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Pharmacodynamic and pharmacokinetic evaluation of morpholine-3-hydroxy-2-pyridine oxime, centrally active antidote for nerve agent poisoning

A new class of 3-hydroxy-2-pyridine oxime compounds has been recently promoted as centrally active antidotes in organophosphate (OP) poisoning, which includes poisoning with OP pesticides (e.g., parathion) or chemical attacks with nerve agents (e.g., sarin, cyclosarin, VX, tabun). Efficient in vitro reactivation of OP-inhibited human AChE (hAChE) was achieved with several new oximes, 1 but morpholine-3-hydroxy-2-pyridine oxime (JR595) was singled out for further investigation of pharmacokinetic (PK) characteristics. Experimentally determined lipophilic coefficient (Chrom logD7.4) and MDCKII-MDR1 cell line test suggested good biodistribution of JR595, most importantly – distribution into the central nervous system without its efflux by P-glycoprotein pump. Moreover, metabolic stability of JR595 was proven in vitro by incubation with both human and mouse liver microsomes, representing the metabolism with cytochrome P450 enzymes. Finally, PK profile was investigated in mice after i.m. application of JR595 in a dose of 100 mg/kg that showed no toxicity symptoms. Brain penetration of JR595 was improved when compared to oximes used in practice (e.g., 2-PAM, HI-6), i.e., 40% of blood concentration at tmax of 15 min. Therapeutic efficacy of JR595 in mice exposed to VX and sarin was improved over 2-PAM but not HI-6, and this result was in correspondence to reactivation of human AChE in vitro.1 Since JR595 showed fast elimination from the organism, additional improvement of therapy could be achieved with repeated oxime application. To exclude interspecies difference, we showed that oxime-enzyme interactions with mouse AChE (mAChE) in reversible inhibition of the enzyme and reactivation kinetics for OP-inhibited enzyme is comparable to those observed with hAChE. In conclusion, we confirmed promising pharmacological effects of the new class of potent centrally active antidote for nerve agent poisoning. 1 Zorbaz et al., Chem. Eur. J., 2018, 24, 9675.

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

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