Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma

BACKGROUND: The objective of this multicentre, randomised, double blind, parallel group study was to compare the efficacy and safety of the addition of salmeterol with that of doubling the dose of fluticasone propionate in asthmatic patients not controlled by a low or intermediate dose of inhaled corticosteroids. METHODS: After a four week run in period of treatment with fluticasone propionate (100 micrograms twice daily if pre-trial dose was 400-600 micrograms inhaled corticosteroids or 250 micrograms twice daily if pre-trial dose was 800-1200 micrograms inhaled corticosteroids), 274 patients were randomised to treatment for 12 weeks with either salmeterol 50 micrograms twice daily plus the run in dose of fluticasone propionate or twice the run in dose of fluticasone propionate (200 or 500 micrograms twice daily). Outcome measures were daily records of peak expiratory flow (PEF), symptom scores, and clinic lung function. RESULTS: The improvements in both the morning and evening PEF were better in the salmeterol than in the fluticasone propionate group, the mean increase in morning PEF being 19 l/min higher (95% CI 11.0 to 26.1) and in evening PEF being 16 l/min (95% CI 18.4 to 24.0) higher in the salmeterol group. The increase in forced expiratory volume in one second (FEV1) was 0.09 1 greater in the salmeterol group than in the fluticasone propionate group after four weeks of treatment (95% CI 0.01 to 0.18), but not after 12 weeks. Both regimens showed an increase in symptom free days and a reduction in the need for rescue salbutamol both during the day and the night, but these improvements were greater in the salmeterol group. There were no significant differences between the groups in adverse effects or in the number of rescue course of oral corticosteroids. CONCLUSIONS: In this group of patients still symptomatic despite 100 or 250 micrograms fluticasone propionate twice daily, the addition of salmetterol caused a greater improvement in lung function and symptom control than doubling the dose of fluticasone propionate.     

Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study.

BACKGROUND--The acute response to bronchodilators in patients with chronic obstructive pulmonary disease (COPD) is modest; it has, however, been suggested that these patients may benefit from long term treatment. METHODS--To investigate the efficacy of salmeterol in smokers with moderate to severe COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 65 years). Prior to inclusion, all patients had a forced expiratory volume in one second (FEV1) of < 60% of predicted and an improvement in FEV1 of < 15% following 400 micrograms inhaled salbutamol. Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. FEV1 was measured before and after nebulised salbutamol prior to randomisation and at the end of each treatment period. RESULTS--Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF, assessed as the difference between the morning PEF and that of the previous evening, was more pronounced during the placebo than during the salmeterol period. The mean spirometric values (including reversibility in FEV1) obtained at the end of the two treatment periods were similar. Compared with placebo, treatment with salmeterol was associated with lower daytime and night time symptom scores and less use of rescue salbutamol both during the day and the night. The patients rated the treatment with salmeterol better than treatment with placebo. CONCLUSIONS--This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta agonists may therefore result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.     

Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial

BACKGROUND: Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by infiltration of CD8+ T cells and CD68+ macrophages and an increased number of neutrophils, whereas few studies have described the presence of eosinophils. Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear, recent studies suggest that combination therapy could be beneficial. A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate (SFC) and fluticasone propionate (FP) alone on inflammatory cells in the airways of patients with COPD. METHODS: Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 microg salmeterol and 500 microg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 microg FP twice daily (n = 20, 15 men, mean age 64 years) or placebo (n = 21, 17 men, mean age 66 years) for 3 months. At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8+ T lymphocytes, CD68+ macrophages, neutrophils and eosinophils were measured. RESULTS: CD8+ cells were significantly reduced by SFC compared with placebo (difference -98.05 cells/mm(2); 95% CI -143.14 to -52.9; p<0.001). Such a marked effect was not seen with FP alone (-44.67 cells/mm(2); 95% CI -90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference -31.68 cells/mm(2); 95% CI -61.07 to -2.29; p = 0.03) but not by FP. SFC did not significantly change neutrophils and eosinophils compared with placebo. CONCLUSIONS: SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone.     

Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients

BACKGROUND: In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms. The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate (FP) and budesonide (B) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients. METHODS: Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second (FEV1) 89.0% predicted and mid forced expiratory flow (FEF25-75) 58.9% predicted, on 400 micrograms/day or less of inhaled corticosteroid, were studied in a double blind, placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms, 500 micrograms, and 1000 micrograms twice daily. Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing. Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours, 10 hours after the eighth dose. RESULTS: The plasma cortisol levels (nmol/ l) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels: F500 333.8, B500 415.2 (95% CI 28.9 to 134.0); F1000 308.3, B1000 380.3 (95% CI 10.5 to 133.5); F2000 207.3, B2000 318.5 (95% CI 5.8 to 216.7); placebo 399.9. Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio (nmol/mmol) at all three dose levels: F500 3.12, B500 5.55 (95% CI 0.16 to 3.79); F1000 2.54, B1000 6.12 (95% CI 1.25 to 5.91); F2000 2.07, B2000 6.09 (95% CI 0.88 to 7.18); placebo 5.23. CONCLUSIONS: With repeated dosing across a dose range of 250-1000 micrograms twice daily, fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol. It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients. Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency, prolonged receptor residency time, greater tissue retention, and a longer elimination half life.


     

Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients. European Study Group.

BACKGROUND: Salmeterol is a potent selective beta 2 agonist that has been shown to have a duration of action in excess of 12 hours. In this study salmeterol and salbutamol were compared over a three month period with a further extension of nine months. METHODS: Three hundred and eighty eight patients with mild to moderate reversible airways obstruction (forced expiratory volume in one second (FEV1) > 50% predicted) were randomised to receive salmeterol (50 micrograms) twice daily or salbutamol (400 micrograms) four times daily, both by dry powder, in a double blind parallel group study. During the first three months detailed assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), asthma symptoms, and bronchodilator use when necessary for the relief of symptoms. Patients continued in the study for a further nine months with the salbutamol dose reduced to 400 micrograms twice daily. Lung function was measured at the clinic and safety data were collected during this period. RESULTS: Salmeterol produced a significantly higher mean morning PEF (mean difference compared with salbutamol 21 (95% CI 12-31) l/min), and a significant reduction in mean diurnal variation in PEF (from 30 l/min at baseline to 11 34 l/min at baseline to 32 l/min during salbutamol treatment). Salmeterol also reduced day and night symptoms and use of rescue bronchodilator. FEV1 increased with both salmeterol and salbutamol treatment over the 12 month treatment period. For both treatments the number of patients reporting exacerbations of asthma and the frequency of these exacerbations remained constant during the study. Thirty six patients in the salmeterol and 49 in the salbutamol group withdrew during the 12 months of the study. CONCLUSIONS: In this study salmeterol (50 micrograms twice daily) was more effective than salbutamol (400 micrograms four times daily) in the control of asthma over three months, and more effective than salbutamol (400 micrograms twice daily) over a further nine months. Neither salmeterol nor salbutamol was associated with any worsening of control of asthma.     

Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists

BACKGROUND: In vitro the long acting beta2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other beta2 agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting beta2 agonists. METHODS: A randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1 of 20% or more (PC(20)) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 microg twice daily by Turbuhaler), salmeterol (100 microg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 microg) was administered immediately thereafter, followed by ipratropium bromide (40 microg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation. RESULTS: There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1 of > or = 30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p<0.0003 for both). Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV1 after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV1 had returned to baseline values in all three treatment groups. CONCLUSION: Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo. Irrespective of this, prior long term treatment with both long acting beta2 agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting beta2 agonists should be made aware that an additional single dose of a short acting beta2 agonist may become less effective.     

Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease

BACKGROUND: An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 microg) does not produce any further bronchodilation than that achieved with salmeterol 50 microg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD. METHODS: Thirty two outpatients received 50 microg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 microg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs-that is, a total cumulative dose of 600 microg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 microg salmeterol + 600 microg oxitropium bromide; (2) 50 microg salmeterol + placebo; (3) placebo + 600 microg oxitropium bromide; (4) placebo + placebo. RESULTS: Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV(1)) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180). CONCLUSIONS: This study shows that acute pretreatment with 50 microg salmeterol does not block the possibility of inducing more bronchodilation with an anticholinergic agent when a higher than normal dosage of the muscarinic antagonist is used.     

Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow.

The effects of treatment with budesonide (200 micrograms twice daily) and terbutaline (500 micrograms four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after budesonide and terbutaline than after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.     

Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients.

BACKGROUND: A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis, each given by metered dose inhaler to asthmatic patients. METHODS: Twelve asthmatic patients of mean age 29.9 years, with a forced expiratory volume in one second (FEV1) 92.9% predicted and forced expiratory flow 25-75% (FEF25-75) 69.5% predicted, on less than or equal to 400 micrograms/day inhaled corticosteroid, were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400, 1000, 1600, 2000 micrograms and fluticasone propionate 500, 1000, 1500, 2000 micrograms. Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later. RESULTS: Serum cortisol levels compared with placebo (mean 325.2 nmol/l) were suppressed by fluticasone at doses of 1500 micrograms (211.6 nmol/l) and 2000 micrograms (112.3 nmol/l) and by budesonide at 2000 micrograms (243.4 nmol/l). Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms (95% CI for difference 42.9 to 219.2). The dose ratio (geometric mean) for the relative potency was 2.89 fold (95% CI 1.19 to 7.07). In terms of percentage suppression versus placebo, fluticasone propionate also produced greater effects (means and 95% CI for difference): budesonide 1600 micrograms (16.0) versus fluticasone propionate 1500 micrograms (40.9) (95% CI -0.6 to 50.6), budesonide 2000 micrograms (26.0) versus fluticasone 2000 micrograms (65.2) (95% CI 10.5 to 67.8). Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range (150 nmol/l) for fluticasone and five of 24 for budesonide. Fluticasone propionate also caused greater ACTH suppression than budesonide (as % versus placebo): budesonide 1600 micrograms (12.0) versus fluticasone propionate 1500 micrograms (31.9) (95% CI 7.6 to 32.1), budesonide 2000 micrograms (13.5) versus fluticasone propionate 2000 micrograms (44.4) (95% CI 13.2 to 48.7). For overnight 10 hour urinary cortisol (nmol/10 hours) there was a difference between the lowest doses of the two drugs: budesonide 400 micrograms (37.2) versus fluticasone propionate 500 micrograms (19.9) (95% CI 6.9 to 27.8). CONCLUSIONS: Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption. Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients.     

Clinical dose-response relationship of fluticasone propionate in adults with asthma

BACKGROUND: A study was undertaken to examine the dose-response relation of inhaled fluticasone in adolescents and adults with asthma. METHODS: A meta-analysis was carried out of randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two doses of fluticasone given twice daily. The main outcome measures were forced expiratory volume in 1 second (FEV1), morning peak expiratory flow (amPEF), beta agonist use, and withdrawals due to exacerbations of asthma. RESULTS: Seven studies of 2431 adolescents and adults with moderate to severe asthma met the inclusion criteria for the meta-analysis. Four studies examined a dose of >500 microg/day. For all outcome measures there were no statistically significant differences between a dose of 200 v 500 microg/day, 500 v 1000 microg/day, and 200 v > or =500 microg/day, although the point estimates favoured the higher doses. The mean improvement for FEV1 and amPEF resulting from an increase in dose from 200 to > or =500 microg/day was 0.07 l (95% CI -0.01 to 0.14) and 5.9 l/min (95% CI -3.0 to 15.3), respectively. The odds ratio for withdrawals with 200 microg/day compared with > or =500 microg/day was 1.27 (95% CI 0.78 to 2.07). CONCLUSIONS: In adolescents and adults with asthma, most of the therapeutic benefit of fluticasone is achieved with a total daily dose of 200 microg/day with minimal further clinical benefit achieved with higher doses. This conclusion is qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids in asthma, which would suggest that some patients may obtain a greater clinical benefit at higher doses.     

Influence of intranasal steroids during the grass pollen season on bronchial responsiveness in children and young adults with asthma and hay fever

BACKGROUND: It has been reported that intranasal corticosteroids can influence bronchial hyperresponsiveness (BHR) in asthmatic subjects with seasonal rhinitis. The purpose of the present study was to evaluate the effect of intranasal fluticasone propionate and beclomethasone dipropionate on BHR and bronchial calibre (forced expiratory volume in one second, FEV(1)) in children and young adults with seasonal rhinitis and mild asthma during two consecutive grass pollen seasons. METHODS: In the first pollen season 25 patients aged 8-28 years were included in a double blind, placebo controlled study. The active treatment group used fluticasone aqueous spray 200 microgram once daily. In the second pollen season 72 patients aged 8-28 years participated in a double blind, placebo controlled study of a similar design to that of the previous year except that an additional treatment group of patients using beclomethasone 200 microg twice daily was included. FEV(1) was measured before and after three and six weeks of treatment; BHR to methacholine (PD(20)) was measured before and after six weeks of treatment. RESULTS: In the first season the mean (SD) logPD(20) of the patients decreased significantly both in the fluticasone group (from 2.43 (0.8) microgram to 1.86 (0.85) microgram) and in the placebo group (from 2.41 (0.42) microgram to 1.87 (0.78) microgram) without any intergroup difference in the change in logPD(20). In the second pollen season the mean logPD(20) in the fluticasone, beclomethasone, and placebo groups did not change significantly. CONCLUSIONS: Intranasal steroids did not influence BHR during two grass pollen seasons in children and young adults with seasonal rhinitis and mild asthma.     

Effect of regular terbutaline on the airway response to inhaled budesonide.

BACKGROUND: The rebound increase in bronchial reactivity and fall in forced expiratory volume in one second (FEV1) following treatment with beta agonists seen in several studies has occurred regardless of concurrent steroid therapy. Little is known about the effect of adding beta agonists to corticosteroids, but in a recent study regular treatment with terbutaline appeared to reduce some of the beneficial effects of budesonide. The effects of budesonide alone and in combination with regular terbutaline treatment on lung function, symptom scores, and bronchial reactivity were therefore examined. METHODS: Sixteen subjects with mild stable asthma inhaled budesonide 800 micrograms twice daily for two periods of 14 days with terbutaline 1000 micrograms three times daily or placebo in a double blind crossover fashion. FEV1 and the dose of histamine or adenosine monophosphate (AMP) causing a 20% fall in FEV1 (PD20) were measured before and 12 hours after the final dose of treatment, and changes from baseline were compared. Seven day mean values for daily morning and evening peak expiratory flow (PEF) values, symptom scores, and rescue medication were compared before and during treatment. RESULTS: Morning and evening PEF rose more with budesonide plus terbutaline than with budesonide alone, with a mean difference of 19 l/min occurring in the evening (95% confidence interval (CI) 2 to 36). There was no difference in symptom scores during treatment. Following treatment the mean increase in FEV1 was 150 ml higher with budesonide alone (95% CI-10 to 300). There was no difference between treatments in change in histamine and AMP PD20. CONCLUSIONS: Evening PEF was greater when budesonide was combined with regular terbutaline. There was no evidence of a difference in bronchial reactivity following the two treatment regimens. The findings of a previous study were not confirmed as the reduction in FEV1 after budesonide and terbutaline was smaller and not statistically significant. Further work is needed to determine whether this disparity in findings in the two studies is due to a type 2 statistical error in this study or a spurious finding in the previous study.     

Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma

Background: Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. Methods: The effect of treatment with inhaled fluticasone propionate (1000 µg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. Results: There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v –5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC₂₀ (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (–1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. Conclusions: Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.     

A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group

BACKGROUND: A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV(1)) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 microg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV(1) and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV(1) and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92. RESULTS: During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV(1) levels and in trough and average FVC levels. The trough FEV(1) response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI -0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0. 07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV(1) than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients). CONCLUSIONS: Tiotropium in a dose of 18 microg inhaled once daily using the HandiHaler was significantly more effective than 40 microg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.     

Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children

BACKGROUND: In a previous single dosing study in asthmatic school children fluticasone propionate produced significantly greater suppression of overnight urinary cortisol excretion than budesonide at high doses of 800 micrograms/day or greater. The aim of this study was to assess whether conventional lower doses of both drugs cause adrenal suppression when given at steady state twice daily by large volume spacer on a microgram equivalent basis in asthmatic school children. METHODS: Eight school children of mean age 12.1 years with stable asthma of mild to moderate severity (forced expiratory volume in one second (FEV1) 78.6% predicted, mid forced expiratory flow rate (FEF25- 75) 72.5% predicted), on 400 micrograms/day or less of inhaled corticosteroid, were studied in a single blind (investigator blind), placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate 100 micrograms bid and 200 micrograms bid. Each dose was given at 08.00 hours and 20.00 hours for four days by metered dose inhaler via their respective large volume spacers with mouth rinsing. Measurements were made of overnight urinary cortisol and creatinine excretion after the eighth dose. RESULTS: Neither drug produced significant suppression of overnight urinary cortisol or cortisol/creatinine excretion compared with pooled placebo and there were no differences between the drugs. Only one subject with each drug at 200 micrograms twice daily had abnormally low urinary cortisol excretion of < 10 nmol/12 hours. Ratios for the fold difference between active treatment versus placebo for urinary cortisol excretion were (as means and 95% confidence intervals for difference): budesonide 100 micrograms b.i.d 1.03 (95% CI 0.46 to 1.61), budesonide 200 micrograms b.i.d 1.04 (95% CI 0.62 to 1.46); fluticasone 100 micrograms b.i.d 1.11 (0.45 to 1.77), fluticasone 200 micrograms b.i.d 1.12 (0.78 to 1.47). Likewise, there were no significant differences in overnight urinary cortisol/creatinine excretion. CONCLUSIONS: With repeated twice daily administration at steady state across a dose range of 200-400 micrograms/day no evidence of significant adrenal suppression was found using the sensitive marker of overnight urinary cortisol excretion for either fluticasone propionate or budesonide given via a large volume spacer. These results emphasise the good safety profile in children of these inhaled steroids at conventional dose levels, which have proven antiasthmatic efficacy.


     

Value of serial peak expiratory flow measurements in assessing treatment response in chronic airflow limitation.

A double blind, randomised, placebo controlled, crossover trial of prednisolone (40 mg/day for 14 days) was carried out in 33 patients with chronic airflow limitation (mean age 62 years, mean FEV1 1.01 litres, mean FEV1/FVC ratio 44%), to assess the value of serial peak expiratory flow (PEF) measurements, taken five times daily in evaluating treatment response by comparison with other objective measurements and with measurements of symptoms. The mean serial PEF after a one week run in period was 189 1 min-1, during the second week of placebo 193 1 min-1, and during the second week on prednisolone 231 1 min-1. The difference in mean PEF values between placebo and prednisolone was significant (p less than 0.01). With regard to the response to steroids of the individual patients, 13 of the 33 had a detectable trend of improvement on visual inspection of serial PEF measurements during prednisolone treatment but only one during placebo administration. Of all the objective measurements made after the run in and after each treatment phase (12 minute walking distance, FEV1, forced vital capacity (FVC), serial PEF), the serial PEF chart provided the best discrimination between placebo and prednisolone treatment. There was no statistically significant association between steroid induced improvement in serial PEF measurements and in breathlessness, partly because of placebo improvements in symptoms in those who had no improvement in serial PEF values. This study indicates the importance of making objective measurements to identify a genuine steroid response rather than relying on symptomatic improvement alone. The best simple measurement to make is serial PEF during steroid trials. This is more sensitive in detecting a steroid response than are the 12 minute walking distance, FEV1, or FVC, and is also less likely than these measurements to show spurious placebo responses.     

Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients.

Salmeterol is a new inhaled beta 2 adrenoceptor agonist, which has been shown in animal experiments to produce a more prolonged bronchodilator effect than currently available beta 2 adrenoceptor agonists. It was studied in eight adult asthmatic patients. Each patient received on separate test days salbutamol 200 micrograms and salmeterol 50, 100, and 200 micrograms according to a randomised, double blind, crossover design. FEV1, peak expiratory flow (PEF), heart rate, blood pressure, and tremor were recorded in the clinic for six hours after drug inhalation; PEF was recorded for a further six hours at home. All three doses of salmeterol produced peak increases in FEV1 (mean 0.5-0.8 l) and PEF (71-100 l/min) similar to those produced by salbutamol 200 micrograms (0.5 l and 74 l/min). After salbutamol FEV1 and PEF had returned to baseline within six hours, but after all three doses of salmeterol more than half of the maximum bronchodilator effect remained after 12 hours. The effects of salbutamol and the two lower doses of salmeterol (50 and 100 micrograms) on cardiovascular measurements and on tremor were similar, whereas after salmeterol 200 micrograms there was a small decrease in diastolic blood pressure and an increase in heart rate and tremor. Thus inhaled salmeterol has a long acting bronchodilator action in asthmatic patients. This effect may be of value in the treatment of asthma, particularly in patients with nocturnal symptoms.     

Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group.

BACKGROUND--High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma. Although effective, they may cause systemic side effects. Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses. METHODS--Fluticasone propionate, 1.5 mg per day, was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate. The study was multicentre, double blind and of a parallel design. For the first three months patients attended the clinic every four weeks and completed daily diary cards. For the next nine months they were only seen at three monthly intervals in the clinic. RESULTS--During the first three months diary card peak expiratory flow (PEF) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate (difference in morning PEF 15 l/min (95% CI 6 to 25)), and these differences were apparent at the end of the first week. The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8% compared with those receiving beclomethasone dipropionate. No significant differences between the two groups were observed in morning plasma cortisol levels, urinary free cortisol levels, or response to synthetic ACTH stimulation. In addition, both the rates of withdrawal and of adverse events were low, and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate. CONCLUSIONS--This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate, with no increase in systemic or other side effects.     

Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease.

BACKGROUND: The aim of this study was to evaluate the effects of single and chronic dosing with salmeterol on exercise capacity and lung function in patients with chronic obstructive pulmonary disease. METHODS: Twenty nine patients of mean (SE) age 64 (1.5) years, forced expiratory volume in one second (FEV1) 42(3)% of predicted, and 5-15% reversibility to salbutamol 200 micrograms were randomised to receive four weeks treatment with salmeterol 50 micrograms twice daily or placebo in a double blind crossover fashion with a one week washout period in between. Measurements of spirometric parameters, static lung volumes, and exercise capacity were made one and six hours after a single dose, and six hours after the final dose of salmeterol or placebo. RESULTS: Salmeterol produced a small increase in FEV1 at one and six hours after a single dose, and this was maintained after chronic dosing (mean difference and 95% CI versus placebo): single dosing at one hour 0.07 (95% CI 0.02 to 0.11) 1, single dosing at six hours 0.16 (95% CI 0.09 to 0.22) 1, chronic dosing at six hours 0.11 (95% CI 0.03 to 0.19) 1. The increase in forced vital capacity (FVC) was greater with salmeterol than with placebo six hours after single but not chronic dosing: single dosing at six hours 0.17 (95% CI 0.04 to 0.29) 1, chronic dosing at six hours 0.02 (95% CI -0.18 to 0.22) 1. Slow vital capacity was increased after treatment with salmeterol compared with placebo one and six hours after single but not after chronic dosing. There were no significant differences in static lung volumes or exercise capacity after single or chronic dosing with salmeterol compared with placebo. Patients reported a significantly lower Borg score for perceived exertion following the six minute walk after chronic treatment with salmeterol compared with placebo. CONCLUSIONS: Salmeterol produced a small improvement in spirometric values compared with placebo consistent with the degree of reversibility originally shown by the subjects to salbutamol 200 micrograms. This was not associated with improvements in static lung volumes or exercise capacity, but there was some symptomatic benefit in that patients were able to walk the same distance in six minutes with less perceived exertion.     

Time course of action of two inhaled corticosteroids, fluticasone propionate and budesonide

BACKGROUND: It is important to be able to compare the efficacy and systemic effects of inhaled corticosteroids but their slow onset of action makes it difficult to measure the maximum response to a given dose. Submaximal responses could be compared if the time course of action of the inhaled corticosteroids being compared was similar. We have compared the time course of action of fluticasone and budesonide, measuring response as change in the provocative dose of adenosine monophosphate causing a 20% fall in forced expiratory volume in 1 second (PD20AMP). METHODS: Eighteen subjects with mild asthma, aged 18-65, took part in a three way randomised crossover study. Subjects took fluticasone (1500 microg/day), budesonide (1600 microg/day), and placebo each for 4 weeks with a washout period of at least 2 weeks between treatments; PD20AMP and forced expiratory volume in 1 second (FEV1) were measured during and after treatment. The time taken to achieve 50% of the maximum response (T50%) was compared as a measure of onset of action. RESULTS: There was a progressive increase in PD20AMP during the 4 weeks of treatment with both fluticasone and budesonide but not placebo; the increase after 1 and 4 weeks was 2.28 and 4.50 doubling doses (DD) for fluticasone and 2.49 and 3.65 DD for budesonide. T50% was 9.3 days for fluticasone and 7.5 days for budesonide with a median difference between fluticasone and budesonide of 0.1 days (95% CI -1.4 to 2.65). There was a wide range of response to both inhaled corticosteroids but good correlation between the response to fluticasone and budesonide within subjects. FEV1 and morning peak expiratory flow rate (PEFR) increased during the first week of both active treatments and were stable thereafter. There was a small progressive improvement in nocturnal symptoms with both active treatments. CONCLUSION: PD20AMP was a more sensitive marker of response to inhaled corticosteroid therapy than FEV1 and PEFR. The time course of action of fluticasone and budesonide on PD20AMP is similar, suggesting that comparative studies of their efficacy using 1 or 2 week treatment periods are valid. When a new inhaled corticosteroid becomes available, a pilot study comparing its time course of action with that of an established corticosteroid should allow comparative studies to be performed more efficiently.