TY - JOUR T1 - Repeated administration of a mutant cocaine esterase: Effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.194639 SP - jpet.112.194639 AU - Gregory T Collins AU - Remy L Brim AU - Kathleen R Noon AU - Diwahar Narasimhan AU - Nicholas W Lukacs AU - Roger K Sunahara AU - James H Woods AU - Mei-Chuan Ko Y1 - 2012/01/01 UR - http://jpet.aspetjournals.org/content/early/2012/04/19/jpet.112.194639.abstract N2 - Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; 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 if 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), as well as long-lasting increases in MAP and HR (n=3). Administration of DM CocE (0.32mg/kg;IV), 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 following the fourth test, these antibodies did not alter the capacity of DM CocE to reduce plasma levels of cocaine, or ameliorate the cardiovascular effects of cocaine. Anti-CocE titers were transient and generally dissipated within eight 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. ER -