A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.

Abstract

AIMS:

RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681.

METHODS:

Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose.

RESULTS:

RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA.

CONCLUSION:

Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

• Authors: Ahmed Elkashef, James Robert Brašić, Louis R Cantelina Jr, Roberta Kahn, Nora Chiang, Weiguo Ye, Yun Zhou, Jurij Mojsiak, Kimberly R Warren, Andrew Crabb, John Hilton, Dean F Wong, Frank Vocci
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 25 Issue 1 Pg. 136-146 (01 2019) ISSN: 1755-5949 [Electronic] England
• PMID: 29923314 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• Acetamides
• Central Nervous System Agents
• Dopamine Uptake Inhibitors
• Phenylurea Compounds
• Radiopharmaceuticals
• Receptor, Cholecystokinin B
• Raclopride
• RP 72540
• Cocaine
• Dopamine

Topics

• Acetamides (adverse effects, pharmacokinetics, pharmacology)
• Adult
• Brain (diagnostic imaging, drug effects, metabolism)
• Central Nervous System Agents (adverse effects, pharmacokinetics, pharmacology)
• Cocaine (pharmacokinetics, pharmacology)
• Cocaine-Related Disorders (diagnostic imaging, drug therapy, metabolism)
• Craving (drug effects)
• Dopamine (metabolism)
• Dopamine Uptake Inhibitors (pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Interactions
• Female
• Humans
• Male
• Middle Aged
• Phenylurea Compounds (adverse effects, pharmacokinetics, pharmacology)
• Pilot Projects
• Positron-Emission Tomography
• Raclopride
• Radiopharmaceuticals
• Receptor, Cholecystokinin B (antagonists & inhibitors)