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:
- 金额:$ 65.98万
- 依托单位:
- 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:
- 关键词:Advanced DevelopmentAmidesAnatomyAnimal ModelAnimalsAutopsyBackBehavioralBenzodiazepinesBrainCardiotoxicityChemicalsChildCholinesterase InhibitorsChromosome abnormalityCognitiveDataData ElementData SetDevelopmentDiazepamDomestic PigDoseDrug KineticsElectrographic Status EpilepticusEnvironmentEpilepsyEvaluationExhibitsExposure toFemaleFormulationFree WillGoalsHumanIn VitroIndividualIntramuscularLaboratoriesLaboratory StudyLithiumMeasuresMedical ResearchMedical emergencyMidazolamModelingMusNeurological outcomeOrganic solvent productPediatricsPharmaceutical PreparationsPhysiologicalPilocarpinePlasmaPopulationProcessProduct ApprovalsProductionRattusResearchResearch InstituteResistanceRodentRouteSafetySamplingSarinSchemeSeizuresSomanSpecial PopulationStandardizationStatus EpilepticusStereoisomerTeratogensTest ResultTestingTherapeuticTimeToxicologyToxinUnited States Dept. of Health and Human ServicesUnited States National Institutes of HealthValproic Acidanimal ruleaqueouschemical threatdesignefficacy studyenantiomergamma-Aminobutyric Acidimmature animalimprovedin vitro testingin vivointerestintraperitonealmalemass casualtymedical countermeasurenerve agentneuroprotectionprogramssafety studysafety testingsexstability testingstandard of carestem cellstetramethylenedisulfotetramine
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/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承诺对当前的护理标准进行重大改进
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
由多种化学威胁剂引起。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
项目成果
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