随机分为两组。安理申组36例,男21例,女15例。年龄（71.8±7.2）岁;对照组36例,男23例,女13例,年龄（72.3±6.9）岁。安理申组给予安理申：5m g/d,1日1次于晚上睡前口服,维持1个月,增加到10m g/d,1日1次,维持两月;对照组给予维生素E 100m g,一日一次口服。两组总疗程为3个月。采用简易精神状态检查表（MM SE）、临床痴呆程度量表（CDR）和日常生活能力量表（ADL）作为评价指标。结果：安理申治疗3个月后MM SE、CDR及ADL分数分别较对照组和治疗前明显改善（P〈0.01）。结论：安理申可显著改变AD患者的认知功能,且安全性良好。     

颈动脉支架成形术、盐酸多奈哌齐对脑梗塞患者认知功能的影响

目的探讨颈动脉支架成形术、盐酸多奈哌齐（安理申）对脑梗塞患者认知功能的影响。方法选取有认知功能障碍的脑梗塞患者,在常规治疗的基础上,将有适应证的患者行颈动脉支架血管成形术,共有患者21例（下称支架组）,未行支架成形术的患者加用盐酸多奈哌齐（5mg,1次/d）治疗,共有25例（下称安理申组）。在治疗前、治疗三月后行简易精神状态量表（MMSE）、日常生活功能量表（ADL）评分,并行统计学分析。结果经治疗3月后支架组和安理申组的MMSE评分、ADL评分明显提高,与治疗前相比有统计学意义（P〈0.05）;支架组MMSE评分及ADL评分较安理申组相比亦有明显提高,两者相比有统计学意义（P〈0.05）。结论颈动脉支架血管成形术和盐酸多奈哌齐均可改善脑梗塞患者的认知功能,但支架术疗效更为显著。     

盐酸多奈哌齐与尼莫地平治疗血管性痴呆的疗效比较

目的:对比观察盐酸多奈哌齐与尼莫地平治疗血管性痴呆(VD)的疗效。方法:选择2007年1月～2009年1月的82例VD患者,将其随机分为盐酸多奈哌齐组与尼莫地平组,每组41例,对比观察2组的临床疗效及对认知能力、痴呆程度和日常生活能力的影响。结果:盐酸多奈哌齐组治疗的显效率、总有效率均明显高于尼莫地平组(P<0.05);盐酸多奈哌齐组治疗后4周、12周简易精神状态量表(MMSE)评分、临床痴呆量表(CDR)评分及日常生活活动能力量表(ADL)评分均较治疗前明显改善,差异有统计学意义(P<0.05)。尼莫地平组治疗后4周、12周MMSE评分与治疗前比较,差异有统计学意义(P>0.05);CDR评分仅在治疗后12周明显下降(P<0.05),治疗后4周CDR评分与治疗前比较,差异无统计学意义(P>0.05);ADL评分治疗后4周、12周与治疗前比较,差异均无统计学意义(P>0.05)。盐酸多奈哌齐组治疗后4周、12周MMSE评分、CDR评分和ADL评分均优于同期尼莫地平组,2组比较差异有统计学意义(P<0.05)。结论:在治疗VD方面,盐酸多奈哌齐治疗VD优于尼莫地平,并且较尼莫地平更能改善患者的认知功能、痴呆程度和日常生活活动能力。     

Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study

Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.     

芹菜甲素对拟痴呆大鼠脑神经元保护机制的研究

目的：探讨芹菜甲素对拟老年性痴呆（AD）大鼠脑神经元的保护机制。方法：给予D-半乳糖注射和三氯化铝灌胃建立慢性中毒型痴呆大鼠模型;在制备AD模型同时用芹菜甲素灌胃;用Y型迷宫试验观察其行为学改变;用免疫组化技术检测大鼠静脉血液中超氧化歧化酶（T—SOD）及丙二醛（MDA）活性的变化;用荧光标记法测定脑细胞内游离钙离子的浓度;采用流式细胞技术、激光共聚焦技术检测神经元细胞凋亡;并分别与对照组比较,观察芹菜甲素对大鼠神经元病变、学习记忆能力的影响。结果：模型组大鼠海马和皮质具有典型的细胞凋亡特征,T—SOD活性降低,MDA含量升高;而芹菜甲素治疗组海马和皮质神经细胞凋亡数减少,T—SOD活性升高,MDA含量降低（P〈0．05或P〈0．01）。结论：芹菜甲素具有明显抗氧化作用和抑制神经细胞凋亡作用,其改善AD大鼠学习记忆功能可能是通过多个环节整体治疗来实现的。     

Donepezil effects on sources of cortical rhythms in mild Alzheimer's disease: Responders vs. Non-Responders

Acetylcholinesterase inhibitors (AChEI) such as donepezil act in mild Alzheimer's disease (AD) by increasing cholinergic tone. Differences in the clinical response in patients who do or do not benefit from therapy may be due to different functional features of the central neural systems. We tested this hypothesis using cortical electroencephalographic (EEG) rhythmicity. Resting eyes-closed EEG data were recorded in 58 mild AD patients (Mini Mental State Examination [MMSE] range 17-24) before and approximately 1 year after standard donepezil treatment. Based on changes of MMSE scores between baseline and follow-up, 28 patients were classified as "Responders" (MMSEvar >or=0) and 30 patients as "Non-Responders" (MMSEvar <0). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were studied with low-resolution brain electromagnetic tomography (LORETA). Before treatment, posterior sources of delta, alpha 1 and alpha 2 frequencies were greater in amplitude in Non-Responders. After treatment, a lesser magnitude reduction of occipital and temporal alpha 1 sources characterized Responders. These results suggest that Responders and Non-Responders had different EEG cortical rhythms. Donepezil could act by reactivating existing yet functionally silent cortical synapses in Responders, restoring temporal and occipital alpha rhythms.     

Early postnatal maternal deprivation in rats induces memory deficits in adult life that can be reversed by donepezil and galantamine

Early postnatal maternal deprivation is known to cause long-lasting neurobiological effects. Here, we investigated whether some of the cognitive aspects of these deficits might be related to a disruption of the cholinergic system. Pregnant Wistar rats were individually housed and maintained on a 12:12 h light/dark cycle with food and water freely available. The mothers were separated from their pups for 3 h per day from postnatal day 1 (PND-1) to PND-10. To do that, the dams were moved to a different cage and the pups maintained in the original home cage, which was transferred to a different room kept at 32 °C. After they reached 120–150 days of age, maternal-deprived and non-deprived animals were either sacrificed for brain acetylcholinesterase measurement, or trained and tested in an object recognition task and in a social recognition task as described by Rossato et al. (2007) [Rossato, J.I., Bevilaqua, L. R.M., Myskiw, J.C., Medina, J.H., Izquierdo, I., Cammarota, M. 2007. On the role hippocampal synthesis in the consolidation and reconsolidation of object recognition memory. Learn. Mem. 14, 36–46] and Lévy et al. (2003) [Lévy, F., Melo. A.I., Galef. B.G. Jr., Madden, M., Fleming. A.S. 2003. Complete maternal deprivation affects social, but not spatial, learning in adult rats. Dev. Psychobiol. 43, 177–191], respectively. There was increased acetylcholinesterase activity in hippocampus and perirhinal cortex of the deprived animals. In addition, they showed a clear impairment in memory of the two recognition tasks measured 24 h after training. Oral administration of the acetylcholinesterase inhibitors, donepezil or galantamine (1 mg/kg) 30 min before training reversed the memory impairments caused by maternal deprivation. The findings suggest that maternal deprivation affects memory processing at adulthood through a change in brain cholinergic systems.     

The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor

BACKGROUND AND PURPOSE: The acetylcholinesterase inhibitor, donepezil, is also a high affinity sigma(1) receptor agonist. We examined the involvement of sigma(1) receptors in its anti-amnesic and neuroprotective properties against amyloid beta(25-35) peptide-induced toxicity in mice. EXPERIMENTAL APPROACH: Mice were given an intracerebroventricular (i.c.v.) injection of Abeta(25-35) peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Abeta(25-35) injection to evaluate oxidative stress. Donepezil, the sigma(1) agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Abeta(25-35) injection, or 24 h after Abeta(25-35) injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively. KEY RESULTS: All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the sigma(1) antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors. CONCLUSIONS AND IMPLICATIONS: The potent anti-amnesic and neuroprotective effects of donepezil against Abeta(25-35)-induced toxicity involve both its cholinergic and sigma(1) agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.     

多奈哌齐和维生素E对轻度认知功能障碍的疗效评价

1文献类型 治疗。 2证据水平 1b。 3文献来源 Petersen RC, Thomas RG, Grundman M, et al.Vitamin E and Donepezil for the treatment of mildcognitive impairment [J]. N Engl J Med, 2005,352：2379-2388.