title: Pharmacological antagonism of lethal effects induced by O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate.
abstract: O-Isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate (VR) is a structural isomer of a more widely known chemical warfare agent O-ethyl S-[2(diisopropylamino)ethyl]methylphosphonothioate (VX). VR has the potential of being used as military threat/sabotage/terrorist agent. The development of a sound medical countermeasure will undoubtedly enhance not only our medical readiness and ability in VR casualty management, but also our defense posture against the deployment of VR in both combat and politically volatile environments. Acute exposure to a lethal dose of VR has been shown to cause cholinergic hyperfunction, incapacitation, seizures, convulsions, cardiorespiratory depression and death. In this study, pharmacological antagonism of VR-induced cardiorespiratory failure and lethality was investigated in guinea pigs chronically instrumented for concurrent recordings of electrocorticogram, diaphragmatic EMG, Lead II ECG, heart rate and neck skeletal muscle EMG. Thirty (30) min prior to intoxication with a 2 x LD50 dose of VR (22.6 micrograms/kg, s.c.), animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.). Immediately after VR intoxication, animals were given pralidoxime chloride (2-PAM; 25 mg/kg, i.m.) and atropine sulfate (2, 8 or 16 mg/kg, i.m.). In animals that displayed seizures and convulsions, diazepam (5 mg/kg, i.m.) was administered 10 min following the onset of epileptiform activities. Responses to pretreatment/therapy modality were evaluated at 24 h post-VR. All animals survived the 2 x LD50 VR challenge. With the exception of an increased heart rate in response to atropine, the myocardial and diaphragmatic (respiratory) activity profiles appeared normal throughout the course of intoxication and recovery. Animals receiving 2 mg/kg atropine all developed fasciculations, seizures, signs of excessive mucoid/salivary secretion, and needed diazepam adjunct therapy. One-half (50%) of the animals receiving 8 mg/kg atropine developed seizure activities and were given diazepam, whereas the other half only showed a brief period of increase in CNS excitability. No fasciculations, seizures or convulsions were noted in animals receiving 16 mg/kg atropine. In summary, although lethality can be prevented with the pretreatment/therapy modality containing 2 mg/kg atropine and diazepam adjunct, a complete CNS and cardiorespiratory recovery from 2 x LD50 of VR requires a minimum of 8 mg/kg atropine.
authors.affiliation: Applied Pharmacology Branch, Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, USA.
authors.forename: F C T
authors.initials: FC
authors.lastname: Chang
authors.forename: B E
authors.initials: BE
authors.lastname: Hoffman
authors.forename: S
authors.initials: S
authors.lastname: DeBus
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology*; D004562:Electrocardiography; D004576:Electromyography; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007536:Isomerism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D012119:Respiration / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D009946:Organothiophosphorus Compounds; C009896:2-isopropyl-S-(2-diisopropylaminoethyl)methylthiophosphonate; D001285:Atropine; D003975:Diazepam