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.

项目概要/摘要该项目旨在促进 (2S,3S)-仲丁基丙基乙酰胺 [(2S,3S)-SPD] 的开发，用于 NIH CounterACT 计划的首要任务是开发化学威胁制剂的缉获。治疗由抗胆碱酯酶神经毒剂（如梭曼和索曼）引起的癫痫发作的医疗对策沙林或 GABA 抑制剂，例如当前使用的四亚甲基二磺四胺 (TETS)。标准护理疗法，在超过短暂延迟的情况下无法阻止此类药物引起的癫痫发作在啮齿类动物中，（2S，3S）-SPD 是一种广泛的药物。光谱抗癫痫剂，可有效阻止苯二氮卓类耐药行为和电图状态此外，美国陆军医学研究中心进行的研究表明，锂-毛果芸香碱模型中的癫痫。化学防御研究所表明 (2S,3S)-SPD 能迅速阻止梭曼诱导的苯二氮卓类药物大鼠在延迟的时间点出现耐药 SE，这是苯二氮卓类药物或其他抗癫痫药物所不具有的效果。因此，(2S,3S)-SPD 有望为当前的护理标准提供重大改进。拟议研究的目的是生成治疗神经毒剂癫痫发作所需的数据。推进肌内制剂 (2S,3S)-SPD 的开发，使其可作为医疗用平民暴露情况下神经毒剂癫痫发作的对策。 (2S,3S)-SPD 将被配制为专为肌内注射而设计的解决方案。管理，一种“无大量伤亡”的给药途径，可提供快速起效的初步毒理学和作用。安全性研究将在动物身上进行，包括评估雄性和雌性安全性的研究在儿童等特殊人群中进行额外的概念验证和剂量范围研究。将建立动物模型，包括 TETS 诱导的癫痫持续状态模型。研究将评估 (2S,3S)-SPD 作为治疗癫痫发作的改进医学对策的潜力项目完成后，将获得一套全面的数据。可用于推进 (2S,3S)-SPD 的开发，作为化学威胁剂的改进处理方法癫痫发作。