No abstract

We have developed a series of antidotes to organophosphate poisoning, hydroxyiminoacetamido alkylamines, that ionize as cations, anions, zwitterions and form an appreciable neutral species at physiologic pH values. As such they cross the blood‐brain barrier and are orally bioavailable. They appear to be effective in mice and macaques in reversing organophosphate toxicity from accumulating sarin and paraoxon (Rosenberg et al., 2017, Chem‐Biol Interact 274, 50–57; Toxicol Lett. https//doi.org/10.1016/jtoxlet.2017.10.025). We examine here the blood and tissue disposition of these agents in the absence of organophosphate to ascertain pharmacokinetic profiles and achieve optimal loading and maintenance dosing of this family of antidotes. Our data show comparable absorption and tissue distribution after tail vein and retro‐orbital injection with only a slight delay when the antidote is administered intramuscularly. Hence, systemic distribution can be rapidly achieved to reverse acute toxicity. Initial studies of tissue disposition show both rapid transfer into the brain, along with rapid clearance from tissues and blood through likely transport mechanisms. Such kinetics are consistent with post‐administration Protection Ratios of the organophosphate after acute exposure and in vitro profiles of reactivation of the organophosphate inhibited enzyme. As with the quaternary oximes such as 2‐PAM and HI‐6, clearance is rapid requiring a parenteral loading dose and then parenteral or oral maintenance dosing to reverse or avert toxicity and fatality. Such studies in mice enable one to consider effective antidote treatment schemes for longer acting pesticides and acute exposure to the volatile sarin and related nerve agents through respiratory and dermal absorption routes.Support or Funding InformationSupported in part by NINDS, UO1‐058046This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.