title: Prophylaxis with human serum butyrylcholinesterase protects Göttingen minipigs exposed to a lethal high-dose of sarin vapor.
abstract: Serum-derived human butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a potential prophylactic nerve agent countermeasure. Previously, we reported the prophylactic efficacy of Hu BChE in Göttingen minipigs against a whole-body exposure to 4.1mg/m(3) of sarin (GB) vapor, which produced lethality over 60min. Since the toxicity of nerve agent is concentration-dependent, in the present study, we investigated the toxic effects of an almost 3-fold higher rate of GB vapor exposure and the ability of Hu BChE to protect minipigs against this exposure. Male minipigs were subjected to: (1) air exposure; (2) GB vapor exposure; or (3) pretreatment with 7.5mg/kg of Hu BChE by i.m. injection, 24h prior to whole-body exposure to 11.4mg/m(3) of GB vapor for 10min. Electrocardiogram, electroencephalogram, and pupil size were monitored throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB bound to red blood cells and plasma. A novel finding was that saline-treated animals exposed to GB vapor did not develop any seizures, but manifested a variety of cardiac and whole blood toxic signs and rapidly died due to respiratory failure. Strikingly, pre-treatment with 7.5mg/kg of Hu BChE not only prevented lethality, but also avoided all cardiac toxic signs manifested in the non-treated cohort. Thus, Hu BChE alone can serve as an effective prophylactic countermeasure versus a lethal high-dose exposure to GB vapor.
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States. Electronic address: Ashima.saxena.civ@mail.mil.
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Hastings
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Operational Toxicology Team, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dabisch
authors.affiliation: Operational Toxicology Team, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Hulet
authors.affiliation: Operational Toxicology Team, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Jakubowski
authors.affiliation: Operational Toxicology Team, Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mioduszewski
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001774:Blood Chemical Analysis; D002091:Butyrylcholinesterase / Q000378:metabolism / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004562:Electrocardiography; D004569:Electroencephalography; D005740:Gases / Q000737:chemistry; D006801:Humans; D008297:Male; D015877:Miosis / Q000139:chemically induced / Q000473:pathology; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000473:pathology; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002619:Chemical Warfare Agents; D005740:Gases; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Cardiotoxicity; High-dose exposure; Human serum butyrylcholinesterase; Minipig; Sarin vapor