Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting?

Drug Design, Development and Therapy

Volumn 7, Issue , 2013, Pages 1387-1398

  Theron, Annette J ^a,b   Steel, Helen C ^a   Tintinger, Gregory R ^a   Feldman, Charles ^c   Anderson, Ronald ^a  

^a UNIVERSITY OF PRETORIA   (South Africa)

^b NATIONAL HEALTH LABORATORY SERVICE   (South Africa)

^c UNIVERSITY OF THE WITWATERSRAND   (South Africa)

Author keywords

Adenylyl cyclase; Corticosteroids; Cyclic AMP; Muscarinic receptor antagonists; Neutrophils; Phosphodiesterase inhibitors

Indexed keywords

ADENOSINE TRIPHOSPHATASE (CALCIUM); ADENYLATE CYCLASE; BETA 2 ADRENERGIC RECEPTOR; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CHOLINERGIC RECEPTOR BLOCKING AGENT; CORTICOSTEROID; CR 3465; CYCLIC AMP; CYCLIC AMP 1; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; GLUCOCORTICOID RECEPTOR; GUANINE NUCLEOTIDE EXCHANGE FACTOR; IBUDILAST; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INOSITOL TRISPHOSPHATE; INTERLEUKIN 10; LEUKOTRIENE RECEPTOR BLOCKING AGENT; LONG ACTING DRUG; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE PHOSPHATASE 1; MONTELUKAST; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE IV; PHOSPHOLIPASE C BETA3; ROFLUMILAST; SHORT ACTING DRUG; STRESS ACTIVATED PROTEIN KINASE; TRANSCRIPTION FACTOR AP 1; UNCLASSIFIED DRUG;

ACUTE LUNG INJURY; ANTIINFLAMMATORY ACTIVITY; ASTHMA; BRONCHIOLITIS OBLITERANS; CALCIUM METABOLISM; CALCIUM TRANSPORT; CHRONIC OBSTRUCTIVE LUNG DISEASE; CYTOKINE PRODUCTION; CYTOSOL; DRUG CLASSIFICATION; DRUG SAFETY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INACTIVATION; ENZYME INDUCTION; EXERCISE INDUCED ASTHMA; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOREGULATION; INFLAMMATORY CELL; INTERSTITIAL CYSTITIS; MULTIPLE SCLEROSIS; NEUROPATHIC PAIN; PNEUMONIA; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; RECEPTOR DOWN REGULATION; RESPIRATORY TRACT INFLAMMATION; REVIEW;

ADENYLYL CYCLASE; CORTICOSTEROIDS; CYCLIC AMP; MUSCARINIC RECEPTOR ANTAGONISTS; NEUTROPHILS; PHOSPHODIESTERASE INHIBITORS;

ADRENERGIC BETA-2 RECEPTOR AGONISTS; ANIMALS; ANTI-INFLAMMATORY AGENTS; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; RECEPTORS, ADRENERGIC, BETA-2; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84888180593     PISSN: 11778881     EISSN: None     Source Type: Journal    
DOI: 10.2147/DDDT.S50995     Document Type: Review

References (137)

1. Cazzola M, Page CP, Rogliani P, Matera MG. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187(7):690-696.
2. Johnson M. Effects of β2-agonists on resident and infiltrating inflammatory cells. J Allergy Clin Immunol. 2002;110(Suppl 6):S282-S290.
3. Bosmann M, Grailer JJ, Zhu K, et al. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. FASEB J. 2012;26(4):2137-2144.
4. Hoyle GW. Mitigation of chlorine lung injury by increasing cAMP levels. Proc Am Thorac Soc. 2012;7(4):284-289.
5. Fuso L, Mores N, Valente S, Malerba M, Montuschi P. Long-acting beta-agonists and their association with inhaled corticosteroids in COPD. Curr Med Chem. 2013;20(12):1477-1495.
6. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M. Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi. Eur Respir J. 2007;29(3):575-581.
7. Woo AY, Wang TB, Zeng X, et al. Stereochemistry of an agonist determines coupling preference of b2-adrenoceptor to different G proteins in cardiomyocytes. Mol Pharmacol. 2009;75(1):158-165.
8. Malerba M, Radaeli A, Morjaria JB. Therapeutic potential for novel ultra long-acting β2-agonists in the management of COPD: biological and pharmacological aspects. Drug Discov Today. 2012;17(9-10):496-504.
9. Tamm M, Richards DH, Beghé B, Fabbri L. Inhaled corticosteroid and long-acting β2-agonist pharmacological profiles: effective asthma therapy in practice. Respir Med. 2012;106 Suppl 1:S9-S19.
10. Yorgancioglu A. Indacaterol in chronic obstructive pulmonary disease: an update for clinicians. Ther Adv Chronic Dis. 2012;3(1):25-36.
11. DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011;39(Database issue):D1035-D1041.
12. De Coupade C, Gear RW, Dazin PF, Sroussi HY, Green PG, Levine JD. Beta 2-Adrenergic receptor regulation of human neutrophil function is sexually dimorphic. Br J Pharmacol. 2004;143(8):1033-1041.
13. Liggett SB. Identification and characterization of a homologous population of beta 2-adrenergic receptors on human alveolar macrophages. Am Rev Respir Dis. 1989;139(2):552-555.
14. Lonati-Galligani M, Pirke KM. Beta 2-adrenergic receptor regulation in circulating mononuclear leukocytes in anorexia nervosa and bulimia. Psychiatry Res. 1986;19(3):189-198.
15. Chong LK, Chess-Williams R, Peachell PT. Pharmacological characterisation of the β-adrenoceptor expressed by human lung mast cells. Eur J Pharmacol. 2002;437(1-2):1-7.
16. Abraham G, Kneuer C, Ehrhardt C, Honscha W, Ungemach FR. Expression of functional beta2-adrenergic receptors in the lung epithelial cell lines 16HBE14o(-), Calu-3 and A549. Biochim Biophys Acta. 2004;1691(2-3):169-179.
17. Yukawa T, Ukena D, Kroegel C, et al. Beta2-adrenergic receptors on eosinophils: binding and functional studies. Am J Resp Crit Care Med. 1990;141(6):1446-1452.
18. Landmann R. Beta-adrenergic receptors in human leukocyte subpopulations. Eur J Clin Invest. 1992;22 Suppl 1:30-36.
19. Anstead MI, Hunt TA, Carlson SL, Burki NK. Variability of peripheral blood lymphocyte beta-2-adrenergic receptor density in humans. Am J Crit Care Med. 1998;157(3 Pt 1):990-992.
20. Oppenheimer J, Nelson HS. Safety of long-acting β-agonists in asthma: a review. Curr Opin Pulm Med. 2008;14(1):64-69.
21. Rogers L, Reibman J. Stepping down asthma treatment: how and when. Curr Opin Pulm Med. 2012;18(1):70-75.
22. Antoniu SA. Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease. Biomarkers. 2010;15(2):97-103.
23. Taylor DR. The beta-agonist saga and its clinical relevance: on and on it goes. Am J Respir Crit Care Med. 2009;179 (11):976-978.
24. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15-26.
25. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.
26. Chung KF, Caramori G, Adcock IM. Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol. 2009;65(9):853-871.
27. Jarjour NN, Wilson SJ, Koenig SM, et al. Control of airway inflammation maintained at a lower steroid dose with 100/50 microg of fluticasone propionate/salmeterol. J Allergy Clin Immunol. 2006;118(1):44-52.
28. Welte T. Optimising treatment for COPD-new strategies for combination therapy. Int J Clin Prac. 2009;63(8):1136-1149.
29. King P. Role of arformoterol in the management of COPD. Int J COPD. 2008;3(3):385-391.
30. Sin DD, Man P, Marciniuk DD, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177(11):1207-1214.
31. Hanania NA. The impact of inhaled corticosteroid and long acting β-agonist combination therapy on outcomes in COPD. Pulm Pharmacol Therap. 2008;21(3):540-550.
32. Pandya CM, Soubani AO. Bronchiolitis obliterans following hematopoietic stem cell transplantation: a clinical update. Clin Transplant. 2012; 24(3):291-306.
33. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant. 2011;46(10):1283-1295.
34. Papazian L. Con: β2-Adrenergic agonists in ALI-ARDS-not recommended or potentially harmful? Am J Resp Crit Care Med. 2011;184(5): 504-506.
35. Roca O, Gómez-Ollés S, Cruz M-J, Huñuz X, Griffiths MJD, Mascians JR. Effects of salbutamol on exhaled breath condensate biomarkers in acute lung injury: prospective analysis. Crit Care. 2008;12(3):R72.
36. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized β2-agonist for treatment of acute lung injury. Am J Respir Crit Care. 2011;184(5):561-568.
37. Gao Smith F, Perkins GD, Gates S, et al. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet. 2012;379(9812): 229-235.
38. Barnes PJ. Effect of β-agonists on inflammatory cells. J Allergy Clin Immunol. 1999;104(2 Pt 2):S10-S17.
39. Hanania NA, Moore RH. Anti-inflammatory activities of beta 2-agonists. Curr Drug Targets Inflamm Allergy. 2004;3(3):271-277.
40. Anderson R, Goolam Mahomed A, Theron AJ, Ramafi G, Feldman C. Effect of rolipram and dibutyryl cyclic AMP on resequestration of cytosolic calcium in FMLP-activated human neutrophils. Br J Pharmacol. 1998;124(3):547-555.
41. Anderson R, Visser SS, Ramafi G, Theron AJ. Accelerated resequestration of cytosolic calcium and suppression of the pro-inflammatory activities of human neutrophils by CGS 21680 in vitro. Br J Pharmacol. 2000;130(4):717-724.
42. Tintinger GR, Steel HC, Theron AJ, Anderson R. Pharmacological control of neutrophil-mediated inflammation: Strategies targeting calcium handling by activated polymorphonuclear leukocytes. Drug Des Dev Ther. 2009;2:95-104.
43. Gravett CM, Theron AJ, Steel HC, et al. Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils. Eur Respir J. 2010;36(6):1417-1424.
44. Ali H, Sozzani S, Fisher I, et al. Differential regulation of formyl peptide and platelet-activating factor receptors. Role of phospholipase Cβ3 phosphorylation by protein kinase A. J Biol Chem. 1998;273(18):11012-11016.
45. Bai Y, Sanderson MJ. Airway smooth muscle relaxation results from a reduction in the frequency of Ca2+ oscillations induced by a cAMP-mediated inhibition of the IP3 receptor. Respir Res. 2006;7:34.
46. Ay B, Iyanoye A, Sieck GC, Prakash YS, Pabelick CM. Cyclic nucleotide regulation of store-operated Ca2+ influx in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006;290(2):L278-L283.
47. Flamand N, Surette ME, Picard S, Bourgoin S, Borgeat P. Cyclic AMP-mediated inhibition of 5-lipoxygenase translocation and leukotriene biosynthesis in human neutrophils. Mol Pharmacol. 2002;62(2):250-256.
48. Luo M, Jones SM, Flamand N, Aronoff DM, Peters-Golden M, Brock TG. Phosphorylation by protein kinase A inhibits nuclear import of 5-lipoxygenase. J Biol Chem. 2005;280(49):40609-40616.
49. Iannnone MA, Wolberg G, Zimmerman TP. Chemotactic peptide induces cAMP elevation in human neutrophils by amplification of the adenylate cyclase response to endogenously produced adenosine. J Biol Chem. 1989;264(34):20177-20180.
50. Theron AJ, Steel HC, Tintinger GR, Anderson R. Endogenous adenosine regulates neutrophil pro-inflammatory activities by cyclic AMP-dependent accelerated clearance of cytosolic calcium. Inflamm Res. 2002;51(12):594-602.
51. Parry GCN, Mackman N. Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-κB-mediated transcription. J Immunol. 1997;159(11):5450-5456.
52. Tacon CR, Newton R, Proud D, Leigh R. Rhinovirus-induced MMP-9 expression is dependent on Fra-1, which is modulated by formoterol and dexamethasone. J Immunol. 2012;188(9):4621-4630.
53. Cobelens PM, Kavelaars A, Vroon A, et al. The β2-adrenergic agonist salbutamol potentiates oral induction of tolerance, suppressing adjuvant arthritis and antigen-specific immunity. J Immunol. 2002;169(9): 5028-5035.
54. Park PH, Huang H, McMullen MR, Bryan K, Nagy LE. Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264-267 macrophages. J Leukoc Biol. 2008;83(5):1258-1266.
55. Alvarez Y, Municio C, Alonso S, Sánchez Crespo M, Fernández N. The induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the coactivators CREB-binding protein and TORC2 and autocrine PGE2. J Immunol. 2009;183(2):1471-1479.
56. Avni D, Ernst O, Philosoph A, Zor T. Role of CREB in modulation of TNFα and IL-10 expression in LPS-stimulated RAW264.7 macrophages. Mol Immunol. 2010;47(7-8):1396-1403.
57. Tamassia N, Zimmermann M, Castellucci M, et al. Cutting edge: An inactive chromatin configuration at the IL-10 locus in human neutrophils. J Immunol. 2013;190(5):1921-1925.
58. Giembycz MA, Kaur M, Leigh R, Newton R. A holy grail of asthma management: toward understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. Br J Pharmacol. 2008;153(6):1090-1104.
59. Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor function via phosphorylation. Ann NY Acad Sci. 2004;1024:86-101.
60. Kumar R, Calhoun WJ. Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation. Biologics. 2008;2(4):845-854.
61. Haske T, Nakao M, Moudgil VK. Phosphorylation of immunopurified rat liver glucocorticoid receptor by the catalytic subunit of cAMP-dependent protein kinase. Mol Cell Biochem. 1994;132(2):163-171.
62. Peñuelas I, Encío IJ, López-Moratalla N, Santiago E. cAMP activates transcription of the human glucocorticoid receptor gene promoter. J Steroid Biochem Mol Biol. 1998;67(2):89-94.
63. Eickelberg O, Roth M, Lörx R, et al. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem. 1999;274(2):1005-1010.
64. Roth M, Johnson PR, Rüdiger JJ, et al. Interaction between glucocorticoids and β2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet. 2002;360(9342): 1293-1299.
65. Usmani OS, Ito K, Maneechotesuwan K, et al. Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. Am J Respir Crit Care Med. 2005;172(6):704-712.
66. Kaur M, Chivers JE, Giembycz MA, Newton R. Long-acting β2-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells. Mol Pharmacol. 2008;73(1):203-214.
67. Anacker C, Zunszain PA, Cattaneo A, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psych. 2011;16(7):738-750.
68. Pace TW, Hu F, Miller AH. Activation of cAMP-protein kinase A abrogates STAT5-mediated inhibition of glucocorticoid receptor signaling by interferon-alpha. Brain Behav Immun. 2011;25(8): 1716-1724.
69. Barnes PJ. Severe asthma: Advances in current management and future therapy. J Allergy Clin Immunol. 2012;129(1):48-59.
70. Perng DW, Su KC, Chou KT, et al. Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages. Pulm Pharmacol Ther. 2012;25(4):312-318.
71. Rossios C, To Y, Osoata G, Ito M, Barnes PJ, Ito K. Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition. Br J Pharmacol. 2012;167(4):775-786.
72. Ohnishi H, Miyahara N, Gelfand EW. The role of Leukotriene B4 in allergic diseases. Allergol Int. 2008;57(4):291-298.
73. Black JL, Oliver BGG, Roth M. Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting β-agonists. Chest. 2009;136(4):1095-1100.
74. Mercado N, Hakim A, Kobayashi Y, et al. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One. 2012;7(7):e41582.
75. Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006;31(12):680-686.
76. Misra UK, Kaczowka S, Pizzo SV. The cAMP-activated GTP exchange factor, Epac1 upregulates plasma membrane and nuclear Akt kinase activities in 8-CPT-2-O-Me-cAMP-stimulated macrophages: Gene silencing of the cAMP-activated GTP exchange Epac1 prevents 8-CPT-2-O-Me-cAMP activation of Akt activity in macrophages. Cell Signal. 2008;20(8):1459-1470.
77. Liu J, Zhao X, Cao J, et al. Differential roles of PKA and Epac on the production of cytokines in the endotoxin-stimulated primary cultured microglia. J Mol Neurosci. 2011;45(2):186-193.
78. Lovén J, Svitacheva N, Jerre A, Miller-Larsson A, Korn SH. Anti-inflammatory activity of beta 2-agonists in primary lung epithelial cells is independent of glucocorticoid receptor. Eur Respir J. 2007;30(5): 848-856.
79. Donnelly LE, Tudhope SJ, Fenwick PS, Barnes PJ. Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages. Eur Respir J. 2010;36(1):178-186.
80. Kobayashi Y, Mercado N, Miller-Larsson A, Barnes PJ, Ito K. Increased corticosteroid sensitivity by a long acting β2 agonist formoterol via β2 adrenoceptor independent protein phosphatase 2A activation. Pulm Pharmacol Ther. 2012;25(3):201-207.
81. Matthay MA, Thompson BT, Brower R. Inflammation-induced desensitization of β-receptors in acute lung injury. Am J Respir Crit Care Med. 2012;185(8):894-895.
82. Finney PA, Belvisi MG, Donnelly LE, et al. Albuterol-induced downregulation of Gsalpha accounts for pulmonary β2-adrenoceptor desensitization in vivo. J Clin Invest. 2000;106(1):125-135.
83. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131(3): 636-645.
84. Hu A, Nino G, Grunstein JS, Fatma S, Grunstein MM. Prolonged heterologous β2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction. Am J Physiol Lung Cell Mol Physiol. 2008; 294(6):L1055-L1067.
85. Su Y, Jackson EK, Gorelik E. Receptor desensitization and blockade of the suppressive effects of prostaglandin E2 and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes. Cancer Immunol Immunother. 2011;60(1):111-122.
86. Fogli S, Stefanelli, Martelli A, et al. Protective effect of high-dose montelukast on salbutamol-induced homologous desensitisation in airway smooth muscle. Pulm Pharmacol Ther. 2013; pii: S1094-5539(13)00136-3.
87. Pauwels RA, Löfdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997;337(20):1405-1411.
88. Donohue JF. Combination therapy for chronic obstructive pulmonary disease: clinical aspects. Proc Am Thorac Soc. 2005;2(4):272-281.
89. Loukides S, Bartziokas K, Vestbo J, Singh D. Novel Anti-inflammatory agents in COPD: Targeting lung and systemic inflammation. Curr Drug Targets. 2013;14(2):235-245.
90. Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol. 2012;12(3):275-286.
91. Moodley T, Wilson S, Joshi T, et al. Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: A novel mechanism for the clinical efficacy of roflumilast in severe COPD. Mol Pharmacol. 2013;83(4):894-906.
92. Anonymous. Roflumilast: doubtful efficacy but clear harms in COPD. Prescrire Int. 2013;22(134):5-9.
93. Tintinger GR, Feldman C, Theron AJ, Anderson R. Montelukast: More than a cysteinyl leukotriene receptor agonist? Sci World J. 2010;10: 2403-2413.
94. Anderson R, Theron AJ, Gravett CM, Steel HC, Tintinger GR, Feldman C. Montelukast inhibits neutrophil pro-inflammatory activity by a cyclic AMP-dependent mechanism. Br J Pharmacol. 2009;156(1):105-115.
95. Keith PK, Koch C, Djandji M, et al. Montelukast as add-on therapy with inhaled corticosteroids alone or inhaled corticosteroids and long-acting beta-2-agonists in the management of patients diagnosed with asthma and concurrent allergic rhinitis (the RADAR trial). Can Respir J. 2009;16 Suppl A:17A-31A.
96. Korn D, Van den Brande P, Potvin E, Dramaix M, Herbots E, Peché R. Efficacy of add-on montelukast in patients with non-controlled asthma: a Belgian open-label study. Curr Med Res Opin. 2009;25(2): 489-497.
97. Bjerg A, Lundbäck B, Lötvall J. The future of combining inhaled drugs for COPD. Curr Opin Pharmacol. 2012;12(3):252-255.
98. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22(6): 912-919.
99. Kornmann O, Dahl R, Centanni S, et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J. 2011;37(2):273-279.
100. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21(1):74-81.
101. Campbell M, Eliraz A, Johansson G, et al. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med. 2005;99(12):1511-1520.
102. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008; 68(14):1975-2000.
103. Tashkin DP, Doherty DE, Kerwin E, et al. Efficacy and safety of a fixed-dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52-week Phase III trial. Int J Chron Obstruct Pulmon Dis. 2012;7: 43-55.
104. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166(8):1084-1091.
105. Chapman KR, Arvidsson P, Chuchalin AG, et al. The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Can Respir J. 2002;9(3):178-185.
106. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361(9356):449-456.
107. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003;58(5):399-404.
108. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124(3): 834-843.
109. Stockley RA, Chopra N, Rice L. Addition of salmeterol to existing treatment in patients with COPD: a 12 month study. Thorax. 2006; 61(2):122-128.
110. Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002;122(1):47-55.
111. Decramer ML, Hanania NA, Lötvall JO, Yawn BP. The safety of long-acting beta2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2013;8: 53-64.
112. Vogelmeier C, Hederer B, Glaab T et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103.
113. Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;177(1):19-26.
114. Larsson K, Janson C, Lisspers K, et al. Combination of budesonide/formoterol more effective than fluticasone/salmeterol in preventing exacerbations in chronic obstructive pulmonary disease: the PATHOS study. J Intern Med. 2013;273(6):584-594.
115. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143(5):317-326.
116. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J. 2006;27(3): 547-555.
117. Powrie DJ, Wilkinson TM, Donaldson GC, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;30(3):472-478.
118. Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT; SAFE Study Group. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J. 2007;14(8):465-472.
119. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19(2):217-224.
120. Cazzola M, Tashkin DP. Combination of formoterol and tiotropium in the treatment of COPD: effects on lung function. COPD. 2009;6(5):405-415.
121. van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J. 2005;26(2):214-222.
122. van Noord JA, Aumann JL, Janssens E, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest. 2006;129(3): 509-517.
123. Tashkin DP, Pearle J, Iazzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for COPD. COPD. 2009;6(1): 17-25.
124. Tashkin DP, Littner M, Andrews CP, Tomlinson L, Rinehart M, Denis-Mize K. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med. 2008;102(4):479-487.
125. Cazzola M, Di Marco F, Santus P, et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther. 2004;17(1): 35-39.
126. Aaron S, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555.
127. Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257-267.
128. Short PM, Williamson PA, Elder DHJ, Lipworth SI, Schembri S, LipworthBJ. The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Chest. 2012;141(1):81-86.
129. Rossi A, Polese G. Indacaterol: a comprehensive review. Int J Chron Obstruct Pulmon Dis. 2013;8:353-363.
130. Wollin L, Pieper MP. Tiotropium bromide exerts ant-inflammatory activity in a cigarette smoke mouse model of COPD. Pulm Pharmacol Ther. 2010;23(4):345-354.
131. Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;9:CD009039.
132. Karner C, Cates CJ. Long-acting beta2-agonists in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;4:CD008989.
133. Mahler DA, D'Urzo A, Bateman ED, et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax. 2012;67(9):781-788.
134. Profita M, Bonanno A, Montalbano AM, et al. β2 long-acting and anticholinergic drugs control TGF-β1-mediated neutrophilic inflammation in COPD. Biochim Biophys Acta. 2012;1822(7):1079-1089.
135. Kerstjens HA, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2): 308-314.
136. Bateman ED, Kornmann O, Ambery C, et al. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther. 2013;26(5):581-587.
137. Sears MR. The FDA-mandated trial of safety of long-acting beta-agonists in asthma: finality or frutility? Thorax. 2013;68(2):195-198.