Abstract
Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The potency of trimedoxime and other commonly used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate tabun-inhibited acetylcholinesterase and to eliminate tabun-induced acute effects was evaluated using in vitro and in vivo methods. In vitro calculated kinetic parameters of reactivation of tabun-inhibited acetylcholinesterase from rat brain homogenate and in vivo determined percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats show that trimedoxime seems to be the most efficacious reactivator in the case of tabun poisonings. Trimedoxime was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in tabun-poisoned rats and mice. The oxime HI-6, so efficacious against soman, does not seem to be sufficiently effective oxime to reactivate tabun-inhibited acetylcholinesterase and to counteract acute lethal effects of tabun.
Highlights
The current standard treatment for poisoning with highly toxic organosphosphorus compounds called nerve agents usually consists of the combined administration of anticholinergic drugs and oximes
While anticholinergic drugs such as atropine are able to counteract the effects of tabun at peripheral cholinergic receptors[4], commonly used reactivators of phosphonylated AChE based on monopyridinium and bispyridinium oximes are not able to counteract the toxic effects of tabun because of very little reactivating efficacy[5]
The ability of tested oximes to reactivate tabun-inhibited AChE in vitro shown as the values of percentage of reactivation generally corresponds to the values of dissociation constant of enzyme-reactivator complex (K ), dissociation constant of enzyme-inhibitor-reactivadis tor complex (K ) and first-order rate constant (k )
Summary
The current standard treatment for poisoning with highly toxic organosphosphorus compounds called nerve agents usually consists of the combined administration of anticholinergic drugs (preferably atropine) and oximes (preferably pralidoxime or obidoxime). Tabun is probably one of the most dangerous compounds among nerve agents, since its deleterious effects are extraordinarily difficult to counteract because of the existence of a lone electron pair located on an amidic group that makes the nucleophilic attack almost impossible[2,3]. While anticholinergic drugs such as atropine are able to counteract the effects of tabun at peripheral cholinergic receptors[4], commonly used reactivators of phosphonylated AChE based on monopyridinium (e.g. pralidoxime) and bispyridinium oximes (e.g. obidoxime, methoxime) are not able to counteract the toxic effects of tabun because of very little reactivating efficacy[5]. One of the candidate for this replacement seems to be another bispyridinium oxime, trimedoxime, that does not belong to the commonly used oximes for the treatment of acute poisoning with nerve agents
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