Wilkinson D G
University of Southampton, Thornhill Research Unit, Moorgreen Hospital, West End, Southampton, SO30 3JB, UK.
Expert Opin Pharmacother. 1999 Nov;1(1):121-35. doi: 10.1517/14656566.1.1.121.
Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.
多奈哌齐（盐酸多奈哌齐，E - 2020，安理申，卫材公司）于1997年3月上市，是英国首个用于阿尔茨海默病（AD）症状性治疗的药物。它在美国早一年上市，美国临床医生此前已经有他克林（THA）的使用经验。多奈哌齐是一种基于哌啶的、强效、特异性、非竞争性且可逆的乙酰胆碱酯酶（AChE）抑制剂。它在结构上与其他已有的胆碱酯酶抑制剂不同，即他克林（一种吖啶化合物）以及氨基甲酸盐类药物毒扁豆碱和卡巴拉汀，并且其药代动力学和耐受性特征也与这些药物不同。实验表明，多奈哌齐可抑制人红细胞中的AChE活性，并提高大鼠大脑皮层和海马体中的细胞外乙酰胆碱水平。在药理学上，多奈哌齐的半衰期约为70小时，适合每日给药一次。临床试验中报告的最常见不良事件为胃肠道反应，通常表现为恶心、呕吐、腹泻和便秘。也有头痛、头晕和睡眠障碍的报告；尚无肝毒性的证据。临床上多项安慰剂对照试验表明，治疗12周或24周后，以阿尔茨海默病评估量表认知子量表（ADAS cog）评估，每日服用5毫克或10毫克多奈哌齐与认知功能的显著改善相关。与安慰剂相比，治疗24周后，轻度至中度AD患者的整体功能和日常生活活动也有显著改善。多奈哌齐是英国首个用于这种致残性疾病的合理治疗药物，因此受到了广泛关注。最初的很多关注都是负面的，表面上是基于科学观点，即没有足够的已发表证据证明其广泛使用的合理性，但这是由如果所有AD患者都有资格使用该药物可能导致的高昂药物成本担忧所驱动的。现在已经从II期、III期试验以及上市后监测中产生了大量数据。本药物评估将回顾多奈哌齐的基础药理学，并结合试验数据以及作者使用该药物的临床经验进行阐述。
