Efficacy of Midazolam and Ketamine Combination Therapy over Midazolam Monotherapy against Soman Exposure in Carboxylesterase Knockout Mice
Abstract
Chemical warfare nerve agents (CWNAs) inhibit acetylcholinesterase (AChE), which leads to status epilepticus (SE), spontaneous recurrent seizures (SRS) and severe neuropathology when treatment is delayed. In addition to binding to AChE, some organophosphorus (OP) CWNAs such as soman (GD) also inhibit carboxylesterase (CaE), which acts as a bioscavenger and can thus reduce the severity of the toxicity of OP agent exposure. Unlike humans, rodents have plasma CaE activity. The CaE knockout (ES1−/−) mouse specifically lacks plasma CaE and might better model human GD exposure compared to wildtype rodents. Delayed treatment of CWNA‐induced SE with midazolam leads to benzodiazepine‐refractory SE. We evaluated combination therapy of midazolam and the NMDA antagonist ketamine in male and female mice for efficacy against soman‐induced lethality, SE and epileptogenesis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2019
- Source ID
- 10.1096/fasebj.2019.33.1_supplement.634.8
Entities
People
- Brenda Marrero‐rosado
- Caroline R. Schultz
- Erica Kundrick
- Katie Walker
- Lucille Lumley
- Marcio De Araujo Furtado
- Michael Stone
- Sean O'brien
Organizations
- Defense Threat Reduction Agency
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- Oak Ridge Institute for Science and Education
- United States Army Medical Research Institute of Chemical Defense