engleski

3-hydroxypyridine aldoximes as efficient uncharged reactivators against organophosphorus nerve agents poisoning

Poisoning by organophosphorus nerve agents (OPNAs) and pesticides is a serious public and military health issue with over 260 fatalities annually wordwide. The acute toxicity of OPNAs results from the irreverisible inhibition of acetylcholinesterase (AChE), which regulates cholinesrgic transmission in the peripheral and in the central nervous system (CNS) by hydrolyzing acetylcholine.Conventional emergency treatment of OPNA poisoning consists of rapid administration of pyridinium oxime antidotes for reactivation of AChE and neuroprotection. However, the reactivation of central AChE is still inefficient due to the fact that positively charged pyridiniums do not cross, or only very poorly the brain blood barrier (BBB). Moreover pyridinium(s) oximes exhibit a quite narrow spectrum of reactivation. Despite decades of research in this field, there are no efficient and general broad-spectrum reactivators for OP-inhibited AChE. As a consequece, remediation of both acute and chronic intoxications of civilian and military population by organophosphorus nerve agents continues to be a challenge of paramount importance. In this context, we have developed families of new uncharged reactivators of OP-inhibited acetylcholinesterases and/or OP-inhibited butyrylcholinesterase able to cross the BBB. These compounds display in vitro reactivation potencies toward VX-, tabun- and paraoxon.inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes (e.g. 2-PAM, HI-6, obidoxime, HLo-7, TMB-4) currently used against nerve agent and pesticide poisoning. Furthermore, these uncharged compounds exhibit a broader reactivity spectrum compared to currently approved remediation drugs.

nerve agents ; reactivators ; acetylcholinesterase

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