Identification of Treatments for Chemical Threat Agent Seizures

摘要-项目2 有必要改进治疗方法以终止癫痫持续状态(SE)并提高以下患者的存活率 暴露于可导致癫痫发作的化学威胁剂。有两大类致惊厥的化学物质 威胁因素：有机磷(OP)抗胆碱酯酶，包括梭曼和二异丙基氟磷酸盐 和GABAA受体拮抗剂，包括毒鼠强(TETS)和印防己毒素。这个 目前治疗化学威胁剂癫痫的标准是苯二氮卓类安定，但 未来可能会使用苯二氮卓咪达唑仑。这些毒剂不能终止化学威胁 在许多情况下，毒剂诱发SE，特别是在暴露后延迟给药时， 而且它们在预防癫痫引起的脑损伤方面也没有效果。在最初的项目阶段，鼠标 建立TETS诱导的SE动物模型。此外，还建立了DFP诱导的大鼠SE模型。 实验室。相当于推荐人体剂量的安定和咪达唑仑具有部分活性 在TETS SE模型中。然而，GABAA受体的正向调节剂别孕酮具有更好的疗效 终止TETS诱导的行为和心电图SE的活性，特别是在给药时 延迟的时间。在有效剂量下，别孕酮没有引起明显的镇静、运动障碍或 对血压或呼吸有不良影响。与其他类似药物不同，别孕酮是独一无二的 适合通过自动注射器进行肌肉注射。DFP诱导的SE未通过以下方式终止 苯二氮卓类或别孕酮。然而，一种有效的AMPA受体perampanel的组合 拮抗剂，肌注别孕酮可有效终止DFP- 诱发的行为学和体感诱发电位。据推测，别孕酮和阿司匹林的联合 Perampanel将代表一种有效和安全的“通用”治疗化学威胁剂癫痫的方法。在……里面 在拟议的研究中，将进行先导化合物别丙孕酮所需的研究 进入高级开发阶段，包括结合标准治疗和非人类治疗的研究 灵长类动物药代动力学和药效试验。概念验证数据将用于Perampanel和 帕金森和别孕酮的联合用药。此外，还将进行额外的抗癫痫测试 项目1中确定的代理，以确定它们是否优于候选治疗。有效性和安全性 将在雄性和雌性动物身上进行测试，以评估性别差异；安全测试将 在幼年和老年动物中进行。项目3将确定候选抗炎治疗以缓解 化学处理剂癫痫发作的长期后果。项目2将评估这些治疗方法是否 与抗癫痫治疗相互作用。这个项目的结果将允许先导化合物 别孕酮将进入高级开发阶段，并评估perampanel或其他 候选抗癫痫药应成为发展的主导者。

Summary – Project 2 There is a need for improved treatments to terminate status epilepticus (SE) and increase survival following exposure to seizure-inducing chemical threat agents. There are two major classes of convulsant chemical threat agents: organophosphate (OP) anticholinesterases, including soman and diisopropylfluorophosphate (DFP), and GABAA receptor antagonists, including tetramethylenedisulfotetramine (TETS) and picrotoxin. The current standard of care treatment for chemical threat agent seizures is the benzodiazepine diazepam, but the benzodiazepine midazolam will likely be used in the future. These agents fail to terminate chemical threat agent induced SE in many situations, particularly when they are administered at delayed times after exposure, and they are not effective at preventing seizure-induced brain damage. In the initial project period, a mouse model of TETS-induced SE was developed. In addition, a rat model of DFP-induced SE was adapted to the laboratory. Diazepam and midazolam at doses equivalent to recommended human doses were partially active in the TETS SE model. However, allopregnanolone, a positive modulator of GABAA receptors, had superior activity in terminating TETS-induced behavioral and electrographic SE, particularly when administered at a delayed time. At effective doses, allopregnanolone did not cause marked sedation, motor impairment or adverse effects on blood pressure or respiration. Unlike other similar agents, allopregnanolone is uniquely suited for intramuscular administration via autoinjector. DFP-induced SE was not terminated by benzodiazepines or allopregnanolone. However, the combination of perampanel, a potent AMPA receptor antagonist, and allopregnanolone administered intramuscularly was highly effective in terminating DFP- induced behavioral and electrographic SE. It is hypothesized that a combination of allopregnanolone and perampanel would represent an effective and safe “universal” treatment for chemical threat agent seizures. In the proposed research, studies will be conducted that are required for the lead compound allopreganolone to enter advanced development, including studies in conjunction with standard therapy as well as non-human primate pharmacokinetic and efficacy testing. Proof-of-concept data will be obtained for perampanel and the combination of perampanel and allopregnanolone. Testing will also be conducted of additional antiseizure agents identified in Project 1 to determine if they are superior to the candidate treatments. Efficacy and safety testing will be conducted in both male and female animals to assess sex differences; and safety tests will be conducted in young and aged animals. Project 3 will identify candidate anti-inflammatory treatments to mitigate the long-term consequences of chemical treat agent seizures. Project 2 will assess whether these treatments interact with the antiseizure treatments. The results from this project will permit the lead compound allopregnanolone to enter advanced development and an assessment of whether perampanel or another candidate antiseizure agent should become development leads.