engleski

Characterizing the therapeutic efficacy of novel oximes synthesized by click chemistry against organophosphorous compounds poisoning

Accidental exposures but also threat of the abuse of organophosphorous compounds (OP) leads to search for more effective treatment regimens against these poisonings. Toxic action of OP, including pesticides and nerve agents, is primarily attributed to irreversible inhibition of acetylcholinesterase (AChE). AChE inhibition results in acetylcholine accumulation in the synaptic cleft with consequences to the central and peripheral nervous system. The current treatment of OP poisonings includes a combination of an antimuscarinic agent (atropine) and an AChE reactivator (oxime). Recently a series of oximes have been synthesized by the copper-catalyzed azide-alkyne cycloadition reaction. The purpose of this investigation was to evaluate the toxicity and protection against OP compounds poisoning provided by three of those oximes: JAR-2-28B, JAR-2-153 and JAR-1-81A (synthesis not yet published). The therapeutic effect of oximes in mice was tested by intraperitoneal administration of oxime (5 or 25% of its LD50) and atropine (10 mg/kg) one minute after OP (given subcutaneously). We used conventional oximes HI-6 and TMB-4 to compare JAR’s efficacy expressed as protective index (PI) and maximal dose of poison (MDP). Tested oximes showed high acute toxicity (8.4 to 26.7 mg/kg b.w.) which is in accordance with an approach for in situ design of high affinity ligands for AChE. Pronounced dose-response relationship was observed against all nerve agent poisoning. Considering tabun intoxication, JAR oximes showed lower therapeutic efficacy than TMB-4. The same stands for soman, sarin and VX poisoning forwhich HI-6 was superior as therapeutic agent. JAR oximes showed relatively good efficiency in therapy of paraoxon poisoned mice regardless the dose. Combined with atropine they ensured survival of all animals against 6.3 to 10.0 LD50 of paraoxon. Despite their high toxicity, JAR oximes were able to provide protection against the lethal effects of OP probably due to their ability to reactivate organophosphate-inhibited AChE.

JAR oximes; organophosphates; therapy

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