Comparison of the therapeutic effects and pharmacokinetics of HI-6, HLö-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 previously developed rat model to evaluate the therapeutic effects of oximes other than acetylcholinesterase (AChE) reactivation (so-called “nonreactivating effects”). To test this, anaesthetized, atropinized and artificially ventilated rats (n=8 or 16) were poisoned with a three times LD50 dose of the potent AChE-inhibitor crotylsarin (CRS, i.v.). CRS-inhibited rat AChE reactivation by the oximes. Five minutes after poisoning the rats were treated (i.v.) with an oxime or saline and 10 min later artificial ventilation was terminated. Survival times were determined. Saline-treated animals died within 15 min. In comparison, treatment with HI-6, HLo-7, HGG-12, HGG-42 or obidoxine resulted in a significant prolongation 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 investigated whether differences 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 and 179 min, respectively. At doses of 75 or 150 μmol/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 failure of neuromuscular transmission (NMT) caused by CRS, albeit with varying potency. All oximes bound with affinities in the micromolar range 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) potency to restore NMT and c) affinity for muscarinic receptors of the various oximes do not correlate with the observed differences in therapeutic effectiveness. There-force, it is concluded that the prolongation of survival must be due to as yet undefined effects in the brain.