COMPARISON OF THE THERAPEUTIC EFFECTS AND PHARMACOKINETICS OF HI-6, HLO-7, HGG-12, HGG-42 AND OBIDOXIME FOLLOWING NON-REACTIVATABLE ACETYLCHOLINESTERASE INHIBITION IN RATS

The oximes HI-6, HLo-7, HGG-12, HGG-42 and obidoxime were used in a pr eviously developed rat model to evaluate the therapeutic effects of ox imes other than acetylcholinesterase (AChE) reactivation (so-called '' nonreactivating effects''). To test this anaesthetized, atropinized an d artificially ventilated rats (n = 8 or 16) were poisoned with a thre e times LD(50) dose of the potent AChE-inhibitor crotylsarin (CRS, i.v .). CRS-inhibited rat AChE dealkylates instantaneously, thereby exclud ing AChE reactivation by the oximes. Five minutes after poisoning the rats were treated (i.v.) with an oxime or saline and 10 min later arti ficial ventilation was terminated. Survival times were determined. Sal ine-treated animals died within 15 min. In comparison, treatment with HI-6, HLo-7, HGG-12, HGG 42 or obidoxime resulted in a significant pro longation of survival time. In the groups treated with HLo-7, HI-6 or HGG-12, 12-37% of the animals survived more than 24 h. It was investig ated whether differences in therapeutic effectiveness are caused by di fferences in pharmacokinetics of the oximes. The plasma half-lives of HI-6, HLo-7, HGG-12, HGG-42 and obidoxime amounted to 67, 63, 27, 55 a nd 179 min, respectively. At doses of 75 or 150 mu mol/kg, all oximes could be detected in brain and medulla oblongata in similar amounts (6 -10 nmol/g tissue). In vitro, all oximes were effective in restoring f ailure of neuromuscular transmission (NMT) caused by CRS, albeit with varying potency. All oximes bound with affinities in the micromolar ra nge to rat brain muscarinic receptors. The present results show that ( 1) prolongation of survival time following lethal intoxication with an organophosphate can be achieved by non-reactivating properties of the oximes and (2) the observed differences in a) pharmacokinetics, b) po tency to restore NMT and c) affinity for muscarinic receptors of the v arious oximes do not correlate with the observed differences in therap eutic effectiveness. Therefore, it is concluded that the prolongation of survival must be due to as yet undefined effects in the brain.