engleski

Antidotal efficacy of bis-pyridinium oxime K048 againsttabun poisoning

Acetylcholinesterase (AChE: EC 3.1.1.7.) is an extremely active enzyme necessary for terminating the action of acetylcholine in cholinergic synapses. Inhibition of AChE enzyme by organophosphorus compounds (pesticides, nerve agents in chemical warfare) leads to an accumulation of neurotransmitter acetylcholine (ACh) resulting in an over-stimulation of the whole cholinergic system. The clinical signs of AChE inhibition manifest as hypersalivation, lacrimation, diarrhoea, tremor, respiratory distress, convulsion and seizures. Together with atropine, pyridinium oximes are known to be successfully used to treat poisoning with many organophosphorus compounds. In this paper new bis-pyridinium oxime K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] was tested as potential antidote in vitro using human erythrocyte AChE inhibited by tabun and in vivo using tabun poisoned mice. Its antidotal effect was compared with TMB-4 [1, 3-bis (4-hydrxyiminomethylpyridinium) propane dibromide], which is the best-known antidote in tabun poisoning. K048 was poor inhibitor of human erythrocyte AChE in vitro (its IC50 value could not be determined). Its protective potency expressed as P50 was 3.3 x 10-3 M, and the reactivating potency (applied in final concentration of 1.4 x 10-3 M) was 98%. In all experiments on mice, oxime doses of ¼ or 5% of its LD50 were used for pre-treatment 15 minutes before tabun-intoxication and for treatment together with atropine one minute after tabun administration. The antidotal efficacy of tested compound was expressed as therapeutic factor (TF) and therapeutic dose (TD). The highest TF and TD (22.5 and 10.0, respectively) were obtained when K048 was used in dose of ¼ of its LD50 in both, pre-treatment and treatment with atropine. Herein we showed that already promising treatment in tabun poisoning by oximes and atropine could be improved if oximes are also used in pre-treatment. Low acute toxicity of K048 ; about three times lower than of TMB-4, makes it interesting for further investigation of tabun poisoning treatment. K048 may even provide a platform for further modifications and development of more potent protectors and reactivators in organophosphorus poisoning.

acetylcholinesterase; tabun; organophosphorus poisoning

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