title: Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys.
abstract: Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Remy L
authors.initials: RL
authors.lastname: Brim
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Noon
authors.forename: Diwahar
authors.initials: D
authors.lastname: Narasimhan
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: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000008:administration & dosage* / Q000276:immunology*; D002319:Cardiovascular System / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006868:Hydrolysis / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects
chemical_list: D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine