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Development of IM Formulation of (2S,3S)-SPD for Nerve Agent Seizures

用于神经毒剂癫痫发作的 (2S,3S)-SPD 肌内注射制剂的开发

基本信息

批准号：
10237326
负责人：
Meir Bialer
金额：
$ 65.98万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237326
关键词：
Advanced Development Amides Anatomy Animal Model Animals Autopsy Back Behavioral Benzodiazepines Brain Cardiotoxicity Chemicals Child Cholinesterase Inhibitors Chromosome abnormality Cognitive Data Data Element Data Set Development Diazepam Domestic Pig Dose Drug Kinetics Electrographic Status Epilepticus Environment Epilepsy Evaluation Exhibits Exposure to Female Formulation Free Will Goals Human In Vitro Individual Intramuscular Laboratories Laboratory Study Lithium Measures Medical Research Medical emergency Midazolam Modeling Mus Neurological outcome Organic solvent product Pediatrics Pharmaceutical Preparations Physiological Pilocarpine Plasma Population Process Product Approvals Production Rattus Research Research Institute Resistance Rodent Route Safety Sampling Sarin Scheme Seizures Soman Special Population Standardization Status Epilepticus Stereoisomer Teratogens Test Result Testing Therapeutic Time Toxicology Toxin United States Dept. of Health and Human Services United States National Institutes of Health Valproic Acid animal rule aqueous chemical threat design efficacy study enantiomer gamma-Aminobutyric Acid immature animal improved in vitro testing in vivo interest intraperitoneal male mass casualty medical countermeasure nerve agent neuroprotection programs safety study safety testing sex stability testing standard of care stem cells tetramethylenedisulfotetramine

项目摘要

Project Summary/Abstract This project seeks to advance the development of (2S,3S)-sec-butylpropylacetamide [(2S,3S)-SPD] for the treatment of chemical threat agent seizures. A priority of the NIH CounterACT Program is the development of medical countermeasures to treat seizures induced by anticholinesterase nerve agents such as soman and sarin or GABA-inhibiting agents such as tetramethylenedisulfotetramine (TETS). Benzodiazepines, the current standard-of-care therapies, fail to stop seizures induced by such agents when there is more than a brief delay between onset of seizures and administration of the treatment agent. In rodents, (2S,3S)-SPD is a broad- spectrum antiseizure agent that effectively stops benzodiazepine-resistant behavioral and electrographic status epilepticus in the lithium-pilocarpine model. Moreover, studies conducted at the U.S. Army Medical Research Institute of Chemical Defense indicate that (2S,3S)-SPD rapidly stops soman-induced benzodiazepine- resistant SE in rats at delayed time points, an effect not shared by benzodiazepines or other antiseizure drugs. Therefore, (2S,3S)-SPD has promise to provide a major improvement to the current standard-of-care for the treatment of nerve agent seizures. The objective of the proposed research is to generate the data required to advance the development of an intramuscular formulation (2S,3S)-SPD so that it is available as a medical countermeasure for nerve agent seizures in the setting of a civilian exposure. A scalable synthesis route for (2S,3S)-SPD will be developed. The API will be formulated in a solution designed for intramuscular administration, a “mass-casualty-friendly” route of delivery that offers fast onset of action. Initial toxicology and safety studies will be conducted in animals, including studies to assess safety in both males and females and in special populations such as children. Additional proof-of-concept and dose-ranging studies in relevant animal models will be conducted, including in a model of TETS-induced status epilepticus. The proposed research will assess the potential of (2S,3S)-SPD as an improved medical countermeasure to treat seizures induced by diverse chemical threat agents. On completion of the project, a comprehensive set of data will be available to advance the development of (2S,3S)-SPD as an improved treatment for chemical threat agent seizures.

项目总结/文摘