Experimental Therapeutics Against the Toxic and Lethal Effects Resulting from Acute Exposure to Nerve Agents Without Carbamate Pretreatment in Guinea Pigs

Our current countermeasure against nerve agent poisoning involves carbamate pretreatment followed by a post-exposure therapy (atropine and oxime). For military/civilian populations not enrolled in the carbamate pretreatment program, atropine and oxime may not offer adequate protection against the toxic/lethal effects of nerve agents. To reduce the reliance on carbamate pretreatment, we have developed a post-exposure therapy mix that can protect against the lethal effect of a 2xLD50 dose of tabun, sarin, soman, cyclo-sarin or VX. Guinea pigs chronically instrumented for concurrent recordings of EEG, cardiorespiratory activities, diaphragm and skeletal muscle EMG were used in this study. The post-exposure therapy mix consisted of scopolamine (0.5 mg/kg), methylatropine (2 mg/kg), physostigmine (0.015 mg/kg), MMB4 (26.1 mg/kg), and phenobarbital (25 mg/kg). Results showed that only mild and short-lasting acute cholinergic effects (salivation, dystonia, tremor) were seen after exposure/therapy. During convalescence, none of the animals exhibited seizures/convulsions, signs of anomalous cardiorespiratory activities, or any debilitating effects. The animals were asymptomatic within 30 min following therapy and survived the agent challenge 24 hr later. In conclusion, the therapy mix used in this study was effective not only in antagonizing nerve agent-induced lethality, but also in protecting the functional integrity of the CNS and cardiorespiratory system. The original document contains color images.This research was supported by the Defense Threat Reduction Agency - Joint Science and Technology Office, Medical S&T Division. RDT&E activity 6.2.