Abstract
In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents used insidiously in terrorism, the methylpyridinium aldoximes have received primary attention, since their development by I.B. Wilson in the 1950's. Yet, these agents, by virtue of their quaternary structures, are limited in crossing the blood-brain barrier and 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 in the mouse of lead ionizable, zwitterionic hydroxyimino-acetamido alkylamines to develop a framework for studying these agents in vivo and generate sufficient data sufficient data for their consideration as appropriate antidotes in humans. Consequently in vitro and in vivo efficacies of immediate structural congeners were explored as feasible backups for animal studies. We have compared oral and parenteral dosing, and developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote are achieved with sequential administration out to 10 hours, with brain exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime shows substantial protection after gastric lavage where as the classic methylpyridinium aldoxime, 2-PAM, is without evident protection. While 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.
- acetylcholinesterase
- blood-brain barrier
- cholinergic pharmacology
- cholinesterases
- intestinal bioavailability
- organophosphates
- pharmacokinetics
- structure-activity relationships
- The American Society for Pharmacology and Experimental Therapeutics