title: Time-dependent reduction in the anticonvulsant effectiveness of diazepam against soman-induced seizures in guinea pigs.
abstract: Near-lethal exposure to nerve agents produces prolonged epileptiform seizures requiring the administration of benzodiazepine anticonvulsant drugs, such as diazepam. Clinically, benzodiazepines are reported to lose anticonvulsant effectiveness the greater the delay between seizure onset and benzodiazepine treatment. This time-dependent diminished effectiveness of diazepam was tested in the present study. Seizures elicited by the nerve agent, soman, were produced in guinea pigs instrumented to record brain electrocorticographic (ECoG) activity. Different groups of animals were administered 10 mg/kg, intramuscularly, of diazepam at 5, 40, 60, 80, or 160 minutes after the onset of seizure activity. There was a progressive loss in the anticonvulsant efficacy of diazepam as the treatment was delayed after seizure onset, but no differences in the time for diazepam to stop seizures. The results show a diminished ability of diazepam to stop nerve-agent-induced seizures the longer treatment is delayed.
authors.affiliation: Pharmacology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, USA. john.mcdonough1@us.army.mil
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: Joseph D
authors.initials: JD
authors.lastname: McMonagle
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity; D003975:Diazepam / Q000494:pharmacology*; D004569:Electroencephalography; D006168:Guinea Pigs; D008297:Male; D010865:Pilot Projects; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy*; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D012999:Soman; D003975:Diazepam