engleski

RS194B pharmacokinetics and antidotal potential in mice to VX and sarin

Lipophilic and uncharged organophosphorus compounds (OP) inhibit peripheral and central nervous system (CNS) cholinesterase within minutes of OP exposure due to rapid OP diffusion through biological membranes. Therapeutic treatment consists of a combined administration of an anticholinergic drug (atropine) and oxime- reactivator of acetylcholinesterase (AChE). Therapy by oximes approved for use (2-PAM, obidoxime, HI-6) is somewhat efficient in reactivating inhibited AChE in blood and peripheral tissues but not in CNS because of slow or limited blood-brain barrier penetration for quaternary pyridinium aldoximes with a permanent cation. To develop antidotal therapy capable of efficient reinstatement of CNS AChE activity, we examined the zwitterionic hydroxyimino-acetamido alkylamine oxime known as RS194B amenable to protonation of the non-ionized species that can cross the blood brain barrier. RS194B is as an effective in vitro reactivator of human AChE inhibited by VX and sarin, therefore we further examined the pharmacokinetic properties, oral bioavailability, and antidotal efficacy of RS194B against OP exposure in mice. The results show that 2 h sequential administrations to 10 h ensure the 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 to mice exposed to sarin and even VX 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 further efficacy, tissue disposition, and pharmacokinetics analysis in other animal species.

acetylcholinesterase ; blood-brain barrier ; central nervous system ; oximes ; plasma

nije evidentirano