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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA023213].
R.K.S. and J.H.W. have served as consultants to Reckitt Benckiser Pharmaceuticals (Richmond, VA). R.L.B., D.N., R.K.S., J.H.W., and M.-C.K. are listed as inventors on patent number PCT/US2008/069659 for DM CocE.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- MAP
- mean arterial pressure
- ANOVA
- analysis of variance
- BChE
- butyrylcholinesterase
- CocE
- cocaine esterase
- DM CocE
- double mutant CocE
- ED
- emergency department
- HR
- heart rate
- PBS
- phosphate-buffered saline
- n.s.
- not significant
- wt
- wild type
- EU
- endotoxin units.
- Received March 22, 2012.
- Accepted April 18, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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