Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease

Elizabeth Gamble, Diana C. Grootendorst, Christopher E. Brightling, Susannah Troy, Yusheng Qiu, Jie Zhu, Debbie Parker, Dean Matin, Swati Majumdar, Antonio M. Vignola, Claus Kroegel, Ferran Morell, Trevor T. Hansel, Stephen Israel Rennard, Christopher Compton, Ohad Amit, Tri Tat, Jeffrey Edelson, Ian D. Pavord, Klaus F. Rabe & 2 others Neil C. Barnes, Peter K. Jeffery

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-α were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV 1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.

Original languageEnglish (US)
Pages (from-to)976-982
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume168
Issue number8
DOIs
StatePublished - Oct 15 2003

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Phosphodiesterase 4 Inhibitors
Chronic Obstructive Pulmonary Disease
Anti-Inflammatory Agents
Sputum
Analysis of Variance
Placebos
Interleukin-8
Cell Count
Biopsy
Leukocyte Elastase
T-Lymphocyte Subsets
In Situ Hybridization
Neutrophils
Tumor Necrosis Factor-alpha
Macrophages
Cilomilast
Lung
Therapeutics
Genes

Keywords

  • Bronchial biopsy
  • Chronic bronchitis
  • Emphysema
  • Induced sputum
  • Inflammation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease. / Gamble, Elizabeth; Grootendorst, Diana C.; Brightling, Christopher E.; Troy, Susannah; Qiu, Yusheng; Zhu, Jie; Parker, Debbie; Matin, Dean; Majumdar, Swati; Vignola, Antonio M.; Kroegel, Claus; Morell, Ferran; Hansel, Trevor T.; Rennard, Stephen Israel; Compton, Christopher; Amit, Ohad; Tat, Tri; Edelson, Jeffrey; Pavord, Ian D.; Rabe, Klaus F.; Barnes, Neil C.; Jeffery, Peter K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 168, No. 8, 15.10.2003, p. 976-982.

Research output: Contribution to journalArticle

Gamble, E, Grootendorst, DC, Brightling, CE, Troy, S, Qiu, Y, Zhu, J, Parker, D, Matin, D, Majumdar, S, Vignola, AM, Kroegel, C, Morell, F, Hansel, TT, Rennard, SI, Compton, C, Amit, O, Tat, T, Edelson, J, Pavord, ID, Rabe, KF, Barnes, NC & Jeffery, PK 2003, 'Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease', American Journal of Respiratory and Critical Care Medicine, vol. 168, no. 8, pp. 976-982. https://doi.org/10.1164/rccm.200212-1490OC
Gamble, Elizabeth ; Grootendorst, Diana C. ; Brightling, Christopher E. ; Troy, Susannah ; Qiu, Yusheng ; Zhu, Jie ; Parker, Debbie ; Matin, Dean ; Majumdar, Swati ; Vignola, Antonio M. ; Kroegel, Claus ; Morell, Ferran ; Hansel, Trevor T. ; Rennard, Stephen Israel ; Compton, Christopher ; Amit, Ohad ; Tat, Tri ; Edelson, Jeffrey ; Pavord, Ian D. ; Rabe, Klaus F. ; Barnes, Neil C. ; Jeffery, Peter K. / Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease. In: American Journal of Respiratory and Critical Care Medicine. 2003 ; Vol. 168, No. 8. pp. 976-982.
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