Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques.
Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques.
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DOI：
10.1016/j.toxlet.2017.10.025
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发表时间：
2018-09-01
影响因子：
3.5
通讯作者：
Taylor P
中科院分区：
文献类型：
--
作者：
Rosenberg YJ;Wang J;Ooms T;Rajendran N;Mao L;Jiang X;Lees J;Urban L;Momper JD;Sepulveda Y;Shyong YJ;Taylor P
Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100 ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80 mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40–100% in < 1 hr and BChE (40% in 8 h). These findings will be used to develop a macaque model with RS194 B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule.
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