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      Use of Propranolol Blockade to Explore the Pharmacology of GSK961081, a Bi-Functional Bronchodilator, in Healthy Volunteers: Results from Two Randomized Trials

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      Drugs in R&D
      Springer International Publishing

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          Abstract

          Purpose

          The objective of this study was to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers.

          Methods

          Two randomized, double-blind, placebo-controlled studies were conducted. Following optimization of the propranolol dosing regimen (study 1), we conducted a five-period crossover study (study 2) in which subjects received the following treatments: dry powder inhaler (DPI) GSK961081 400 µg + oral placebo, DPI GSK961081 1,200 µg + oral placebo, DPI GSK961081 400 µg + oral propranolol 80 mg, DPI GSK961081 1,200 µg + oral propranolol 80 mg and DPI and oral placebo. GSK961081 (or inhaled placebo) was dosed at 0 h. Propranolol (or oral placebo) was dosed at −8, −2, 4, 10, and 16 h. The primary endpoint for both studies was bronchodilation, measured by specific airway conductance (sGaw), which was assessed at 0, 1, 4, 7, 12, 22, and 24 h in study 2. Tolerability and pharmacokinetics were secondary endpoints.

          Results

          Studies 1 and 2 enrolled 18 and 23 subjects, respectively. In study 2, bronchodilation was seen for 24 h following GSK961081 400 and 1,200 μg. In the presence of β 2 blockade, GSK961081 1,200 μg demonstrated bronchodilation in the first 4 h after dosing (treatment difference from placebo at 1 h: 1.206; 90 % confidence interval [CI] 1.126–1.292; and at 4 h: 1.124; 90 % CI 1.078–1.173) but not at 7 h onwards. In the presence of β 2 blockade, GSK961081 400 μg demonstrated bronchodilation in the first 1 h after dosing (treatment difference from placebo: 1.193; 90 % CI 1.117–1.274), but not at 4 h onwards. Adverse events were reported for 21 (study 1) and 15 subjects (study 2); none were serious, and there were no deaths.

          Conclusion

          The duration of bronchodilation as a result of receiving the muscarinic antagonist component alone was shorter than that from the muscarinic antagonist β 2 agonist combination. Removing the β 2 agonist component may underestimate the contribution of the muscarinic antagonist component to the bronchodilation of the combination.

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          Most cited references26

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          The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD.

          Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled beta(2)-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting beta(2)-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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            Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.

            This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.
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              Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD.

              The combination of short-acting beta(2)-agonists and anticholinergics in the treatment of COPD has been well documented, but data on combination of long-acting agents are lacking. A randomized, open-label, placebo-controlled, three-way crossover study was conducted comparing 2-week treatment periods of tiotropium alone to tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium. Lung function (FEV(1), FVC, and resting inspiratory capacity [IC]) serially over 24 h was measured in 95 patients with stable COPD at baseline and after 2 weeks of each treatment. Mean baseline FEV(1) was 1.05 L (38% of predicted). There was a circadian variation in FEV(1), FVC, and IC at baseline that was maintained during all treatment periods. Average FEV(1) (0 to 24 h) improved by 0.08 L with tiotropium, by 0.16 L with tiotropium plus formoterol once daily, and by 0.20 L with tiotropium plus formoterol twice daily (p 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV(1) for 12 h, but in FVC and IC for < 12 h. Peak increase in FEV(1) was 0.23 L (22% of baseline) with tiotropium and 0.39 L (37% of baseline) with tiotropium plus formoterol (p < 0.0001). Compared with tiotropium alone, add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime (p < 0.01) and with add-on formoterol twice daily also during the nighttime (p < 0.05). The combination of tiotropium and formoterol was well tolerated. In the treatment of COPD, there is benefit from adding formoterol once or twice daily to tiotropium once daily in terms of improvement in airflow obstruction, resting hyperinflation, and the use of rescue salbutamol.
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                Author and article information

                Contributors
                +44 (0)20 8047 6634 , virginia.h.norris@gsk.com
                Journal
                Drugs R D
                Drugs R D
                Drugs in R&D
                Springer International Publishing (Cham )
                1174-5886
                1179-6901
                30 September 2014
                30 September 2014
                December 2014
                : 14
                : 4
                : 241-251
                Affiliations
                [ ]GlaxoSmithKline, GSK House, 980 Great West Road, Brentford, Middlesex, TW8 9GS UK
                [ ]GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UB11 1BT UK
                Article
                60
                10.1007/s40268-014-0060-x
                4269816
                25265895
                c814dfbb-ade9-4d8b-8ec2-da104f12577a
                © The Author(s) 2014

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Categories
                Original Research Article
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                © Springer International Publishing Switzerland 2014

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