Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: a placebo-controlled double-blind trial. Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-month comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. The National Mucolytic Study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. Effect of long-term treatment with sobrerol on the exacerbations of chronic bronchitis. In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness. [Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities]. A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. A double-blind placebo-controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease. [Antibiotic treatment for acute episodes of chronic obstructive pulmonary disease]. Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease.
The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD.
                In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations.
                Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups.
                Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane.
                ISRCTN07600011. The need to manage the key symptoms of chronic obstructive pulmonary disease (COPD) (breathlessness, cough and sputum) is an important treatment objective. Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism. The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies; the results of a 3-month, placebo-controlled multi-centre study are reported. Effect on patient symptoms was determined using a novel patient-reported assessment instrument, the Breathlessness, Cough and Sputum Scale (BCSS). Patients with smoking-related COPD were required to complete a 2-week baseline period before being randomized to one of three treatment groups; sibenadet (500 microg three times daily) plus placebo (twice daily); salmeterol (50 microg twice daily) plus placebo (three times daily); placebo (twice daily) plus a second placebo (three times daily). All treatments were delivered via pressurized metered dose inhaler (pMDI) for 12 weeks. From enrolment, patients were required to complete daily diary cards to record symptoms of breathlessness, cough and sputum, medication use and adverse events. The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period. Secondary measures included assessment of lung function, rescue medication use, exacerbations, health-related quality of life, opinion of efficacy and safety. Although an initial reduction in BCSS total score (indicating symptom improvement) was seen with sibenadet therapy, this effect was not maintained for the study duration. Salmeterol therapy, however, resulted in a sustained reduction in BCSS total score. No notable benefit over placebo was seen in lung function, exacerbations or health-related quality of life with either active treatment. While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy, they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD. Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications.
                To prospectively evaluate the effectiveness of a long-acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization.
                Randomized, double-blind study.
                26 Veterans Affairs medical centers.
                1829 patients with moderate to severe COPD (mean baseline FEV(1), 36% predicted).
                Once-daily tiotropium (18 microg) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators.
                The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.
                Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, -5.7 percentage points [95% CI, -10.4 to -1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, -3.0 percentage points [CI, -5.9 to -0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates.
                Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months.
                Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD. Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD.
                To investigate whether treatment with the inhaled corticosteroid fluticasone propionate (FP) or the anti-oxidative agent N-acetylcysteine (NAC) are effective in primary care patients.
                The study was a 3-year placebo-controlled randomised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment. Patients were (ex-)smokers with chronic bronchitis or COPD. Interventions were inhaled FP 500microg b.i.d., oral NAC 600mg o.d., or placebo. Exacerbation rate and quality of life measured with the Chronic Respiratory Questionnaire (CRQ) were the primary outcomes, FEV(1) decline and respiratory symptoms secondary outcomes.
                286 patients recruited from 44 general practices were randomised. Exacerbation rate was 1.35 times higher for NAC (p=0.054) and 1.30 times higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo.
                No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis. Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes.
                In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat.
                The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation.
                N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD. Seventy-four pulmonologists and one allergist were recruited to assess the efficacy and safety of iodinated glycerol (Organidin), 60 mg qid, vs placebo in patients with stable chronic obstructive bronchitis in a randomized, double-blind, placebo-controlled, parallel design. A total of 361 patients (180 to iodinated glycerol and 181 to placebo) who complained of cough and difficulty bringing up sputum entered the eight-week study. Evaluations were based upon eight primary symptom efficacy parameters (cough frequency, cough severity, chest discomfort, dyspnea, ease in bringing up sputum, patient and physician global assessments, and a derived patients' global assessment), and six secondary parameters (frequency of aerosol bronchodilator use, incidence and duration of acute exacerbations, frequency of concomitant medication use, incidences of adverse experiences and dropouts). Cough frequency, cough severity, chest discomfort, patients' ease in bringing up sputum, patients' overall condition, and a derived subject global assessment were significantly (p less than 0.05) improved by iodinated glycerol as compared with placebo within eight weeks of treatment. Dyspnea showed a trend toward improvement and the physicians' global evaluation showed no significant difference between groups. Similar findings were noted in a subgroup analysis of moderately-to-severely affected patients. The mean duration (days) of acute exacerbations and number of dropouts attributable to adverse experiences were significantly less (p less than 0.05) in the iodinated glycerol group.(ABSTRACT TRUNCATED AT 250 WORDS) The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) remains controversial because of a lack of placebo-controlled studies. We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD.
                We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, and South Africa, 281 outpatient current or ex-smokers, aged between 50 and 75 years. They had a forced expiratory volume in 1 s (FEV1) of between 35% and 90% of predicted normal values, a ratio of FEV1 to forced vital capacity of 70% or less and bronchodilator reversibility of less than 15%, as well as a history of chronic bronchitis. Patients were randomly assigned fluticasone propionate 500 microg (n=142) or placebo (n=139) twice daily via a metered-dose inhaler for 6 months. The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment, the number and severity of exacerbations, clinic lung function, diary card symptoms and peak expiratory flow and 6 min walking distance.
                51 (37%) patients in the placebo group compared with 45 (32%) in the fluticasone propionate group had had at least one exacerbation by the end of treatment (p=0.449). Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group (86% vs 60%, p<0.001). Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group (p<0.001, p=0.048, respectively), as did clinic FEV1 (p<0.001), forced vital capacity (p<0.001), and mid-expiratory flow (p=0.01). Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo (p=0.004 and p=0.016, respectively). At the end of treatment, patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo (p=0.032). Fluticasone propionate was tolerated as well as placebo, with few adverse effects and without a clinically important effect on mean serum cortisol concentration.
                Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Inhaled corticosteroids may have an important role in the long-term treatment of COPD. To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease.
                Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention.
                Ten clinical centers in the United States and Canada.
                A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease.
                Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler.
                Rate of change and cumulative change in FEV1 over a 5-year period.
                Participants in the two smoking intervention groups showed significantly smaller declines in FEV1 than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study.
                An aggressive smoking intervention program significantly reduces the age-related decline in FEV1 in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1. Inhaled corticosteroids (ICS) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies. However, the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease (COPD) is unknown. We have performed a double-blind, placebo-controlled, randomized study to compare fluticasone propionate (FP) 500 microg twice daily via a dry powder inhaler and placebo (P) over a 3-month period in subjects with COPD. Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment. Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis. Compared with P (n = 14), subjects on inhaled FP (n = 16) had no significant reductions in the primary endpoints: CD8+, CD68+ cells, or neutrophils, considered to be of importance in COPD. However, there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group. CD4+ cells were significantly raised in the P group in both subepithelium and epithelium. Symptoms significantly improved, and there were significantly fewer exacerbations in subjects on FP, compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD, and this may explain, in part, the decrease in exacerbations seen in long-term studies with fluticasone propionate. Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammatory process in the large and small airways, as well as in the lung parenchyma. Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented, its role in stable COPD is not clear. We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 (IL-8) levels in bronchoalveolar lavage (BAL) and their correlation with spirometry and symptom scores. Twenty-six patients with stable COPD were randomised, in a double-blinded, placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period. The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy (mean+/-sem, 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months, P=0.004) and a reduction in the mean percentages of neutrophils (17.16+/-2.67% vs. 13.25+/-2.28% P=0.002). The improvement in sputum production was of borderline (P=0.058) significance but there was no improvement in lung function. In stable patients with COPD, treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation, as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL. To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid.
                A 4-year prospective study.
                Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands.
                The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study.
                During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily.
                Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups.
                Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients. 706 chronic bronchitic patients were admitted to a double-blind controlled multicenter study to evaluate the effect of the prolonged administration of sobrerol on exacerbations, clinical signs and respiratory function indexes. Patients were treated at random with sobrerol 300 mg b.i.d. or placebo b.i.d. for 3 consecutive months during the winter of 1983/1984. At the beginning of the study, sex, body surface, smoking habits, environment, anti-influenzal vaccination, concomitant pathologies and therapies, respiratory anamnesis, clinical condition and spirometric indexes were equivalent in the two groups. Among the patients admitted to the study, 76% of the sobrerol group did not complain of any exacerbations compared to 58% of the placebo group (p less than 0.001), moreover the risk of exacerbation was about twice higher than with the drug. The use of antibiotics was equivalent in the two groups, whilst the consumption of bronchodilators/theophyllines was markedly lower in the sobrerol group. The response of the clinical signs (dyspnea and auscultatory semeiotics) and of the spirometric indexes (RV, VC and FEV1) to therapy, was significantly higher in the patients treated with sobrerol compared to the placebo group. The opinion expressed by the experimenter and by the patient at the end of each month of treatment was again in favor of sobrerol. Side effects, which were minor and no different from those claimed by the patients treated with placebo, and the hematological and hematochemical assessments, carried out before and after treatment, support the good tolerance of sobrerol. These results let us hope for a more appropriate use of the mucus-regulating agents, particularly in the chronic bronchopulmonary pathologies for which these drugs seem to represent the most rational care. Systemic corticosteroids have been recommended as a therapeutic option in patients with moderate to severe COPD. In an early stage of the disease, i.e. chronic bronchitis with mild or no airflow obstruction, a trial with inhaled steroids could reveal potential benefits, particularly in terms of a modulation of airway inflammation. We therefore investigated the effect of inhaled fluticasone (1000 microg day(-1)) on markers of airway inflammation in 19 patients with chronic bronchitis (mean+/-SEM FEV1, 83.4+/-3.0% predicted; FEV1/VC, 67.5+/-2.4%) in a double-blind, cross-over, placebo-controlled manner. Visits were performed before and after two 4-week treatment periods. separated by a 4-week washout period. Lung function, the concentration of exhaled nitric oxide, differential cell counts in induced sputum and the number of cells positive for iNOS, as well as the levels of LDH, ECP, neutrophil elastase and IL-8 in sputum supernatants were determined. Although the total cell number decreased significantly after fluticasone (geometric mean 12.3 vs. 7.7 x 10(6)/ml; P<0.05) it was not significantly different from the change observed after placebo (14.2 vs. 10.6 x 10(6)/ml; n.s.). None of the other parameters showed statistically significant changes after fluticasone or placebo and the results did not depend on the presence of airway hyperresponsiveness. We conclude that in patients with chronic bronchitis short-term treatment with inhaled corticosterids did not improve lung function or inflammatory parameters to an extent which was statistically significant as compared to spontaneous variability. This multicentre trial was undertaken to confirm previous results indicating that long-term treatment with oral acetylcysteine reduces the exacerbation rate in patients with chronic bronchitis. Two hundred and eighty-five patients, smokers or ex-smokers, with chronic bronchitis started a pre-trial placebo-period of 1 month. After this run-in period 259 patients were included in the trial and randomized into two parallel groups. The patients were treated in a double-blind way either with acetylcysteine 200 mg b.i.d. or placebo b.i.d. for 6 months. The trial was completed by 98 patients in the acetylcysteine group and by 105 patients in the placebo group. Initially, there were no significant differences between the groups. Twice weekly, the patients filled in a diary card concerning symptoms. The number of exacerbations was assessed from these cards and at visits 2, 4 and 6 months after institution of therapy. The exacerbation rate was significantly lower in the acetylcysteine group in which 40% of the patients remained free from exacerbations compared to 19% in the placebo group. Sick-leave due to acute exacerbation was significantly less common in the acetylcysteine group. The drug was well tolerated. Treatment of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma. It seems that only certain subgroups of patients with COPD benefit from steroid treatment. A study was undertaken to examine whether inhaled fluticasone propionate (FP) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness (BHR).
                Twenty three patients with COPD were studied. Patients had to be persistent current smokers between 40 and 70 years of age. Non-specific BHR was defined as a PC(20) for histamine of <or=8 mg/ml. Patients received either 2 x 500 microg FP or placebo for 6 months. Expiratory volumes were measured at monthly visits, BHR was determined at the start of the study and after 3 and 6 months, and bronchial biopsy specimens were taken at the start and after 6 months of treatment. Biopsy specimens from asymptomatic smokers served as controls.
                In contrast to asthma, indices of BHR were not significantly influenced by treatment with FP. Forced expiratory volume in 1 second (FEV(1)) showed a steep decline in the placebo group but remained stable in patients treated with FP. FEV(1)/FVC, and maximal expiratory flows at 50% and 25% FVC (MEF(50), MEF(25)) were significantly increased in the FP treated patients compared with the placebo group. Biopsy specimens were analysed for the presence of CD3+, CD4+, CD8+, MBP+, CD15+, CD68+, CD1a, and tryptase cells. FP treatment resulted in marginal reductions in these indices of inflammation.
                In patients with COPD and BHR, FP has a positive effect on indices of lung function compared with placebo. Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced. Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practices during a three months clinical trial.
                A randomized, double blind, placebo controlled study including COPD-patients (FEV1/FVC < 70 %, FEV1 < or = 70 % predicted; age > or = 40 years; > or = 10 pack years) of different severities was performed. The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests (spirometry) before (trough value) and 2 hours after inhalation of study medication.
                1639 patients (1236 Tiotropium bromide, 403 placebo; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol: 7.9 +/- 7.5 % predicted [mean +/- sd]) were randomized. After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 (23 - 24 h after last inhalation; + 79 +/- 17 ml), and 2 h after Tiotropium bromide inhalation (+ 128 +/- 19 ml) (all values vs. placebo, adjusted mean +/- se, p < 0.0001). FVC and IVC were also improved significantly. In mild COPD (FEV1 > or = 50 - 70 %) improvements were most pronounced (trough FEV1 + 113 +/- 29 ml, 2 h post-inhalation + 181 +/- 33 ml; all values vs. placebo., p < 0.0001). 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo (p = 0.0151). The time to first exacerbation was prolonged (p = 0.0092 vs. placebo).
                Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities. In 69 out-patients with chronic bronchitis in 6 centres the effects of acetylcysteine 600 mg daily, 3 days a week for 6 months, and a placebo have been compared in a double-blind controlled trial. Thirty-five patients were treated with the mucolytic and 34 with the dummy preparation. In the former the clinical course of the chronic bronchitis improved to a greater extent and a significantly lower number of exacerbations was observed. The advantages of long-term oral treatment with the mucolytic in chronic bronchitis suggest that it may be useful as an alternative to long-term antibiotic prophylaxis, or to complement brief courses of antibiotics, in addition to the usual physiotherapy. Treatment of chronic obstructive pulmonary disease (COPD) with inhaled and oral corticosteroids is common, although their exact role is unclear. Previous studies suggest these drugs may reduce decline in lung function in this group of patients. We report a study investigating the effect of inhaled beclomethasone diproprionate (BDP) on lung function and symptoms in a group of patients with COPD. Treatment was given for 2 years, and the decline in FEV1 in individual patients calculated over this period. Ninety-eight patients were randomized for the study, 59 completing 2 years of treatment. Patients withdrawn had more severe airflow obstruction. Decline in FEV1, measured both prior to and after bronchodilator, was less in patients receiving inhaled BDP, although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction. Exacerbation rates were also reduced by inhaled BDP, but again the differences failed to reach conventional levels of statistical significance. The results of this study are consistent with previous published work, but further insight into the long-term role of corticosteroids in COPD await the publication of large studies which have recently been completed. Although the changes seen in this study and others are numerically small, the rate of decline in FEV1 returned to normal levels expected from age-related decline, and hence such treatment combined with other strategies may well have a significant role in the long-term treatment of this condition. Antibiotic therapy for acute episodes of chronic obstructive pulmonary disease (COPD) is a controversial issue still not clarified. In order to evaluate the effectivity of the antibiotic therapy, we designed a double-blind controlled and randomized clinical trial, in which 90 patients hospitalized due to an acute episode of COPD were divided into three groups: group I, cotrimoxazole (29 patients); group II, amoxicillin-clavulanic acid (32 patients) and group III, placebo (29 patients). Gasometric and spirometric measures were taken in addition to clinical evaluation at hospital admission and discharge using a numerical valoration system. All patients were treated with common bronchodilators. The three groups were homogeneous at their admission and there were no statistical differences at their discharge. We conclude that antibiotics do not play a relevant role in the improvement of acute episodes of COPD. In COPD, hospital admissions and readmissions account for the majority of health-care costs. The aim of this prospective randomized controlled study was to determine if early pulmonary rehabilitation, commenced as an inpatient and continued after discharge, reduced acute health-care utilization.
                Consecutive COPD patients (n = 397), admitted with an exacerbation, were screened: 228 satisfied the eligibility criteria, of whom 97 consented to randomization to rehabilitation or usual care. Both intention-to-treat and per-protocol analyses are reported with adherence being defined a priori as participation in at least 75% of rehabilitation sessions.
                The participants were elderly with severe impairment of pulmonary function, poor health-related quality of life and high COPD-related morbidity. The rehabilitation group demonstrated a 23% (95% CI: 11-36%) risk of readmission at 3 months, with attendees having a 16% (95% CI: 0-32%) risk compared with 32% (95% CI: 19-45%) for usual care. These differences were not significant. There were a total of 79 COPD-related readmission days (1.7 per patient, 95% CI: 0.6-2.7, P = 0.19) in the rehabilitation group, compared with 25 (1.3 per patient, 95% CI: 0-3.1, P = 0.17) for the attendees and 209 (4.2 per patient, 95% CI: 1.7-6.7) for usual care. The BMI, airflow obstruction, dyspnoea and exercise capacity index showed a non-significant trend to greater improvement among attendees compared with those receiving usual care (5.5 (2.3) and 5.6 (2.7) at baseline, improving to 3.7 (1.9) and 4.5 (2.5), respectively, at 3 months). No adverse effects were identified.
                Early inpatient-outpatient rehabilitation for COPD patients admitted with an exacerbation was feasible and safe, and was associated with a non-significant trend towards reduced acute health-care utilization. The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown.
                To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD.
                We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily.
                We recorded post-bronchodilator FEV1, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p=0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p=0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration.
                In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast. Antimicrobial therapy remains a controversial issue in nonsevere exacerbations of chronic obstructive pulmonary disease (COPD).
                To evaluate the efficacy of antibiotic therapy in moderate exacerbations of mild-to-moderate COPD. METHODs: This study involved a multicenter, parallel, double-blind, placebo-controlled, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers of 10 pack-years or more with spirometrically confirmed mild-to-moderate COPD (FEV(1) > 50% predicted and FEV(1)/FVC ratio < 0.7) and diagnosed with an exacerbation were enrolled in the study. The patients were randomized to receive amoxicillin/clavulanate 500/125 mg three times a day or placebo three times a day for 8 days.
                The primary outcome measure was clinical cure at end of therapy visit (EOT) at Days 9 to 11. A total of 310 subjects fulfilled all the criteria for efficacy analysis. A total of 117 patients with amoxicillin/clavulanate (74.1%) and 91 with placebo (59.9%) were considered cured at EOT (difference, 14.2%; 95% confidence interval, 3.7-24.3). The median time to the next exacerbation was significantly longer in patients receiving antibiotic compared with placebo (233 d [interquartile range, 110-365] compared with 160 d [interquartile range, 66-365]; P < 0.05). The best C-reactive protein serum cut-off for predicting clinical failure with placebo was 40 mg/L, with an area under the curve of 0.732 (95% confidence interval, 0.614-0.851).
                Treatment of ambulatory exacerbations of mild-to-moderate COPD with amoxicillin/clavulanate is more effective and significantly prolongs the time to the next exacerbation compared with placebo.
In participants with chronic bronchitis or COPD, treatment with a mucolytic may produce a small reduction in acute exacerbations, but may have little or no effect on the overall quality of life. The effects on exacerbations shown in early trials were larger than those found in the more recent studies. This may be because the earlier smaller trials were at higher risk of selection or publication bias, so the benefits of treatment may not be as large as suggested by the previous evidence.