Gasior M, Ungard J T, Witkin J M
Drug Development Group, Behavioral Neuroscience Branch, Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1999 Sep;290(3):1148-56.
Seizures and status epilepticus are among the neurological complications of cocaine overdose in humans. The aim of the present study was to evaluate the protective effectiveness and therapeutic index (separation between anticonvulsive and side effect profiles) of 14 newly approved and potential antiepileptic drugs using a murine model of acute cocaine toxicity and the inverted-screen test for behavioral side effect testing. Cocaine (75 mg/kg i.p.) produces clonic seizures (approximately 90% of mice), and conventional antiepileptic drugs have been reported to be either ineffective or only effective at doses producing significant sedative/ataxic effects. Clobazam, flunarizine, lamotrigine, topiramate, and zonisamide were ineffective against seizures up to doses producing significant motor impairment. In contrast, felbamate, gabapentin, loreclezole, losigamone, progabide, remacemide, stiripentol, tiagabine, and vigabatrin produced dose-dependent protection against cocaine-induced convulsions with varied separations between their anticonvulsant and side effect profiles: the protective index values (toxic TD(50)/anticonvulsive ED(50)) ranged from 1.26 (felbamate) to 7.67 (loreclezole), and gabapentin had the highest (protective index >152). Thus, several drugs were identified with greater protective efficacy and reduced motor impairment compared with classic antiepileptic drugs. Based on the proposed mechanism of action of these new anticonvulsants, it is noteworthy that 1) drugs that enhance gamma-aminobutyric acid-mediated neuronal inhibition in a manner distinct from barbiturates and benzodiazepines offer the best protective/behavioral side effect profiles, and 2) functional antagonists of Na(+) and Ca(2+) channels are generally ineffective. Overall, this study provides the first description of the effectiveness of new antiepileptic drugs against experimentally induced cocaine seizures and points to several drugs that deserve clinical scrutiny for this indication.
癫痫发作和癫痫持续状态是人类可卡因过量所致的神经并发症。本研究的目的是使用急性可卡因毒性小鼠模型和行为副作用测试的倒屏试验，评估14种新批准的和潜在的抗癫痫药物的保护效果和治疗指数（抗惊厥和副作用特征之间的分离度）。可卡因（75mg/kg腹腔注射）可引起阵挛性癫痫发作（约90%的小鼠），据报道传统抗癫痫药物要么无效，要么仅在产生显著镇静/共济失调作用的剂量下才有效。氯巴占、氟桂利嗪、拉莫三嗪、托吡酯和唑尼沙胺在达到产生显著运动障碍的剂量之前对癫痫发作均无效。相比之下，非氨酯、加巴喷丁、洛雷唑、氯西加酮、普罗加比、瑞马西胺、司替戊醇、噻加宾和氨己烯酸对可卡因诱导的惊厥产生剂量依赖性保护作用，其抗惊厥和副作用特征之间的分离度各不相同：保护指数值（毒性半数致死量TD(50)/抗惊厥半数有效量ED(50)）范围为1.26（非氨酯）至7.67（洛雷唑），加巴喷丁的保护指数最高（保护指数>152）。因此，与经典抗癫痫药物相比，确定了几种具有更高保护效力和更低运动障碍的药物。基于这些新型抗惊厥药物的作用机制推测，值得注意的是：1）以不同于巴比妥类和苯二氮䓬类的方式增强γ-氨基丁酸介导的神经元抑制作用的药物具有最佳的保护/行为副作用特征；2）Na(+)和Ca(2+)通道的功能性拮抗剂通常无效。总体而言，本研究首次描述了新型抗癫痫药物对实验诱导的可卡因癫痫发作的有效性，并指出了几种值得针对该适应症进行临床研究的药物。
