title: Amelioration of the cardiovascular effects of cocaine in rhesus monkeys by a long-acting mutant form of cocaine esterase.
abstract: A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in electrocardiograph (ECG) parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5-10 min, and saline-like HR measures restored within 20-40 min of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Carey
authors.forename: Diwahar
authors.initials: D
authors.lastname: Narasimhan
authors.forename: Joseph
authors.initials: J
authors.lastname: Nichols
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Berlin
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D011994:Recombinant Proteins; D002265:Carboxylic Ester Hydrolases; C498183:CocE protein; D003042:Cocaine