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Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT01398943
Recruitment Status : Completed
First Posted : July 21, 2011
Results First Posted : July 25, 2017
Last Update Posted : December 11, 2017
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Ryan Harris, Augusta University

Study Description
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
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 or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: Tetrahydrobiopterin (BH4) Dietary Supplement: Antioxidant Cocktail Not Applicable

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
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
Study Start Date : September 2010
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases
U.S. FDA Resources

Arms and Interventions
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm Intervention/treatment
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


Outcome Measures
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :
  1. 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 :
  1. 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.


Eligibility Criteria
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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
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

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
First Posted: July 21, 2011    Key Record Dates
Results First Posted: July 25, 2017
Last Update Posted: December 11, 2017
Last Verified: November 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