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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：
10693904
负责人：
Doodipala Samba Reddy
金额：
$ 73.44万
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/10693904
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 Epilepsy Event Exhibits Exposure to FDA approved Female Formulation GABA-A Receptor Glial Fibrillary Acidic Protein Goals Injections Intoxication Lead Letters Life 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 Predisposition Prevention Protocols documentation Rattus Refractory Regimen Risk Safety Sarin Schools Seizures Sex Differences Soman Special Population Status Epilepticus Synapses Testing Therapeutic Toxicokinetics Treatment Effectiveness Treatment Protocols Validation Work aged aging population animal rule attenuation behavior test cohort design efficacy evaluation efficacy testing efficacy validation experimental study ganaxolone lead optimization male medical countermeasure mortality 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.

项目摘要该项目的主要目标是开发一种神经类固醇疗法，以减轻癫痫发作和发病率所造成的神经毒剂和有机磷化合物。暴露于神经毒剂或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。电流苯二氮卓类抗惊厥药不能充分保护SE，持续30分钟的长时间癫痫发作活动或神经元损伤和死亡的时间更长。最近神经类固醇已被确定为抗惊厥药能有效控制成人模型OP发作和脑损伤。然而，儿童和老人更容易受到神经毒剂的神经毒性，但很少有医疗对策，保护这些人口。该项目旨在通过优化一种特定的抗惊厥剂来解决这一差距，神经毒剂，以阻止癫痫发作，并防止儿童和老年人的脑损伤。最近的研究表明，神经类固醇，增强阶段性和突触外紧张性抑制是强大的抗惊厥药，神经毒剂引起的癫痫和脑损伤暴露后神经类固醇治疗已被证明是在OP中毒模型中，比咪达唑仑更有效的抗惊厥和神经保护剂。的目标该项目是为了确定合成神经类固醇加奈索酮（GX）的有效性和安全性， Spectrum抗惊厥药用于儿童和老年模型神经毒剂和OP中毒。主要重点关注IND使GX在儿科中的疗效优化、机制和安全性验证大鼠该项目将解决三个具体目标：（目标1）：确定GX对DFP和梭曼的疗效，目的2：确定GX对DFP-和DFP-的有效性，梭曼诱导的老年大鼠癫痫发作和神经病理学;以及（目的3）：确定药物动力学和 GX在儿童和老年大鼠中的安全性特征，并根据动物规则途径准备IND前申请。渐进式“进行/不进行”里程碑计划包括关键研究成功的量化标准，四个主要结局指标：（i）抗惊厥疗效;（ii）急性神经保护剂疗效;（iii）预防慢性神经变性和神经炎症;和（iv）癫痫和长期神经系统疾病的衰减功能障碍该项目成果的总体影响将对发展救生事业产生很大影响抗惊厥药物OP中毒的儿童和老年人的人口，这是一个高度优先的民用治疗 CounterACT计划的一部分。