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

项目总结/摘要 本项目旨在推进（2S，3S）-仲丁基丙基乙酰胺[（2S，3S）-SPD]的开发， 治疗化学威胁剂癫痫发作。NIH CounterACT计划的一个优先事项是开发 治疗由抗胆碱酯酶神经剂如梭曼和 沙林或GABA抑制剂，如四亚甲基二磺基四胺（TETS）。苯二氮卓类，目前 标准护理疗法，当存在超过短暂的延迟时，不能阻止由这些药物诱导的癫痫发作 在癫痫发作和治疗剂给药之间。在啮齿类动物中，（2S，3S）-SPD是一种广泛的- 有效阻止苯二氮卓类耐药性行为和电描记状态的光谱抗癫痫药 锂-匹罗卡品模型中的癫痫。此外，美国陆军医学研究所进行的研究表明， 化学防御研究所的研究表明，（2S，3S）-SPD可迅速阻止梭曼诱导的苯二氮卓类药物- 在延迟的时间点，大鼠对SE耐药，苯二氮卓类药物或其他抗癫痫药物不具有这种作用。 因此，（2S，3S）-SPD有望为目前的护理标准提供重大改进， 神经毒剂癫痫的治疗拟议研究的目的是生成所需的数据， 推进肌内制剂（2S，3S）-SPD的开发，使其可用作医疗 在平民暴露的情况下缴获神经毒剂的对策。可扩展的合成路线， (2S，3S）-SPD将被开发。API将配制成用于肌内给药的溶液。 这是一种"对大规模伤亡友好"的交付途径，提供了快速的行动开始。初步毒理学和 将在动物中进行安全性研究，包括评估雄性和雌性动物安全性的研究， 特殊人群，如儿童。相关研究中的其他概念验证和剂量范围研究 将进行动物模型，包括TETS诱导的癫痫持续状态模型。拟议 研究将评估（2S，3S）-SPD作为治疗癫痫发作的改进医疗对策的潜力 是由多种化学威胁物引起的项目完成后，将提供一套全面的数据， 可用于推进（2S，3S）-SPD作为化学威胁剂的改进处理的开发 癫痫发作

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.