engleski

Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning

Organophosphorous compounds (OP) are widely used in agriculture and in public health, but also developed as nerve warfare agents. The mechanism of OP poisoning involves phosphorylation of the serine hydroxyl group in the active site of acetylcholinesterase (AChE) leading to the inactivation of this essential enzyme which has an important role in neurotransmission. 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 OP poisoning. The use of organophosphorous pesticides as highly toxic compounds is restricted in most parts of the world. Despite regulatory efforts some of them like parathion are still widely (mis)used. Paraoxon, the active metabolite of the insecticide parathion, is one of the most potent acetylcholinesterase-inhibiting compounds available. The present study was performed to assess and compare a therapeutic efficacy of six experimental bispyridinium oximes (K027, K033, K048, K074, K075 and K203) combined with atropine in paraoxon-poisoned mice. Currently used oximes HI-6 and TMB-4 were included for comparison. The studied oximes (5% or 25% of their LD50) plus atropine (10 mg/kg) were given intraperitoneally one minute after paraoxon (given subcutaneously). Their therapeutic efficacywasexpressed as protective index (PI) and maximal dose of poison (MDP). Except K033, all experimental oximes showed better antidotal activity than HI-6 and TMB-4 in paraoxon-poisoned mice. Doseresponse relationship was obtained for oximes K074, K075 and K203. Considering the lower dose K027 and K048 were the mostpotent against paraoxon intoxication, while from the point of acute toxicity the most effective were K075 and K203. Convenient stereochemical arrangements (functional aldoxime group at position four ; propane-, butane- or butene-like linker) along with excellent results of this study are in agreement with already shown reactivating potency of these oximes.

Bispyridinium oximes; paraoxon; therapy

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