A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

Abstract

RATIONALE:

Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively.

OBJECTIVES:

We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation.

METHODS:

We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks.

MEASUREMENTS AND MAIN RESULTS:

Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups.

CONCLUSIONS:

Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).

• Authors: J Michael Wells, Patricia L Jackson, Liliana Viera, Surya P Bhatt, Joshua Gautney, Guy Handley, R Wilson King, Xin Xu, Amit Gaggar, William C Bailey, Mark T Dransfield, J Edwin Blalock
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 192 Issue 8 Pg. 934-42 (Oct 15 2015) ISSN: 1535-4970 [Electronic] United States
• PMID: 26151090 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Benzamides
• Cyclopropanes
• Phosphodiesterase 4 Inhibitors
• Roflumilast
• Proline
• Epoxide Hydrolases
• Serine Endopeptidases
• PREPL protein, human
• Prolyl Oligopeptidases
• Glycine
• leukotriene A4 hydrolase

Topics

• Aged
• Aminopyridines (therapeutic use)
• Benzamides (therapeutic use)
• Bronchitis, Chronic (drug therapy, enzymology, immunology)
• Cyclopropanes (therapeutic use)
• Double-Blind Method
• Epoxide Hydrolases (immunology, metabolism)
• Exercise Tolerance
• Female
• Forced Expiratory Volume
• Glycine (metabolism)
• Humans
• Inflammation
• Male
• Middle Aged
• Neutrophils (immunology)
• Phosphodiesterase 4 Inhibitors (therapeutic use)
• Proline (metabolism)
• Prolyl Oligopeptidases
• Pulmonary Disease, Chronic Obstructive (drug therapy, enzymology, immunology)
• Quality of Life
• Serine Endopeptidases (immunology, metabolism)
• Signal Transduction (immunology)
• Spirometry
• Sputum (enzymology)
• Treatment Outcome
• Vital Capacity