help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Published ahead of print on June 19, 2003, doi:10.1164/rccm.200212-1490OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 8, October 2003, 976-982

A more recent version of this article appeared on October 15, 2003
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200212-1490OCv1
168/8/976    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gamble, E.
Right arrow Articles by Jeffery, P. K
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gamble, E.
Right arrow Articles by Jeffery, P. K

Submitted on January 28, 2003
Accepted on June 16, 2003

Anti-inflammatory effects of the phosphodiesterase 4 inhibitor cilomilast (Ariflo) in COPD

Elizabeth Gamble1, Diana C Grootendorst2, Christopher E Brightling3, Susannah Troy4, Yusheng Qui5, Jie Zhu5, Debbie Parker3, Antonio M Vignola6, Claus Kroegel7, Ferran Morell8, Trevor T Hansel9, Stephen I Rennard10, Christopher Compton4, Amit Ohad11, Tat Tri12, Jeffrey Edelson11, Ian D Pavord3, Klaus F Rabe3, Neil C Barnes1, and Peter K Jeffery5*

1 Respiratory Medicine, London Chest Hospital, London, United Kingdom, 2 Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands, 3 Respiratory Medicine, Glenfield Hospital, Leicester, United Kingdom, 4 Glaxo Smithkline Pharmaceuticals, Harlow, United Kingdom, 5 Lung Pathology and Gene Therapy, Faculty of Medicine, Imperial College, Royal Brompton Hospital, London, United Kingdom, 6 Instituto di Fisiopatologia Respiratoria, Palerma, Italy, 7 Pneumology and Allergy, University Medical Clinic, Jena, Germany, 8 Servei de Pneumologia, Clinica Tres Torres, Hopital Vall d'Hebron, Barcelona, Spain, 9 Royal Brompton Hospital, London, United Kingdom, 10 University of Nebraska Medical Center, Omaha, NE, USA, 11 Glaxo Smithkline Pharmaceuticals, Collegeville, PA, USA, 12 Imperial College School of Medicine, London, United Kingdom

* To whom correspondence should be addressed. E-mail: p.jeffery{at}ic.ac.uk.

Cilomilast (Ariflo), a new oral phosphodiesterase-4 (PDE4) selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its anti-inflammatory effects in fifty-nine patients with COPD randomized to receive cilomilast 15mg bid or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at 5 further visits. IL-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets and CD68+ macrophages. Cells expressing the genes for IL-8 and TNF{alpha} were identified by in-situ hybridisation and quantified. Compared to placebo, ANOVA analysis of the change from baseline showed that cilomilast did not alter any sputum endpoint, nor FEV1. 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. PDE4 inhibitors represent a promising new class of anti-inflammatory treatment in this disease.
Key words: inflammation, bronchial biopsy, induced sputum, emphysema, chronic bronchitis




This article has been cited by other articles:


Home page
 Eur Respir JHome page
J. Vestbo, L. Tan, G. Atkinson, J. Ward, and on behalf of the UK-500,001 Global Study Team
A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD
Eur. Respir. J., May 1, 2009; 33(5): 1039 - 1044.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
Y. Nakanishi, D. Kobayashi, Y. Asano, T. Sakurai, M. Kashimura, S. Okuyama, Y. Yoneda, S. D. Shapiro, and K. Takayama
Clarithromycin Prevents Smoke-induced Emphysema in Mice
Am. J. Respir. Crit. Care Med., February 15, 2009; 179(4): 271 - 278.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. Cazzola, W. MacNee, F. J. Martinez, K. F. Rabe, L. G. Franciosi, P. J. Barnes, V. Brusasco, P. S. Burge, P. M. A. Calverley, B. R. Celli, et al.
Outcomes for COPD pharmacological trials: from lung function to biomarkers
Eur. Respir. J., February 1, 2008; 31(2): 416 - 469.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
J. B. Snoeck-Stroband, T. S. Lapperre, M. M. E. Gosman, H. M. Boezen, W. Timens, N. H. T. ten Hacken, J. K. Sont, P. J. Sterk, P. S. Hiemstra, and the Groningen Leiden Universities Corticosteroids
Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies
Eur. Respir. J., January 1, 2008; 31(1): 70 - 77.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
S. Siddiqui, F. Hollins, S. Saha, and C. E. Brightling
Inflammatory cell microlocalisation and airway dysfunction: cause and effect?
Eur. Respir. J., December 1, 2007; 30(6): 1043 - 1056.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
D. C Grootendorst, S. A Gauw, R. M Verhoosel, P. J Sterk, J. J Hospers, D. Bredenbroker, T. D Bethke, P. S Hiemstra, and K. F Rabe
Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD
Thorax, December 1, 2007; 62(12): 1081 - 1087.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
N. Barnes
Reducing inflammation in COPD: the evidence builds
Thorax, November 1, 2007; 62(11): 927 - 928.
[Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
N. A. Hanania and J. F. Donohue
Pharmacologic Interventions in Chronic Obstructive Pulmonary Disease: Bronchodilators
Proceedings of the ATS, October 1, 2007; 4(7): 526 - 534.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
W. C. Bailey and D. P. Tashkin
Pharmacologic Therapy: Novel Approaches for Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, October 1, 2007; 4(7): 543 - 548.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
Y. Hoshino, T. Nakamura, A. Sato, M. Mishima, J. Yodoi, and H. Nakamura
Neurotropin Demonstrates Cytoprotective Effects in Lung Cells through the Induction of Thioredoxin-1
Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 438 - 446.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. Gamble, D. C. Grootendorst, K. Hattotuwa, T. O'Shaughnessy, F. S. F. Ram, Y. Qiu, J. Zhu, A. M. Vignola, C. Kroegel, F. Morell, et al.
Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis
Eur. Respir. J., September 1, 2007; 30(3): 467 - 471.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
D. J. Powrie, T. M. A. Wilkinson, G. C. Donaldson, P. Jones, K. Scrine, K. Viel, S. Kesten, and J. A. Wedzicha
Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD
Eur. Respir. J., September 1, 2007; 30(3): 472 - 478.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
S. Battaglia, T. Mauad, A. M van Schadewijk, A. M Vignola, K. F Rabe, V. Bellia, P. J Sterk, and P. S Hiemstra
Differential distribution of inflammatory cells in large and small airways in smokers
J. Clin. Pathol., August 1, 2007; 60(8): 907 - 911.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. M. A. Calverley, F. Sanchez-Toril, A. McIvor, P. Teichmann, D. Bredenbroeker, and L. M. Fabbri
Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., July 15, 2007; 176(2): 154 - 161.
[Abstract] [Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
S. D Martina, M. S Ismail, and K. S Vesta
Cilomilast: Orally Active Selective Phosphodiesterase-4 Inhibitor for Treatment of Chronic Obstructive Pulmonary Disease
Ann. Pharmacother., October 1, 2006; 40(10): 1822 - 1828.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. J. Barnes, B. Chowdhury, S. A. Kharitonov, H. Magnussen, C. P. Page, D. Postma, and M. Saetta
Pulmonary Biomarkers in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., July 1, 2006; 174(1): 6 - 14.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
O. Leclerc, V. Lagente, J-M. Planquois, C. Berthelier, M. Artola, T. Eichholtz, C. P. Bertrand, and F. Schmidlin
Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice
Eur. Respir. J., June 1, 2006; 27(6): 1102 - 1109.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
L. M. Fabbri, F. Luppi, B. Beghe, and K. F. Rabe
Update in chronic obstructive pulmonary disease 2005.
Am. J. Respir. Crit. Care Med., May 15, 2006; 173(10): 1056 - 1065.
[Full Text] [PDF]

Home page
 ThoraxHome page
S Scott, P Walker, and P M A Calverley
COPD exacerbations {middle dot} 4: Prevention
Thorax, May 1, 2006; 61(5): 440 - 447.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
N. C. Barnes, Y.-S. Qiu, I. D. Pavord, D. Parker, P. A. Davis, J. Zhu, M. Johnson, N. C. Thomson, P. K. Jeffery, and on behalf of the SCO30005 Study Group
Antiinflammatory Effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Lung Disease
Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 736 - 743.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
Q. Hamid
How can we improve our assessment of inflammation in clinical studies of COPD that use bronchial biopsies?
Eur. Respir. J., February 1, 2006; 27(2): 248 - 249.
[Full Text] [PDF]

Home page
 Eur Respir JHome page
E. Gamble, Y. Qiu, D. Wang, J. Zhu, A. M. Vignola{dagger}, C. Kroegel, F. Morell, T. T. Hansel, I. D. Pavord, K. F. Rabe, et al.
Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design
Eur. Respir. J., February 1, 2006; 27(2): 293 - 299.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
S. I. Rennard, N. Schachter, M. Strek, K. Rickard, and O. Amit
Cilomilast for COPD: Results of a 6-Month, Placebo-Controlled Study of a Potent, Selective Inhibitor of Phosphodiesterase 4
Chest, January 1, 2006; 129(1): 56 - 66.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
M. A. Giembycz
Phosphodiesterase-4: Selective and Dual-Specificity Inhibitors for the Therapy of Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, November 1, 2005; 2(4): 326 - 333.
[Abstract] [Full Text] [PDF]

Home page
 ERRHome page
P. J. Barnes
New approaches to COPD
Eur. Respir. Rev., September 1, 2005; 14(94): 2 - 11.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P. J. Barnes and R. A. Stockley
COPD: current therapeutic interventions and future approaches
Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. A. Wallace, L. A. Johnston, E. Huston, D. MacMaster, T. M. Houslay, Y.-F. Cheung, L. Campbell, J. E. Millen, R. A. Smith, I. Gall, et al.
Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene
Mol. Pharmacol., June 1, 2005; 67(6): 1920 - 1934.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
R. Buhl and S. G. Farmer
Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2005; 2(1): 83 - 93.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. J. Smith, L. B. Cieslinski, R. Newton, L. E. Donnelly, P. S. Fenwick, A. G. Nicholson, P. J. Barnes, M. S. Barnette, and M. A. Giembycz
Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8+ T-Lymphocytes
Mol. Pharmacol., December 1, 2004; 66(6): 1679 - 1689.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
S. I. Rennard
Antiinflammatory Therapies Other Than Corticosteroids
Proceedings of the ATS, November 1, 2004; 1(3): 282 - 287.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
D N R Payne, Y Qiu, J Zhu, L Peachey, M Scallan, A Bush, and P K Jeffery
Airway inflammation in children with difficult asthma: relationships with airflow limitation and persistent symptoms
Thorax, October 1, 2004; 59(10): 862 - 869.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
R. D. Murdoch, B. Zussman, J. P. Schofield, and D. M. Webber
Lack of Pharmacokinetic Interactions Between Cilomilast and Theophylline or Smoking in Healthy Volunteers
J. Clin. Pharmacol., September 1, 2004; 44(9): 1046 - 1053.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
D. C. Grootendorst and K. F. Rabe
Mechanisms of Bronchial Hyperreactivity in Asthma and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2004; 1(2): 77 - 87.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H. A.M. Kerstjens and W. Timens
Phosphodiesterase 4 Inhibitors: Antiinflammatory Therapy for Chronic Obstructive Pulmonary Disease at Last?
Am. J. Respir. Crit. Care Med., October 15, 2003; 168(8): 914 - 915.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society 		  ATS Par News