Novel pediatric anticonvulsants for nerve agents

项目摘要 该项目的主要目标是开发一种神经类固醇疗法，以减轻癫痫发作和由 儿童和老年人的神经毒剂和有机磷(OP)化合物。暴露于神经毒剂 或OP中毒可导致持续性癫痫发作、癫痫持续状态(SE)和严重的脑损伤。当前 苯二氮卓类抗惊厥药不能充分保护SE，即持续30分钟或 时间更长，并有严重的神经元损伤和死亡。最近，神经类固醇已被确认为抗惊厥药物 可以有效地控制成年模型的OP发作和脑损伤。然而，孩子和老人们 更容易受到神经毒剂的神经毒性影响，但几乎没有可用的医学对策来 保护这些人口。该项目试图通过优化一种特定的抗惊厥药物来解决这一差距。 神经毒剂在儿科和老年人群中用于阻止癫痫发作和防止脑损伤。最新研究 表明神经类固醇增强时相和突触外紧张性抑制是强效的抗惊厥药物。 神经毒剂引起的癫痫发作和脑损伤。暴露后的神经类固醇治疗已被证明是 在OP中毒模型中，咪达唑仑比咪达唑仑更有效的抗惊厥和神经保护作用。的目标是 本项目旨在确定合成神经类固醇甘纳索酮(GX)的有效性和安全性。 儿童和老年模型神经毒剂和OP中毒的SPECTRUM抗惊厥药。主 重点是GX在儿科治疗中启用IND的疗效优化、机制和安全性验证 老鼠。该项目将解决三个具体目标：(目标1)：确定GX对DFP-和梭曼-的疗效。 诱导癫痫发作与儿童神经病理学；(目的2)：确定GX对DFP和DFP的疗效。 梭曼诱导的老年大鼠癫痫发作和神经病理学；以及(目标3)：确定梭曼的药代动力学和 GX在儿童和老年大鼠中的安全性概况，并准备一份动物规则途径下的IND前应用。 渐进的“进行/不进行”里程碑计划包括关键研究成功与否的量化标准 关于四个主要观察指标：(一)抗惊厥疗效；(二)急性神经保护剂疗效；(三)预防 慢性神经变性和神经炎症；以及(Iv)癫痫和长期神经学症状的缓解 功能障碍。该项目成果的总体影响将对救生发展产生非常大的影响 儿童和老年人群OP中毒的抗惊厥药物，这是一种高度优先的平民治疗方法 对抗程序的字段。

Project Summary The main goal of this project is to develop a neurosteroid therapy to mitigate seizures and morbidity caused by nerve agents and organophosphate (OP) compounds in children and elderly population. Exposure to nerve agents or OP poisoning can result in persistent seizures, status epilepticus (SE), and severe brain injury. Current benzodiazepine anticonvulsants do not sufficiently protect from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. Recently neurosteroids have been identified as anticonvulsants that can effectively control OP seizures and brain injury in adult models. However, the children and elderly are more vulnerable to nerve agent neurotoxicity, but very few medical countermeasures are available to protect these populations. This project seeks to address this gap by optimizing a specific anticonvulsant against nerve agents to stop seizures and prevent brain damage in the pediatric and elderly population. Recent studies shows that neurosteroids that enhance phasic and extrasynaptic tonic inhibition are strong anticonvulsants against seizures and brain damage caused by nerve agents. Post-exposure neurosteroid therapy has been shown to be more effective anticonvulsant and neuroprotective than midazolam in OP intoxication models. The objective of this project is to determine the efficacy and safety of the synthetic neurosteroid ganaxolone (GX) as ‘broad- spectrum’ anticonvulsant for nerve agent and OP intoxication in pediatric and aged models. The main emphasis is focused on IND-enabling efficacy optimization, mechanism, and safety validation of GX in pediatric rats. The project will address three specific aims: (Aim 1): To determine the efficacy of GX against DFP- and soman- induced seizures and neuropathology in pediatric rats; (Aim 2): To determine the efficacy of GX against DFP- and soman-induced seizures and neuropathology in aged rats; and (Aim 3): To determine the pharmacokinetic and safety profile of GX in pediatric and aged rats and prepare a pre-IND application under the Animal Rule pathway. The progressive “go/no-go” milestones plan includes quantitative criteria for the success of key studies focusing on four primary outcome measures: (i) anticonvulsant efficacy; (ii) acute neuroprotectant efficacy; (iii) prevention of chronic neurodegeneration and neuroinflammation; and (iv) attenuation of epilepsy and long-term neurological dysfunction. The overall impact of the project’s outcomes will be very high for the development of lifesaving anticonvulsant drug for OP intoxication in pediatric and elderly population, which is a high priority civilian therapeutic field for the CounterACT program.