title: A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides.
abstract: The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl₂, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.
authors.affiliation: Battelle, 505 King Avenue, JM-7, Columbus, OH 43201-2693, USA. Electronic address: wilhelmc@battelle.org.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Wilhelm
authors.affiliation: Battelle, 505 King Avenue, JM-7, Columbus, OH 43201-2693, USA. Electronic address: snidert@battelle.org.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Snider
authors.affiliation: Battelle, 505 King Avenue, JM-7, Columbus, OH 43201-2693, USA. Electronic address: babinm@battelle.org.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Babin
authors.affiliation: National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA. Electronic address: jettd@ninds.nih.gov.
authors.forename: David A
authors.initials: DA
authors.lastname: Jett
authors.affiliation: National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Electronic address: platoffg@niaid.nih.gov.
authors.forename: Gennady E
authors.initials: GE
authors.lastname: Platoff
authors.affiliation: National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA. Electronic address: dy70v@nih.gov.
authors.forename: David T
authors.initials: DT
authors.lastname: Yeung
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001285:Atropine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002619:Chemical Warfare Agents / Q000737:chemistry* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002802:Cholinesterases / Q000097:blood; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000009:adverse effects; D006168:Guinea Pigs; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D062025:Organophosphate Poisoning / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010575:Pesticides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011897:Random Allocation
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018727:Muscarinic Antagonists; D010091:Oximes; D010575:Pesticides; D011726:Pyridinium Compounds; C058577:HLo 7; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D001285:Atropine; D002802:Cholinesterases
keywords: Efficacy; Guinea pig; Intramuscular; Oxime; Toxicity