Davis K L, Thal L J, Gamzu E R, Davis C S, Woolson R F, Gracon S I, Drachman D A, Schneider L S, Whitehouse P J, Hoover T M
Mount Sinai Medical Center, New York, NY 10029-6574.
N Engl J Med. 1992 Oct 29;327(18):1253-9. doi: 10.1056/NEJM199210293271801.
In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.
Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.
At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.
In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.
在阿尔茨海默病中，大脑胆碱能神经元功能显著下降。然而，胆碱酯酶抑制剂治疗的研究结果相互矛盾。我们进行了一项多中心试验，以评估胆碱酯酶抑制剂他克林（1,2,3,4 - 四氢 - 9 - 吖啶胺一水合盐酸盐）是否能改善阿尔茨海默病患者的认知功能。
在632例可能患有阿尔茨海默病的合格患者中，215例在初步交叉阶段接受他克林治疗时病情有所改善，该阶段用于确定反应性和最佳剂量。在一项为期六周的双盲试验中，将这215例患者随机分配接受安慰剂或其最佳剂量的他克林（每日4次，每次10或20毫克）。疗效的主要指标是阿尔茨海默病评估量表的认知子量表和临床总体印象变化量表；次要指标包括简易精神状态检查表和日常生活活动评估。
在为期六周的试验结束时，接受他克林治疗的患者的平均调整后认知子量表得分（阿尔茨海默病评估量表）为30.3，而接受安慰剂治疗的患者为32.7。这表明他克林组的认知表现下降幅度较小（减少2.4分）（P < 0.001）。两组的总体评分没有差异。他克林组日常生活活动的下降幅度明显较小。简易精神状态检查表的结果有利于他克林，但差异较小且无统计学意义（他克林组得分为16.0，安慰剂组为15.3；P = 0.08）。胃肠道症状、转氨酶水平升高和头痛是最常见的副作用；所有这些副作用都可以通过减少剂量或停止治疗来逆转。
在这项针对对他克林有明显反应的阿尔茨海默病患者的短期研究中，他克林治疗导致认知功能下降在统计学上显著降低，尽管这种降低幅度不足以被研究医生对患者的总体评估所察觉。
