Atropine and/or Diazepam Therapy Protects against Soman-Induced Neural and Cardiac Pathology

Toxic doses of the organophosphonate anticholinesterase agentsoman can produce neural and cardiac lesions in animals thatsurvive the acute poisoning. The ability of two standard antidotedrugs, atropine and diazepam. along with the oxime pralidoxime(2-PAM) Cl, were evaluated for their ability to block thesepathological effects. Rats were challenged with a fixed dose(85 µkg, sc) of soman and treated im 5 min later with25 mg/kg 2-PAM CI and one of the following combinations of atropine(0.0, 1.0, 3.2, 10.0, or 32.0 mg/kg) and diazepam (0.0, 0.1,0.32, 1.0, or 3.2 mg/kg) in a balanced design. The severityof acute anticholinesterase intoxication signs was rated 1 hrafter exposure. My weights and behavioral reactivity ratingswere obtained daily for 16 days after exposure; brains and heartsof all surviving subjects were then evaluated for pathologicalchanges. Soman challenge resulted in 33% lethality in animalsthat received only 2-PAM therapy; both atropine and diazepamreduced lethality in a dose-dependent fashion. Across all treatmentconditions >50% of the deaths occurred later than 24 hr afterintoxication and treatment. Acute intoxication signs were differentiallymoderated by the two drugs. atropine reduced all six signs ina dose-dependent fashion; diazepam had no effect on lacrimationand eye bulb protrusion, antagonized signs of salivation andmotor abnormalities in a dose-dependent manner, and antagonizedthe effects of soman on signs of physical activity and coordinationonly at low doses. All doses of diazepam and the highest doseof atropine moderated body weight loss and a syndrome of behavioralhyperreactivity observed after exposure. Brain pathology wassignificantly reduced by all doses of diazepam and/or the highestdose of atropine, but no single drug or drug combination waseffective in protecting all animals in a group from some brainpathology. Both drugs blocked the development of cardiac lesionsin a dose-dependent fashion. The results demonstrate that diazepamor high doses of atropine can antagonize the development ofbrain lesions that result from soman exposure. Pharmacologicalmanagement of epileptiform motor abnormalities during the acuteintoxication is critical for this effect. In contrast, soman-inducedcardiac pathology may occur secondarily as a consequence ofthe severe brain lesions or develop independently of brain lesionformation due possibly to sympathetic overstimulation.