The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD

Pulmonary Pharmacology and Therapeutics

Volumn 23, Issue 4, 2010, Pages 257-267

  Cazzola, Mario ^a   Molimard, Mathieu ^b  

^a UNIVERSITY OF ROME TOR VERGATA   (Italy)

^b UNIVERSITÉ DE BORDEAUX   (France)

Author keywords

Chronic obstructive pulmonary disease; Combination therapy; Long acting 2 agonists; Long acting muscarinic antagonists

Indexed keywords

ACLIDINIUM PLUS FORMOTEROL FUMARATE; ADIDINIUM BROMIDE; ARFORMOTEROL; BEA 2180 BR; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BRONCHODILATING AGENT; CARMOTEROL; CARMOTEROL PLUS TIOTROPIUM; DAROTROPIUM BROMIDE; FLUTICASONE PROPIONATE; FORMOTEROL; FORMOTEROL FUMARATE; GLYCOPYRRONIUM BROMIDE; GSK 573719; GSK 961081; INDACATEROL; IPRATROPIUM BROMIDE; LAS 100977; MUSCARINIC RECEPTOR BLOCKING AGENT; OLODATEROL; OLODATEROL PLUS TIOTROPIUM; PF 00610355; QVA 149; SALBUTAMOL; SALMETEROL; TIOTROPIUM BROMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VILANTEROL; VILANTEROL PLUS DAROTROPIUM BROMIDE; VILANTEROL PLUS GSK 573719;

BETA ADRENERGIC STIMULATION; BRONCHODILATATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL EFFECTIVENESS; CLINICAL TRIAL; DRUG EFFICACY; DRUG INDICATION; DRUG RECEPTOR BINDING; HUMAN; MONOTHERAPY; MORNING DOSAGE; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE;

ADRENERGIC BETA-AGONISTS; ANIMALS; BRONCHODILATOR AGENTS; DELAYED-ACTION PREPARATIONS; DRUG SYNERGISM; DRUG THERAPY, COMBINATION; HUMANS; MUSCARINIC ANTAGONISTS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; RECEPTORS, ADRENERGIC, BETA-2;

EID: 77953232163     PISSN: 10945539     EISSN: 15229629     Source Type: Journal    
DOI: 10.1016/j.pupt.2010.03.003     Document Type: Review

References (93)

1. GOLD. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (updated 2008). Available at .
2. Celli B.R., and MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23 (2004) 932-946
3. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 59 Suppl. 1 (2004) 1-232
4. Cazzola M., and Matera M.G. Long-acting bronchodilators are the first-choice option for the treatment of stable COPD. Chest 125 (2004) 9-11
5. Hanania N.A., and Donohue J.F. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators. Proc Am Thorac Soc 4 (2007) 526-534
6. Tashkin D.P., and Cooper C.B. The role of long-acting bronchodilators in the management of stable COPD. Chest 125 (2004) 249-259
7. Belmonte K.E. Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease. Proc Am Thorac Soc 2 (2005) 297-304
8. Barnes P.J. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med 117 Suppl. 12A (2004) 24S-32S
9. Sarria B., Naline E., Zhang Y., Cortijo J., Molimard M., Moreau J., et al. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol 283 5 (2002) L1125-L1132
10. Canning B.J., and Fischer A. Neural regulation of airway smooth muscle tone. Respir Physiol 125 (2001) 113-127
11. Roux E., Molimard M., Savineau J.-P., and Marthan R. Muscarinic stimulation of airway smooth muscle cells. Gen Pharmacol 31 (1998) 349-356
12. Johnson M. The β-adrenoceptor. Am J Respir Crit Care Med 158 (1998) S146-S153
13. Postma D.S., Keyzer J.J., Koeter G.H., Sluiter H.J., and De Vries K. Influence of the parasympathetic and sympathetic nervous system on nocturnal bronchial obstruction. Clin Sci 69 (1985) 251-258
14. Gaultier C., Reinberg A., and Girard E. Circadian rhythms in lung resistance and dynamic lung compliance of healthy children. Effects of two bronchodilators. Respir Physiol 31 (1977) 169-182
15. Furlan R., Guzzetti S., Crivellaro W., Dassi S., Tinelli M., Baselli G., et al. Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation 81 (1990) 537-547
16. Calverley P.M., Burge P.S., Spencer S., Anderson J.A., and Jones P.W. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax 58 8 (2003) 659-664
17. Anthonisen N., and Wright E. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 133 (1986) 814-819
18. Tashkin D.P., Celli B., Decramer M., Liu D., Burkhart D., Cassino C., et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J 31 (2008) 742-750
19. Cazzola M., and Tashkin D.P. Combination of formoterol and tiotropium in the treatment of COPD: effects on lung function. COPD 6 (2009) 404-415
20. Daniel E.E., Kannan M., Davis C., and Posey-Daniel V. Ultrastructural studies on the neuromuscular control of human tracheal and bronchial muscle. Respir Physiol 63 (1986) 109-128
21. Cazzola M., Matera M.G., and O'Donnell K.M. Association of β2-adrenergic agonists and tiotropium: is the combination justified?. Arch Bronconeumol 41 Suppl. 2 (2005) 24-31
22. 2-adrenoceptors. J Appl Physiol 65 (1988) 700-705
23. 2-adrenoceptor stimulant, on neuroeffector transmission in human bronchial tissue. Respiration 58 (1991) 163-166
24. Wessler I., Reinheimer T., Brunn G., Anderson G.P., Maclagan J., and Racké K. β-Adrenoceptors mediate inhibition of [3H]-acetylcholine release from the isolated rat and guinea-pig trachea: role of the airway mucosa and prostaglandins. Br J Pharmacol 113 (1994) 1221-1230
25. 2-Adrenoceptor activation augments acetylcholine release from tracheal parasympathetic nerves. Am J Physiol 268 (1995) L950-L956
26. Belvisi M.G., Patel H.J., Takahashi T., Barnes P.J., and Giembycz M.A. Paradoxical facilitation of acetylcholine release from parasympathetic nerves innervating guinea-pig trachea by isoprenaline. Br J Pharmacol 117 (1996) 1413-1420
27. 2-adrenoceptors on cholinergic and adrenergic nerve endings of the guinea pig trachea. Am J Physiol Lung Cell Mol Physiol 276 (1999) L420-L425
28. 2-adrenoceptors in human isolated bronchi (abstract). Am J Respir Crit Care Med 157 (1998) A723
29. 2-agonists on ACh release and smooth muscle contraction in the trachea. Am J Physiol 274 (1998) L32-L38
30. Kume H., Graziano M.P., and Kotlikoff M.I. Stimulatory and inhibitory regulation of calcium-activated potassium channels by guanine nucleotide-binding proteins. Proc Natl Acad Sci U S A 89 (1992) 11051-11055
31. Patel H.J., Giembycz M.A., Keeling J.E., Barnes P.J., and Belvisi M.G. Inhibition of cholinergic neurotransmission in guinea pig trachea by NS1619, a putative activator of large-conductance, calcium-activated potassium channels. J Pharmacol Exp Ther 286 (1998) 952-958
32. Brichetto L., Song P., Crimi E., Rehder K., and Brusasco V. Modulation of cholinergic responsiveness through the β-adrenoceptor signal transmission pathway in bovine trachealis. J Appl Physiol 95 (2003) 735-741
33. Schramm C.M., Chuang S.T., and Grunstein M.M. cAMP generation inhibits inositol 1,4,5-trisphosphate binding in rabbit tracheal smooth muscle. Am J Physiol 269 5 Pt 1 (1995) L715-L719
34. Yang C.M., Hsu M.C., Tsao H.L., Chiu C.T., Ong R., Hsieh J.T., et al. Effect of cAMP elevating agents on carbachol-induced phosphoinositide hydrolysis and calcium mobilization in cultured canine tracheal smooth muscle cells. Cell Calcium 19 3 (1996) 243-254
35. Ethier M.F., Dextradeur T., Schaefer O.P., and Madison J.M. Effects of salmeterol on muscarinic inhibition of adenylyl cyclase in bovine trachealis cells. Life Sci 67 (2000) 2753-2758
36. 2-sympathomimetics contribute to their relaxant effects in airway smooth muscle cells?. Pulm Pharmacol Ther 11 (1998) 253-261
37. Cazzola M., and Matera M.G. The effective treatment of COPD: anticholinergics and what else?. Drug Discov Today Ther Strateg 3 (2006) 277-286
38. 2-agonist carmoterol and tiotropium bromide in the control of airway changes induced by different challenges in guinea-pigs. Pulm Pharmacol Ther 20 (2007) 250-257
39. Dorinsky P.M., Reisner C., Ferguson G.T., Menjoge S.S., Serby C.W., and Witek Jr. T.J. The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD. Chest 115 (1999) 966-971
40. 2-adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide), given by aerosol alone or in sequence. N Engl J Med 315 (1986) 735-739
41. LeDoux E.J., Morris J.F., Temple W.P., and Duncan C. Standard and double dose ipratropium bromide and combined ipratropium bromide and inhaled metaproterenol in COPD. Chest 95 (1989) 1013-1016
42. COMBIVENT Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. Chest 105 (1994) 1411-1419
43. 2 agonists in patients with chronic obstructive pulmonary disease. Am J Med 100 (1996) 40S-48S
44. COMBIVENT Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 112 (1997) 1514-1521
45. Friedman M., Serby C.W., Menjoge S.S., Wilson J.D., Hilleman D.E., and Witek Jr. T.J. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 115 (1999) 635-641
46. Cazzola M., Santangelo G., Piccolo A., Salzillo A., Matera M.G., D'Amato G., et al. Effect of salmeterol and formoterol in patients with chronic obstructive pulmonary disease. Pulm Pharmacol 7 (1994) 103-107
47. Mahler D.A., Donohue J.F., Barbee R.A., Goldman M.D., Gross N.J., Wisniewski M.E., et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 115 (1999) 957-965
48. 2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163 (2001) 1087-1092
49. Dahl R., Greefhorst L.A., Nowak D., Nonikov V., Byrne A.M., Thomson M.H., et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164 (2001) 778-784
50. Matera M.G., Caputi M., and Cazzola M. A combination with clinical recommended dosages of salmeterol and ipratropium is not more effective than salmeterol alone in patients with chronic obstructive pulmonary disease. Respir Med 90 (1996) 497-499
51. Sichletidis L., Kottakis J., Marcou S., Constantinidis T.C., and Antoniades A. Bronchodilatory responses to formoterol, ipratropium, and their combination in patients with stable COPD. Int J Clin Pract 53 (1999) 185-188
52. van Noord J.A., de Munck D.R., Bantje T.A., Hop W.C., Akveld M.L., and Bommer A.M. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 15 (2000) 878-885
53. Chapman K.R., Arvidsson P., Chuchalin A.G., Dhillon D.P., Faurschou P., Goldstein R.S., et al. The addition of salmeterol 50 μg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Can Respir J 9 (2002) 178-185
54. D'Urzo A.D., De Salvo M.C., Ramirez-Rivera A., Almeida J., Sichletidis L., Rapatz G., et al. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium: a 3-week, randomized, double-blind, within-patient, multicenter study. Chest 119 (2001) 1347-1356
55. Casaburi R., and Conoscenti C.S. Lung function improvements with once-daily tiotropium in chronic obstructive pulmonary disease. Am J Med 117 Suppl. 1 (2004) 33-40
56. Vincken W., van Noord J.A., Greefhorst A.P., Bantje T.A., Kesten S., Korducki L., et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 19 (2002) 209-216
57. Cazzola M., Santus P., D'Adda A., Pizzolato S., Di Marco F., and Centanni S. Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD. Pulm Pharmacol Ther 22 (2009) 177-182
58. Donohue J.F. Therapeutic responses in asthma and COPD. Bronchodilators. Chest 126 (2004) 125S-137S
59. Kerstjens H.A., Bantje T.A., Luursema P.B., Sinninghe Damste H.E., de Jong J.W., Lee A., et al. Effects of short-acting bronchodilators added to maintenance tiotropium therapy. Chest 132 (2007) 1493-1499
60. 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?. Curr Opin Pharmacol 3 (2003) 270-276
61. Cazzola M., Di Marco F., Santus P., Boveri B., Verga M., Matera M.G., et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 17 (2004) 35-39
62. 1 and FVC responses when measured over 24 hours following single-dose administration in subjects with moderate-to-severe COPD (abstract). Chest 128 (2005) 258s
63. Cazzola M., Noschese P., Salzillo A., De Giglio C., D'Amato G., and Matera M.G. Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients. Respir Med 99 (2005) 524-528
64. Cazzola M., Centanni S., Santus P., Verga M., Mondoni M., Di Marco F., et al. The functional impact of adding salmeterol to tiotropium in patients with stable COPD. Respir Med 98 (2004) 1214-1221
65. Takahashi T., Belvisi M.G., Patel H., Ward J.K., Tadjkarimi S., Yacoub M.H., et al. Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways. Am J Respir Crit Care Med 150 (1994) 1640-1645
66. Anderson P., Lötvall J., and Linden A. Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro. Lung 174 (1996) 159-170
67. van Noord J.A., Smeets J.J., Custers F.L., Korducki L., and Cornelissen P.J. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 19 (2002) 639-644
68. van Noord J.A., Aumann J.L., Janssens E., Smeets J.J., Verhaert J., Disse B., et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 26 (2005) 214-222
69. van Noord J.A., Aumann J.L., Janssens E., Verhaert J., Smeets J.J., Mueller A., et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 129 (2006) 509-517
70. Terzano C., Petroianni A., Conti V., Ceccarelli D., Graziani E., Sanduzzi A., et al. Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD. Respir Med 102 (2008) 1701-1707
71. Tashkin D.P., Donohue J.F., Mahler D.A., Huang H., Goodwin E., Schaefer K., et al. Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir Med 103 (2009) 516-524
72. Tashkin D.P., Littner M., Andrews C.P., Tomlinson L., Rinehart M., and Denis-Mize K. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med 102 (2008) 479-487
73. van Noord J., Aumann L., Janssens E., Smeets J., Mueller A., and Cornelissen P. Combination therapy of tiotropium plus salmeterol superior to single agent therapy in terms of dyspnea improvement in COPD (abstract). Chest 128 (2005) 177S
74. Tashkin D., Pearle J., Iezzoni D., and Varghese S.T. Treatment with formoterol plus tiotropium is more effective than treatment with tiotropium alone in patients with stable chronic obstructive pulmonary disease: findings from a randomized, placebo-controlled trial. COPD: J Chron Obstruct Pulmon Dis 6 (2009) 17-25
75. Donohue J. Minimal clinically important differences in COPD lung function. COPD: J Chron Obstruct Pulmon Dis 2 (2004) 111-124
76. Tashkin D.P. COPD treatment with formoterol + tiotropium provides a greater improvement in lung function than treatment with tiotropium alone regardless of concomitant ICS use (abstract). Am J Respir Crit Care Med 177 (2008) A961
77. Tashkin D.P., Pearle J.L., and Varghese S. Improvement of lung function with coadministered formoterol and tiotropium regardless of smoking status in patients with chronic obstructive pulmonary disease (abstract). Chest 134 (2008) 103S
78. Vogelmeier C., Kardos P., Harari S., Gans S.J., Stenglein S., and Thirlwell J. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Respir Med 102 (2008) 1511-1520
79. Aaron S.D., Vandemheen K.L., Fergusson D., Maltais F., Bourbeau J., Goldstein R., et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 146 (2007) 545-555
80. Tashkin D., Celli B., Decramer M., Burkhart D., Kesten S., and Cassino C. Prescribing patterns according to COPD treatment guidelines in patients enrolled in a global clinical trial (abstract). Proc Am Thorac Soc 3 (2006) A111
81. Calverley P.M., Anderson J.A., Celli B., Ferguson G.T., Jenkins C., Jones P.W., et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 356 (2007) 775-789
82. Rabe K.F., Timmer W., Sagkriotis A., and Viel K. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest 134 (2008) 255-262
83. Singh D., Brooks J., Hagan G., Cahn A., and O'Connor B.J. Superiority of "triple" therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax 63 (2008) 592-598
84. Cazzola M., Andò F., Santus P., Ruggeri P., Di Marco F., Sanduzzi A., et al. A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD. Pulm Pharmacol Ther 20 (2007) 556-561
85. Cazzola M., and Matera M.G. Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol 155 (2008) 291-299
86. Cazzola M., and Matera M.G. Emerging inhaled bronchodilators: an update. Eur Respir J 34 (2009) 757-769
87. Magnussen H., Paggiaro P., Jack D., Owen R., Higgins M., and Kramer B. Bronchodilator treatment with indacaterol once-daily vs formoterol twice-daily in COPD: a 52-week study. Am J Respir Crit Care Med 179 (2009) A6184
88. Fogarty C, Hebert J, Iqbal A, Owen R, Higgins M, Kramer B. Indacaterol once-daily provides effective 24-h bronchodilation in COPD patients: a 26-week evaluation vs placebo and tiotropium. Presented at the European Respiratory Society 19th annual congress, Vienna, September 12-16, 2009.
89. van Noord JA, Buhl R, LaForce C, Martin C, Jones F, Dolker M et al. QVA149, a novel combination of indacaterol and glycopyrronium, demonstrates superior bronchodilation compared with indacaterol or placebo in patients with COPD. Presented at the European Respiratory Society 19th annual congress, Vienna, September 12-16, 2009.
90. Fabbri L, van de Maele B, Lemmens B, Martin C, Horton R, Dolker M et al. Cardiovascular safety of QVA149, a novel combination of indacaterol and glycopyrronium, compared with indacaterol and placebo in patients with COPD. Presented at the European Respiratory Society 19th annual congress, Vienna, September 12-16, 2009.
91. [accessed November 2009].
92. Welte T., Miravitlles M., Hernandez P., Erikkson G., Peterson S., Polanowski T., et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in COPD patients. Am J Respir Crit Care Med 180 (2009) 741-750
93. Pistolesi M., Camiciottoli G., Paoletti M., Marmai C., Lavorini F., Meoni E., et al. Identification of a predominant COPD phenotype in clinical practice. Respir Med 102 (2008) 367-376