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 longacting 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 ϭ 2) and long-lasting increases in MAP and HR (n ϭ 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.

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

“…Impedance-based measurement of respiratory function has been extensively described in humans, and the approach of combined cardiopulmonary assessments has been validated in monkeys (56). The basal values of these physiological parameters in this study are in line with those reported in rhesus monkeys (40,52,54). BU08028 at antinociceptive doses and ∼10-to 30-fold higher doses did not cause significantly respiratory depression or adverse cardiovascular events, whereas fentanyl produced a rapid, severe decrease in respiratory rate.…”

“…To characterize the safety profile of BU08028, we implanted radiotelemetric transmitters in monkeys for real-time measurements of different physiological functions (52). A systemic dose (0.01 mg/kg) of BU08028 that produced full antinociceptive effects did not significantly affect the respiratory function of freely moving monkeys, i.e., no respiratory depression ( Fig.…”

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

“…Plasma was collected in polypropylene tubes containing 20 ml of a solution of 1 mg/ml sodium fluoride and 60% acetic acid and then stored at 280°C. Pharmacokinetic procedures were based on previous studies in which plasma cocaine levels were assessed in rhesus monkeys (Collins et al, 2012).…”

Experimental Treatments for Cocaine Toxicity: A Difficult Transition to the Bedside

“…However, an immune response was noted with repeated administrations of CocE, and as antiCocE antibodies increased, the clinical response to treatment declined (Ko et al, 2009). Double mutant CocE (T172R/ G173Q) given to rhesus monkeys 10 minutes after cocaine improved mean arterial pressure, heart rate, and locomotor activity, even as anti-double mutant CocE antibody titers increased in the animals after repeated administrations (Collins et al, 2011(Collins et al, , 2012. Effective enzymatic therapy for acute cocaine toxicity has the potential to be curative, although significant caveats to its administration will apply.…”