title: Post-exposure therapy with recombinant human BuChE following percutaneous VX challenge in guinea-pigs.
abstract: Poisoning by nerve agents via the percutaneous (p.c.) route is an issue because the slow absorption of agent could result in poisoning which outlasts the protection provided by conventional pharmacological therapy. The bioscavenger approach is based on the concept of binding nerve agent in the bloodstream, thus preventing nerve agent from reaching the target tissues and inhibiting acetylcholinesterase activity. One bioscavenger that has been extensively studied is human butyrylcholinesterase (huBuChE). Protexia® is a pegylated form of recombinant huBuChE. We used a guinea-pig model of p.c. nerve agent poisoning, using an implanted telemetry system to collect physiological data. Guinea-pigs were poisoned with the nerve agent VX (0.74 mg/kg) (∼2.5 × LD₅₀). Two hours following VX exposure, Protexia (72 mg/kg) or saline control was administered intramuscularly. All guinea-pigs treated with Protexia (n=8) survived, compared to no survivors in a saline-treated control group (n=8). Survival following VX and Protexia treatment was associated with minimal incapacitation and observable signs of poisoning, and the mitigation or prevention of the detrimental physiological changes (e.g. seizure, bradycardia and hypothermia) observed in control animals. The opportunity for post-exposure treatment may have utility in both civilian and military scenarios, and this is a promising indication for the use of a bioscavenger.
authors.affiliation: Physiology, Pharmacology and Behaviour Team, Biomedical Sciences Department, Building 4, Dstl Porton Down, Salisbury SP40JQ, UK. HMUMFORD@dstl.gov.uk
authors.forename: Helen
authors.initials: H
authors.lastname: Mumford
authors.forename: John K
authors.initials: JK
authors.lastname: Troyer
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry; D004566:Electrodes; D004569:Electroencephalography; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption; D016019:Survival Analysis; D013686:Telemetry
chemical_list: D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D004337:Drug Carriers; D009946:Organothiophosphorus Compounds; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; C009680:VX-agent