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）并增加生存 暴露于癫痫发作引起的化学威胁药物。有两种主要的抽搐化学品 威胁剂：有机磷酸盐（OP）抗胆碱酯酶，包括SOMAN和二异丙氟磷酸盐 （DFP）和GABAA受体拮抗剂，包括四甲基二硫代氨基胺（TET）和picrototoxin。 当前的化学威胁剂护理水平治疗癫痫发作是苯二氮卓的地西epa，但 将来可能会使用苯二氮卓类咪达唑仑。这些代理无法终止化学威胁 代理在许多情况下诱发的SE，尤其是在暴露后延迟时间给药时， 而且它们无法有效防止癫痫发作诱导的脑损伤。在最初的项目期间，鼠标 开发了TET诱导的SE模型。此外，将DFP诱导的SE的大鼠模型改编为 实验室。地西epam和咪达唑仑的剂量等效于推荐的人剂量是部分活跃的 在TETS SE模型中。但是，GABAA受体的正调节剂Allopregnanolone具有优越性 在终止TET诱导的行为和电图SE中的活性，尤其是在A. 延迟时间。在有效剂量时，Allopregnanolone不会引起明显的镇静，运动障碍或 对血压或呼吸的不利影响。与其他类似的代理不同，Allopregnanolone是独特的 适用于通过自动注射器进行肌内给药。 DFP诱导的SE没有被终止 苯二氮卓类药物或异烷醇。但是，Perampanel（潜在的AMPA接收器）的组合 拮抗剂和肌内施用的异烷酮在终止DFP-方面非常有效 诱发行为和电视SE。假设Allopregnanolone和 Perampanel将代表对化学威胁剂癫痫发作的有效且安全的“普遍”处理。在 拟议的研究将进行研究，这些研究是铅化合物异源龙酮所必需的 输入高级开发，包括与标准疗法以及非人类的研究 灵长类动力学和有效测试。将获得Perampanel和Perampanel的概念证明数据 Perampanel和Allopregnanolone的组合。还将进行额外的抗原 项目1中确定的代理人确定它们是否优于候选治疗方法。功效和安全性 将在男性和雌性动物中进行测试以评估性别差异；安全测试将是 在年轻动物和老年动物中进行。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 与抗性治疗相互作用。该项目的结果将允许铅化合物 分型allopregnanolone进入高级发展，并评估Perampanel还是其他 候选动力剂应成为发展潜在客户。