Abstract

Prolonged seizures are a hallmark feature of intoxication with anticholinesterase nerve agents such as soman. While benzodiazepine drugs are typically used to control these seizures, studies in both rats and guinea pigs have shown that potent, centrally acting anticholinergic drugs such as scopolamine can also terminate such seizures. The present study was performed to determine if scopolamine could produce similar anticonvulsant effects in a nonhuman primate model of soman intoxication. Adult male African green monkeys, implanted with telemetry devices to record cortical electroencephalographic activity, were pretreated with pyridostigmine (0.02 mg/kg, intramuscularly [im]) and 40 min later challenged with 15 µg/kg (im) of the nerve agent soman. One min after soman exposure the animals were treated with atropine (0.4 mg/kg, im) and the oxime 2-PAM (25.7 mg/kg, im). One min after the start of seizure activity the animals were administered scopolamine (0.01–0.1 mg/kg, im), using an up-down dosing design over successive animals. Scopolamine was highly effective in stopping soman-induced seizures with an ED₅₀ = 0.0312 mg/kg (0.021–0.047 mg/kg = 95% confidence limits). Seizure control was rapid, with all epileptiform activity stopping on average 21.7 min after scopolamine treatment. A separate pK study showed that scopolamine absorption peaked approximately 10 min after im administration and a dose of 0.032 mg/kg produced maximum plasma levels of 17.62 ng/ml. The results show that scopolamine exerts potent and rapid anticonvulsant action against soman-induced seizures and that it may serve as a valuable adjunct to current antidote treatments for nerve agent intoxication.

摘要

长时间癫痫发作是抗胆碱酯酶神经毒剂（如索曼）中毒的一个标志性特征。虽然苯二氮卓类药物通常用于控制这些癫痫发作，但对大鼠和豚鼠的研究表明，强效、中枢作用的抗胆碱能药物（如东莨菪碱）也可以终止此类癫痫发作。本研究旨在确定东莨菪碱是否可以在非人类灵长类动物中毒模型中产生类似的抗惊厥作用。成年雄性非洲绿猴植入遥测设备以记录皮层脑电图活动，用吡啶斯的明（0.02 mg/kg，肌肉内 [im]）预处理，40 分钟后用 15 µg/kg (im) 的神经毒剂 soman 进行攻击。人体暴露后一分钟，动物用阿托品（0.4 mg/kg，im) 和肟 2-PAM (25.7 mg/kg, im)。在癫痫发作活动开始后一分钟，对动物施用东莨菪碱（0.01-0.1 mg/kg，im），对连续动物使用上下剂量设计。东莨菪碱在阻止 ED 引起的人诱发的癫痫发作方面非常有效₅₀ = 0.0312 mg/kg（0.021–0.047 mg/kg = 95% 置信限）。癫痫发作控制迅速，所有癫痫样活动在东莨菪碱治疗后平均停止 21.7 分钟。一项单独的 pK 研究表明，东莨菪碱的吸收在 im 给药后约 10 分钟达到峰值，0.032 mg/kg 的剂量产生的最大血浆水平为 17.62 ng/ml。结果表明，东莨菪碱对人体诱发的癫痫发作具有强效和快速的抗惊厥作用，并且它可以作为当前神经毒剂中毒解毒剂治疗的有价值的辅助手段。