Organophosphate Poisoning: A Method to Test Therapeutic Effects of Oximes other Than Acetylcholinesterase Reactivation in the Rat.

摘要

A method was developed to study exclusively 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 inhibition, did not result in any AChE reactivation. Anaesthetized, atropinized and artificially ventilated rats were intoxicated with 3xLD50 CRS and treated 5 minutes later with the bispyridinium oxime HI-6. Fifty percent of these animals survived more than 24 hours following termination of artificial ventilation at 10 minutes after oxime treatment. The mean survival time of the remaining animals was 66 minutes, whereas all untreated animals died with 4 minutes. HI-6, when added in vitro to isolated intact hemidiaphragms, or to diaphragm or brain homogenates from rats which had been sacrificed 1 minute following 3xLD50 CRS, failed to reactivate the inhibited AChE. If blood was sampled (before and) after HI-6 administration to CRS-intoxicated rats, no HI-6-induced AChE reactivation was observed. Yet, a clear improvement 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.