Cocaine esterase (CocE) is a product of the bacterium Rhodococcus sp. which grows in the rhizospheres of coca plants in South America. The bacterium uses CocE to break down cocaine to provide its sole source of carbon and nitrogen. CocE is the most efficient cocaine esterase yet observed. We have studied it in vitro and in vivo in rodents and found that it is able to reverse immediately the effects of lethal doses of cocaine in these animals. Although CocE appears to be a superb treatment for cocaine overdose, its usefulness as a treatment for cocaine abuse is limited by its very short half life. A funded grant (DA021416) is currently developing mutants of CocE that have greater thermostability and longer durations of action and testing them in rodent models of cocaine toxicity. The purpose of the current application is to evaluate native CocE in non-human primates as a step in the process of making this enzyme available for treatment of cocaine overdose in humans. Each year of the project will evaluate a single version of CocE, starting with the native enzyme, and proceeding through mutants that have been shown to have substantially longer durations of action. Three types of studies will be conducted sequentially in each year with each enzyme. The first will identify effective doses of the enzyme for reducing the cardiovascular effects of cocaine and clearing a range of doses of cocaine from the plasma of rhesus monkeys. The second study will focus on measuring immunological responses to each enzyme when it is administered repeatedly at intervals that should maximize development of titers. The effect of CocE titer development on the ability of the enzyme to reduce the effects of cocaine will also be studied in this process. The third study involves determination of the ability of CocE and its longer-acting mutants to prevent the reinforcing effects of cocaine and to modify the cardiovascular effects of self-administered cocaine. Dose-response functions for each enzyme will be obtained repeatedly and blood samples analyzed for titer development so that tolerance to the effects of CocE can be monitored.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023213-03
Application #
7751338
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Patel, Amrat
Project Start
2008-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$509,123
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ko, Mei-Chuan (2015) Neuraxial opioid-induced itch and its pharmacological antagonism. Handb Exp Pharmacol 226:315-35
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Hu, Eric; Calò, Girolamo; Guerrini, Remo et al. (2010) Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain 148:107-13
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