title: Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX.
abstract: Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2×LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ∼24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5×LD(50) of soman or 8×LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents.
authors.affiliation: Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. 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: James M
authors.initials: JM
authors.lastname: Fedorko
authors.forename: Irwin
authors.initials: I
authors.lastname: Koplovitz
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
mesh_terms: D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000493:pharmacokinetics / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D008297:Male; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D012999:Soman / Q000633:toxicity*
chemical_list: D000931:Antidotes; D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D009946:Organothiophosphorus Compounds; D012999:Soman; C009680:VX-agent