title: Pretreatment with human serum butyrylcholinesterase alone prevents cardiac abnormalities, seizures, and death in Göttingen minipigs exposed to sarin vapor.
abstract: Human serum butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a prophylactic countermeasure against organophosphorus nerve agents. This study was designed to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to a lethal dose of sarin (GB) vapor. Male Göttingen minipigs were subjected to: air exposure, GB vapor exposure, or pretreatment with Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection 24 h prior to exposure to 4.1 mg/m(3) of GB vapor for 60 min. Electrocardiograms (ECG), electroencephalograms (EEG), and pupil size were recorded throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB present. Untreated animals exposed to GB vapor exhibited cardiac abnormalities and generalized seizures, ultimately succumbing to respiratory failure. Pretreatment with 3.0 or 6.5 mg/kg of Hu BChE delayed blood gas and acid-base disturbances and the onset of cardiac and neural toxic signs, but failed to increase survivability. Pretreatment with 7.5 mg/kg of Hu BChE, however, completely prevented toxic signs, with blood chemistry and ECG and EEG parameters indistinguishable from control during and after GB exposure. GB bound in plasma was 200-fold higher than plasma from pigs that did not receive Hu BChE, suggesting that Hu BChE scavenged GB in blood and prevented it from reaching other tissues. Thus, prophylaxis with Hu BChE alone not only increased survivability, but also prevented cardiac abnormalities and neural toxicity in minipigs exposed to a lethal dose of GB vapor.
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States. Ashima.saxena@us.army.mil
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dabisch
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Hulet
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Hastings
authors.forename: Edward M
authors.initials: EM
authors.lastname: Jakubowski
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mioduszewski
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D002091:Butyrylcholinesterase / Q000008:administration & dosage* / Q000097:blood; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000517:prevention & control*; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002619:Chemical Warfare Agents; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase