DOSE-RESPONSE EFFECTS OF ATROPINE AND HI-6 TREATMENT OF ORGANOPHOSPHORUS POISONING IN GUINEA-PIGS

HI-6 1-pyridino-3-(4-carbamoyl-1-pyridino)-2-oxapropane dichloride) ha s been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (Op) poisoning. The dose respons e effects of atropine (ATR) and HI-6 were investigated to more fully e xplore the interaction of these compounds in the treatment of OP poiso ning. ATR, HI-6 and various combinations of the two drugs were evaluat ed against lethal poisoning by soman (GD) and tabun (GA) in guinea pig s. The effect of adjunctive diazepam treattment on the efficacy of atr opine and HI-6 against soman was also investigated.. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with AT R and/or HI-6. When used, diazepam was injected immediately after ATRHI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing th e nerve agent LD50 in the presence of treatment by the LD50 in the abs ence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective tha n HI-6 alone and was significantly more effective against soman than a gainst tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanc ed the efficacy of HI-6 and atropine against soman. It is concluded th at 1) ATR has a large effect on the efficacy of HI-6 against OP poison ing, 2) the dose of AIR must be carefully selected in studies investig ating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam i s a useful adjunct to atropine and HI-6.