title: Immobilization of Russian VX skin depots by localized cooling: implications for decontamination and medical countermeasures.
abstract: The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD₅₀ for VR topically applied on the ear was 100 μg/kg. Treatment of VR exposed animals (5 × LD₅₀) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective.
authors.affiliation: Defence Research & Development Canada - Suffield, Box 4000, Medicine Hat, Alberta, Canada T1A8K6. John.Mikler@drdc-rddc.gc.ca
authors.forename: J
authors.initials: J
authors.lastname: Mikler
authors.forename: C
authors.initials: C
authors.lastname: Tenn
authors.forename: F
authors.initials: F
authors.lastname: Worek
authors.forename: G
authors.initials: G
authors.lastname: Reiter
authors.forename: H
authors.initials: H
authors.lastname: Thiermann
authors.forename: M
authors.initials: M
authors.lastname: Garrett
authors.forename: S
authors.initials: S
authors.lastname: Bohnert
authors.forename: T W
authors.initials: TW
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000627:therapeutic use; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D003666:Decontamination / Q000379:methods*; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000201:enzymology / Q000517:prevention & control*; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D034421:Sus scrofa; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D009946:Organothiophosphorus Compounds; D002802:Cholinesterases; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate