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Table of Contents
Vol. 19, No. 5, 2010
Issue release date: July 2010
Section title: Review
Open Access Gateway
Med Princ Pract 2010;19:330–338

New Therapies for Chronic Obstructive Pulmonary Disease

Barnes P.J.
National Heart and Lung Institute, Imperial College London, London, UK
email Corresponding Author

Prof. Peter J. Barnes

National Heart and Lung Institute

Imperial College School of Medicine

Dovehouse Street, London SW3 6LY (UK)

Tel. +44 207 351 8174, Fax +44 207 351 5675, E-Mail p.j.barnes@imperial.ac.uk


  1. Barnes PJ: Chronic obstructive pulmonary disease: a growing but neglected epidemic. PLoS Med 2007;4:e112.
  2. Mannino DM, Buist AS: Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370:765–773.
  3. Barnes PJ, Shapiro SD, Pauwels RA: Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003;22:672–688.
  4. Barnes PJ: Emerging pharmacotherapies for COPD. Chest 2008;134:1278–1286.
  5. Barnes PJ: Future treatments for COPD and its comorbidities. Proc Am Thorac Soc 2008; 5:857–864.
  6. Barnes PJ, Celli BR: Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–1185.
  7. Barnes PJ: Theophylline for COPD. Thorax 2006;61:742–743.
  8. Barnes PJ: Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008;8:183–192.
  9. Makita H, Nasuhara Y, Nagai K, Ito Y, Hasegawa M, Betsuyaku T, Onodera Y, Hizawa N, Nishimura M: Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease. Thorax 2007;62:932–937.
  10. Sturton G, Persson C, Barnes PJ: Small airways: an important but neglected target in the treatment of obstructive airway diseases. Trends Phamacol Sci 2008;29:340–345.
  11. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J: Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
  12. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, Jones PW, Mahler DA, Make B, Miravitlles M, Page CP, Palange P, Parr D, Pistolesi M, Rennard SI, Rutten-van Molken MP, Stockley R, Sullivan SD, Wedzicha JA, Wouters EF: Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008; 31:416–469.
  13. Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, Saetta M: Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:6–14.
  14. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J: Global strategy for the diagnosis, management, and prevention of COPD – 2006 Update. Am J Respir Crit Care Med 2007;176:532–555.
  15. Cazzola M, Matera MG: Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol 2008;155:291–299.
  16. Sturton RG, Nicholson AG, Trifilieff A, Barnes PJ: Pharmacological characterisation of indacaterol, a novel once-daily inhaled β2-adrenoceptor agonist, on small airways in human and rat precision-cut lung slices. J Pharmacol Exp Ther 2008;324:270–275.
  17. Rennard S, Bantje T, Centanni S, Chanez P, Chuchalin A, D’Urzo A, Kornmann O, Perry S, Jack D, Owen R, Higgins M: A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med 2008;102:1033–1044.
  18. Hansel TT, Neighbour H, Erin EM, Tan AJ, Tennant RC, Maus JG, Barnes PJ: Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma. Chest 2005;128:1974–1979.
  19. Cazzola M: Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD. Curr Opin Investig Drugs 2009;10:482–490.
  20. van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJ: Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006;129:509–517.
  21. Ray NC, Alcaraz L: Muscarinic antagonist-beta-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review. Expert Opin Ther Pat 2009;19:1–12.
  22. Hays JT, Ebbert JO: Varenicline for tobacco dependence. N Engl J Med 2008;359:2018–2024.
  23. Siu EC, Tyndale RF: Non-nicotinic therapies for smoking cessation. Annu Rev Pharmacol Toxicol 2007;47:541–564.
  24. Barnes PJ: Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 2004;56:515–548.
  25. Barnes PJ: Cytokine networks in asthma and chronic obstructive pulmonary disease. J Clin Invest 2008;118:3546–3556.
  26. Hicks A, Monkarsh SP, Hoffman AF, Goodnow R Jr: Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: preclinical and clinical developments. Expert Opin Investig Drugs 2007;16:1909–1920.
  27. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue JF, Watt R, Hung KL, Schlenker-Herceg R, Barnathan ES, Murray ES: The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:926–934.
  28. Paul-Pletzer K: Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today (Barc) 2006;42:559–576.
  29. Donnelly LE, Barnes PJ: Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol Sci 2006;27:546–553.
  30. Mahler DA, Huang S, Tabrizi M, Bell GM: Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 2004;126:926–934.
  31. O’Connor BJ, Leaker BR, Barnes PJ, Nicholson G, Grahames C, Larsson B, Gaw A, Snell N, Newbold P: Inhibition of LPS-induced neutrophilic inflammation in healthy volunteers. Eur Respir J 2007;30(suppl 51):1294.
  32. Costa C, Rufino R, Traves SL, Lapa E, Silva JR, Barnes PJ, Donnelly LE: CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest 2008;133:26–33.
  33. Koli K, Myllarniemi M, Keski-Oja J, Kinnula VL: Transforming growth factor-beta activation in the lung: focus on fibrosis and reactive oxygen species. Antioxid Redox Signal 2008;10:333–342.
  34. Wang IM, Stepaniants S, Boie Y, Mortimer JR, Kennedy B, Elliott M, Hayashi S, Loy L, Coulter S, Cervino S, Harris J, Thornton M, Raubertas R, Roberts C, Hogg JC, Crackower M, O’Neill G, Pare PD: Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med 2008;177:402–411.
  35. Leung SY, Niimi A, Noble A, Oates T, Williams AS, Medicherla S, Protter AA, Chung KF: Effect of transforming growth factor- beta receptor I kinase inhibitor 2,4-disubstituted pteridine (SD-208) in chronic allergic airway inflammation and remodeling. J Pharmacol Exp Ther 2006;319:586–594.
  36. Hu J, Van Den Steen PE, Sang QX, Opdenakker G: Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 2007;6:480–498.
  37. Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL: Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 2007;62:706–713.
  38. Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases. Lancet 2009;342:1905–1917.
    External Resources
  39. Suissa S, Barnes PJ: Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009;34:13–16.
  40. Giembycz MA: Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? Br J Pharmacol 2008;155:288–290.
  41. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G: Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005;172:848–853.
  42. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081–1087.
  43. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM: Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161.
  44. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685–694.
  45. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF: Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695–703.
  46. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, Barnes PJ, Barnette MS, Giembycz MA: Discovery of BRL 50481, a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages and CD8+ T-lymphocytes. Mol Pharmacol 2004;66:1679–1689.
  47. Giembycz MA: Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:326–333.
  48. Banner KH, Press NJ: Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 2009;157:892–906.
  49. Birrell MA, Wong S, Hardaker EL, Catley MC, McCluskie K, Collins M, Haj-Yahia S, Belvisi MG: IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. Mol Pharmacol 2006;69:1791–1800.
  50. Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A, Maestrelli P, Maselli R, Vatrella A, Fabbri LM, Zuin R, Marsico SA, Saetta M: Increased activation of p38 MAPK in COPD. Eur Respir J 2008;31:62–69.
  51. Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS, Giembycz MA, Barnes PJ, Donnelly LE: Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol 2006;149:393–404.
  52. Medicherla S, Fitzgerald M, Spicer D, Woodman P, Ma JY, Kapoun AM, Chakravarty S, Dugar S, Protter AA, Higgins LS: p38a selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 2007;324:921–929.
  53. Tudhope SJ, Finney-Hayward TK, Nicholson AG, Mayer RJ, Barnette MS, Barnes PJ, Donnelly LE: Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage. J Pharmacol Exp Ther 2008;324:306–312.
  54. Medina-Tato DA, Ward SG, Watson ML: Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology 2007;121:448–461.
  55. Ward S, Sotsios Y, Dowden J, Bruce I, Finan P: Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chem Biol 2003;10:207–213.
  56. Marwick JA, Caramori G, Stevenson CC, Casolari P, Jazrawi E, Barnes PJ, Ito K, Adcock IM, Kirkham PA, Papi A: Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 2009;179:542–548.
  57. Belvisi MG, Hele DJ, Birrell MA: Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation. Eur J Pharmacol 2006;533:101–109.
  58. Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal VJ, Reddy RC: PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin- induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;294:L891–L901.
  59. Remels AH, Schrauwen P, Broekhuizen R, Willems J, Kersten S, Gosker HR, Schols AM: Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J 2007;30:245–252.
  60. Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ: Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007;2: CD002991.
  61. Suissa S, Ernst P, Vandemheen KL, Aaron SD: Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–933.
  62. Barnes PJ: Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 2009;71:451–464.
  63. Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM: Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kB suppression. J Exp Med 2006;203:7–13.
  64. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ: Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004;200:689–695.
  65. Fox JC, Spicer D, Ito K, Barnes PJ, Fitzgerald MF: Oral or inhaled corticosteroid combination therapy with low dose theophylline reverses corticosteroid insensitivity in a smoking mouse model. Proc Am Thorac Soc 2007;2:A637.
  66. Kirkham P, Rahman I: Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther 2006;111:476–494.
  67. Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S: Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 2009;106:250–255.
  68. Charron C, Sumakuza T, Oomura S, Ito K: EM-703, a non-antibacterial erythromycin derivative, restores HDAC2 activition diminished by hypoxia and oxidative stress. Proc Am Thorac Soc 2007;175:A640.
  69. Stinchcombe SV, Maden M: Retinoic acid-induced alveolar regeneration: critical differences in strain sensitivity. Am J Respir Cell Mol Biol 2008;38:185–191.
  70. Roth MD, Connett JE, D’Armiento JM, Foronjy RF, Friedman PJ, Goldin JG, Louis TA, Mao JT, Muindi JR, O’Connor GT, Ramsdell JW, Ries AL, Scharf SM, Schluger NW, Sciurba FC, Skeans MA, Walter RE, Wendt CH, Wise RA: Feasibility of retinoids for the treatment of emphysema study. Chest 2006;130:1334–1345.
  71. Varanou A, Page CP, Minger SL: Human embryonic stem cells and lung regeneration. Br J Pharmacol 2008;155:316–325.
  72. Loebinger MR, Janes SM: Stem cells for lung disease. Chest 2007;132:279–285.
  73. Salvi SS, Barnes PJ: Chronic obstructive pulmonary disease in non-smokers. Lancet 2009;374:733–743.
  74. Stolk J, Versteegh MI, Montenij LJ, Bakker ME, Grebski E, Tutic M, Wildermuth S, Weder W, el Bardiji M, Reiber JH, Rabe KF, Russi EW, Stoel BC: Densitometry for assessment of effect of lung volume reduction surgery for emphysema. Eur Respir J 2007;29:1138–1143.