title: Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig.
abstract: Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl2. The 24-hr median lethal dose (LD50) for the four by intramuscular (IM) injection and the median effective dose (ED50) were determined. In the ED50 study, male guinea pigs clipped of hair received 2x LD50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED90) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 µmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl2. Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED90 < 149 µmol/kg against all three topical OPs tested.
authors.affiliation: Battelle, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Snider
authors.forename: Michael C
authors.initials: MC
authors.lastname: Babin
authors.forename: David A
authors.initials: DA
authors.lastname: Jett
authors.forename: Gennady E
authors.initials: GE
authors.lastname: Platoff
authors.forename: David T
authors.initials: DT
authors.lastname: Yeung
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology* / Q000633:toxicity; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009768:Obidoxime Chloride / Q000494:pharmacology / Q000633:toxicity; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000209:etiology; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000494:pharmacology* / Q000633:toxicity; D010575:Pesticides / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology / Q000633:toxicity; D011726:Pyridinium Compounds / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors
chemical_list: D000931:Antidotes; D001285:Atropine; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018727:Muscarinic Antagonists; D009768:Obidoxime Chloride; D009946:Organothiophosphorus Compounds; D010091:Oximes; D010575:Pesticides; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C058577:HLo 7; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); C009680:VX-agent; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate; C028797:pralidoxime