This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double‐dummy, double‐blind, placebo‐controlled 3‐period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. Ata 2‐week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3‐hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti‐inflammatory compounds in early development.

The present study aimed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function, indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist.In 50 patients (mean forced expiratory volume in one second (FEV1) 94% predicted), steroid doses (800 mg beclomethasone dipropionate) were first reduced to 50% and then to 25%, for 6 weeks each. One group received a placebo and the other group received montelukast (10 mg).The first reduction did not cause significant effects. During the second, FEV1 and peak expiratory flow decreased in both groups (pv0.001). Daytime symptoms were not altered with placebo but were reduced by montelukast (pv0.05). Night-time symptoms were slightly elevated with placebo (pv0.05) but not montelukast, as well as the use of supplemental salbutamol. Changes in provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast.These data demonstrate that a 75% reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast, whereas changes in clinical state seemed to favour montelukast treatment. It therefore appears that potential effects of montelukast, in the presence of low-dose steroids, could not be attributed to single indices of lung function or airway inflammation.

The onset of bronchoprotection as obtained by various b 2 -agonists has not been examined in a comparitive study. In this study, the onset of bronchodilation and protection against exercise-induced bronchoconstriction in asthmatics after inhalation of the long-acting b 2 -agonists formoterol and salmeterol and the shortacting b 2 -agonist terbutaline were measured.Twenty-five subjects with asthma and a history of exercise-induced bronchoconstriction (mean baseline forced expiratory volume in one second (FEV1): 90% predicted; mean fall in FEV1 after exercise: 31% from baseline) were enrolled in this double-blind, double-dummy, placebo-controlled, randomized, four-period crossover study. Exercise challenges were performed on 12 days at either 5, 30, or 60 min after inhalation of a single dose of formoterol (12 mg Turbuhaler1), salmeterol (50 mg Diskus1), terbutaline (500 mg Turbuhaler1) or placebo.Exercise-induced bronchoconstriction (maximum fall in FEV1 or area under the curve) did not differ significantly between terbutaline, formorerol and salmeterol either 5, 30, or 60 min after inhalation of the study medication. In contrast, the onset of bronchodilation was slower after salmeterol compared to terbutaline and formoterol (pv0.05, each), which both showed a similar time course. At all time points between 5 and 60 min, formoterol provided significantly greater bronchodilation than salmeterol (pv0.05).These data indicate that equipotent doses of the bronchodilators salmeterol, formoterol and terbutaline were similarly effective with respect to their short-term protective potency against exercise-induced bronchoconstriction, despite the fact that the time course of bronchodilation was significantly different between the three b 2 -agonists.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Richter et al. Effect of azelastine, montelukast, and their combination........ 2 A c c e p t e d m a n u s c r i p t ABSTRACTObjectives: Histamine and cysteinyl leukotrienes play an important role in early (EAR) and late (LAR) allergen reactions. Although protection by anti-histamines and anti-leukotrienes has been studied extensively, little is known about the effect of their combination. We, therefore, assessed the effect of clinically recommended doses of azelastine and montelukast alone and in combination on EAR and LAR.Methods: Seventeen patients (mean age 31y, 14m/3f) with asthma and proven EAR and LAR received an oral dose of 4 mg azelastine twice daily, or 10 mg montelukast once daily, or both for one week, in a double-blind, double-dummy, cross-over fashion. FEV 1 was measured after singledose allergen challenges during EAR (0-2 hours) and LAR (2-9 hours).Results: Azelastine, montelukast and their combination protected against both EAR and LAR (p<0.004, each) by 46 % and 43 %, 76 % and 59 %, and 89 % and 78 %, respectively. Azelastine was not as effective during EAR but equally effective to montelukast during LAR. The combination was superior to each drug alone during both EAR and LAR (p<0.05, each). Conclusion:The combination of azelastine and montelukast in clinically recommended doses has a greater effect in suppressing early and late allergen reactions than each drug alone. Abstract: 200) (Word Count of

No abstract