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      Efficacy of tiotropium and indacaterol monotherapy and their combination on dynamic lung hyperinflation in COPD: a random open-label crossover study

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          Background and objective

          The difference in efficacy of long-acting muscarinic antagonists (LAMAs) and long-acting β 2-agonists (LABAs) for dynamic lung hyperinflation (DLH) in COPD is unclear. The purpose of this study was to elucidate the difference in efficacy of LAMA and LABA alone and the combination thereof for DLH.

          Subjects and methods

          Thirty stable patients were enrolled and randomly divided into two groups following baseline measurements. One group was treated with 5 μg tiotropium (Respimat inhaler) for 4 weeks following a 4-week treatment with 150 μg indacaterol, while the other group was treated with indacaterol for 4 weeks following a 4-week treatment with tiotropium. For both groups, these treatments were followed by a combination of the two drugs for 4 weeks. Pulmonary function tests, including DLH evaluated by metronome-paced incremental hyperventilation and exercise tolerance evaluated by the shuttle-walk test, were performed at the end of each treatment period.


          In total, 23 patients completed this study. Both tiotropium and indacaterol alone significantly increased forced expiratory volume in 1 second, exercise tolerance, and improved health status. Tiotropium significantly improved DLH, but indacaterol did not. The combination therapy resulted in further improvements in lung function and exercise tolerance, but not in DLH.


          The efficacy of tiotropium in inhibiting DLH following metronome-paced incremental hyperventilation may be superior to that of 150 μg indacaterol, although the effects on airflow obstruction were the same, and the combination therapy showed further improvement in airflow obstruction, but not in DLH.

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          Most cited references 15

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          Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.

          We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months.
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            The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease.

            This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease.
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              In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action.

              Here, we describe the preclinical pharmacological profile of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel, chirally pure inhaled beta(2) adrenoceptor agonist, in comparison with marketed drugs. Indacaterol is close to a full agonist at the human beta(2) adrenoceptor (E(max) = 73 +/- 1% of the maximal effect of isoprenaline; pEC(50) = 8.06 +/- 0.02), whereas salmeterol displays only partial efficacy (38 +/- 1%). The functional selectivity profile of indacaterol over beta(1) human adrenoceptors is similar to that of formoterol, whereas its beta(3) adrenoceptor selectivity profile is similar to that of formoterol and salbutamol. In isolated superfused guinea pig trachea, indacaterol has a fast onset of action (30 +/- 4 min) similar to formoterol and salbutamol, and a long duration of action (529 +/- 99 min) comparable with salmeterol. In the conscious guinea pig, when given intratracheally as a dry powder, indacaterol inhibits 5-hydroxytryptamine-induced bronchoconstriction for at least 24 h, whereas salmeterol, formoterol, and salbutamol have durations of action of 12, 4, and 2 h, respectively. When given via nebulization to anesthetized rhesus monkeys, all of the compounds dose-dependently inhibit methacholine-induced bronchoconstriction, although indacaterol produces the most prolonged bronchoprotective effect and induces the lowest increase in heart rate for a similar degree of antibronchoconstrictor activity. In conclusion, the preclinical profile of indacaterol suggests that this compound has a superior duration of action compatible with once-daily dosing in human, together with a fast onset of action and an improved cardiovascular safety profile over marketed inhaled beta(2) adrenoceptor agonists.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                01 November 2017
                : 12
                : 3195-3201
                [1 ]Department of Clinical Laboratory Sciences, School of Health Sciences
                [2 ]Department of Biomedical Laboratory Science, Graduate School of Medicine
                [3 ]First Department of Internal Medicine, School of Medicine, Shinshu University, Matsumoto, Japan
                Author notes
                Correspondence: Keisaku Fujimoto, Department of Clinical Laboratory Sciences, School of Health Sciences, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390 8621, Japan, Tel/fax +81 263 37 2393, Email keisaku@
                © 2017 Fujimoto et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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