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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.

项目总结