Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques

Yvonne J. Rosenberg, Jerry Wang, Tara Ooms, Narayanan Rajendran, Lingjun Mao, Xiaoming Jiang, Jonathan Lees, Lori Urban, Jeremiah D. Momper, Yadira Sepulveda, Yan-Jye Shyong, Palmer Taylor

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)229-234
Number of pages6
JournalToxicology Letters
Volume293
DOIs
Publication statusPublished - 2018 Sep 1

Fingerprint

Paraoxon
Oximes
Macaca
Acetylcholinesterase
Insecticides
Organophosphates
Sarin
Organophosphate Poisoning
Neurotoxins
Neurology
Occupational Exposure
Atropine
Pesticides
Synapses
Poisoning
Cholinergic Agents
Nervous System
Brain
Animals
Health

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Rosenberg, Yvonne J. ; Wang, Jerry ; Ooms, Tara ; Rajendran, Narayanan ; Mao, Lingjun ; Jiang, Xiaoming ; Lees, Jonathan ; Urban, Lori ; Momper, Jeremiah D. ; Sepulveda, Yadira ; Shyong, Yan-Jye ; Taylor, Palmer. / Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques. In: Toxicology Letters. 2018 ; Vol. 293. pp. 229-234.
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abstract = "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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Rosenberg, YJ, Wang, J, Ooms, T, Rajendran, N, Mao, L, Jiang, X, Lees, J, Urban, L, Momper, JD, Sepulveda, Y, Shyong, Y-J & Taylor, P 2018, 'Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques', Toxicology Letters, vol. 293, pp. 229-234. https://doi.org/10.1016/j.toxlet.2017.10.025

Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques. / Rosenberg, Yvonne J.; Wang, Jerry; Ooms, Tara; Rajendran, Narayanan; Mao, Lingjun; Jiang, Xiaoming; Lees, Jonathan; Urban, Lori; Momper, Jeremiah D.; Sepulveda, Yadira; Shyong, Yan-Jye; Taylor, Palmer.

In: Toxicology Letters, Vol. 293, 01.09.2018, p. 229-234.

Research output: Contribution to journalArticle

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AU - Rosenberg, Yvonne J.

AU - Wang, Jerry

AU - Ooms, Tara

AU - Rajendran, Narayanan

AU - Mao, Lingjun

AU - Jiang, Xiaoming

AU - Lees, Jonathan

AU - Urban, Lori

AU - Momper, Jeremiah D.

AU - Sepulveda, Yadira

AU - Shyong, Yan-Jye

AU - Taylor, Palmer

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AB - 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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