Rational polytherapy in the treatment of cholinergic seizures

描述(申请人提供)：有机磷产生的癫痫发作迅速变得自我维持，独立于其最初的胆碱能触发，对标准治疗(苯二氮卓类药物)无效，是一个悬而未决的问题，并可能构成非常严重的军事和恐怖威胁。这一建议是基于这样一种假设，即在治疗胆碱能癫痫时，多药联用优于单一疗法。根据我们的观察，这些发作导致突触GABAA受体的内化和丢失，以及突触NMDA受体的增加，我们建议研究对这些发作的三联疗法。这将结合1/a GABAA受体激动剂，它将通过刺激残留的突触GABAA受体来部分恢复抑制；2/a NMDA拮抗剂，将通过阻断一些NMDA受体来减少兴奋；以及3/a抗惊厥药，将增加对非GABA部位的抑制。我们建议探索以下药物的组合：1/咪达唑仑，一种GABAA受体激动剂，易于肌肉内给药。2/a NMDA受体拮抗剂，可以是非特异性的(地佐西平或氯胺酮)或NR2B亚单位偏好(R025-6981或非氨基甲酸酯)，以及3/a作用于非GABA部位的抗惊厥药物，如快速灭活钠通道(丙戊酸盐)；或缓慢灭活钠通道(乳糖胺)；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，这样的三种药物组合可以在几乎没有意识抑制的情况下，阻止大剂量锂和匹罗卡品诱导的癫痫发作，并且对深度麻醉剂量的苯二氮卓类药物无效。锂-匹罗卡品模型中最好的2种和3种药物组合将在梭曼诱导的癫痫模型中进行研究。在该项目结束时，我们将确定一种有效的三药组合，该组合可以在行为毒性很小或没有行为毒性的情况下阻止苯二氮卓-难治性胆碱能癫痫发作，并准备在亚人类灵长类动物身上进行测试，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.