Toxicological considerations of acetylcholinesterase reactivators

The more or less systematic studies on the specific activity of oximes as reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds provide a panoramic image of their pharmacological and toxicological profiles. Established structure-activity relationships are still unable to adequately predict their antidotal efficacy. However, the in vivo behavior of oximes is a direct consequence of their physico-chemical properties, considerably limiting the passive transport across the biological barriers.

This paper discusses the efficacy of oximes from a biokinetic perspective. The non-homogenous distribution of oximes versus OP in tissues was considered and correlated with the highly variable AChE reactivation at both peripheral and central levels. The acute toxicity and formation of highly toxic phosphylated oximes are presented as possible sources for reduced therapeutic efficacy.

Biokinetic of oximes is 'structure dependent', with variable, tissue-specific distribution and activity. The existing knowledge does not allow to state true limits for a minimum extent of AChE reactivation in different tissues granting the survival of intoxicated organisms. An increased penetration of biological barriers is not automatically equivalent to a high extent of reactivation or antidotal efficacy and most probably, induces significant risks because of the intrinsic toxicity of the oxime.