Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma (original) (raw)
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International journal of immunopathology and pharmacology, 2016
Inhaled corticosteroids (ICS)/long-acting beta-agonists (LABA) association offers a better asthma control than a higher steroid dose with short-acting beta-agonists as needed. In this study, we evaluated the effect of the association on bronchial hyperreactivity (BHR) and peak expiratory flow (PEF) variability, as such parameters are positively correlated with increased asthma morbidity and exacerbations. Thirty-six adult patients with mild persistent asthma were enrolled. After a 7-day run-in, they were randomly assigned to three therapy regimens for 6 weeks: Group 1, fluticasone 125 μg + formoterol 5 μg in the same device; Group 2, fluticasone 125 μg + formoterol 12 μg as needed; Group 3, fluticasone 250 μg + formoterol 12 μg as needed. We evaluated changes induced in weekly PEF variability (measured during the entire study and 4 weeks of follow-up) and pre- and post-study PD20 methacholine (MCH). Weekly PEF variability decreased in all groups during treatment with the greatest re...
Step-Down Compared to Fixed-Dose Treatment With Inhaled Fluticasone Propionate in Asthma*
CHEST Journal, 2005
Background: Inhaled corticosteroids (ICSs) are an effective treatment of asthma even when administered at a low dose. Once asthma is controlled, current guidelines recommend that the dose of ICS be reduced to the lowest possible and effective dose. Although the most appropriate strategy for the stepping down has not yet been defined, quantification of sputum eosinophils and bronchial hyperresponsiveness (BHR) are indeed measures of asthma control. Objective: To compare the efficacy of step-down and fixed-dose strategies in the control of BHR to methacholine and eosinophilic inflammation patients with mild-to-moderate asthma. Methods: We performed a double-blind, randomized study to compare inhaled fluticasone propionate (FP), 1,000 g/d, then reduced to 200 g/d (group 1; n ؍ 18) to a fixed dose of FP, 200 g/d (group 2; n ؍ 17) administered for 6 weeks and then 8 weeks in reducing the provocative dose of methacholine causing a 20% fall in FEV 1 (PD 20 ) and sputum eosinophils in 35 patients. The duration of the efficacy was also followed subsequently after 8 weeks of placebo treatment. Results: PD 20 remarkably increased with both treatment strategies, but differences between groups were not significant. Sputum eosinophils (median values, percentage) at baseline and after each treatment period were not different (group 1, 16.4 to 1.0 to 2.7%; group 2, 16.7 to 2.8 to 2.8%, respectively). The percentages of patients in whom sputum eosinophilia was normalized (< 3%) were as follows: group 1, 69% and 60%; group 2, 50% and 57%. After placebo treatment, sputum eosinophils were still "normalized" in approximately one third of patients.
Significant variability in response to inhaled corticosteroids for persistent asthma
Journal of Allergy and Clinical Immunology, 2002
Background: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. Objective: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. Methods: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV 1 and PC 20 ; risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 µg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 µg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 µg/day.
Bmj, 2001
ObjectiveTo examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma.Design Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone.Setting Medline, Embase, and GlaxoWellcome's internal clinical study registers.Main outcome measures FEV1, morning and evening peak expiratory flow, night awakenings, β agonist use, and major exacerbations.Results Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 μg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 μg/day and peaked by 500 μg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 μg/day was achieved at doses of 70-170 μg/day and 90% by 100-250 μg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 μg/day. The odds ratio for patients remaining in a study at a dose of 200 μg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV1 for an inhaled dose of 200 μg/day against higher doses showed a difference in FEV1 of 0.13 of a standard deviation (−0.02 to 0.29).Conclusions In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 μg, and the maximum effect is achieved with a dose of around 500 μg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 μg/day. What is already known on this topicInhaled corticosteroids are recommended for most patients with asthma, with the dose being increased as required to obtain controlA therapeutic dose range of fluticasone propionate of 200-2000 μg/day is recommended in the British National Formulary for adults with asthmaWhat this study addsPublished data are insufficient to determine with confidence the dose-response relation of inhaled fluticasone at doses of >500 μg/dayThe dose-response curve for inhaled fluticasone in moderate to severe asthma in adolescents and adults, for all major clinical outcome measures, including exacerbations, begins to plateau at 100-200 μg/day and peaks at around 500 μg/dayThis study partially explains why adding a long acting β agonist to inhaled corticosteroids is more efficacious than increasing the dose of inhaled steroid beyond this dose range
Systemic Effect Comparisons of Six Inhaled Corticosteroid Preparations
American Journal of Respiratory and Critical Care Medicine, 2002
The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects (microgram dose producing equal systemic cortisol suppression) of inhaled corticosteroids (ICS). Steroid naive asthma subjects (n ϭ 156) were enrolled at six centers. A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses. Systemic effect was evaluated by hourly plasma cortisol concentrations (8 P. M. to 8 A. M .), 12-and 24-hour urine cortisol concentrations, and a morning blood osteocalcin. The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect. For the six ICS and matching placebos (beclomethasone-chlorofluorocarbon [CFC], budesonide dry powder inhaler [DPI], fluticasone DPI, fluticasone-CFC metered dose inhaler [MDI], flunisolide-CFC, and triamcinolone-CFC), only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect. Thus microgram comparison of all ICS could only be performed at a 10% cortisol suppression: flunisolide-CFC Ϫ 936; triamcinolone-CFC Ϫ 787; beclomethasone-CFC Ϫ 548; fluticasone DPI Ϫ 445; budesonide DPI Ϫ 268; fluticasone-CFC MDI Ϫ 111. This study represents the first step in evaluation of ICS efficacy based on equisystemic (cortisol suppression) effects of a given ICS, rather than doses judged arbitrarily to be comparable on a microgram basis.
Journal of Allergy and Clinical Immunology, 2000
Background: There are limited published data regarding the efficacy of once-versus twice-daily administration of fluticasone propionate. Objective: Our purpose was to evaluate the effectiveness of fluticasone propionate powder 200 µg/d administered as a once-or twice-daily dosage regimen in patients who were currently being treated with bronchodilators only (BD patients) and in patients who required inhaled corticosteroids for maintenance treatment of asthma (ICS patients). Methods: Five hundred seventy patients were randomly assigned to receive one of the following inhaled treatments through the Diskus device (Glaxo Wellcome, Research Triangle Park, NC) for 12 weeks: fluticasone propionate 100 µg twice daily (FP100BID) or 200 µg once daily (FP200QD) or placebo. Results: BD patients treated with FP100BID, FP200QD, and placebo had mean increases in FEV 1 from baseline to end point of 0.49 L, 0.37 L, and 0.21 L, respectively (P < .001, FP100BID vs placebo; P = .05, FP200QD vs placebo). ICS patients treated with FP100BID and FP200QD had mean increases in FEV 1 of 0.27 L and 0.11 L, respectively, compared with a decrease in FEV 1 of-0.08 L with placebo (P < .001, FP100BID vs placebo; P = .023, FP200QD vs placebo). BD patients treated with FP100BID and FP200QD had mean increases in morning peak expiratory flow from baseline to end point of 31 L/min and 27 L/min, respectively, compared with a 1 L/min increase in patients treated with placebo. ICS patients treated with FP100BID had a mean increase in morning peak expiratory flow (from baseline to end point) of 18 L/min compared with mean decreases of-3 L/min and-12 L/min in the FP200QD and placebo groups, respectively. More patients were withdrawn from placebo (26% and 48%, in BD and ICS patients, respectively) than from fluticasone propionate (7%-9% [BID-QD] and 18%-32% [BID-QD], in BD and ICS patients, respectively) because of failure to meet predetermined asthma stability criteria. Conclusion: The efficacies of FP100BID and FP200QD were comparable with regard to improvement in pulmonary function and asthma stability in BD patients. In ICS patients, asthma control was maintained with FP200QD, whereas FP100BID provided greater improvements in pulmonary function and asthma stability. (
Respiratory Medicine, 2003
Twenty-seven subjects with moderate asthma atthe time of diagnosis, well controlled under regular fluticasone propionate (FP) (250 mg b.i.d.) for 6 months at least, were randomized to receive in double-blind fashion: FP125 mg b.i.d. (Group1) or FP 50 mg b.i.d. (Group 2) or placebo (Group 3) for 3 months or until symptom recurrence.Daily symptom score and peak expiratory flow were monitored. At the beginning and at the end of the study, subjects underwent methacholine challenge and sputum induction.Recurrence of symptoms occurred shortly after randomization in all subjects receiving placebo. None from Group 1 or 2 experienced symptom recurrence during the study. No significant differencein clinical and functional data, andin sputum eosinophilpercentageswas observed betweenthe beginningand the end of the study in both Groups 1 and 2. Subjects from Group 3 showed a significant increase of sputum eosinophils (Po0.05) and a significant decrease in provocative dose of methacholine (Po0.05) when asthma symptoms recurred. Therefore, very low doses of FP (50 mg b.i.d.) are effective in maintaining for 3 months a good control of the disease in asthmatics already stable under high-dose fluticasone, considering both clinical and functional outcomes and markers of airway inflammation.