The murine asthma model shows that switching off airway β2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 μg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 μg/day compared with placebo plus HFA-BDP at 400 μg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 μg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): −0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43–1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45–1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10–0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.
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Research Article|
July 29 2014
The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma
William J. Anderson;
William J. Anderson
*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
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Philip M. Short;
Philip M. Short
*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
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Peter A. Williamson;
Peter A. Williamson
*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
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Arvind Manoharan;
Arvind Manoharan
*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
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Brian J. Lipworth
*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
Correspondence: Professor Brian J. Lipworth (email b.j.lipworth@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 22 2014
Revision Received:
May 27 2014
Accepted:
June 18 2014
Accepted Manuscript online:
June 18 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (11): 635–643.
Article history
Received:
April 22 2014
Revision Received:
May 27 2014
Accepted:
June 18 2014
Accepted Manuscript online:
June 18 2014
Citation
William J. Anderson, Philip M. Short, Peter A. Williamson, Arvind Manoharan, Brian J. Lipworth; The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma. Clin Sci (Lond) 1 December 2014; 127 (11): 635–643. doi: https://doi.org/10.1042/CS20140249
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