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The PDE4 inhibitor roflumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD
  1. Diana C Grootendorst (d.c.grootendorst{at}lumc.nl)
  1. Leiden University Medical Center, Netherlands
    1. Stefanie A Gauw
    1. Leiden University Medical Center, Netherlands
      1. Renate M Verhoosel
      1. Leiden University Medical Center, Netherlands
        1. Peter J. Sterk (p.j.sterk{at}lumc.nl)
        1. Leiden University Medical Center, Netherlands
          1. Jeannette J Hospers
          1. ALTANA Pharma, Germany
            1. Dirk Bredenbroker
            1. ALTANA Pharma, Germany
              1. Thomas D Bethke
              1. ALTANA Pharma, Germany
                1. Pieter S Hiemstra (p.s.hiemstra{at}lumc.nl)
                1. Leiden University Medical Center, Netherlands
                  1. Klaus F. Rabe (k.f.rabe{at}lumc.nl)
                  1. Leiden University Medical Center, Netherlands

                    Abstract

                    Roflumilast is a targeted, oral, once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in COPD. Results from in vitro studies with roflumilast indicate that roflumilast has anti-inflammatory properties that may be applicable for the treatment of COPD. In this cross-over study, 38 patients with COPD (mean (SD) age 63.1 (7.0) y, post-bronchodilator FEV1 61.0 (12.6) %predicted) received 500 μg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected prior to and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Roflumilast significantly reduced the absolute number of neutrophils and eosinophils per gram of sputum, compared with placebo, by 35.5% (95%CI 15.6, 50.7; p=0.0017) and 50.0% (26.8, 65.8; p=0.0005), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p>0.05). Soluble IL-8, neutrophil elastase, ECP and á2-macroglobulin in sputum, together with TNFá release from blood cells, were significantly reduced by roflumilast compared to placebo treatment (p<0.05 for all). Post-bronchodilator FEV1 improved significantly during roflumilast as compared to placebo treatment. The mean difference between treatments was 68.7 (12.9, 124.5) mL (p=0.018). In conclusion, PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of COPD patients. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV1.

                    • anti-inflammatory
                    • clinical trial
                    • inflammation
                    • lung function

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