Rational polytherapy in the treatment of cholinergic seizures

描述（由申请人提供）：有机磷引起的癫痫发作迅速自我维持，不依赖于其原始胆碱能触发，对标准治疗（苯二氮卓类）无效，是一个尚未解决的问题，可能是一个非常严重的军事和恐怖主义威胁。这一建议是基于这样的假设，即在胆碱能癫痫的治疗中，多药治疗上级单药治疗。根据我们的观察，这些癫痫发作引起的内在化和损失的突触GABAA受体，并增加突触NMDA受体，我们建议研究三联疗法的癫痫发作。这将结合联合收割机：1/GABAA受体激动剂，其通过刺激残留的突触GABAA受体而部分恢复抑制; 2/NMDA拮抗剂，其通过阻断一些NMDA受体而减少兴奋;和3/抗惊厥剂，其将增加非GABA位点的抑制。我们建议探索以下药物的组合：1/咪达唑仑，一种易于肌内给药的GABAA受体激动剂。2/NMDA受体拮抗剂，其可以是非特异性的（地佐环平或氯胺酮）或NR 2B亚基偏好性的（R 025 -6981或非氨酯），和3/作用于非GABA位点的抗惊厥药，如快速灭活钠通道（丙戊酸盐）;或缓慢灭活钠通道（拉考沙胺）;或钾通道（依佐加滨）;或突触前囊泡（左乙拉西坦）。我们的初步结果表明，这种三种药物组合可以停止由高剂量锂和毛果芸香碱诱导的癫痫发作，并且对深度麻醉剂量的苯二氮卓类药物无效，最佳的2-和3-药物组合将在梭曼诱导的癫痫发作模型中进行研究。在这个项目结束时，我们将确定一种有效的三种药物组合，它可以以很少或没有行为毒性的代价阻止苯二氮卓类难治性胆碱能癫痫发作，并准备在非人类灵长类动物中进行测试，然后包括在我们的治疗试剂盒中。

DESCRIPTION (provided by applicant): The seizures generated by organophosphates quickly become self-sustaining, independent of their original cholinergic trigger, and refractory to standard treatment (benzodiazepines), and represent an unresolved problem and potentially a very serious military and terrorist threat. This proposal is based on the hypothesis that in the treatment of cholinergic seizures, polypharmacy is superior to monotherapy. Based on our observations that these seizures cause internalization and loss of synaptic GABAA receptors, and increases in synaptic NMDA receptors, we proposed to study triple therapy for those seizures. This would combine 1/ a GABAA receptor agonist, which would partially restore inhibition by stimulating the residual synaptic GABAA receptors; 2/ an NMDA antagonist which would reduce excitation by blocking some NMDA receptors; and 3/ an anticonvulsant which would increase inhibition at non-GABA sites. We propose to explore combinations of the following drugs: 1/ Midazolam, a GABAA receptor agonist which is easily delivered intra-muscularly. 2/ a NMDA receptor antagonist which could be non-specific (dizocilpine or ketamine) or NR2B subunit-preferring (R025-6981 or felbamate), and 3/ an anticonvulsant acting at a non-GABA site such as rapidly inactivating sodium channels (valproate); or slowly inactivating sodium channels (lacosamide); or potassium channels (ezogabine); or presynaptic vesicles (levetiracetam). Our preliminary results suggest that such three-drug combinations can, with little depression of consciousness, stop seizures induced by high-dose lithium and pilocarpine and refractory to a profoundly anesthetic dose of benzodiazepine, the best 2- and 3-drug combinations in a lithium-pilocarpine model will be studied in a model of soman-induced seizures. At the end of this project, we will have identified an effective three-drug combination which can stop benzodiazepine-refractory cholinergic seizures at the cost of little or no behavioral toxicity, and is ready to be tested in subhuman primates and then included in our therapeutic kits.