engleski

Post-exposure treatment with the oxime RS194B rapidly reactivates brain acetylcholinesterase activity in mice exposed to sarin and VX

Acetylcholinesterase (AChE) has a vital function in cholinergic neurotransmission but is irreversibly disrupted after exposure to organophosphate (OP) nerve agents, resulting in onset of toxicity symptoms which may lead to death. Currently used therapy consists of quaternary pyridinium aldoximes as reactivators of inhibited AChE, given along with atropine. The permanent cation precludes these reactivators rapidly crossing the BBB in appreciable concentrations to reactivate synaptic AChE, thereby restricting their activity to the periphery. Alternatives encompass oximes lacking a permanent cationic charge or presenting a tertiary amine as found in the zwitterionic hydroxyiminoacetamido alkylamines (RS194B). We have shown RS194B to be an effective in vitro reactivator of human AChE inhibited by VX, sarin, other methylphosphonates and various alkylphosphorates. Here we examine the pharmacokinetic properties, oral bioavailability and antidotal efficacy of RS194B against OP exposure in mice. The results show that 2 h sequential administrations out to 10 h result in steady-state plasma and brain levels of the oxime. Moreover, within the 40 min period brain concentrations of RS194B exceed the plasma concentrations prior to the next administration. Also, RS194B substantially protected mice when administered by gastric lavage prior to OP exposure, whereas 2-PAM exhibited no protection when similarly administered. Furthermore, the observed recovery of the mice brain activity after administering RS194B after exposure to both, VX and sarin is consistent with its rapid tissue disposition and BBB penetration. Those results, along with low toxicity of RS194B in mice, make this oxime a lead candidate for analyzing efficacy, tissue disposition and pharmacokinetics in other animal species. Acknowledgements: This work was supported by the Croatian Science Foundation (4307) and National Institutes of Health (NS UO1-058046).

CNS-active antidote, nerve agents, pharmacokinetics, tissue disposition

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