title: A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates.
abstract: A long-acting, thermostable bacterial cocaine esterase (CocE) has been identified that rapidly degrades cocaine with a K(M) of 1.33+0.085 μM. In vivo evaluation of CocE has shown protection against convulsant and lethal effects of cocaine in rodents, confirming the therapeutic potential of CocE against cocaine overdose. However, the current study is the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomogrpahy neuroimaging of [(11)C]cocaine was used to evaluate the time course of cocaine elimination from brain in the presence and absence of CocE in nonhuman primates. Systemic administration of CocE eliminated cocaine from the rhesus-monkey brain approximately three times faster than control conditions via peripheral actions through attenuating the input function from blood plasma. The efficiency of this process is sufficient to alleviate or prevent adverse central nervous system effects induced by cocaine. Although the present study used tracer doses of cocaine to access brain clearance, these findings further support the development of CocE for the treatment of acute cocaine toxicity.
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Howell
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Nye
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Stehouwer
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Voll
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mun
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Narasimhan
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nichols
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sunahara
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Goodman
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Division of Neuropharmacology and Neurologic Diseases, Emory University, Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003042:Cocaine / Q000493:pharmacokinetics*; D062787:Drug Overdose / Q000188:drug therapy; D004795:Enzyme Stability; D008253:Macaca mulatta; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012240:Rhodococcus / Q000201:enzymology
chemical_list: D011994:Recombinant Proteins; D002265:Carboxylic Ester Hydrolases; C498183:CocE protein; D003042:Cocaine