Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Abstract

We studied bispyridinium oxime K203 [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyimino methylpyridinium)-but-2-ene dibromide] with tabun-inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and its antidotal effect on tabun-poisoned mice and rats in vivo. We compared it with oximes K048 and TMB-4, which have proven the most effi cient oxime antidotes in tabun poisoning by now. Tabun-inhibited AChE was completely reactivated by K203, with the overall reactivation rate constant of 1806 L mol -1 min -1 . This means that K203 is a very potent reactivator of tabun-inhibited AChE. In addition, K203 reversibly inhibited AChE (K i = 0.090 mmol L ), and exhibited its protective effect against phosphorylation of AChE by tabun in vitro. In vivo, a quarter of the LD 50 K203 dose insured survival of all mice after the application of as many as 8 LD 50 doses of tabun, which is the highest dosage obtained compared to K048 and TMB-4. Moreover, K203 showed high therapeutic potency in tabun-poisoned rats, preserving cholinesterase activity in rat plasma up to 60 min after poisoning. This therapeutic improvement obtained by K203 in tabun-poisoning places this oxime in the spotlight for further development.

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

“…Structurally, they are bispyridinium oximes that differ in the length of the connection chain between two pyridinium rings, the position of the oxime group, and the number of oxime groups in a molecule. Promising results using several of the previously mentioned oximes were obtained for poisoning by the nerve agent tabun, as well as in the case of pesticide poisoning (8,14,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Although the use of OP pesticides is under restriction in most parts of the world, especially in developed countries, some, such as parathion, are still widely (mis)used (30).…”

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…Therefore, the second oxime, involved into the combination, should be the oxime sufficiently effective against tabun. For our experiments, trimedoxime or the oxime K203 was chosen because trimedoxime has at least some effect against tabun-inhibited AChE (13) and the oxime K203 was found to be a promising oxime against tabun (11,19,30).…”

“…Recently, the oxime K203 [1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide] was synthesized at our Department of Toxicology (30) and its pharmacokinetics was studied (7). Based on in vitro and in vivo evaluation of its reactivating, therapeutic and neuroprotective efficacy, it was considered to be the promising oxime against tabun but not against cyclosarin and soman (11,12,14,15,16,19).…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…Firstly, their acute toxicity was found lower than toxicity of trimedoxime or obidoxime in mice and rats (Table 4; Calic 2006, Lorke 2008, Kovarik 2009, Musilek 2010. Whereas reactivator K048 was only slightly less toxic than obidoxime, compound K027 was found to be less or comparable toxic with methoxime or asoxime that are the least toxic commercial reactivators ( Table 2).…”