Identification of Treatments for Chemical Threat Agent Seizures

查获化学威胁剂的治疗方法的确定

基本信息

批准号：
10204124
负责人：
MICHAEL A. ROGAWSKI
金额：
$ 41.3万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204124
关键词：
AMPA Receptors Acute Advanced Development Adverse effects Allopregnanolone Animal Model Animals Anti-Inflammatory Agents Anticonvulsants Atropine Behavioral Benzodiazepines Blood Pressure Brain Injuries California Chemicals Cholinesterase Inhibitors Cholinesterases Collaborations Convulsants Data Development Diazepam Dose Drug Kinetics Electrographic Status Epilepticus Exposure to Female Formulation Future Human Intoxication Intramuscular Isoflurophate Laboratories Lead Macaca mulatta Medical Research Midazolam Modeling Monitor Mus Neurologic Neuroprotective Agents Nicotinic Receptors Organophosphates Outcome Paraoxon Pharmaceutical Preparations Picrotoxin Primates Publishing Rattus Readiness Receptor Inhibition Refractory Research Research Institute Respiration Rodent Model Safety Sedation procedure Seizures Sex Differences Soman Status Epilepticus Technology Testing Therapeutic Time Toxin Treatment Protocols aged animal rule chemical threat efficacy study efficacy testing improved male medical countermeasure motor impairment mouse model nerve agent neuropathology nonhuman primate novel predicting response prevent receptor research study safety study safety testing standard of care tetramethylenedisulfotetramine therapeutic candidate therapeutic development

项目摘要

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.

摘要 – 项目 2 需要改进治疗来终止癫痫持续状态 (SE) 并提高术后生存率接触引起癫痫发作的化学威胁剂引起惊厥的化学物质主要有两类。威胁物质：有机磷酸酯 (OP) 抗胆碱酯酶，包括梭曼和二异丙基氟磷酸盐 (DFP) 和 GABAA 受体拮抗剂，包括四亚甲基二磺四胺 (TETS) 和印防己毒素。目前化学威胁剂癫痫发作的护理治疗标准是苯二氮卓类地西泮，但未来可能会使用苯二氮卓类咪达唑仑，这些药物无法终止化学威胁。在许多情况下，尤其是在暴露后延迟给药时，制剂会诱发 SE，并且它们不能有效预防小鼠癫痫发作引起的脑损伤。此外，还开发了 TETS 诱导的 SE 模型，以适应 DFP 诱导的 SE 模型。实验室的地西泮和咪达唑仑的剂量相当于推荐的人体剂量，部分有效。然而，在 TETS SE 模型中，GABAA 受体的正调节剂 allopregnanolone 具有优越性。终止 TETS 诱导的行为和电图 SE 的活性，特别是在以在有效剂量下，四氢孕酮不会导致明显的镇静、运动障碍或与其他类似药物不同，四氢孕酮对血压或呼吸的不良影响是独特的。适合通过自动注射器进行肌肉注射，DFP 诱导的 SE 不会被终止。然而，苯二氮卓类药物或四氢孕酮与吡仑帕奈（一种有效的 AMPA 受体）组合。拮抗剂，肌肉注射四氢孕酮对于终止 DFP- 非常有效。行为诱导和电图 SE 被重新认识到四氢孕酮和吡仑帕奈将代表一种有效且安全的化学威胁制剂缉获的“通用”治疗方法。拟议的研究，将进行先导化合物 allopeganolone 所需的研究进入高级开发，包括与标准疗法以及非人类疗法结合的研究将获得吡仑帕奈和灵长类动物药代动力学和功效测试的概念验证数据。吡仑帕奈和别孕酮的组合也将进行额外的抗惊厥测试。项目 1 中确定的药物，以确定它们是否优于候选治疗方法。将在雄性和雌性动物中进行测试以评估性别差异，并将进行安全测试；项目 3 将确定候选抗炎治疗方法以缓解症状。项目 2 将评估化学治疗剂癫痫发作的长期后果。该项目的结果将允许先导化合物与抗癫痫治疗相互作用。别孕酮进入高级开发阶段并评估吡仑帕奈或其他药物候选抗癫痫药物应成为开发先导。