title: Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates.
abstract: Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: chambers@cvm.msstate.edu.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Chambers
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: emeek@cvm.msstate.edu.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Meek
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: jpb280@msstate.edu.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Bennett
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: wsb33@cvm.msstate.edu.
authors.forename: W Shane
authors.initials: WS
authors.lastname: Bennett
authors.affiliation: Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, P.O. Box 9775, Mississippi State, MS 39762, USA. Electronic address: hwc2@msstate.edu.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Chambers
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: cal57@msstate.edu.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Leach
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: rpb62@msstate.edu.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Pringle
authors.affiliation: Department of Pathobiology/Population Medicine, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: wills@cvm.msstate.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wills
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D008297:Male; D009946:Organothiophosphorus Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010091:Oximes / Q000627:therapeutic use*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*; D016019:Survival Analysis
chemical_list: D000110:Acetylcholinesterase; D000931:Antidotes; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011759:Pyrrolidines; C422416:N-ethylmercapto-3-4-dihydroxy-2-hydroxymethylpyrrolidine; C009680:VX-agent; C028797:pralidoxime
keywords: Acetylcholinesterase reactivators; Anticholinesterase; Nerve agent surrogates; Organophosphate; Prevention of lethality