Novel pediatric anticonvulsants for nerve agents

用于神经毒剂的新型儿科抗惊厥药

• 批准号: 10004277
• 负责人: Doodipala Samba Reddy
• 金额: $ 75.6万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10004277
• 关键词: Acute; Address; Adult; Age; Amendment; Anticonvulsants; Antidotes; Atropine; Behavior; Benzodiazepines; Biological; Brain; Brain Injuries; Child; Childhood; Cholinergic Agents; Chronic; Clinical; Clinical Trials; Consultations; Data; Development; Dose; Drug Kinetics; Elderly; Electroencephalography; Epilepsy; Event; Exhibits; Exposure to; FDA approved; Female; Formulation; GABA-A Receptor; Glial Fibrillary Acidic Protein; Goals; Injections; Intoxication; Lead; Letters; Mediating; Memory; Metabolic; Midazolam; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurologic; Neurologic Dysfunctions; Neuronal Injury; Neurons; Neuroprotective Agents; Organophosphates; Outcome; Outcome Measure; Pathway interactions; Pesticides; Pharmaceutical Preparations; Phase; Pilot Projects; Population; Prevention; Protocols documentation; Rattus; Refractory; Regimen; Risk; Safety; Sarin; Schools; Seizures; Sex Differences; Soman; Status Epilepticus; Synapses; Testing; Therapeutic; Toxicokinetics; Treatment Effectiveness; Treatment Protocols; Validation; Work; aged; aging population; animal rule; attenuation; base; behavior test; cohort; design; efficacy testing; experimental study; ganaxolone; lead optimization; male; medical countermeasure; mortality; named group; nerve agent; neuroinflammation; neuropathology; neuroprotection; neurosteroids; neurotoxicity; novel; novel therapeutics; organophosphate poisoning; pesticide poisoning; prevent; primary outcome; programs; safety study; secondary outcome; sex; stem; success

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.

项目摘要 该项目的主要目的是开发一种神经固醇疗法，以减轻由癫痫发作和发病率。 儿童和老年人群中的神经剂和有机磷酸盐（OP）化合物。暴露于神经毒剂 或OP中毒会导致持续性癫痫发作，癫痫持续状态（SE）和严重的脑损伤。当前的 苯二氮卓抗惊厥药不能充分保护SE，持续30分钟或 明显的神经元损伤和死亡率更长。最近，神经类似于抗惊厥药 这可以有效控制成人模型中的癫痫发作和脑损伤。但是，孩子们和较早的 更容易受到神经毒性神经毒性的影响，但很少有医疗对策可用于 保护这些人群。该项目旨在通过优化针对特定的抗惊厥药来解决这一差距 神经剂阻止癫痫发作并防止小儿和老年人口的脑损伤。最近的研究 表明增强阶段性和突触外强调抑制的神经类固醇是强烈的抗惊厥药 神经剂引起的癫痫发作和脑损伤。暴露后神经类动物疗法已显示为 与咪达唑仑相比，在OP INTACTIC模型中，比咪达唑仑更有效。目的 该项目是为了确定合成神经类固醇甘氧酮（GX）的效率和安全性，为' 在小儿和老年模型中，频谱的抗惊厥药和OP侵入性。主 重点是针对小儿GX的效率优化，机制和安全验证 老鼠。该项目将针对三个具体目标：（目标1）：确定GX对DFP和SOMAN-的效率 小儿大鼠诱发癫痫发作和神经病理学； （AIM 2）：确定GX对DFP和DFP的效率 老年大鼠的Soman引起的癫痫发作和神经病理学； （目标3）：确定药代动力学和 GX在小儿和老年大鼠中的安全性概况，并根据动物规则途径准备预先申请。 进步的“ Go/no-Go”里程碑计划包括关注关注的关键研究成功的定量标准 在四项主要结果措施中：（i）抗惊厥效率； （ii）急性神经保护剂效率； （iii）预防 慢性神经变性和神经炎症； （iv）癫痫和长期神经系统的衰减 功能障碍。该项目成果的总体影响将很高，以开发救生 小儿和原始人口中的OP侵入药物的抗惊厥药，这是优先的平民治疗 反对程序的字段。