Human Serum Butyrylcholinesterase: A Bioscavenger for the Protection of Humans from Organophosphorus Exposure

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a pretreatment drug for organophosphate (OP) poisoning in humans. Toward this effort, a procedure for the large-scale purification of Hu BChE from Cohn fraction IV-4 was developed, its pharmacokinetic properties w...

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Bibliographic Details
Main Authors: Saxena, Ashima, Sun, Wei, Hastings, Nicholas B, Doctor, Bhupendra P, Dabisch, Paul A, Hulet, Stanley W, Jakubowski, Edward M, Mioduszewski, Robert J
Format: Report
Language:English
Subjects:
ACETYLCHOLINESTERASE
ANIMALS
Biochemistry
BLOOD SERUM
DRUGS
EXPOSURE(PHYSIOLOGY)
INJECTIONS(MEDICINE)
NERVE AGENTS
ORGANOPHOSPHATES
PHARMACOKINETICS
POISONING
VAPORS
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Summary:Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a pretreatment drug for organophosphate (OP) poisoning in humans. Toward this effort, a procedure for the large-scale purification of Hu BChE from Cohn fraction IV-4 was developed, its pharmacokinetic properties were established, its shelf life was evaluated at various temperatures, and its safety and efficacy were examined. It was shown to protect mice, rats, guinea pigs, and monkeys against multiple LD50 challenges of OP nerve agents by i.v. or s.c. bolus injections. Since inhalation is the most likely route of exposure 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. The study was conducted in minipigs because the pig offers many similarities in anatomy and physiology to humans. Male G ttingen minipigs were subjected to one of the following treatments: (1) Air exposure; (2) GB vapor exposure; and (3) pretreatment with 7.5 mg/kg of Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection, 24 h prior to whole-body exposure to GB vapor at a concentration of 4.1 mg/m3 for 60 min or 11.4 mg/m3 for 10 min. 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. Baseline blood AChE and BChE activities were 2.5 0.1 U/ml and 0.14 0.01 U/ml, respectively. Animals pretreated with 7.5 mg/kg of Hu BChE showed peak blood BChE activity of 41.2 0.9 U/ml with a mean residence time of 287 53 h. See also ADA562561. RTO-MP-HFM-181 Human Performance Enhancement for NATO Military Operations (Science, Technology and Ethics) (Amelioration des performances humaines dans les operations militaires de l'OTAN (Science, Technologie et Ethique)). RTO Human Factors and Medicine Panel (HFM) Symposium held in Sofia, Bulgaria, on 5-7 October 2009., The original document contains color images.