Dexmedetomidine for Reversal of Cocaine's Effects on the Heart

Study of Dexmedetomidine for the Reversal of Cocaine's Effects on Myocardial Perfusion

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.

Study Overview

• Status: Completed
• Conditions: Chest Pain; Acute Coronary Syndrome
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Intranasal cocaine; Drug: Normal Saline

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.

• Study Type: Interventional
• Enrollment (Actual): 115
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine and intranasal cocaine; Intranasal cocaine administration (2 mg/kg) then Dexmedetomidine (0.3-0.6 mcg/kg) infusion	Drug: Dexmedetomidine; Dexmedetomidine (0.3-0.6 mcg/kg) infusion.; Other Names: Precedex; Drug: Intranasal cocaine; Intranasal cocaine (2 mg/kg)
Placebo Comparator: Normal saline and intranasal cocaine; Intranasal cocaine administration (2 mg/kg) then Saline (over 10 minutes I.V. infusion)	Drug: Intranasal cocaine; Intranasal cocaine (2 mg/kg); Drug: Normal Saline; Normal saline infusion (10 cc)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial Perfusion	Myocardial perfusion will be measured by myocardial contrast echocardiography after dexmedetomidine administration and compared to baseline. There will be no repeat dosing of dexmedetomidine. No longer term outcomes are measured.	Baseline and Immediately after acute administration of study drug (Day 1)

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Lincy Foundation
• Investigators: Principal Investigator: Ronald G Victor, MD, Cedars-Sinai Medical Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): January 15, 2014
• Study Completion (Actual): January 15, 2014

Study Registration Dates

• First Submitted: August 19, 2013
• First Submitted That Met QC Criteria: August 21, 2013
• First Posted (Estimate): August 22, 2013

Study Record Updates

• Last Update Posted (Actual): January 14, 2020
• Last Update Submitted That Met QC Criteria: January 10, 2020
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Dexmedetomidine; Cocaine; Myocardial Contrast Echocardiography
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pain; Neurologic Manifestations; Chest Pain; Acute Coronary Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Hypnotics and Sedatives; Anesthetics, Local; Dopamine Uptake Inhibitors; Vasoconstrictor Agents; Dexmedetomidine; Cocaine
• Other Study ID Numbers: Pro19549