title: Protection against paraoxon toxicity by an intravenous pretreatment with polyethylene-glycol-conjugated recombinant butyrylcholinesterase in macaques.
abstract: Recombinant (r) butyrylcholinesterase (rBChE) produced in CHO cells is being developed as a prophylactic countermeasure against neurotoxicity resulting from exposure to organophosphates (OPs) in the form of pesticides and nerve agents. To evaluate the efficacy of a parenteral pretreatment, a PEGylated macaque (Ma) form of rBChE was administered into homologous animals to ensure good plasma retention without immunogenicity. Thus, macaques were administered PEG-rMaBChE at either 5 or 7mg/kg intravenously (i.v.) and exposed subcutaneously to 12μg/kg of the potent pesticide paraoxon (Px) at 1h or at 1 and 72h, respectively. Protection was measured by the ability of rBChE prophylaxis to prevent the inhibition of circulating acetylcholinesterase on red blood cells (RBC-AChE). In rBChE-pretreated animals, no inhibition of RBC-AChE activity after the first Px exposure and only a 10-20% reduction after the second exposure were observed as compared to a 75% RBC-AChE inhibition usually obtained without pretreatment. In addition, these studies raised other interesting issues. The lipophilic nature of Px, appears to result in early and transient inhibition of RBC-AChE as a result of transfer of OP bound to RBC even in BChE-pretreated animals. The protection by a single injection of rBChE against two administrations of Px represents the first example of protection by an i.v. rBChE pretreatment against a pesticide such as Px and bodes well for a parenteral rHuBChE pretreatment as an OP countermeasure in humans.
authors.affiliation: PlantVax Inc, Rockville, MD 20850, United States. Electronic address: yjr@plantvax.com.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Rosenberg
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, United States.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Gearhart
authors.affiliation: PlantVax Inc, Rockville, MD 20850, United States.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Mao
authors.affiliation: PlantVax Inc, Rockville, MD 20850, United States.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jiang
authors.affiliation: PlantVax Inc, Rockville, MD 20850, United States.
authors.forename: Segundo
authors.initials: S
authors.lastname: Hernandez-Abanto
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D061605:Administration, Intravenous; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D008251:Macaca; D062025:Organophosphate Poisoning / Q000517:prevention & control*; D010261:Paraoxon / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D010261:Paraoxon
keywords: Aerosol delivery; Butyrylcholinesterase; Monkey model; Paraoxon; Protection