Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

This study has been completed.

Sponsor:

Collaborator:

American Heart Association

Information provided by (Responsible Party):

Ryan Harris, Augusta University

ClinicalTrials.gov Identifier:

NCT01398943

First received: July 19, 2011

Last updated: August 15, 2017

Last verified: August 2017

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) Dietary Supplement: Antioxidant Cocktail


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double (Participant, 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: COPD Lung Diseases

Drug Information available for: Nitric oxide

U.S. FDA Resources

Further study details as provided by Ryan Harris, Augusta University:

Primary Outcome Measures:

Flow-Mediated Dilation (FMD) [ Time Frame: Post FMD was taken approximately 110 min after baseline ]
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:

Pulse Wave Velocity [ Time Frame: Post PWV was taken approximately 90 min after baseline ]
A measure of vascular stiffness at baseline and several hours after each experimental intervention.


Enrollment:	60
Study Start Date:	September 2010
Study Completion Date:	June 2015
Primary Completion Date:	June 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: COPD Patients Patients with COPD AOC protocol: 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.) Antioxidant Cocktail: 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid BH4 protocol: 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 after administering a single dose = 5 mg/kg of Tetrahydrobiopterin (BH4)	Drug: Tetrahydrobiopterin (BH4) single dose = 5 mg/kg Other Name: Kuvan (Sapropterin Dihydrochloride) Dietary Supplement: Antioxidant Cocktail 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid
Experimental: Controls Healthy age- and sex- matched controls AOC protocol: 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.) Antioxidant Cocktail: 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid BH4 protocol: 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 after administering a single dose = 5 mg/kg of Tetrahydrobiopterin (BH4)	Drug: Tetrahydrobiopterin (BH4) single dose = 5 mg/kg Other Name: Kuvan (Sapropterin Dihydrochloride) Dietary Supplement: Antioxidant Cocktail 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

Arms

Assigned Interventions

Experimental: COPD Patients

Patients with COPD

AOC protocol: 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.) Antioxidant Cocktail: 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

BH4 protocol: 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 after administering a single dose = 5 mg/kg of Tetrahydrobiopterin (BH4)

Drug: Tetrahydrobiopterin (BH4)

single dose = 5 mg/kg

Other Name: Kuvan (Sapropterin Dihydrochloride)

Dietary Supplement: Antioxidant Cocktail

1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

Experimental: Controls

Healthy age- and sex- matched controls

Drug: Tetrahydrobiopterin (BH4)

single dose = 5 mg/kg

Other Name: Kuvan (Sapropterin Dihydrochloride)

Dietary Supplement: Antioxidant Cocktail

1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

Detailed Description:

Flow-Mediated Dilation (FMD) - Subjects will lie in the supine position for 20 minutes to obtain hemodynamic steady state. A blood pressure cuff (Hokanson) will be placed around the forearm (distal to the Doppler transducer) and rapidly inflated to 250 mmHg for 5 minutes (circulatory arrest). Simultaneous ultrasound images of the vessel (B-mode) and Doppler waveforms will be collected 10 seconds prior to and for 2 minutes following deflation of the cuff. All B-mode images will be analyzed using automated edge detection software (Medical Imaging Applications), while intensity weighted velocity spectra segments will be saved to the GE Logiq 7 hard drive for off-line blood velocity waveform analysis. P.I. has utilized the traditional method of brachial artery flow-mediated dilation (FMD) induced by reactive hyperemia to assess vascular endothelial function in populations ranging from young healthy adults to older adults with pathological conditions.

Spygmocor - Pulse Wave Velocity (PWV) - A Spygmocor® device will be used at baseline and following each protocol to assess PWV. PWV analysis provides a non-invasive assessment of arterial stiffness. Increased arterial stiffness is known to be associated with cardiovascular disease. The participant is required to lie in a resting position for approximately 30-45 minutes. The research assistant will place ECG electrode sensors at the carotid, femoral, radial and distal artery locations. A highly sensitive pen-like device, called a tonometer, is then gently applied to record the velocity of the blood flow between each of the points.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
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

Locations


United States, Georgia
Augusta University
Augusta, Georgia, United States, 30912

Sponsors and Collaborators

Augusta University

American Heart Association

Investigators


Principal Investigator:	Ryan A Harris, PhD	Augusta University

More Information

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Responsible Party:	Ryan Harris, Assistant Professor, Director Laboratory of Integrative Vascular and Exercise Physiology, Augusta University
ClinicalTrials.gov Identifier:	NCT01398943 History of Changes
Other Study ID Numbers:	AHA00115CS
Study First Received:	July 19, 2011
Results First Received:	November 17, 2016
Last Updated:	August 15, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes

Keywords provided by Ryan Harris, Augusta University:


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

Additional relevant MeSH terms:


Lung Diseases Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Chronic Disease Respiratory Tract Diseases Disease Attributes Pathologic Processes Vitamins Vitamin E Thioctic Acid Nitric Oxide Antioxidants Micronutrients Growth Substances	Physiological Effects of Drugs Bronchodilator Agents Autonomic Agents Peripheral Nervous System Agents Anti-Asthmatic Agents Respiratory System Agents Free Radical Scavengers Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Endothelium-Dependent Relaxing Factors Vasodilator Agents Gasotransmitters Protective Agents Vitamin B Complex

ClinicalTrials.gov processed this record on September 20, 2017

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