Identification of Treatments for Chemical Threat Agent Seizures

查获化学威胁剂的治疗方法的确定

• 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
• 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

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 需要改进治疗以终止癫痫持续状态（SE）并增加以下患者的存活率： 暴露于危险化学威胁剂。有两大类致惊性化学物质 威胁剂：有机磷（OP）抗胆碱酯酶，包括梭曼和二异丙基氟磷酸 (DFP)和GABAA受体拮抗剂，包括四亚甲基二磺基四胺（TETS）和印防己毒素。的 目前治疗化学威胁剂发作的标准是苯二氮卓类安定，但 苯二氮卓咪达唑仑将来可能会被使用。这些药剂无法终止化学威胁 在许多情况下，药物诱导SE，特别是在暴露后延迟给药时， 并且它们不能有效地防止糖尿病引起的脑损伤。在项目初期，一只老鼠 建立TETS诱发SE模型。此外，DFP诱导的SE大鼠模型适用于 实验室地西泮和咪达唑仑的剂量相当于推荐的人体剂量，具有部分活性 在TETS SE模型中。然而，GABAA受体的阳性调节剂别孕烯醇酮具有上级 终止TETS诱导的行为和电图SE的活性，特别是当以 延迟时间在有效剂量下，别孕烯醇酮不会引起明显的镇静、运动障碍或 对血压或呼吸的不良影响。与其他类似的药物不同，别孕烯醇酮是独特的 适于通过自动注射器肌内给药。DFP诱导的SE不能被 苯并二氮杂卓或别孕烯醇酮。然而，perampanel（一种强效AMPA受体） 拮抗剂和别孕烯醇酮肌肉注射是非常有效的终止DFP- 诱发行为和电图SE。假设别孕烯醇酮和 perampanel将是一种有效和安全的“通用”化学威胁剂缉获治疗方法。在 拟议的研究，研究将进行所需的铅化合物别孕烯醇酮， 进入高级开发阶段，包括与标准治疗以及非人类 灵长类动物药代动力学和功效测试。将获得perampanel和 perampanel和别孕烯醇酮的组合。还将进行额外的抗癫痫试验 项目1中确定的药物，以确定它们是否上级候选治疗。疗效和安全性 将在雄性和雌性动物中进行试验，以评估性别差异;安全性试验将 在年轻和年老的动物中进行。项目3将确定候选抗炎治疗，以减轻 化学处理剂缉获的长期后果。项目2将评估这些治疗方法是否 与抗癫痫治疗相互作用。该项目的结果将允许铅化合物 别孕烯醇酮进入高级发育阶段，并评估perampanel或其他 候选的抗癫痫药物应该成为发展的先导。