A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

Abstract

Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP‐inhibited AChE. However, animal model studies and recent clinical trials using insecticide‐poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood–brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP‐inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1–2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non‐invasive treatment, especially in isolated rural settings.image

Recent advances in cholinergic mechanisms: A preface for the ISCM2022 special issue

“…This highlights the need for a novel efficacious therapy, which is the focus of the manuscript by Rosenberg et al. (2023). This study presented significant progress in the development of a safe oxime antidote with favorable pharmacokinetics and oral bioavailability.…”

“…The currently available oximes employed to reduce symptoms of cholinergic crises and enhance survival following high-dose organophosphate (OP) insecticides exposure in animals and agricultural workers may only provide limited benefit. This highlights the need for a novel efficacious therapy, which is the focus of the manuscript by Rosenberg et al (2023). This study presented significant progress in the development of a safe oxime antidote with favorable pharma- A new outlook on the modulation of cholinergic signal transduction with butyrylcholinesterase (BChE) and its involvement in lipid mechanism is reviewed by Gok et al (2023).…”