Clinical trial NCT01927640: Dexmedetomidine for Reversal of Cocaine's Effects on the Heart
Official title: Study of Dexmedetomidine for the Reversal of Cocaine's Effects on Myocardial Perfusion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Chest Pain
Acute Coronary Syndrome
Keywords: Cocaine
Dexmedetomidine
Myocardial Contrast Echocardiography
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Lincy Foundation
First posted: 2013-08-22
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will use myocardial contrast echocardiography performed during a continuous intravenous infusion of Definity microbubbles (Perflutren lipid microbubbles) to determine if dexmedetomidine (an intravenous central sympatholytic drug) can reverse all the cardiovascular effects of low-dose intranasal cocaine-including vasoconstriction in the coronary microcirculation-both in cocaine-naïve and non-treatment seeking cocaine-addicted subjects.

Detailed description: Each subject will be participating in three study visits: Screening Visit, Visit 1: a low-dose dobutamine visit and Visit 2: a low-dose cocaine visit. At the dobutamine visit, the subject will only receive low-dose dobutamine, which will be used as an internal inotropic/vasodilator control for cocaine. At the cocaine visit, the subject will receive low-dose intranasal cocaine followed by either the active study drug (dexmedetomidine) or an inactive placebo (saline). Both cocaine and dobutamine will increase myocardial contractility and oxygen demand, thereby stimulating metabolic vasodilation. If, as predicted, cocaine also causes α-adrenergic agonist in the coronary microcirculation, then myocardial blood flow should increase less with cocaine then with dobutamine for a given level of myocardial oxygen demand. We will study if dexmedetomidine, a central sympatholytic, can normalize this cocaine effect. We previously have used dobutamine as a comparator for cocaine in our research. At both visits, myocardial contrast echocardiography will be used to measure regional myocardial perfusion.

Eligibility criteria: Inclusion Criteria:

* Healthy adult subjects ages of 18-65 years without any history of substance abuse (other than tobacco), including narcotics, abuse of prescription painkillers, cocaine or any other recreational drug

Exclusion Criteria:

* Known or suspected right-to-left, bi-directional, or transient right-to-left cardiac shunts or detected by screening echocardiogram performed prior to I.V. infusion of Definity microbubbles
* Hypersensitivity or prior reactions to Definity microbubbles
* Pregnant or nursing women
* Any evidence of cardiopulmonary disease by history or physical examination, including subjects who are taking any cardiovascular medications of any sort
* History of hypertension or BP at time of consent \> 140/90 mm Hg
* Any history of substance abuse (other than tobacco), including narcotics, prescription painkillers, cocaine or any other recreational drug (any person that says they have EVER tried these drugs will be excluded from this study)
* Subjects reporting alcohol intake of more than 2 drinks/day
* Severe psychiatric illness (e.g., schizophrenia, suicidal depression) in addition to drug dependence, which may signify a high risk of addiction
* Diabetes mellitus or any other systemic illness
* Individuals with a history of pseudocholinesterase deficiency
* Hypersensitivity to dexmedetomidine or lorazepam
* The presence of alcohol by breathalyzer
* Subjects who have poor echocardiography images will be screen failed.
* Persons with mechanically, magnetically, or electrically activated implants, such as cardiac pacemakers, neurostimulators, and infusion pumps (MRI only).
* Persons with ferromagnetic implants and ferromagnetic foreign bodies, such as intracranial, aneurysm clips, shrapnel and intraocular metal chips as these could become dislodged (MRI only).
* Persons unable to tolerate MRI imaging secondary to an inability to lie supine or severe claustrophobia (MRI only).
* Persons whose renal function test does not meet CSMC standard of care MRI contrast protocol requirements (GFR \<45ml/min).
* Persons with allergy to animal dander or animal-instigated asthma
* Persons with a history of kidney or liver disease.

Primary outcomes:
measure: Myocardial Perfusion
timeFrame: Baseline and Immediately after acute administration of study drug (Day 1)
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Ronald G Victor, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kontak AC, Victor RG, Vongpatanasin W. Dexmedetomidine as a novel countermeasure for cocaine-induced central sympathoexcitation in cocaine-addicted humans. Hypertension. 2013 Feb;61(2):388-94. doi: 10.1161/HYPERTENSIONAHA.112.203554. Epub 2013 Jan 2.
citation: Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li JL, Victor RG, Vongpatanasin W. Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. J Am Coll Cardiol. 2007 Aug 14;50(7):626-33. doi: 10.1016/j.jacc.2007.03.060. Epub 2007 Jul 30.
citation: Tuncel M, Wang Z, Arbique D, Fadel PJ, Victor RG, Vongpatanasin W. Mechanism of the blood pressure--raising effect of cocaine in humans. Circulation. 2002 Mar 5;105(9):1054-9. doi: 10.1161/hc0902.104714.
citation: Crandall CG, Vongpatanasin W, Victor RG. Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med. 2002 Jun 4;136(11):785-91. doi: 10.7326/0003-4819-136-11-200206040-00006.
citation: Vongpatanasin W, Mansour Y, Chavoshan B, Arbique D, Victor RG. Cocaine stimulates the human cardiovascular system via a central mechanism of action. Circulation. 1999 Aug 3;100(5):497-502. doi: 10.1161/01.cir.100.5.497.
citation: Jacobsen TN, Grayburn PA, Snyder RW 2nd, Hansen J, Chavoshan B, Landau C, Lange RA, Hillis LD, Victor RG. Effects of intranasal cocaine on sympathetic nerve discharge in humans. J Clin Invest. 1997 Feb 15;99(4):628-34. doi: 10.1172/JCI119205.