Sit_2018_J.Pharmacol.Exp.Ther_367_363

Reference

Title : Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure - Sit_2018_J.Pharmacol.Exp.Ther_367_363
Author(s) : Sit RK , Kovarik Z , Macek Hrvat N , Zunec S , Green C , Fokin VV , Sharpless KB , Radic Z , Taylor P
Ref : Journal of Pharmacology & Experimental Therapeutics , 367 :363 , 2018
Abstract : In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes have received primary attention since their early development by I. B. Wilson in the 1950s. Yet these agents, by virtue of their quaternary structure, are limited in rates of crossing the blood-brain barrier, and they require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine in mice to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored as leads or backups for animal studies. We compared oral and parenteral dosing, and we developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote were achieved with sequential administrations out to 10 hours, with brain levels exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime showed substantial protection after gavage, whereas the classic methylpyridinium aldoxime (2-pyridinealdoxime methiodide) was without evident protection. Although further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.
ESTHER : Sit_2018_J.Pharmacol.Exp.Ther_367_363
PubMedSearch : Sit_2018_J.Pharmacol.Exp.Ther_367_363
PubMedID: 30190337

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Sit RK, Kovarik Z, Macek Hrvat N, Zunec S, Green C, Fokin VV, Sharpless KB, Radic Z, Taylor P (2018)
Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure
Journal of Pharmacology & Experimental Therapeutics 367 :363

Sit RK, Kovarik Z, Macek Hrvat N, Zunec S, Green C, Fokin VV, Sharpless KB, Radic Z, Taylor P (2018)
Journal of Pharmacology & Experimental Therapeutics 367 :363