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.

Public Health Relevance

This research seeks to advance the development of (2S,3S)-sec-butylpropylacetamide [(2S,3S)-SPD],a treatment for nerve agent seizures, a medical emergency resulting from exposure to certain seizure -inducing chemical toxins that may be inadvertently or intentionally released into the environment. The new treament is expected to terminate seizures more effectively than the current standard-of-care, leading to improved neurological outcome and greater survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS112102-02
Application #
9991952
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jett, David A
Project Start
2019-08-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618