Williams B R
School of Pharmacy and Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles 90033, USA.
Am J Health Syst Pharm. 1999 Mar 1;56(5):427-32. doi: 10.1093/ajhp/56.5.427.
The pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of metrifonate, a long-acting cholinesterase inhibitor, are discussed. Attempts to correct the central cholinergic deficits associated with Alzheimer's disease have included administration of cholinergic precursors, cholinergic agonists, and cholinesterase inhibitors. To date, two reversible cholinesterase inhibitors-tacrine and donepezil-have been marketed. Metrifonate, an organophosphate, is converted nonenzymatically to 2,2-dichlorovinyl dimethyl phosphate (DDVP), the active enzyme inhibitor. DDVP produces irreversible inhibition of brain cholinesterase that lasts for several days; enzyme recovery is dependent on synthesis of new enzyme. Several preclinical studies have demonstrated cognition-enhancing effects of metrifonate in animals. Trials in humans have shown improvement on the Alzheimer's Disease Assessment Scale, in Mini-Mental State Examination scores, and in the Clinician's Interview-Based Impression of Change with caregiver input. Clinical improvement noted with metrifonate appears similar to that seen with other cholinesterase inhibitors. Adverse effects noted in clinical trials have been associated primarily with the gastrointestinal tract and have been mild. Metrifonate appears to be a promising agent for the treatment of the symptoms of Alzheimer's disease.
本文讨论了长效胆碱酯酶抑制剂敌百虫的药理学、药代动力学、临床疗效及不良反应。纠正与阿尔茨海默病相关的中枢胆碱能缺陷的尝试包括给予胆碱能前体、胆碱能激动剂及胆碱酯酶抑制剂。迄今为止，已有两种可逆性胆碱酯酶抑制剂——他克林和多奈哌齐上市。敌百虫作为一种有机磷化合物，可非酶促转化为活性酶抑制剂2,2-二氯乙烯基二甲基磷酸酯（DDVP）。DDVP对脑胆碱酯酶产生不可逆抑制，持续数天；酶的恢复依赖于新酶的合成。多项临床前研究已证实敌百虫对动物有认知增强作用。人体试验表明，在阿尔茨海默病评估量表、简易精神状态检查表评分以及有护理人员参与的基于临床医生访谈的变化印象方面均有改善。敌百虫引起的临床改善似乎与其他胆碱酯酶抑制剂相似。临床试验中观察到的不良反应主要与胃肠道有关，且症状较轻。敌百虫似乎是一种治疗阿尔茨海默病症状的有前景的药物。
