Text Size

Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

This study is currently recruiting participants.
Verified August 2012 by Georgia Regents University
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Ryan Harris, Georgia Health Sciences University
ClinicalTrials.gov Identifier:
NCT01398943
First received: July 19, 2011
Last updated: August 6, 2012
Last verified: August 2012
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:

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 2014 (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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01398943

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

Locations
United States, Georgia
Georgia Health Sciences University Recruiting
Augusta, Georgia, United States, 30912
Contact: Ryan A Harris, PhD     706-721-5998     ryharris@georgiahealth.edu    
Sponsors and Collaborators
Georgia Regents University
American Heart Association
Investigators
Principal Investigator: Ryan A Harris, PhD Georgia Regents University
  More Information

Publications:

Responsible Party: Ryan Harris, Assistant Professor, Director Laboratory of Integrative Vascular and Exercise Physiology, Georgia Health Sciences University
ClinicalTrials.gov Identifier: NCT01398943     History of Changes
Other Study ID Numbers: AHA00115CS
Study First Received: July 19, 2011
Last Updated: August 6, 2012
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:
Chronic Disease
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Disease Attributes
Pathologic Processes
Respiratory Tract Diseases
Antioxidants
Thioctic Acid
Nitric Oxide
Salicylates
Sodium Salicylate
Salicylsalicylic acid
Omega-N-Methylarginine
 Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Free Radical Scavengers

ClinicalTrials.gov processed this record on May 16, 2013