Protection against paraoxon toxicity by an intravenous pretreatment with polyethylene-glycol-conjugated recombinant butyrylcholinesterase in macaques
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- 作者：Yvonne J. Rosenberg ; Jeffery Gearhart ; Lingjun Mao ; Xiaoming Jiang ; Segundo Hern ; ez-Abanto
- 关键词：Butyrylcholinesterase ; Aerosol delivery ; Paraoxon ; Protection ; Monkey model
- 刊名：Chemico-Biological Interactions
- 出版年：5 March, 2014
- 年：2014
- 卷：210
- 期：Complete
- 页码：20-25
- 全文大小：454 K
文摘
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 7 mg/kg intravenously (i.v.) and exposed subcutaneously to 12 渭g/kg of the potent pesticide paraoxon (Px) at 1 h or at 1 and 72 h, 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.