Thal L J, Schwartz G, Sano M, Weiner M, Knopman D, Harrell L, Bodenheimer S, Rossor M, Philpot M, Schor J, Goldberg A
Department of Neurosciences, University of California San Diego, La Jolla 92093-0624, USA.
Neurology. 1996 Dec;47(6):1389-95. doi: 10.1212/wnl.47.6.1389.
A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects.
During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales.
At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests.
This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.
在1111名轻度至中度阿尔茨海默病（AD）患者中开展了一项多中心试验，以评估胆碱酯酶抑制剂水杨酸毒扁豆碱控释剂的疗效。
在剂量滴定期间，受试者每日接受18毫克、24毫克或30毫克的毒扁豆碱或安慰剂。经过2周的洗脱期后，366名假定有改善的受试者被随机分配，在一项为期6周的双盲试验中接受安慰剂或其最佳剂量的毒扁豆碱。无反应的患者（439名）被随机分配，在另一项双盲试验中接受安慰剂或其最高耐受剂量的毒扁豆碱。主要疗效指标包括阿尔茨海默病评估量表（ADAS）的认知子量表和临床总体印象变化量表（CGIC）。次要指标包括简易精神状态检查表和两个日常生活活动量表。
在为期6周的双盲阶段结束时，在意向性分析中，接受毒扁豆碱治疗的患者在ADAS上的得分比接受安慰剂治疗的患者高1.75分（p = 0.003），在CGIC上高0.26分（p = 0.012）。次要结局指标无显著改善。在剂量滴定阶段对毒扁豆碱无反应的患者，在重新暴露的双盲期内对任何结局指标均无反应。常见不良事件包括恶心、呕吐、腹泻和厌食。肝功能检查无显著变化。
本研究表明，在基于表现的认知功能仪器和临床医生的总体评估方面，毒扁豆碱和安慰剂之间存在统计学上的显著差异。效应量的大小较小，且仅发生在初始剂量滴定研究期有反应的患者亚组中。然而，结果表明，在一部分患者中，毒扁豆碱在6周的治疗期内可诱导一定程度的认知改善。
