Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

Abstract

Highly toxic organophosphorus-type (OP) chemical warfare agents (nerve agents) and OP pesticides may be used by terrorists and during military conflicts emphasizing the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators (oximes) is considered to be ineffective with certain nerve agents due to low oxime efficacy. Despite research over decades none of the oximes has turned out to be a broad spectrum reactivator to cover the whole range of potential threat agents. The prospective oxime HI 6 is a weak reactivator of tabun- and pesticide-inhibited AChE, while the established oxime obidoxime mainly lacks efficacy with cyclosarin-inhibited enzyme. In order to investigate the feasibility of combining obidoxime and HI 6, human AChE inhibited by sarin, cyclosarin, VX, tabun and paraoxon was reactivated by these oximes either alone or in combination. Two major findings of this study were that a combination of HI 6 and obidoxime did not impair reactivation, compared with HI 6 or obidoxime alone, but broadened the spectrum compared with the individual oximes. By using different oxime concentrations a combination of oxime doses may be suggested which could be an alternative to individual obidoxime or HI 6 autoinjectors.

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

“…In vitro evaluation of the potency of the combination of two oximes to reactivate nerve agents inhibited AChE showed that combining two oximes had no negative effects on the reactivation of nerve agent-inhibited AChE and, in addition, it had a beneficial effects by broadening the spectrum of the individual oximes (38). 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). The beneficial effects of the combination of oximes compared to a single oxime treatment in reactivating nerve agent-inhibited AChE could be explained by an elevated plasma oxime level and synergetic effects of both oximes (38). Nevertheless, our results demonstrate that the combination of the oxime HI-6 with trimedoxime or K203 did not bring any beneficial effect for the potency of single oximes (HI-6, trimedoxime, K203) to reduce acute neurotoxic effects of cyclosarin.…”

Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

“…Nowadays, several scientists re-open this approach. However, there will be probably problem with licensing of such antidotal mixture consisting of two compounds 38 .…”

Design, evaluation and structure—Activity relationship studies of the AChE reactivators against organophosphorus pesticides

“…The combination of these two oximes did not impair the reactivation, but broadened the spectrum when compared with the individual oximes. 51 Jun et al tested 1-5 on erythrocyte AChE and plasma BChE inhibited by POX. The compounds 3-4 were suggested as the only oximes able to reactivate POX-inhibited AChE.…”