Organophosphate poisoning: a method to test therapeutic effects of oxamines other than acetylcholinesterase activation in the rat

Abstract

A method was developed to study exlusively those therapeutic effects of oximes that are not related to reactivation of organophosphate-inhibited acetylcholinesterase (AChE). The model uses the organophosphorus compound crotylsarin (CRS), which proved to be a potent, irreversible, peripherally and centrally active AChE inhibitor with a very short biological half-life. CRS inhibited AChE appeared to age very rapidly, because in vitro addition of oximes immediately following inbition, did not result in any AChE reactivation. Anesthetized, atropinized and artificially ventilated rats were intoxicated with 3 × LD 50 CRS and treated 5 min later with the bipysridinuime HI-6. Fifty percent of these animals survived more than 24 h following termination of artificial ventilation at 10 min after oxime treatment. The mean survival time of the remaining was 66 min, whereas all untreated animals died within 4 min HI-6, when added in vitro to isolated intact hemidiaphragms of brain homogenates from rat which had been killed 1 min following 3 × LD 50 CRS, failed to reactive the inhibited AChE. If blood was sampled (before and) after HI-6 administration to CRS-intoxicated rats. no HI-6 induced AChE ractviation was observed. Yet, a clear improvement of molecular of the neuromuscular transmission in the hindleg muscles of these animals was found following HI-6 injection. With this model, decisive evidence is obtained that non-reactivating effects of HI-6 by themselves are therapeutically relevant.