title: The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.
abstract: 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.
authors.affiliation: *Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
authors.forename: William J
authors.initials: WJ
authors.lastname: Anderson
authors.affiliation: *Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Short
authors.affiliation: *Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Williamson
authors.affiliation: *Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Arvind
authors.initials: A
authors.lastname: Manoharan
authors.affiliation: *Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lipworth
mesh_terms: D000328:Adult; D001249:Asthma / Q000188:drug therapy*; D001507:Beclomethasone / Q000009:adverse effects / Q000627:therapeutic use*; D001985:Bronchial Provocation Tests; D003404:Creatinine / Q000652:urine; D004268:DNA-Binding Proteins / Q000097:blood; D004311:Double-Blind Method; D004802:Eosinophilia / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000627:therapeutic use*; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D009687:Nuclear Proteins / Q000097:blood; D011188:Potassium / Q000097:blood; D011433:Propranolol / Q000009:adverse effects / Q000627:therapeutic use*; D014157:Transcription Factors; D005466:Fluorocarbons
chemical_list: D001507:Beclomethasone; D003404:Creatinine; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D006854:Hydrocortisone; D009687:Nuclear Proteins; D011188:Potassium; D011433:Propranolol; D014157:Transcription Factors; C474280:FEV protein, human; C094049:apaflurane; D005466:Fluorocarbons