Rational polytherapy in the treatment of cholinergic seizures

描述（由申请人提供）：由有机磷引起的癫痫发作很快就会自我维持，独立于其最初的胆碱能触发因素，对标准治疗（苯二氮卓类药物）难治，并且代表一个未解决的问题，潜在的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，即在治疗胆碱能性癫痫时，多种药物治疗优于单一药物治疗。根据我们的观察，这些癫痫发作引起突触GABAA受体的内化和丧失，以及突触NMDA受体的增加，我们建议研究三联疗法治疗这些癫痫发作。这将联合1/ a GABAA受体激动剂，通过刺激残留的突触GABAA受体来部分恢复抑制；2/一个NMDA拮抗剂，通过阻断一些NMDA受体来减少兴奋；3/一种抗惊厥药，会增加对非gaba位点的抑制。我们建议探索以下药物的组合：1/咪达唑仑，一种易于肌内递送的GABAA受体激动剂。2/ a NMDA受体拮抗剂，可能是非特异性的（二唑西平或氯胺酮）或NR2B亚基偏好（R025-6981或非胺酸酯），3/ a抗惊厥药作用于非gaba位点，如快速灭活钠通道（丙戊酸酯）；或缓慢灭活钠通道（拉科沙胺）；或钾通道（ezogabine）；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在意识几乎不受抑制的情况下，停止高剂量锂和匹洛卡平引起的癫痫发作，并且对苯二氮卓类药物的深度麻醉剂量难以耐受，锂-匹洛卡平模型中最佳的2和3种药物组合将在索曼诱发癫痫发作模型中进行研究。在该项目结束时，我们将确定一种有效的三药组合，可以以很少或没有行为毒性为代价阻止苯二氮卓类难治胆碱能癫痫发作，并准备在亚人类灵长类动物中进行测试，然后纳入我们的治疗试剂盒。

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.