Ahmed Elkashef1, James Robert Brašić2, Louis R Cantelina3, Roberta Kahn1, Nora Chiang1, Weiguo Ye2, Yun Zhou2, Jurij Mojsiak1, Kimberly R Warren4, Andrew Crabb2, John Hilton2, Dean F Wong2,5,6,7,8, Frank Vocci1,9. 1. Medications Development Division, The National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. 2. Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. 3. Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 4. Department of Psychology, Morgan State University, Baltimore, MD, USA. 5. Department of Psychiatry and Behavioral Sciences, Baltimore, MD, USA. 6. Department of Neurology, Baltimore, MD, USA. 7. Soloman H Snyder Department of Neurosciences, Baltimore, MD, USA. 8. Department of Environmental Health and Engineering, Bloomberg School of Public Health, Baltimore, MD, USA. 9. Friends Research Institute, Baltimore, MD, USA.
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.
RCT Entities:
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: James Robert Brasić; Yun Zhou; John L Musachio; John Hilton; Hong Fan; Andrew Crabb; Christopher J Endres; Melvin J Reinhardt; Ahmet S Dogan; Mohab Alexander; Olivier Rousset; Marika A Maris; Jeffrey Galecki; Ayon Nandi; Dean F Wong Journal: Synapse Date: 2009-04 Impact factor: 2.562
Authors: Darren R Quelch; Sarah L Withey; David J Nutt; Robin J Tyacke; Christine A Parker Journal: Neuropharmacology Date: 2014-06-06 Impact factor: 5.250
Authors: Ahmed Elkashef; James Robert Brašić; Louis R Cantelina; Roberta Kahn; Nora Chiang; Weiguo Ye; Yun Zhou; Jurij Mojsiak; Kimberly R Warren; Andrew Crabb; John Hilton; Dean F Wong; Frank Vocci Journal: CNS Neurosci Ther Date: 2018-06-20 Impact factor: 5.243