Mant T, Troetel W M, Imbimbo B P
Guy's Drug Research Unit, Guy's Hospital, London, United Kingdom.
J Clin Pharmacol. 1998 Jul;38(7):610-7. doi: 10.1002/j.1552-4604.1998.tb04467.x.
Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double-blind, randomized, rising-dose, five-way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40-mg dose developed profound AChE inhibition (58-59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose-related fashion according to a sigmoidal (logistic) function. The mean (+/- SEM) maximum inhibition of AChE activity (Imax) was 14.5+/-3.3%, 20.4+/-2.3%, 28.7+/-2.9%, 45.2+/-1.3% and 53.6+/-2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half-life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single-dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose-related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.
依替斯的明是一种正在研发用于阿尔茨海默病症状性治疗的新型乙酰胆碱酯酶（AChE）抑制剂。本研究旨在确定9名健康老年志愿者中依替斯的明的最大耐受剂量和药效学。受试者按照双盲、随机、剂量递增、五交叉设计接受单次口服8毫克、20毫克、32毫克和40毫克依替斯的明以及安慰剂。治疗期间密切监测不良事件、血压、心率、体温、用力呼气量、唾液流量和瞳孔活动。通过检测红细胞中的AChE活性来评估依替斯的明的药效学活性。8毫克、20毫克和32毫克剂量的依替斯的明耐受性良好。接受40毫克剂量的4名受试者中有2人出现了深度AChE抑制（58 - 59%）并报告了严重不良事件（恶心、呕吐、晕厥和心动过缓），这使得其余受试者无法进一步给药。服用依替斯的明对仰卧心率、体温和瞳孔直径产生微弱影响。对血压、用力呼气量、唾液流量和近点聚焦无影响。AChE活性根据S形（逻辑）函数呈剂量相关方式受到抑制。安慰剂、8毫克、20毫克、32毫克和40毫克依替斯的明给药后，AChE活性的平均（±SEM）最大抑制率分别为14.5±3.3%、20.4±2.3%、28.7±2.9%、45.2±1.3%和53.6±2.9%。理论最大反应（Emax）为72.9%，产生最大反应一半的剂量（ED50）为29.5毫克。在24小时时，残余的AChE抑制率在9%至15%之间，酶恢复的半衰期约为10小时。健康老年受试者单次口服依替斯的明后的最大耐受剂量为32毫克。单次口服依替斯的明可产生持续的、剂量相关的AChE活性抑制。不良事件与AChE抑制程度相关。
