Journal
ARHIV ZA HIGIJENU RADA I TOKSIKOLOGIJU-ARCHIVES OF INDUSTRIAL HYGIENE AND TOXICOLOGY
Volume 60, Issue 1, Pages 19-26Publisher
INST MEDICAL RESEARCH & OCCUPATIONAL HEALTH
DOI: 10.2478/10004-1254-60-2009-1890
Keywords
acetylcholinesterase; bioscavenger; butyrylcholinesterase; K048; nerve agents; TMB-4; pyridinium oxime
Funding
- Ministry of Science, Education and Sports of the Republic of Croatia [022-0222148-2889, 022-0222148-2139]
- NATO [CBP.EAP.RIG.981791, CBP.EAP.CLG 983024]
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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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