Wagstaff A J, McTavish D
Adis International Limited, Auckland, New Zealand.
Drugs Aging. 1994 Jun;4(6):510-40. doi: 10.2165/00002512-199404060-00006.
Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.
他克林是一种中枢性胆碱酯酶抑制剂，对单胺水平和离子通道具有额外的药理活性。据推测，这些额外特性中的一些或全部可能也与该药物的作用方式相关。他克林在药理和临床反应方面存在广泛的个体差异，这可能与生物利用度的个体差异有关。他克林在每日剂量为80至160毫克时，似乎能改善一部分阿尔茨海默病患者的认知功能和行为缺陷。在设计最佳的试验中，30%至51%的可评估患者在阿尔茨海默病评估量表的认知子量表上至少提高了4分，而接受安慰剂的患者这一比例为16%至25%。当使用整体评估量表时，判定有类似比例的他克林接受者病情有所改善。在每日剂量达160毫克之前存在显著的剂量反应关系。然而，在试验过程中有大量患者退出，许多是因为与他克林相关的转氨酶水平升高。约50%的他克林接受者出现肝酶水平升高（约25%达到临床显著性）。他克林接受者出现胆碱能症状的频率也高于接受安慰剂者。开始治疗时建议每隔6周逐渐增加他克林剂量，每次增加剂量后需每周监测血清转氨酶6周。尽管有反应者比例低以及与治疗相关的肝脏不良反应发生率高这些局限性，但他克林似乎能使一部分阿尔茨海默病患者的认知和行为功能有可测量的改善——这在一个此前缺乏可接受治疗选择的领域是一项值得欢迎的进展。
