591
Views
37
CrossRef citations to date
0
Altmetric
Drug Discovery Case History

The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease

, , &
Pages 733-744 | Received 23 Dec 2015, Accepted 27 Apr 2016, Published online: 21 May 2016

References

  • Chung KF. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol. 2006 8;533:110–117. doi:10.1016/j.ejphar.2005.12.059
  • Castro A, Jerez MJ, Gil C, et al. Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors. Med Res Rev. 2005;25:229–244. doi:10.1002/(ISSN)1098-1128.
  • Maurice DH, Ke H, Ahmad F, et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13:290–314. doi:10.1038/nrd4228.
  • Page CP, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol. 2011;204:391–414. doi:10.1007/978-3-642-17969-3_17.
  • Spina D, Landells LJ, Page CP. The role of phosphodiesterase enzymes in allergy and asthma. Adv Pharmacol. 1998;44:33–89.
  • Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci. 2010;35:91–100. doi:10.1016/j.tibs.2009.09.007.
  • Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1–18. doi:10.1042/BJ20021698.
  • Billington CK, Le Jeune IR, Young KW, et al. A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2008;38:1–7. doi:10.1165/rcmb.2007-0171OC.
  • Schudt C, Tenor H, Hatzelmann A. PDE isoenzymes as targets for anti-asthma drugs. Eur Respir J. 1995;8:1179–1183.
  • Jin SL, Goya S, Nakae S, et al. Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol. 2010;126:1252–9.e12. doi:10.1016/j.jaci.2010.08.014.
  • Matera MG, Page C, Cazzola M. PDE inhibitors currently in early clinical trials for the treatment of asthma. Expert Opin Investig Drugs. 2014;23:1267–1275. doi:10.1517/13543784.2014.921157.
  • Matera MG, Rogliani P, Calzetta L, et al. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs. 2014;74:1983–1992. doi:10.1007/s40265-014-0303-8.
  • Barber R, Baillie GS, Bergmann R, et al. Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers. Am J Physiol Lung Cell Mol Physiol. 2004;287:L332–43. doi:10.1152/ajplung.00384.2003.
  • Gobejishvili L, Avila DV, Barker DF, et al. S-adenosylmethionine decreases lipopolysaccharide-induced phosphodiesterase 4B2 and attenuates tumor necrosis factor expression via cAMP/protein kinase A pathway. J Pharmacol Exp Ther. 2011;337:433–443. doi:10.1124/jpet.110.174268.
  • Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol. 2012;12:275–286. doi:10.1016/j.coph.2012.02.016.
  • Brown WM. Cilomilast GlaxoSmithKline. Curr Opin Investig Drugs. 2005;6:545–558.
  • Celgene. Oral OTEZLA® (apremilast) approved by the European Commission for the treatment of both patients with psoriasis and psoriatic arthritis [cited 2016 Mar 18]. Available from: http://ir.celgene.com/releasedetail.cfm?releaseid=891728.
  • Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159:842–855. doi:10.1111/j.1476-5381.2009.00559.x.
  • Amschler H Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors. PCT Patent WO95/01338;1995.
  • Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297:267–279.
  • Giembycz MA, Field SK. Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010;4:147–158.
  • Knebel NG, Herzog R, Reutter F, et al. Sensitive quantification of roflumilast and roflumilast N-oxide in human plasma by LC-MS/MS employing parallel chromatography and electrospray ionisation. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;893-894:82–91. doi:10.1016/j.jchromb.2012.02.038.
  • Lahu G, Hünnemeyer A, Diletti E, et al. Population pharmacokinetic modelling of roflumilast and roflumilast N-oxide by total phosphodiesterase-4 inhibitory activity and development of a population pharmacodynamic-adverse event model. Clin Pharmacokinet. 2010;49:589–606. doi:10.2165/11536600-000000000-00000.
  • Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010;23:235–256. doi:10.1016/j.pupt.2010.03.011.
  • Mori F, Pérez-Torres S, De Caro R, et al. The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J Chem Neuroanat. 2010;40:36–42. doi:10.1016/j.jchemneu.2010.03.004.
  • Bundschuh DS, Eltze M, Barsig J, et al. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001;297:280–290.
  • Jones NA, Boswell-Smith V, Lever R, et al. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther. 2005;18:93–101. doi:10.1016/j.pupt.2004.10.001.
  • Mata M, Sarria B, Buenestado A, et al. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax. 2005;60:144–152. doi:10.1136/thx.2004.025692.
  • Buenestado A, Grassin-Delyle S, Guitard F, et al. Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. Br J Pharmacol. 2012;165:1877–1890. doi:10.1111/j.1476-5381.2011.01667.x.
  • Kwak HJ, Song JS, Heo JY, et al. Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-κB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation. J Pharmacol Exp Ther. 2005;315:1188–1195. doi:10.1124/jpet.105.092056.
  • Buenestado A, Chaumais MC, Grassin-Delyle S, et al. Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma. PLoS One. 2013;8:e74640. doi:10.1371/journal.pone.0074640.
  • Victoni T, Gicquel T, Bodin A, et al. Roflumilast n-oxide associated with PGE2 prevents the neutrophil elastase-induced production of chemokines by epithelial cells. Int Immunopharmacol. 2015;30:1–8. doi:10.1016/j.intimp.2015.11.019.
  • Victoni T, Gleonnec F, Lanzetti M, et al. Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells. PLoS One. 2014;9:e85243. doi:10.1371/journal.pone.0085243.
  • Milara J, Armengot M, Bañuls P, et al. Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro. Br J Pharmacol. 2012;166:2243–2262. doi:10.1111/j.1476-5381.2012.01929.x.
  • Schmid A, Baumlin N, Ivonnet P, et al. Roflumilast partially reverses smoke-induced mucociliary dysfunction. Respir Res. 2015;16:135. doi:10.1186/s12931-015-0294-3.
  • Martorana PA, Beume R, Lucattelli M, et al. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med. 2005;172:848–853. doi:10.1164/rccm.200411-1549OC.
  • Martorana PA, Lunghi B, Lucattelli M, et al. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med. 2008;8:17. doi:10.1186/1471-2466-8-17.
  • Fitzgerald M, Spicer D, Mcaulay AE, et al. Roflumilast but not methylprednisolone inhibited cigarette smoke-induced pulmonary inflammation in guinea pigs [abstract]. Eur Respir J Suppl. 2006;663s:P3850.
  • McCluskie K, Klein U, Linnevers C, et al. Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. J Pharmacol Exp Ther. 2006;319:468–476. doi:10.1124/jpet.106.105080.
  • Susuki-Miyata S, Miyata M, Lee BC, et al. Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. Proc Natl Acad Sci U S A. 2015;112:E1800–9. doi:10.1073/pnas.1418716112.
  • Sanz MJ, Cortijo J, Taha MA, et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007;152:481–492. doi:10.1038/sj.bjp.0707428.
  • Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet. 2005;365:167–175. doi:10.1016/S0140-6736(05)17708-3.
  • Grootendorst DC, Gauw SA, Verhoosel RM, et al. The PDE4 inhibitor roflumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD. Thorax. 2007;62:1081–1087. doi:10.1136/thx.2006.075937.
  • Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast – an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366:563–571. doi:10.1016/S0140-6736(05)67100-0.
  • Calverley PM, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176:154–161. doi:10.1164/rccm.200610-1563OC.
  • Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53–67. doi:10.1111/j.1476-5381.2011.01218.x.
  • Garnock-Jones KP. Roflumilast: a review in COPD. Drugs. 2015;75:1645–1656. doi:10.1007/s40265-015-0463-1.
  • Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18. doi:10.1186/1465-9921-12-122.
  • Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685–694.
  • Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest. 2013;143:1302–1311. doi:10.1378/chest.12-1489.
  • Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695–703. doi:10.1016/S0140-6736(09)61252-6.
  • Pan L, Guo YZ, Zhang B, et al. Does roflumilast improve dyspnea in patients with chronic obstructive pulmonary disease? A meta-analysis. J Thorac Dis. 2013;5:422–429. doi:10.3978/j.issn.2072-1439.2013.08.26.
  • Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31:416–469. doi:10.1183/09031936.00099306.
  • O’Donnell DE, Bredenbröker D, Brose M, et al. Physiological effects of roflumilast at rest and during exercise in COPD. Eur Respir J. 2012;39:1104–1112. doi:10.1183/09031936.00096511.
  • Lee SD, Hui DS, Mahayiddin AA, et al. Roflumilast in Asian patients with COPD: a randomized placebo-controlled trial. Respirology. 2011;16:1249–1257. doi:10.1111/j.1440-1843.2011.02038.x.
  • Zheng J, Yang J, Zhou X, et al. Roflumilast for the treatment of COPD in an Asian population: a randomized, double-blind, parallel-group study. Chest. 2014;145:44–52. doi:10.1378/chest.13-1252.
  • Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;11:CD002309.
  • Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2013;7:13–24. doi:10.1177/1753465812466167.
  • Yan JH, Gu WJ, Pan L. Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: a meta-analysis. Pulm Pharmacol Ther. 2014;27:83–89. doi:10.1016/j.pupt.2013.04.004.
  • Luo J, Wang K, Liu D, et al. Can roflumilast, a phosphodiesterase-4 inhibitor, improve clinical outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease? A meta-analysis. Respir Res. 2016;17:18. doi:10.1186/s12931-016-0330-y.
  • Taegtmeyer AB, Leuppi JD, Kullak-Ublick GA. Roflumilast – a phosphodiesterase-4 inhibitor licensed for add-on therapy in severe COPD. Swiss Med Wkly. 2012;142:w13628.
  • Beghè B, Rabe KF, Fabbri LM. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am J Respir Crit Care Med. 2013;188:271–278. doi:10.1164/rccm.201301-0021PP.
  • White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144:758–765. doi:10.1378/chest.12-2332.
  • European Medicines Agency. Daxas – Roflumilast [cited 2015 Dec 20]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/001179/WC500089626.pdf.
  • FDA. US Food and Drug Administration FDA approves new drug to treat chronic obstructive pulmonary disease [cited 2015 Dec 20]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncemen ts/ucm244989. htm.
  • Wan Y, Sun SX, Corman S, et al. A longitudinal, retrospective cohort study on the impact of roflumilast on exacerbations and economic burden among chronic obstructive pulmonary disease patients in the real world. Int J Chron Obstruct Pulmon Dis. 2015;10:2127–2136. doi:10.2147/COPD.S80106.
  • Fu AZ, Sun SX, Huang X, et al. Lower 30-day readmission rates with roflumilast treatment among patients hospitalized for chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:909–915. doi:10.2147/COPD.S83082.
  • Worndl E, Hunt EB, Kennedy MP, et al. Roflumilast in COPD. Chest. 2015;148:e31. doi:10.1378/chest.15-0664.
  • Yu T, Fain K, Boyd CM, et al. Benefits and harms of roflumilast in moderate to severe COPD. Thorax. 2014;69:616–622. doi:10.1136/thoraxjnl-2013-203884.
  • Puhan MA, Yu T, Boyd CM, et al. Quantitative benefit-harm assessment for setting research priorities: the example of roflumilast for patients with COPD. BMC Med. 2015;13:157. doi:10.1186/s12916-015-0398-0.
  • De Backer W, Vos W, Van Holsbeke C, et al. The effect of roflumilast in addition to BA/LAMA/ICS treatment in COPD patients. Eur Respir J. 2014;44:527–529. doi:10.1183/09031936.00011714.
  • Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385:857–866. doi:10.1016/S0140-6736(14)62410-7.
  • Muñoz-Esquerre M, Diez-Ferrer M, Montón C, et al. Roflumilast added to triple therapy in patients with severe COPD: a real life study. Pulm Pharmacol Ther. 2015;30:16–21. doi:10.1016/j.pupt.2014.10.002.
  • Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD [Updated 2016; cited 2016 Mar 17]. Available from: http://www.goldcopd.org/uploads/users/files/GOLD_Report%202016.pdf.
  • Cazzola M, Rogliani P, Novelli L, et al. Inhaled corticosteroids for chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2013;14:2489–2499. doi:10.1517/14656566.2013.848856.
  • Wouters EFM, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005;60:480–487. doi:10.1136/thx.2004.034280.
  • Hanania NA, Calverley PM, Dransfield MT, et al. Pooled subpopulation analyses of the effects of roflumilast on exacerbations and lung function in COPD. Respir Med. 2014;108:366–375. doi:10.1016/j.rmed.2013.09.018.
  • Lahu G, Facius A. Application of population pharmacokinetic modeling to explore the impact of alternative roflumilast dosing regimens on tolerability. Int J Clin Pharmacol Ther. 2013;51:832–836.
  • Hwang H, Shin JY, Park KR, et al. Effect of a dose-escalation regimen for improving adherence to roflumilast in patients with chronic obstructive pulmonary disease. Tuberc Respir Dis (Seoul). 2015;78(4):321–325. doi:10.4046/trd.2015.78.4.321
  • Samyshkin Y, Schlunegger M, Haefliger S, et al. Cost-effectiveness of roflumilast in combination with bronchodilator therapies in patients with severe and very severe COPD in Switzerland. Int J Chron Obstruct Pulmon Dis. 2013;8:79–87. doi:10.2147/COPD.S37486.
  • Moll K, Sun SX, Ellis JJ, et al. Impact of roflumilast on exacerbations of COPD, health care utilization, and costs in a predominantly elderly Medicare Advantage population. Int J Chron Obstruct Pulmon Dis. 2015 Mar;16(10):565–576.
  • Samyshkin Y, Kotchie RW, Mörk AC, et al. Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic bronchitis in the United Kingdom. Eur J Health Econ. 2014;15:69–82. doi:10.1007/s10198-013-0456-5.
  • Bateman ED, O’Byrne PM, Buhl R, et al. Roflumilast for asthma: weighing the evidence. Pulm Pharmacol Ther. 2015;35(Suppl):S1–3. doi:10.1016/j.pupt.2015.08.001.
  • Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131:636–645. doi:10.1016/j.jaci.2012.12.1564.
  • Cazzola M, Picciolo S, Matera MG. Roflumilast in chronic obstructive pulmonary disease: evidence from large trials. Expert Opin Pharmacother. 2010;11(3):441–449. doi:10.1517/14656560903555201.
  • Committee for proprietary medicinal products (CPMP). Points to consider on clinical investigation of medicinal products in the chronic treatment of patients with chronic obstructive pulmonary disease (COPD) [ cited 2015 Dec 21]. Available from: http://www.emea.europa.eu/pdfs/human/ewp/056298en.pdf.
  • Walker EP Panel votes against new PDE4 inhibitor for COPD [updated 2010; [cited 2015 Dec 21]. Available from: http://www.medpagetoday.com/Pulmonology/SmokingCOPD/19448.
  • Cazzola M. The divergent opinions of regulatory authorities on roflumilast are puzzling but we need new drugs for treating chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2010;4:195–198. doi:10.1177/1753465810377636.
  • Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894–942. doi:10.1378/chest.14-1676.
  • Kankaanranta H, Harju T, Kilpeläinen M, et al. Diagnosis and pharmacotherapy of stable chronic obstructive pulmonary disease: the Finnish guidelines. Basic Clin Pharmacol Toxicol. 2015;116:291–307. doi:10.1111/bcpt.12366.
  • Miravitlles M, Soler-Cataluña JJ, Calle M, et al. Guía Española de la EPOC (GesEPOC). Tratamiento farmacológico de la EPOC estable. Aten Primaria. 2012;44:425–437. doi:10.1016/j.aprim.2012.04.005.
  • Bettoncelli G, Blasi F, Brusasco V, et al. The clinical and integrated management of COPD. An official document of AIMAR (Interdisciplinary Association for Research in Lung Disease), AIPO (Italian Association of Hospital Pulmonologists), SIMER (Italian Society of Respiratory Medicine), SIMG (Italian Society of General Medicine). Multidiscip Respir Med. 2014;9:25.
  • Koblizek V, Chlumsky J, Zindr V, et al. Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157:189–201. doi:10.5507/bp.2013.039.
  • Cazzola M, Rogliani P, Matera MG. Escalation and de-escalation of therapy in COPD: myths, realities and perspectives. Drugs. 2015;75:1575–1585. doi:10.1007/s40265-015-0450-6.
  • Milara J, Lluch J, Almudever P, et al. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014;134:314–322. doi:10.1016/j.jaci.2014.02.001.
  • Segreti A, Stirpe E, Rogliani P, et al. Defining phenotypes in COPD: an aid to personalized healthcare. Mol Diagn Ther. 2014;18:381–388. doi:10.1007/s40291-014-0100-9.
  • Tashkin DP. Roflumilast: the new orally active, selective phophodiesterase-4 inhibitor, for the treatment of COPD. Expert Opin Pharmacother. 2014;15:85–96. doi:10.1517/14656566.2013.837159.
  • Barker BL, Brightling CE. Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clin Sci (Lond). 2013;124:371–387. doi:10.1042/CS20120340.
  • Suissa S, Rabe KF. Point: were industry-sponsored roflumilast trials appropriate? yes. Chest. 2014;145:937–939. doi:10.1378/chest.14-0112.
  • Rho J, Ho N, Prasad V. Counterpoint: were industry-sponsored roflumilast trials appropriate? no. Chest. 2014;145:939–942. doi:10.1378/chest.14-0114.
  • Sapey E, Stockley RA. COPD exacerbations. 2: aetiology. Thorax. 2006;61:250–258. doi:10.1136/thx.2005.041822.
  • Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit gCare Med. 2011;184:662–671. doi:10.1164/rccm.201104-0597OC.
  • Wells JM, Jackson PL, Viera L, et al. A randomized, placebo-controlled trial of roflumilast effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:934–942. doi:10.1164/rccm.201503-0543OC.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.