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Archives of Industrial Hygiene and Toxicology

The Journal of Institute for Medical Research and Occupational Health

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Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Zrinka Kovarik1 / Ana Vrdoljak1 / Suzana Berend1 / Maja Katalinić1 / Kamil Kuč1 / Kamil Musilek1 / Božica Radić1

Institute for Medical Research and Occupational Health, Zagreb, Croatia1

Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic2

This content is open access.

Citation Information: Archives of Industrial Hygiene and Toxicology. Volume 60, Issue 1, Pages 19–26, ISSN (Print) 0004-1254, DOI: 10.2478/10004-1254-60-2009-1890, March 2009

Publication History

Published Online:
2009-03-27

Evaluation of Oxime K203 as Antidote in Tabun Poisoning

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 (Ki = 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.

Procjena oksima K203 kao antidota pri otrovanju tabunom

Proučavali smo bispiridinijski oksim K203 [(E)-1-(4-karbamilpiridinij)-4-(4-hidroksiiminometilpiridinij)-but-2-ene dibromid] u uvjetima in vitro - studirajući njegove interakcije s ljudskom acetilkolinesterazom (AChE) i butirilkolinesterazom (BChe) inhibiranim tabunom te u uvjetima in vivo - određivanjem njegova antidotskog učinka na miševe i štakore otrovane tabunom. Radi usporedbe uključili smo rezultate dobivene s oksimima K048 i TMB-4 kao najučinkovitijim oksimima kod otrovanja tabunom.

K203 je potpuno reaktivirao AChE inhibiranu tabunom sa sveukupnom brzinom reaktivacije od 1806 L mol-1 min-1 što ga svrstava u najučinkovitije reaktivatore AChE inhibirane tabunom. K203 je reverzibilno inhibirao AChE (Ki = 0,090 mmol L-1) i BChE (Ki = 0,91 mmol L-1) pokazujući svoja in vitro zaštitna svojstva od inhibicije tabunom. Terapija dozom K203 od 1/4 njegove LD50 omogućila je preživljavanje svih miševa nakon otrovanja dozom tabuna od 8,0 LD50. Time je K203 pokazao bolju učinkovitost u usporedbi s K048 ili TMB-4. K tome, K203 je značajno zaštitio štakore od otrovanja tabunom kompenzirajući toksični učinak tabuna na aktivnost kolinesteraze i do 60 min nakon trovanja. Pokazano poboljšanje terapeutske učinkovitosti K203 ističe ovaj oksim pretečom za daljnji razvoj antidota u otrovanju tabunom.

Keywords: acetylcholinesterase; bioscavenger; butyrylcholinesterase; K048; nerve agents; TMB-4; pyridinium oxime

Keywords: acetilkolinesteraza; butirilkolinesteraza; K048; TMB-4; piridinijski oksim; tabun; živčani bojni otrovi

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