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.

项目摘要/摘要该项目旨在推进（2s，3s）-sec-butyl-propylacetamide [（2s，3s）-spd] 化学威胁剂癫痫发作的处理。 NIH抵抗计划的优先事项是开发治疗抗胆碱酯酶神经毒剂（例如索曼和索曼）和沙林或GABA抑制剂，例如四甲基二硫胺（TET）。苯二氮卓类药物，电流护理标准疗法，无法停止在短暂延迟不止的情况下引起的癫痫发作在癫痫发作和治疗剂的给药之间。在啮齿动物中，（2s，3s）-spd是一个宽阔的频谱抗性剂有效地阻止苯二氮卓类行为和电学状态锂 - 苯甲吡啶模型中的癫痫肽。此外，在美国陆军医学研究中进行的研究化学防御研究所表明，（2s，3s）-SPD迅速停止了Soman诱导的苯二氮卓类 - 在延迟时间点大鼠的抗性SE，苯二氮卓类药物或其他固定药物没有共同的作用。因此，（2s，3s）-SPD有望为当前护理标准提供重大改进神经剂癫痫发作的治疗。拟议研究的目的是生成所需的数据推进肌肉内公式（2s，3s）-SPD的开发，以便它可以作为医疗在平民暴露的情况下，神经毒剂癫痫发作的对策。可扩展的合成路线（2s，3s）-SPD将开发。 API将在设计用于肌内的溶液中配制行政管理，一种“大众友好型”的交付途径，提供了快速的行动。初始毒理学和安全研究将在动物中进行，包括评估男性和女性的安全性的研究以及在儿童等特殊人群中。相关的其他概念证明和剂量范围研究将进行动物模型，包括在TET诱导的癫痫持续状态模型中。提议研究将评估（2s，3s）-SPD的潜力，以改善治疗癫痫发作的医学对策由不同的化学威胁代理引起。项目完成后，将一组全面的数据可用于推动（2s，3s）-SPD的开发作为化学威胁剂的改进治疗方法癫痫发作。