fluticasone and Substance-Withdrawal-Syndrome

Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting beta2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration.. The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 microg FP + 50 microg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study.. The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone.. Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.

Topics: Administration, Inhalation; Albuterol; Analysis of Variance; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Fluticasone; Humans; Male; Medical Records; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Substance Withdrawal Syndrome

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Contusions; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Substance Withdrawal Syndrome

Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone.. 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol.. All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration.. Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD.

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Contusions; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Hydrocortisone; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Substance Withdrawal Syndrome

The aim of this double-blind single center study (the COPE study) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate (FP) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease. After 4 months of treatment with FP (1,000 microg/day), 244 patients were randomized to either continue FP or to receive placebo for 6 months: 123 patients continued FP (FP group), and 121 received placebo (placebo group). In the FP group, 58 (47%) patients developed at least one exacerbation compared with 69 (57%) in the placebo group. The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 (95% confidence interval [CI] 1.1-2.1). In the placebo group 26 patients (21.5%) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients (4.9%) in the FP group (relative risk = 4.4; 95% CI 1.9-10.3). Over a 6-month period, a significant difference in favor of the FP group was observed in the total score (+2.48 95% CI 0.37-4.58), activity domain (+4.64 95% CI 1.60-7.68), and symptom domain (+4.58 95% CI 1.05-8.10) of the St. George's Respiratory Questionnaire. This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Androstadienes; Double-Blind Method; Exercise Tolerance; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recurrence; Severity of Illness Index; Smoking; Substance Withdrawal Syndrome; Treatment Outcome

Some patients with severe asthma are difficult to control and suffer from frequent exacerbations, whereas others remain stable with anti-inflammatory therapy. To investigate mechanisms of exacerbations, we compared 13 patients 20 to 51 yr of age (11 female, two male) with difficult-to-control asthma (two or more exacerbations during the previous year) and 15 patients 20 to 47 yr of age (13 female, two male) with severe but stable asthma (no exacerbations) after matching for sex, age, atopy, lung function, airway responsiveness, and medication. Exacerbations were induced by double-blind, controlled tapering of inhaled corticosteroids (fluticasone propionate) at weekly intervals. FEV1, airway responsiveness for methacholine (PC20MCh) and hypertonic saline (HYP slope), eosinophils and soluble markers (ECP, albumin, IL-6, IL-8) in induced sputum were assessed at baseline and during exacerbation (peak flow < 60% of personal best), or after 5 wk if no exacerbation occurred. Steroid tapering caused a decrease (mean +/- SEM) in FEV1 (12.1 +/- 3.1% pred; p = 0.045), PC20MCh (2.1 +/- 0.4 doubling dose; p = 0.004) and HYP slope (1.7 +/- 0.3 doubling dose; p = 0.001), and an increase in sputum eosinophils (10 +/- 3%; p = 0.008) and soluble markers for the two groups combined, without significant differences between the groups. Patients with difficult-to-control asthma had more exacerbations than did the stable asthmatics during both steroid tapering (7 versus 2; p = 0.022) and corticosteroid treatment (6 versus 0; p = 0.003). Exacerbations during steroid treatment in the patients with difficult-to-control asthma were associated with a decrease in FEV1 and PC20MCh, but not in HYP slope or increase in sputum eosinophils. We conclude that tapering of inhaled corticosteroids induces a rapid, reversible flare-up of eosinophilic airway inflammation. Patients with difficult-to-control asthma may develop exacerbations despite treatment with inhaled corticosteroids, which appear to have an eosinophil-independent mechanism. This implies that assessment of the nature of exacerbations may contribute to improved treatment for these patients.

Topics: Administration, Inhalation; Adult; Airway Resistance; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchial Provocation Tests; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Recurrence; Sputum; Substance Withdrawal Syndrome

Inhaled corticosteroid (ICS) therapy improves asthma outcome. Both the anti-inflammatory efficacy and toxicities of ICS therapy are dose dependent. Therefore, there is interest in monitoring airway inflammation during ICS dose adjustments.. Fraction of expired nitric oxide (FENO) and exhaled breath condensate (EBC) pH were studied as noninvasive, corticosteroid-responsive markers of airway inflammation.. We prospectively studied the effect of stepwise ICS wean on FENO and EBC pH over 6 months in otherwise healthy adults with moderate persistent asthma.. Eighteen subjects completed the initial dose titration and 13 completed the protocol. Of these, 7 weaned off ICS completely and 6 had exacerbations. FENO rose significantly with ICS withdrawal, though there was heterogeneity in the starting level and the degree of rise. EBC pH was collected at home in all subjects and fell more in subjects who had an exacerbation than in those who did not. The decrease in pH was associated with hazard of exacerbation.. FENO can be a patient-specific index of airway inflammation during ICS dose titration; change in EBC pH is one home marker that might possibly be used during ICS dose titration. However, additional studies are required.

Topics: Adolescent; Adult; Androstadienes; Asthma; Breath Tests; Bronchodilator Agents; Female; Fluticasone; Humans; Hydrogen-Ion Concentration; Male; Nitric Oxide; Prospective Studies; Substance Withdrawal Syndrome; Young Adult

The feasibility of moderately severe airway hyperresponsiveness (AH) was examined as an inclusion criterion for clinical trials in asthmatic children. During the baseline period of a long-term clinical trial in asthmatic children, maintenance therapy with fluticasone (200 microg x day(-1)) was stopped for a maximum of 8 weeks and methacholine challenges were performed at 2-week intervals or earlier if the patients' condition deteriorated. Patients were eligible to continue the study if the provocative dose of methacholine causing a 20% fall in forced expired volume in one second (FEV1) (PD20) was <80 microg. Fifty-one per cent of the children did not develop a PD20 < 80 microg after withdrawal of fluticasone. Patients with or without a PD20 <80 microg did not differ in duration of asthma, duration of treatment, or peak flow variation. Patients with a PD20 <80 microg had higher levels of total and specific immunoglobulin-E, and lower levels of FEV1 and mean maximal expiratory flow than patients with a PD20 > or = 80 microg. Forty-four per cent of the patients with a PD20 > or = 80 microg did not have any symptoms during the wash-out period and 39% of these patients remained free from symptoms during one year follow-up. The results of this study suggest that recruiting asthmatic children for clinical trials may be difficult if airways hyperresponsiveness is used as the sole inclusion criterion.

Topics: Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Child; Clinical Trials as Topic; Feasibility Studies; Female; Fluticasone; Humans; Long-Term Care; Male; Methacholine Chloride; Patient Selection; Substance Withdrawal Syndrome