Original scientific paper

https://doi.org/10.2478/10004-1254-60-2009-1890

Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Zrinka Kovarik orcid.org/0000-0001-9863-886X ; Institute for Medical Research and Occupational Health, Zagreb, Croatia
Ana Lucić Vrdoljak ; Institute for Medical Research and Occupational Health, Zagreb, Croatia
Suzana Berend orcid.org/0000-0002-7710-8250 ; Institute for Medical Research and Occupational Health, Zagreb, Croatia
Maja Katalinić orcid.org/0000-0001-7043-4291 ; Institute for Medical Research and Occupational Health, Zagreb, Croatia
Kamil Kuča orcid.org/0000-0001-9664-1109 ; Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic
Kamil Musilek orcid.org/0000-0002-7504-4062 ; Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic
Božica Radić ; Institute for Medical Research and Occupational Health, Zagreb, Croatia

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 (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.

Keywords

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

Hrčak ID:

34843

URI

https://hrcak.srce.hr/34843

Publication date:

27.3.2009.

Article data in other languages: croatian

Visits: 2.625 *