title: Evaluation of oxime k203 as antidote in tabun poisoning.
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 (Ki = 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.
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia. zrinka.kovarik@imi.hr
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Ana Lucić
authors.initials: AL
authors.lastname: Vrdoljak
authors.forename: Suzana
authors.initials: S
authors.lastname: Berend
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuc
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Bozica
authors.initials: B
authors.lastname: Radić