engleski

Evaluation of oxime K203 as antidote in tabun poisoning

We studied the interaction of 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 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. The main reason for K203's advantage over K048 and TMB-4 is its combination of a higher affinity for phosphorylated AChE and the fast rate of the nuchleophilic displacement of the phosphoryl-moiety from the active site serine. 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 (TD=5.0). 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.

acetylcholinesterase; butyrylcholinesterase; nerve agents; pyridinium oxime; tabun; antidote; bioscavenger

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