RS194B oxime mediated AChE-reactivation and protection in lethal sarin and insecticide organophosphate exposed macaques is accompanied by oxime-independent BChE increases; likely a result of liver damage

Abstract

In both non-human primate and rodent models, the RS194B oxime is currently the most efficacious single administration post-exposure treatment against highly toxic organophosphate agents; rapidly reversing severe symptoms within 1–2 h and preventing death. This exceptional protective efficacy, which results from its ability to rapidly cross the BBB and remove the conjugated OP moiety from the active serine of OP-inhibited-AChE and BChE, allows for studies using severely OP-intoxicated macaques. We have compared here the reactivation of RBC-AChE and soluble BChE in the circulation to determine the relevance of each enzyme in survival; as an important aid in further oxime development. The results indicate that RS194B oxime administration to severely intoxicated macaques following exposure to inhaled sarin and paraoxon, and orally to diethyl-phosphorothioate insecticides, chlorpyrifos and parathion, results in very rapid AChE reactivation (>60 % in 1 h), sufficient by itself for protection, while the observed lower and slower increases in BChE activity play an insignificant role. Unexpectedly, increases in BChE activity appear to be biphasic in treated macaques, comprising an early oxime-dependent increase followed by a later increase observed after oxime has been eliminated from the blood; the latter increase also being observed in sarin-exposed and untreated animals. This previously unreported oxime-independent BChE recovery was observed in all OP-exposed macaques and is compatible with release/secretion of native BChE from stores in the liver as a result of OP-mediated damage; such increases being too fast to represent water-mediated reactivation or biosynthesis.