Novel pediatric anticonvulsants for nerve agents

用于神经毒剂的新型儿科抗惊厥药

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目的主要目标是开发一种神经类固醇疗法，以减轻由癫痫引起的癫痫发作和发病率儿童和老年人接触神经毒剂和有机磷酸酯 (OP) 化合物。 OP 中毒可导致持续性癫痫发作、癫痫持续状态 (SE) 和严重脑损伤。苯二氮卓类抗惊厥药不能充分预防 SE（持续 30 分钟的长时间癫痫发作）或最近神经类固醇已被确定为抗惊厥药。可以有效控制成人模型中的 OP 癫痫发作和脑损伤，但儿童和老年人则不然。更容易受到神经毒剂神经毒性的影响，但很少有医疗对策可以该项目旨在通过优化特定的抗惊厥药物来弥补这一差距。神经毒剂可阻止儿童和老年人的癫痫发作并预防脑损伤。表明增强阶段性和突触外紧张性抑制的神经类固醇是强抗惊厥药神经毒剂暴露后治疗引起的癫痫发作和脑损伤已被证明。在OP中毒模型中比咪达唑仑更有效的抗惊厥和神经保护作用。该项目旨在确定合成神经类固醇加奈索酮 (GX) 作为“广泛用途”的功效和安全性。 Spectrum’ 抗惊厥剂，用于儿童和老年模型中的神经毒剂和 OP 中毒。重点关注 GX 在儿科中的 IND 功效优化、机制和安全性验证该项目将解决三个具体目标：（目标 1）：确定 GX 对 DFP- 和 Soman- 的功效。在儿科大鼠中诱发癫痫发作和神经病理学；（目标 2）：确定 GX 对 DFP- 和老年大鼠中索曼诱发的癫痫发作和神经病理学；以及（目标 3）：确定药代动力学和 GX 在儿科和老年大鼠中的安全性概况，并根据动物规则途径准备 IND 前申请。渐进的“进行/不进行”里程碑计划包括重点研究成功的量化标准四个主要结果指标：(i) 抗惊厥功效；(ii) 急性神经保护功效；(iii) 预防慢性神经退行性变和神经炎症；以及（iv）癫痫和长期神经系统疾病的减轻该项目成果的总体影响对于救生领域的发展将非常重要。用于治疗儿童和老年人 OP 中毒的抗惊厥药物，是高度优先的民用治疗药物 CounterACT 程序的字段。