Dose-Response Effects of Atropine and Hi-6 Treatment of Organophosphorus Poisoning in Guinea Pigs

Abstract

HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine 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 ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. 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 the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against 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 enhanced the efficacy of HI-6 and atropine against soman. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating 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 is a useful adjunct to atropine and HI-6.

Investigation of oxidative stress in blood, brain, kidney, and liver after oxime antidote HI-6 application in a mouse experimental model

“…The maximal possible (i.e., safe) dose of oxime reactivator is recommended, for this reason, in any application to poisoned individuals (Bartosova et al 2006). However, it should be emphasized that the application of HI-6 as an antidote has only limited efficacy without the coapplication of atropine (Koplovitz et al 1995). We investigated the effect of HI-6 without any coapplication with atropine or diazepines, so the observed biological impacts could be attributed to HI-6 only.…”

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

“…Such an association between mortality and status epilepticus is well recognized in the clinical medical literamre (Shorvon, 1994;Towne et al, 1994;Krumholz et al, 1995). The fact that control of nerve agent seizures is so strongly linked to protection from the lethal effects of nerve agents may explain the requirement for the high doses of atropine that have been routinely used in studies of the protective effects of carbamate pretreatment (Berry and Davis, 1970;Dimhuber et al, 1979;Maxwell et al, 1988) or oxime therapies (Melchers et al, 1994;Worek and Szinicz, 1993;Worek et al, 1994;Koplovitz et al, 1995). These findings lend perspective to the older reports that inclusion of a benzodiazepine to standard atropine and oxime therapy would increase the protective ratios against OP nerve agent exposure (Rump et al, 1973;Johnson and Wilcox, 1975;Boskovic, 1981).…”

Proceedings of the 2001 ECBC Scientific Conference on Chemical and Biological Defense Research, 6-8 March 2001, Marriott's Hunt Valley Inn, Hunt Valley, MD

“…Such an association between mortality and status epilepticus is well recognized in the clinical medical literature (Towne et al 1994; Krumholz et al 1995). The fact that control of nerve agent seizures is so strongly linked to protection from the lethal effects of nerve agents may explain the requirement for such high doses of atropine that have been routinely used in studies of the protective effects of carbamate pretreatment (Dirnhuber et al 1979;Maxwell et al 1988) or oxime therapies (Melchers et al 1994;Worek et al 1994; Koplovitz et al 1995). These findings lend perspective to the older reports that inclusion of a benzodiazepine to standard atropine and oxime therapy would increase the protective ratios against OP nerve agent exposure (Johnson and Wilcox 1975;Boskovic 1981).…”