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Archives of Industrial Hygiene and Toxicology

The Journal of Institute for Medical Research and Occupational Health

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0004-1254
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Volume 60, Issue 1 (Mar 2009)

Issues

Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Zrinka Kovarik / Ana Vrdoljak / Suzana Berend / Maja Katalinić / Kamil Kuča
  • Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kamil Musilek
  • Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Božica Radić
Published Online: 2009-03-27 | DOI: https://doi.org/10.2478/10004-1254-60-2009-1890

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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About the article


Published Online: 2009-03-27

Published in Print: 2009-03-01


Citation Information: Archives of Industrial Hygiene and Toxicology, ISSN (Online) 0004-1254, DOI: https://doi.org/10.2478/10004-1254-60-2009-1890.

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