engleski

Pharmacological analysis of centrally active oxime for nerve agent poisoning

Oximes are a class of compounds used as antidotes following poisoning with organophosphorus (OP ; e.g., nerve agents) compounds that act as irreversible inhibitors of acetylcholinesterase (AChE) and lead to cholinergic crisis due to acetylcholine (ACh) accumulation and overstimulation of ACh receptors. A class of neutral oximes, 3- hydroxy-2- pyridine aldoximes, was synthesized and their in vitro reactivation potential for AChE inhibited by five different OPs was analyzed, as were the physicochemical properties important for blood-brain barrier penetration.a This study extended our investigation and determined their lipophilicity and acid-base character, metabolic stability and cytotoxicity. The lead oxime, 3-hydroxy-6-(4- morpholinobutyl)picolinaldehyde oxime (JR595), with high reactivation potential, metabolic stability, and low cytotoxicity was tested further. It was shown to be a highly permeable compound and not a P-glycoprotein efflux pump substrate. Pharmacokinetic study in mice showed relatively fast absorption of JR595 into blood after its i.m. administration, but also a fast distribution-elimination phase. Maximal brain concentrations of JR595 were 40 % of the corresponding blood concentrations and were achieved 15 minutes post-application. JR595 with atropine was also tested as post-exposure therapy in VX- and sarin-exposed mice. It showed protection against multiple LD50 doses of nerve agents, and it was better than protection with 2-PAM, while comparable to HI- 6. Still, JR595 has limited antidotal effect due to short circulation time, but an improved outcome could be achieved with repeated administration of the oxime. In conclusion, the development of new antidotes should focus on achieving reactivation in both the central nervous system and periphery, while their flawed pharmacokinetic profile could be overcome by changing the delivery methods and dosage regime.

organophosphorous compounds ; pharmacology ; antidote ; acetylcholinesterase reactivator ; centrally active

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