Efficacy of a combination of acetylcholinesterase reactivators, HI-6 and obidoxime, against tabun and soman poisoning of mice

Abstract

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl)pyridinio)methoxy) methyl)-2-(hydroxyimino)methyl)pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime[1,1'-(oxy bis(methylene)) bis(4-(hydroxyimino)methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6 + 31.9 mg obidoxime against 1052 microns/kg obidoxime against 390 microns/kg challenge of soman).(ABSTRACT TRUNCATED AT 250 WORDS)

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…These results correspond to in vivo results from mice, rats and guinea-pigs published by several authors (4,18,25). It was found that the mixture of the oxime HI-6 and trimedoxime in the presence of atropine and diazepam ensures the higher degree of protection against poisoning by tabun, sarin and VX than the mixtures of HI-6 with pralidoxime or obidoxime (17).…”

Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice

“…In the cases of toxogonin and TMB-4, two of the most efficient oximes in the treatment of tabun poisoning (Clement 1983) there are two oxime groups in the 4 position; one in each of the pyridinium rings. However, it must be emphasized, especially in the case of HI-6, that the reactivation of tabun inhibited acetylcholinesterase does not seem to be a prerequisite for the therapeutic benefit of the oxime to be realized (Clement et al 1987). HI-6 was ineffective against tabun poisoning in mice (Clement 1983) and did not reactivate tabun inhibited acetylcholinesterase (Clement et al 1987).…”

In vivo experimental approach to treatment against tabun poisoning

“…Pyridinium compounds reversibly bind to the AChE active site and interfere with the binding of phosphorylating agents 11 . In the case of imminent threat of tabun exposure, pretreament should have an important role, because tabuninduced deleterious effects are extraordinarily difficult to counteract with currently used oximes 8,9,20,36 . In order to improve the efficacy of standard therapy, we determined the protective index of various combinations of atropine, oximes, and pyridostigmine given to mice before tabun poisoning.…”

“…Although the oxime TMB-4 reactivates tabun-inhibited AChE showing beneficial effects in tabun-poisoned animals [6][7][8] , it is the most toxic of the four most investigated oximes: 2-PAM (pralidoxime chloride), HI-6, obidoxime, and TMB-4 9 . Therefore, there is still a need to develop not only the most effective, but also the least toxic, organophosphate antidote.…”