盐酸多奈哌齐治疗血管性痴呆临床观察

目的观察盐酸多奈哌齐治疗血管性痴呆的疗效。方法60例血管性痴呆患者随机分为治疗组与对照组,均在脑血管病常规药物治疗基础上,分别服用盐酸多奈哌齐、吡拉西坦12wk。应用简易智能状态量表(MMSE)、日常生活自理量表(ADL)及画钟测验,观察2组疗效及治疗后痴呆改善程度。结果与对照组治疗后比较,治疗组治疗后的MMSE、ADL、画钟测验均有明显改善(P依次<0.01、<0.05、<0.01)。治疗组有2例在服药3d内出现腹痛、头晕、恶心等轻度胆碱能兴奋性不良反应,继续用药症状消失。结论盐酸多奈哌齐治疗血管性痴呆疗效可靠,药物耐受性好,安全性高。     

P300 auditory event-related potentials and neuropsychological study during donepezil treatment in vascular dementia

Abstract After Alzheimer’s disease (AD), vascular dementia (VaD) is the most common cause of dementia among the elderly. Abnormalities in neurotransmitter pathways are common pathogenic mechanisms shared by AD and VaD. For one month we studied the effects of donepezil, an acetylcholinesterase inhibitor (5 mg daily), on the cognitive system using P300 auditory event-related potentials (P300) and neuropsychological tests in 10 patients affected by probable VaD according to the NINDS-AIREN criteria. Our data showed a significant improvement of neuropsychological items and P300 latency after one month of donepezil treatment. In conclusion both P300 and neuropsychological tests are indicated in patients with VaD to confirm the efficacy of donepezil treatment during follow-up.     

Acetylcholinesterase inhibitor donepezil in the treatment of cognitive deficit in schizophrenia. Subanalysis of the active branch from Czech extended double blind study

The article mentions the conclusions of most evidential works investigating donepezil in the treatment of cognitive deficit in schizophrenia. It focuses on an analysis of a sub-group of 20 patients receiving treatment of the donepezil in an extended Czech double-blind placebo controlled study.     

安理申对早期Alzheimer病患者血清BDNF浓度的影响

目的探讨碱酯酶(AChE)抑制剂安理申对早期Alzheimer病患者血浆BDNF浓度的影响。方法应用ELISA法对41例早期AD患者和29例年龄相匹配的健康对照组血清的BDNF浓度进行检测,AD患者在口服安理申前及口服安理申(10mg/d)治疗12个月后进行检测。结果AD患者治疗前BDNF的血清浓度为(18.6±3.3)ng/ml,低于将抗对照组的(24.1±5.6)ng/ml,治疗12个月后,AD患者血清BDNF浓度增加到(23.7±6.2)ng/ml,与对照组比较无明显差异。结论AD患者存在血清BD-NF持续降低,AChE抑制剂安理申能增加患者血清BDNF浓度,可能具有一定的神经保护作用。     

盐酸多奈哌齐对血管性痴呆小鼠海马神经细胞神经元蛋白激酶C表达变化的影响

目的探讨盐酸多奈哌齐对血管性痴呆（Vascular dementia,VD）小鼠海马神经元蛋白激酶C（protein kinase C,PKC）变化的影响。方法将3月龄雄性昆明小鼠随机分为假手术组、模型组、多奈哌齐治疗组。采用双侧颈总动脉结扎,反复缺血-再灌注制备VD模型,药物治疗30d。术后第29、30天,分别进行跳台试验和水迷宫试验观察各组小鼠行为学改变。采用免疫组织化学法观察各组海马CA1区神经元PKC表达的变化。结果药物治疗组小鼠学习、记忆成绩较模型组明显改善（P〈0.05）。模型组PKC免疫反应阳性神经元平均光密度值为（0.2730±0.0709）,与假手术组（0.3206±0.0642）和药物组（0.3036±0.0688）相比均显著降低（P〈0.05）,而药物组与假手术组间无明显差别（P〉0.05）。结论反复缺血-再灌注导致VD小鼠海马神经元PKC表达减少;多奈哌齐通过抑制中枢神经系统中乙酰胆碱的降解,可增加VD小鼠海马神经元PKC表达,从而改善VD小鼠学习、记忆能力,推测此也是该药物改善VD小鼠学习、记忆障碍的一个重要环节。     

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

Rationale Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer’s disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of β-amyloid (Aβ) and behavioral deficits during adulthood are useful for investigating this question. Objectives The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Aβ plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9–10 months of age, Tg2576-transgenic [Tg(+)] mice develop Aβ plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(−)] mice. Methods Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(−) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Aβ plaque number was quantified. Results Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(−) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(−) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Aβ plaques. Conclusions These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aβ plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.     

The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer's disease patients

The increased pro-inflammatory cytokine production was previously observed in Alzheimer's disease (AD). We sought to explore whether acetylcholinesterase inhibitor (AChEI) therapy ameliorates clinical symptoms in AD through down-regulation of inflammation. Expression and release of monocyte chemotactic protein-1 (MCP-1), a positive regulator of Th2 differentiation, and interleukin (IL)-4, an anti-inflammatory cytokine from peripheral blood mononuclear cells (PBMC) in AD patients, were investigated. PBMC were purified from AD patients at time of enrollment (T0) and after 1 month of treatment with AChEI (T1) and from healthy controls (HC). Supernatants were analyzed for cytokine levels by ELISA methods. mRNA expression were determined by RT-PCR. Expression and production of MCP-1 and IL-4 were significantly increased in AD subjects under therapy with the AChEI Donepezil, compared to the same AD patients at time of enrollment (P < 0.001). Our data suggest another possible explanation for the ability of Donepezil [diethyl(3,5-di-ter-butyl-4-hydroxybenzyl)phosphonate] to delay the progression of AD; in fact, Donepezil may modulate MCP-1 and IL-4 production, which may reflect a general shift towards type Th0/Th2 cytokines which could be protective in AD disease. The different amounts of MCP-1 and IL-4 observed might reflect the different states of activation and/or responsiveness of PBMC, that in AD patients could be kept in an activated state by pro-inflammatory cytokines.     

Effects of histamine H(3) antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.     

Analysis and enantioresolution of donepezil by capillary electrophoresis

The analysis of donepezil, a centrally acting acetylcholine esterase inhibitor, is described by a CZE method suitable for applications in pharmaceutical field. A rapid migration of the analyte was obtained under acidic conditions (pH 3.0); with detection wavelength of 320 nm a LOD of 0.8×10⁻³ mg/ml was provided. Applications on real sample (pharmaceuticals) were carried out using two different instruments with comparable results in terms of reproducibility and accuracy. The use of chiral selectors in the running buffer allowed the enantioseparation of donepezil; charged cyclodextrins (carboxymethyl-β-cyclodextrin and sulfated-β-cyclodextrin) were suitable for the chiral resolution of the analyte. Interesting results were also obtained using human serum albumin. The protein-based CE enantioseparation was carried out at pH 7.4 avoiding the partial filling technique due to the good absorptivity of donepezil at 320 nm. Interestingly, the use of bicine as BGE provided a significative improvement in the enantioresolution compared to that obtained by phosphate buffer.