Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Zrinka Kovarik; Ana Vrdoljak; Suzana Berend; Maja Katalinić; Kamil Kuča; Kamil Musilek; Božica Radić

doi:10.2478/10004-1254-60-2009-1890

Abstract

We studied bispyridinium oxime K203 [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-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 efficient 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^-1) and BChE (K_i = 0.91 mmol L^-1), and exhibited its protective effect against phosphorylation of AChE by tabun in vitro. In vivo, a quarter of the LD₅₀ K203 dose insured survival of all mice after the application of as many as 8 LD₅₀ 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.

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Evaluation of Oxime K203 as Antidote in Tabun Poisoning

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