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Intramuscular diazepam pharmacokinetics in soman‐exposed guinea pigs
Author(s) -
Capacio B. R.,
Whalley C. E.,
Byers C. E.,
McDonough J. H.
Publication year - 2001
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.813
Subject(s) - diazepam , pharmacokinetics , anticonvulsant , cmax , soman , pharmacology , convulsion , chemistry , anesthesia , medicine , epilepsy , acetylcholinesterase , biochemistry , psychiatry , enzyme
Abstract Intramuscular (i.m.) diazepam is included by the US military as an anticonvulsant in the standard therapeutic regimen for organophosphorus nerve agent intoxication. In this study we investigated the pharmacokinetics of diazepam after i.m. administration while monitoring pharmacodynamic (electroencephalogram, EEG) data in soman‐exposed guinea pigs. Prior to experiments the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered pyridostigmine (0.026 mg kg −1 i.m.) 30 min prior to soman (56 µg kg −1 , 2 × LD 50 ; subcutaneously, s.c.), which was followed in 1 min by atropine sulfate (2 mg kg −1 i.m.) and pralidoxime chloride (25 mg kg −1 i.m.). All animals receiving this regimen developed seizure activity. Diazepam (10 mg kg −1 i.m.) was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure terminated or not terminated at 30 min after diazepam. Serial blood samples were obtained from each animal. Diazepam (10 mg kg −1 i.m.) terminated seizure activity in 52% of the animals within 30 min. The pharmacokinetics were characterized by a one‐compartment model with first‐order absorption and elimination. The maximum plasma concentrations ( C max ) were 991 and 839 ng ml −1 for seizure terminated and not terminated, respectively. Mean plasma concentrations of diazepam were significantly different ( P < 0.05) for seizure terminated vs not terminated groups at 30 min. The plasma C max in seizure‐terminated animals in this study is similar to the minimum range of plasma diazepam (200–800 ng ml −1 ) reported to suppress seizure activity in humans. It has been reported in an earlier study that the minimum effective i.m. dose (0.1 mg kg −1 ) required to prevent soman‐induced convulsions in Rhesus monkeys produces a mean C max of 50 ng ml −1 for diazepam. The data from our current study suggest that a higher dose (and corresponding C max ) is necessary to terminate ongoing seizure activity. Copyright © 2001 John Wiley & Sons, Ltd.