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

التفاصيل البيبلوغرافية
العنوان:	A single post-exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.
المؤلفون:	Rosenberg YJ; PlantVax Inc, Rockville, Maryland, USA., Garcia K; IIT Research Institute, Chicago, Illinois, USA., Diener J; IIT Research Institute, Chicago, Illinois, USA., Sullivan D; IIT Research Institute, Chicago, Illinois, USA., Donahue S; Teledyne FLIR, Pittsburg, Pennsylvania, USA., Mao L; PlantVax Inc, Rockville, Maryland, USA., Lees J; PlantVax Inc, Rockville, Maryland, USA., Jiang X; PlantVax Inc, Rockville, Maryland, USA., Urban LA; PlantVax Inc, Rockville, Maryland, USA., Momper JD; Department of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA., Ho KY; Department of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA., Taylor P; Department of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
المصدر:	Journal of neurochemistry [J Neurochem] 2024 Apr; Vol. 168 (4), pp. 370-380. Date of Electronic Publication: 2023 Apr 06.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Wiley on behalf of the International Society for Neurochemistry Country of Publication: England NLM ID: 2985190R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1471-4159 (Electronic) Linking ISSN: 00223042 NLM ISO Abbreviation: J Neurochem Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2001- : Oxford, UK : Wiley on behalf of the International Society for Neurochemistry Original Publication: New York : Raven Press
مواضيع طبية MeSH:	Acetamides* , Chlorpyrifos/toxicity , Cholinesterase Reactivators/chemistry , Cholinesterase Reactivators/pharmacology , Insecticides/toxicity , Nerve Agents* , Parathion/adverse effects , Parathion/toxicity, Animals ; Mice ; Acetylcholinesterase/chemistry ; Butyrylcholinesterase/chemistry ; Cholinesterase Inhibitors/chemistry ; Macaca ; Organophosphorus Compounds/toxicity ; Oximes/pharmacology ; Oximes/chemistry ; Oximes/therapeutic use
مستخلص:	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. (© 2023 International Society for Neurochemistry.)
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معلومات مُعتمدة:	NS U01-058046 United States NS NINDS NIH HHS; R43NS108879 United States NS NINDS NIH HHS; NS U01-058046 United States NS NINDS NIH HHS; R43NS108879 United States NS NINDS NIH HHS
فهرسة مساهمة:	Keywords: diethylphosphorothioate insecticides AChE reactivation; macaques; oxime antidote; post‐exposure; survival
المشرفين على المادة:	0 (Acetamides) EC 3.1.1.7 (Acetylcholinesterase) EC 3.1.1.8 (Butyrylcholinesterase) JCS58I644W (Chlorpyrifos) 0 (Cholinesterase Inhibitors) 0 (Cholinesterase Reactivators) 0 (Insecticides) 0 (Nerve Agents) 0 (Organophosphorus Compounds) 0 (Oximes) 61G466064D (Parathion) 0 (RS194B)
تواريخ الأحداث:	Date Created: 20230214 Date Completed: 20240415 Latest Revision: 20240419
رمز التحديث:	20240420
DOI:	10.1111/jnc.15777
PMID:	36786545
قاعدة البيانات:	MEDLINE

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تدمد:	1471-4159
DOI:	10.1111/jnc.15777