Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

This study is currently recruiting participants. (see Contacts and Locations)

Verified December 2014 by Georgia Regents University

Sponsor:

Collaborator:

American Heart Association

Information provided by (Responsible Party):

Ryan Harris, Georgia Regents University

ClinicalTrials.gov Identifier:

NCT01398943

First received: July 19, 2011

Last updated: December 9, 2014

Last verified: December 2014

History of Changes

Purpose

More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.

Condition	Intervention
Pulmonary Disease, Chronic Obstructive	Drug: Tetrahydrobiopterin (BH4) Drug: non-acetylated salicylate Dietary Supplement: High Fat Meal Drug: L-NMMA Dietary Supplement: Antioxidant Cocktail


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Prevention
Official Title:	Regulation of Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease: A Mechanistic Approach

Resource links provided by NLM:

MedlinePlus related topics: Antioxidants COPD Lung Diseases

Drug Information available for: Sodium salicylate Salsalate Nitric oxide Sapropterin

U.S. FDA Resources

Further study details as provided by Georgia Regents University:

Primary Outcome Measures:

Flow-Mediated Dilation (FMD) [ Time Frame: 1-4 days ] [ Designated as safety issue: No ]
Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function at baseline and several hours after each experimental intervention.

Secondary Outcome Measures:

Active Hyperemia Induced Flow-Mediated Dilation [ Time Frame: 1-4 days ] [ Designated as safety issue: No ]
Active hyperemia induced via localized exercise eliminates the systemic pulmonary limintation and allows for the assessment of skeletal muscle function.


Estimated Enrollment:	240
Study Start Date:	September 2010
Estimated Primary Completion Date:	June 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Increase in NO Bioavailability Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following an increase in nitric oxide bioavailability (BH4).	Drug: Tetrahydrobiopterin (BH4) single dose = 5 mg/kg Other Name: Kuvan (Sapropterin Dihydrochloride)
Experimental: Decrease in NO Bioavailability Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following a decrease in nitric oxide bioavailability (high fat meal).	Dietary Supplement: High Fat Meal The high-fat meal ([900 calories], 50 g of fat, 14 g of saturated fat, 225 mg of cholesterol) will consist of an Egg McMuffin®, Sausage McMuffin®, and two hash brown patties (McDonald's Corporation®). Additional water will be allowed ad libidum. The P.I. along with others have used this meal to attenuate FMD in healthy adults with the mechanism suggested to be through an increase in lipemia induced oxidative stress.
Experimental: Inhibition of NO Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following competitive inhibition of nitric oxide production (L-NMMA).	Drug: L-NMMA dosage range = 4 mg/kg/min
Experimental: Inhibition of Inflammation Brachial artery flow-mediated dilation and biomarkers of inflammation (IL-6, IL-1β, TNF-α, NF-kβ) will be assessed at baseline and following 4 days of therapeutic doses (3,000 mg per day) of Salsalate (non-acetylated salicylate) treatment or placebo. This treatment dose is the standard therapy prescribed for patients with inflammatory arthritis.	Drug: non-acetylated salicylate 3,000 mg per day for 4 days Other Name: Salsalate
Experimental: Inhibition of Oxidative Stress Brachial artery flow-mediated dilation, direct assessment of oxidative stress via EPR spectroscopy (O2-) and biomarkers of oxidative stress (8-isoprostane, LH, SOD) will be assessed at baseline and 2 hours following ingestion of a single oral antioxidant cocktail (1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid.)	Dietary Supplement: Antioxidant Cocktail 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Patients with COPD (GOLD stages II-IV) and matched healthy controls
Caucasian or African American
Both men and women
Current and former smokers

Exclusion Criteria:

GOLD Stage I
Clinical diagnosis of heart disease, hypertension, or metabolic disease
Vasoactive medications (i.e. nitrates, beta-blockers, ACE inhibitors, Viagra, etc.)
Pulmonary hypertension
Hypothyroidism
Hyper-homocysteinemia
Interstitial lung disease
Phenylketonuria
Pregnancy
Sleep apnea
Anemia
Raynod's phenomenon
Gangrene of the digits
History of low platelets or coagulopathies
Aspirin sensitivity or allergy

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01398943

Contacts


Contact: Ryan A Harris, PhD	706-721-5998	ryharris@gru.edu
Contact: Nichole Siegler, BS	706-721-5998	masiegler@gru.edu

Locations


United States, Georgia
Georgia Health Sciences University	Recruiting
Augusta, Georgia, United States, 30912
Contact: Ryan A Harris, PhD 706-721-5998 ryharris@gru.edu

Sponsors and Collaborators

Georgia Regents University

American Heart Association

Investigators


Principal Investigator:	Ryan A Harris, PhD	Georgia Regents University

More Information

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Responsible Party:	Ryan Harris, Assistant Professor, Director Laboratory of Integrative Vascular and Exercise Physiology, Georgia Regents University
ClinicalTrials.gov Identifier:	NCT01398943 History of Changes
Other Study ID Numbers:	AHA00115CS
Study First Received:	July 19, 2011
Last Updated:	December 9, 2014
Health Authority:	United States: Food and Drug Administration

Keywords provided by Georgia Regents University:


flow-mediated dilation arterial stiffness intima-media thickness pulse wave velocity dual energy x-ray absorptiometry inflammatory markers blood lipids tetrahydrobiopterin	Salsalate body mass index hemoglobin A1c complete blood count oxidative stress biomarkers pulmonary function test ankle brachial index

Additional relevant MeSH terms:


Lung Diseases Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Respiratory Tract Diseases Nitric Oxide Anti-Asthmatic Agents Antioxidants Autonomic Agents Bronchodilator Agents Cardiovascular Agents Endothelium-Dependent Relaxing Factors	Free Radical Scavengers Gasotransmitters Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Peripheral Nervous System Agents Pharmacologic Actions Physiological Effects of Drugs Protective Agents Respiratory System Agents Therapeutic Uses Vasodilator Agents

ClinicalTrials.gov processed this record on March 03, 2015

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