Electrophilic Fatty Acid Derivatives in Asthma

NCT ID: NCT01733485

Last Updated: 2017-07-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2017-06-30

Brief Summary

Asthma is an inflammatory disease, which means it causes swelling in the lungs to cause shortness of breath and/or wheezing. There are several asthma medications that help to reduce this problem.

The objective of this research study is to characterize the presence of electrophilic fatty acids in the bronchial airway of subjects with controlled asthma at baseline and after treatment with Aspirin, Indomethacin, or no treatment at all. The presence of electrophilic fatty acids may indicate inflammation. Aspirin and Indomethacin are known to respectively increase and inhibit the formation of electrophilic fatty acids. By gaining a better understanding of how electrophilic fatty acids work and how they respond to different treatment, researchers hope to be able to find better ways to lessen airway inflammation in asthma in the future.

Detailed Description

Relevant to asthma, the chemical identities and potent anti-inflammatory signaling actions of endogenously-produced Electrophilic Fatty acid OXidation products (EFOXs) have recently been described. Endogenous EFOXs include nitro and alpha and beta-unsaturated ketone derivatives of unsaturated fatty acids that are generated as byproducts of a) fatty acid oxidation and nitration by inflammatory-derived reactive species and b) enzymatic fatty acid oxygenation reactions catalyzed by cyclooxygenase-2 and lipoxygenases. Recent data reveal that multiple salutary post-translational protein modifications are induced by EFOXs. Specifically, the covalent adduction of functionally-significant thiols in signaling proteins occurs, with these reactions modulating critical inflammatory signaling pathways. These signaling proteins include the nuclear lipid receptor PPARg and the redox-sensitive transcription factors NF kappaB and Keap1/Nrf2. This proposed research investigates the concept that the reversible reaction of EFOXs with critical transcription factors results in the regulation of adaptive responses to inflammation.

In this clinical study, bronchoalveolar lavage fluid (BAL) will be obtained from asthmatics treated with COX-2 inhibitors that enhance (aspirin) and inhibit (indomethacin) COX-2 dependent EFOX generation, as well as from those assigned to no intervention. BAL will be obtained from healthy, non-smoking adults with controlled asthma having at least a 12% increase in FEV1 after short-acting bronchodilator treatment or a positive methacholine response (reduction in FEV1 ≥ 20% at or before 16 mg/ml). A total of 30 asthmatic subjects will be randomized (10 per arm) to a) aspirin, b) indomethacin or c) no intervention groups

Conditions

Asthma; Electrophilic Fatty Acids

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Aspirin

Group Type: ACTIVE_COMPARATOR

Aspirin

Intervention Type: DRUG

500 mg/8 h for 5 days

Indomethacin

Group Type: ACTIVE_COMPARATOR

Indomethacin

Intervention Type: DRUG

25 mg/8 h for 5 days

Control

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Aspirin

500 mg/8 h for 5 days

Intervention Type: DRUG

Indomethacin

25 mg/8 h for 5 days

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Diagnosis of mild to moderate asthma
• No evidence of a previous asthma exacerbation in the preceding 6 weeks (defined as increased severity of respiratory symptoms requiring systemic steroids or escalation of therapy; b) asthma control questionnaire (ACQ) score less than 1.

Exclusion Criteria

• Diagnosis of severe asthma, vocal cord dysfunction, cystic fibrosis, COPD, CAD, hypertension, diabetes or renal failure that is not well controlled
• Greater than 10 pack-year history of smoking;
• Stopped smoking less than 1 year prior to study,
• Taking any aspirin or other NSAIDS on the week prior to bronchoscopy,
• Taking omega-3 fatty acid supplements
• If a subject is currently taking an omega-3 fatty acid supplement and is interested in the study, after a 30 day wash out, the participant can be re-screened and evaluated for participation.
• Taking pioglitazone or rosiglitazone (synthetic thiazolidinedione PPARg ligands);
• other known pulmonary diseases;
• Inability to undergo bronchoscopy,
• Contraindications or allergy to aspirin or indomethacin,
• Asthmatics with known hypersensitivity to aspirin, and
• Steroid (systemic) dependent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sally E. Wenzel MD

OTHER

Sponsor Role: lead

Responsible Party

Sally E. Wenzel MD

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Fernando Holguin, MD MPH

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

U10HL098177

Identifier Type: NIH

Identifier Source: org_study_id

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