Efficacy of human serum butyrylcholinesterase against sarin vapor.
Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a pretreatment drug for organophosphate (OP) poisoning in humans. It was shown to protect mice, rats, guinea pigs, and monkeys against multiple LD(50) challenges of OP nerve agents by i.v. or s.c. bolus injections. Since inhalation is the most likely route of exposure to OP nerve agents on the battlefield or in public places, the aim of this study was to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to sarin (GB) vapor. Male Göttingen minipigs were subjected to one of the following treatments: (1) air exposure; (2) GB vapor exposure; (3) pretreatment with 3 mg/kg of Hu BChE followed by GB vapor exposure; (4) pretreatment with 6.5 mg/kg of Hu BChE followed by GB vapor exposure; (5) pretreatment with 7.5 mg/kg of Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection, 24h prior to whole-body exposure to GB vapor at a concentration of 4.1 mg/m(3) for 60 min, a dose lethal to 99% of untreated exposed pigs (LCt99). EEG, ECG, and pupil size were monitored throughout exposure, and blood drawn from a surgically implanted jugular catheter before and throughout the exposure period, was analyzed for acetylcholinesterase (AChE) and BChE activities, and the amount of GB present in plasma. All animals exposed to GB vapor alone or pretreated with 3 or 6.5 mg/kg of Hu BChE, died following exposure to GB vapor. All five animals pretreated with 7.5 mg/kg of Hu BChE survived the GB exposure. The amount of GB bound in plasma was 200-fold higher compared to that from plasma of pigs that did not receive Hu BChE, suggesting that Hu BChE was effective in scavenging GB in blood. Additionally, pretreatment with 7.5 mg/kg of Hu BChE prevented cardiac abnormalities and seizure activity observed in untreated animals and those treated with lower doses of Hu BChE.
Saxena
Ashima
A
Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. ashima.saxena@us.army.mil
Sun
Wei
W
Dabisch
Paul A
PA
Hulet
Stanley W
SW
Hastings
Nicholas B
NB
Jakubowski
Edward M
EM
Mioduszewski
Robert J
RJ
Doctor
Bhupendra P
BP
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001682:Biological Availability; D002091:Butyrylcholinesterase / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D006801:Humans; D008297:Male; D012524:Sarin / Q000633:toxicity*; D013552:Swine; D013556:Swine, Miniature
D000931:Antidotes; D002619:Chemical Warfare Agents; D012524:Sarin; D002091:Butyrylcholinesterase