Bronchodilator effect of zafirlukast in subjects with chronic obstructive pulmonary disease

Cysteinyl leukotrienes (LT) are involved in airway inflammation and mucus hypersecretion, characteristically present in asthma and chronic obstructive pulmonary disease (COPD). Zafirlukast is an LT receptor antagonist that improves airway function within 1-3 h after oral administration in subjects with chronic persistent asthma. Through a randomised, double-blind, crossover and placebo-controlled study, we assessed the short-term effects of zafirlukast in patients with severe COPD. We enrolled 23 subjects (seven women) aged 59.4 (1.67) yr [mean (SEM)] with a smoking history of 60.7 (5.2) pack-yr. At screening day the mean FEV(1)was 0.876 (0.72) l; FEV(1) % predicted=35 (3)% and 107 (14) ml increment post-salbutamol. They came two different days, apart from each other at least 72 h. After baseline spirometry, a single oral dose of 40 mg zafirlukast or the corresponding placebo was administered. FVC and FEV(1) was measured every 30 min until 2 hrs. On zafirlukast day, the mean FEV(1) at 90 min [0.813 (0.64) l] and the mean FVC at 90 min [1.76 (0.1) l] were significantly higher than the respective means at placebo day (mean FEV(1)=0.747 (0.55) l; mean FVC=1.63 (0.1) l; p<0.05 Tukey Kramer multiple comparisons test). The maximum mean increase in FEV(1) was 75 (19) ml. A positive correlation was found between absolute response to salbutamol in FEV(1) and the response to zafirlukast (r=0.41; p<0.04). In conclusion, these findings suggest that zafirlukast has a bronchodilator or antibronchoconstrictor effect in COPD patients with severe airflow limitation.     

Comparison of the bronchodilating effect of salmeterol and zafirlukast in combination with that of their use as single treatments in asthma and chronic obstructive pulmonary disease.

BACKGROUND: It has been suggested that the effect of a beta2-agonist is additive with that of a cysteinyl leukotriene 1 receptor antagonist. OBJECTIVES: The present study was designed to answer the question of whether combined administration of inhaled salmeterol and oral zafirlukast at the standard doses would result in greater bronchodilation in patients with chronic airway obstruction than the use of either drug alone. METHODS: The study was performed using a double-blind, double-dummy, crossover, randomised design, and was conducted on 4 non-consecutive days. Sixteen patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 10 non-smoker asthmatic patients received 40 mg of oral zafirlukast, 50 microg of inhaled salmeterol, 50 microg of inhaled salmeterol plus 40 mg of oral zafirlukast of placebo. Lung function was assessed before drug administration and 30, 60, 120, 180 and 240 min thereafter. At the end of the 4-hour period, each patient received 400 microg of inhaled salbutamol and spirometric testing was performed 30 min later. RESULTS: In both asthmatic and COPD patients, the overall effect of salmeterol and zafirlukast on the forced expiratory volume in 1 s (FEV1) was considered extremely significant (p < 0.0001), with a maximum bronchodilation above baseline after 180 min (20.7 and 11.0%, respectively) in asthmatics and after 2 h (21.7 and 11.2%, respectively) in COPD subjects. Zafirlukast did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone in either asthmatic or COPD patients. Nevertheless, 7 out of 16 COPD patients and 7 out of 10 asthmatic patients had a further improvement after the combination of salmeterol and zafirlukast. The mean difference in pre- and post-salbutamol FEV1 values in both asthmatic and COPD patients after zafirlukast was significant (p < 0.05), but that after salmeterol and the combination of the two drugs was not significant (p > 0.05). The difference between placebo and zafirlukast was not significant following inhaled salbutamol given 4 h after each treatment. Conclusions: Both salmeterol and zafirlukast induced a significant increase in FEV1, although salmeterol elicited a greater improvement in both asthmatic and COPD patients. Apparently, zafirlukast at the clinically recommended dose did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone, either in asthma or COPD. In any case, evaluation of the effect of the combination over a 12-hour period is mandatory.     

Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil Aerolizer) with salbutamol (Ventodisk)

Formoterol fumarate is a beta2-agonist bronchodilator that combines a fast onset of action with a long duration of action. Its fast onset of action is well documented in asthma but has not been directly compared with that of salbutamol in patients with chronic obstructive pulmonary disease (COPD). This randomized, double-blind, placebo-controlled study was conducted to assess the bronchodilatory effects over the first 3 h after inhalation of single doses of formoterol 24 microg delivered via the Aerolizer dry powder inhaler device (double-blind), or salbutamol 400 microg delivered by a Diskhaler dry powder inhaler (single-blind) in patients with COPD. A total of 24 patients with COPD were randomized [mean age 61.6 +/- 7.8 years, mean forced expiratory volume in 1 sec (FEV1) 1.38 +/- 0.32 l and 45.8 +/- 9.6% of predicted]. Inhalation of formoterol or salbutamol resulted in similar increases in FEV from 0 to 3 h post-dose. Both drugs produced similar bronchodilation by 5 min, which became almost maximal by 30 min. The primary efficacy variable, the area under the curve (AUC) of the FEV increase above predose baseline from 0 to 30 min (AUC(0-30 min)), demonstrated significant effects for formoterol (mean 5.89 +/- 4.67 l min(-1)), and salbutamol (mean 6.06 +/- 4.34 l min(-1)), which were not statistically different from each other but statistically significantly higher (P<0.0001) than that observed with placebo (-0.32 +/- 2.59 l min(-1)). In addition, both formoterol and salbutamol produced similar and rapid increases in forced vital capacity (FVC). In summary, this study confirms the rapid onset of action of formoterol and indicates that the onset of action of formoterol and salbutamol are similar in patients with COPD.     

Does a single dose of the phosphodiesterase 4 inhibitor,cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?

Maintenance treatment with PDE(4) inhibitor cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, cilomilast, or cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD.     

Effect of cetirizine dihydrochloride on the airway response to hypertonic saline aerosol in patients with chronic obstructive pulmonary disease (COPD)

Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV(1) 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5 min after prior inhalation of salbutamol, and 45 min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV(1)) and inspiratory (FIV(1)) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV(1) was smallest at screening (P<0.01), without a significant difference between treatments. Regarding FIV(1), however, the percent fall from baseline was higher after placebo (Delta=-10.1%; P<0.05) compared to screening (0.4%) or cetirizine (-4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of alpha(2)-macroglobulin after cetirizine compared to placebo (P=0.045). The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations.     

Addition of an extra dose of salmeterol Diskus to conventional dose of salmeterol Diskus in patients with COPD

Patients experiencing dyspnoea can request an additional dose of salmeterol during the dose interval for the control of their symptoms, although under treatment with salmeterol. In this study we have explored the effects on respiratory function of an additive dose of salmeterol Diskus in 15 chronic obstructive pulmonary disease (COPD) patients in regular treatment with a conventional dose of 50 microg salmeterol. On two different days, patients inhaled 50 microg Diskus. After 240 min, they inhaled additional 50 microg salmeterol Diskus (salmeterol arm) or placebo Diskus (placebo arm). Lung function was controlled before first drug administration and 0.5, 1, 2, 3, 4, 4.5, 6, 8, 10, and 12 h thereafter. The mean (95% CI) peak increase in FEV1 from baseline was reached after 4 h in the salmeterol arm (0.174 L; 0.144-0204) and after 5 h (0.141 L; 0.115-0.168) inthe placebo arm; after 12 h, the mean (95% Cl) increase in FEV1 from basal values was still 0.149 L (0.119-0.179) in salmeterol arm, but only 0.041 L (0.017-0.064) in placebo arm. The mean (95% CI) FEV1 AUC0-12h for all patients were 2.01 (1.72-2.30) L when salmeterol was added and 1.30 (1.03-1.58) L when placebo was inhaled. The difference (mean; 95% CI) between the FEV1 AUC0-12h of the two arms (0.71 L; 0.47-0.95) was statistically significant (P<0.0001), although the difference (mean; 95% CI) between the FEV1 AUC0-4h of the two treatments (0.08 L; -0.02-0.18) was notstatistically significant (P=0.126). The addition of an extra dose of salmeterol did not significantly increase the heart rate or decrease the SpO2. This study suggests that the addition of an extra dose of salmeterol does not give room for further increase in peak FEV1, but the effect of adding salmeterol to salmeterol is largely additive when considering the duration of action and safe.     

Effects of 2 weeks of treatment with fluticasone propionate 100 mcg b.d. by comparison with zafirlukast 20 mg b.d. on bronchial hyper-responsiveness in patients with mild to moderate asthma

This study was designed to compare the effects of low-dose inhaled fluticasone propionate (100 mcg twice daily) with those of the leukotriene antagonist, zafirlukast (20 mg twice daily), on bronchial hyper-responsiveness. The study recruited 30 patients (nine men, 21 women; mean age 45 years) with forced expiratory volume in 1 sec (FEV1) > 50% and airway reversibility to salbutamol > or =15%. This was a single centre, double-blind, double-dummy cross-over study, composed of two successive 2-week treatment periods, each preceded by a 2-4 week single-blind placebo period. Following 2 weeks of treatment with fluticasone propionate and zafirlukast, the mean provocational concentration causing a 20% fall in FEV1 (PC20) histamine was 1.61 mg ml(-1) (SD 2.34) and 0.99 mg ml(-1) (SD 1.74) respectively. Taking baseline differences into account, the difference between treatments was equivalent to 0.77 doubling doses of histamine (95% CI, 0.05-1.50; P=0.037). Morning peak flow values were significantly higher (17 l min(-1); P=0.049) after treatment with fluticasone propionate during the second week of treatment. Both treatments were well tolerated. The results of this short-term study show that compared with zafirlukast, a low dose of fluticasone propionate offers greater clinical benefit and is more cost effective.     

Safety and tolerability of high-dose formoterol (via Aerolizer) and salbutamol in patients with chronic obstructive pulmonary disease

To evaluate the safety and tolerability of high-dose formoterol and salbutamol in patients with chronic obstructive pulmonary disease (COPD). In this two-way crossover, double-blind, double-dummy study, 17 adults with mild-to-moderate COPD were randomized to receive either formoterol 24 microg (2 x 12 microg via Aerolizer), or salbutamol 600 microg (6 x 100 microg via metered-dose inhaler), and the appropriate double-dummy q.i.d. at 4-h intervals for 3 consecutive days (total daily dose: 96 and 2400 microg, respectively). After a 4-7-day washout period, patients were switched to the other treatment. Treatment with high-dose formoterol and salbutamol was equally well tolerated, with no reports of serious adverse events. Both agents were associated with decreased plasma potassium (mean minimum values: 3.4 and 3.3 mmol/l for formoterol and salbutamol, respectively; P=0.914), increased serum glucose (mean maximum values: 9.0 and 8.7 mmol/l, respectively; P=0.373), and small increases in mean QTc interval (mean maximum 439 ms with both treatments; P=0.813). No clinically relevant between-treatment differences in adverse events or laboratory values occurred. Both drugs improved lung function (mean maximum forced expiratory volume in 1s [FEV(1)] 2.6 l with both treatments; P=0.624), with the improvement being significantly greater with formoterol than with salbutamol on all 3 days of treatment (mean area under the curve [AUC](0-24 h) of FEV(1) formoterol vs. salbutamol on days 1-3, all P<0.05). High-dose formoterol via Aerolizer (up to 96 microg/day) has a comparable tolerability profile to that of salbutamol in patients with mild-to-moderate COPD.     

Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol.

Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied. Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 microg b.i.d. or matching placebo was given for 10-14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 microg, 100 microg, and 200 microg was inhaled via a spacer at 5 min intervals, with a further 400 microg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry. Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0-15) and 45 (AUC0-45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration. It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.     

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.     

A comparison of bronchodilating drugs in the treatment of stable COPD]

The purpose of this study was to establish the optimal bronchodilating drug among therapies currently available for clinical treatment of the stable phase of chronic obstructive pulmonary disease (COPD). The efficacy of ipratropium bromide 40 micrograms, salbutamol 200 micrograms, and ipratropium bromide 40 micrograms plus salbutamol 200 micrograms was compared in 14 patients with COPD. Daily PEFR was obtained during the last seven days of a 2 week period incorporating drug inhalation four times daily. FEV1 and FVC were assessed on the final day of the treatment period. In the absence of bronchodilating medication, FEV1 was 1.27 +/- 0.13 l (52.9 +/- 5.1% pred). With ipratropium bromide 40 micrograms alone, FEV1 was 1.43 +/- 0.13 l (59.8 +/- 5.3% pred). A similar value was obtained for salbutamol 200 micrograms: 1.45 +/- 0.14 l (61.0 +/- 5.4% pred). However, FEV1 following the administration of ipratropium bromide 40 micrograms in combination with salbutamol 200 micrograms was 1.51 +/- 0.13 l (63.6 +/- 5.3% pred). The percent increase in FEV1 (compared to the value obtained without medication) was significantly higher with combined ipratropium bromide 40 micrograms plus salbutamol 200 micrograms (122.2 +/- 3.8%) than with either ipratropium bromide 40 micrograms (114.8 +/- 5.5%) or salbutamol 200 micrograms (116.5 +/- 4.4%) alone. Furthermore, the daily post-dilator PEFR improved significantly more with the combined therapy four times a day (311 +/- 29 l/min) than with either ipratropium bromide 40 micrograms (296 +/- 30 l/min) or salbutamol 200 micrograms (303 +/- 29 l/min) therapy alone. There was no discernible difference between results obtained with ipratropium bromide 40 micrograms versus salbutamol 200 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvements with tiotropium in COPD patients with concomitant asthma

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma have different diagnostic criteria and treatment paradigms. Both are common and can occur in the same patient. We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma. METHODS: A 12-week randomized, double-blind, placebo-controlled, parallel group trial with tiotropium 18 mcg daily was performed. Patients continued usual respiratory medications except for inhaled anticholinergics. Inclusion criteria: Physician diagnosis of COPD and asthma, age >or= 40 years, smoking >10 pack years, post-bronchodilator forced expiratory volume in 1s (FEV(1))<80% predicted, FEV(1)/forced vital capacity (FVC)<70%, >or= 12%, and >or= 200 ml increase in FEV(1) following inhaled bronchodilator, treatment with inhaled steroids >or= 1 year. Spirometry was measured serially for 6h on days 1, 29 and 85. RESULTS: Four hundred and seventy-two patients were randomized. Baseline characteristics were balanced. Mean age=59.6 years, 61.4% were men, and FEV(1)=1.55l (53.0% predicted). Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1) area under the curve (AUC) from 0 to 6h (difference=186+/-24 ml, p<0.001) and for morning pre-dose FEV(1) (difference=98+/-23 ml, p<0.001). Significant differences in favor of tiotropium were observed for pre-dose FVC (difference=128+/-34 ml, p<0.001) and FVC AUC 0-6h (difference=232+/-35 ml, p<0.001). Compared to baseline, the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 (p<0.05). CONCLUSIONS: Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication.     

Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.     

Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: A crossover, placebo-controlled comparison of onset and duration of action.

BACKGROUND: In contrast to the well-known activity profile in asthma, the precise efficacy and optimum dose schedules of long-acting beta(2)-agonists in chronic obstructive pulmonary disease (COPD) are not clear. OBJECTIVE: In this study, we aimed to compare the onset and the duration of action of a single inhalation of formoterol and salmeterol in COPD patients having partially reversible airway obstruction. METHODS: In a double-blind, randomized, crossover and placebo-controlled study design, the respiratory functions of 22 patients (mean age 57.3+/-5.4 years) having mild to severe COPD (5 mild, 8 moderate and 9 severe) and partially reversible airway obstruction [mean baseline reversibility of forced expiratory volume in 1 s (FEV(1)) 19.3+/-3.1%] were evaluated after inhalation of 12 microg formoterol and 50 microg salmeterol. RESULTS: Regarding the onset of bronchodilator action, the mean absolute increase of 0.20 liters in FEV(1) 10 min after inhalation of formoterol was significantly higher than baseline and that of placebo (0.04 liters), whereas that of salmeterol (0.11 liters) did not reach statistical significance. At 20 min, both formoterol (0.25 liters) and salmeterol (0.20 liters) produced a significant increase in FEV(1) compared with baseline and with that of placebo (0.04 liters). The peak bronchodilator effects occurring at 60 and 120 min following formoterol (0.39 liters) and salmeterol (0.40 liters) inhalation, respectively, were significantly higher than the corresponding levels of placebo (0.02 and -0.12 liters, respectively). Concerning the duration of action, the 12-hour values of both formoterol (0.25 liters) and salmeterol (0.22 liters) were significantly higher than that of placebo (-0.12 liters). The area under the curve values of FEV(1) of formoterol (3.5+/-1.3 l.h) and salmeterol (3.2+/-1.2 l x h) averaged over 12 h were comparable and higher than placebo values (1.2+/-0.5 l x h). After formoterol inhalation 2 patients experienced tremor and 1 had palpitation; 1 tremor and 1 headache attack were noted after salmeterol. For the pharmacologically predictable side effects, there was no difference between the drugs. CONCLUSIONS: In conclusion, this study revealed that a single dose of 12 microg formoterol and 50 microg salmeterol provided comparable bronchodilation within 12 h and had tolerable side effects in patients with mild to severe COPD having partially reversible airway obstruction.     

Bronchodilator tolerance: the impact of increasing bronchoconstriction.

Chronic exposure to beta-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma. In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 microg q.i.d. or placebo given via Diskhaler for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV1) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 microg, 100 microg and 200 microg was inhaled at 0, 5, and 10 min. FEV1 was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)0-40 FEV1 were compared between treatments and by degree of bronchoconstriction. Regular salbutamol resulted in attenuation of the acute response to beta-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV1 of 0, 15 and 30%, the AUC0-40 FEV1 with salbutamol were 11.2, -14.6 and -35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC0-40 FEV1. Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance.     

Effect of ketotifen on the bronchodilation induced by salbutamol

Twelve subjects with stable asthma each inhaled two puffs (200 micrograms) of salbutamol on 2 separate days 3 h after double-blind oral administration of ketotifen (two 1-mg capsules) or identical placebo. FEV1 was recorded before and at intervals for 4 h after inhalation of salbutamol. Overall, the FEV1 was significantly greater during the 4-hour period after premedication with ketotifen (p less than 0.02) and the difference between the effect of placebo and ketotifen was statistically significant at 120, 180 and 240 min after salbutamol (p less than 0.05).     

Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD

In the present trial, we compared the broncholytic efficacy of the combination therapy with 50 microg salmeterol + 250 microg fluticasone and 12 microg formoterol + 400 microg budesonide, both in a single inhaler device, in 16 patients with moderate-to-severe COPD. The study was performed using a single-blind crossover randomized study. Lung function, pulse oximetry (SpO2) and heart rate were monitored before and 15, 30, 60, 120, 180, 240, 300, 360, 480, 600, and 720 min after bronchodilator inhalation. Both combinations were effective in reducing airflow obstruction. FEV1 AUC(0-12 h) was 2.83 l (95% CI: 2.13-3.54) after salmeterol/fluticasone and 2.57 l (95% CI: 1.97-3.2) after formoterol/budesonide. Formoterol/budesonide elicited the mean maximum improvement in FEV1 above baseline after 120 min (0.29 l; 95% CI: 0.21-0.37) and salmeterol/fluticasone after 300 min (0.32 l; 95% CI: 0.23-0.41). At 720 min, the increase in FEV1 over baseline values was 0.10 l (95% CI: 0.07-0.12) after salmeterol/fluticasone and 0.10 l (95% CI: 0.07-0.13) after formoterol/budesonide. The mean peak increase in heart rate occurred 300 min after formoterol/budesonide (1.5 b/min; 95% CI--2.3 to 5.3) and 360 min after salmeterol/fluticasone (2.6 b/min; 95% CI--1.9 to 7.0). SpO2 did not change. All differences between salmeterol/fluticasone and formoterol/budesonide were not significant (P > 0.05) except those in FEV1 at 120 and 360 min. The results indicate that an inhaled combination therapy with a long-acting beta2-agonist and an inhaled corticosteroid appears to be effective in improving airway limitation after acute administration in patients suffering from COPD.     

Clinical equivalence between salbutamol hydrofluoroalkane pMDI and salbutamol Turbuhaler at the same cumulative microgram doses in paediatric patients

This study aimed to demonstrate equivalent efficacy and safety between salbutamol delivered via the HFA134a pMDI (Hydrofluoroalkane 134a pressurised Metered Dose Inhaler) and the Turbuhaler dry powder inhaler in asthmatic children. This was a randomised, double-blind, double-dummy, placebo-controlled, crossover study in 10 asthmatic children aged 6-15 years who demonstrated at least 10% reversibility of FEV1 after inhaling 400 microg of salbutamol. On 5 single study days subjects received either placebo or cumulative doses of 100, 200, 400 and 800 microg of salbutamol at 30 minute intervals. Both devices were placebo on one study day while each device was active on two study days. FEV1 was measured before and 20 minutes after each dose. Heart rate was measured before spirometry. Mean FEV1 and heart rate at each time point and the area under the dose response time curve (AUC) were analysed using ANOVA. FEV1 increased similarly after cumulative doses of salbutamol on each of the study days, irrespective of device. Mean treatment difference in AUC was 0.01 L. min (95%CI -0.05 to 0.08 L). Heart did not differ at any dose. It is concluded that salbutamol delivery from a HFA pMDI and Turbuhaler is equivalenton a microgram basis in asthmatic children for efficacy and safety.     

Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study

BACKGROUND: International guidelines recommend the long-acting anticholinergic, tiotropium, or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids (ICS) in the treatment of COPD has also been confirmed for severe and very severe COPD, but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking. METHODS: This 6-week multicentre, randomised, double-blind, triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily (n=56) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily (n=51) in patients with moderate-to-very severe COPD. Serial spirometry was performed over 12h after 6 weeks of treatment. The primary endpoint was forced expiratory volume in 1s (FEV1) area under the curve from 0 to 12h (AUC0-12h) on Day 43. RESULTS: Randomization failed to provide treatment groups with comparable baseline characteristics for smoking history, current smokers, duration of COPD, FEV1, forced vital capacity (FVC) and reversibility. Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group. Fewer patients in the tiotropium showed a 12% and 200 ml acute increase to short-acting bronchodilators at baseline. However, treatment with tiotropium alone resulted in comparable bronchodilation compared with salmeterol plus fluticasone, as measured by all the spirometric parameters at the end of the 6-week study period. FEV1 AUC0-12h was 1.55+/-0.03 l in the tiotropium group vs. 1.57+/-0.04 l in the salmeterol plus fluticasone groups (p=0.63). Trough (predose) FEV1 was 1.54+/-0.03 l in the tiotropium group vs. 1.46+/-0.03 l in the combination group (p=0.07), and peak FEV(1) was 1.68+/-0.04 l vs. 1.66+/-0.04 l, respectively, (p=0.77). FVC AUC0-12h, trough and peak were also comparable between groups at study end (p>0.05, for all). Further, rescue salbutamol use was similar in the tiotropium and combination groups and both treatment regimens were well tolerated. CONCLUSIONS: Six weeks of treatment with tiotropium resulted in comparable bronchodilation compared with salmeterol plus fluticasone in patients with moderate-to-very severe COPD, despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline. The results of this pilot study will aid planning for further large-scale comparative studies.     

A randomized, placebo-controlled trial of bronchodilators for bronchoscopy in patients with COPD

BACKGROUND: In contrast to asthma, the indication for bronchodilators prior to bronchoscopy in patients with COPD has not been properly investigated. We therefore performed a randomized, double-blind, placebo-controlled trial to determine whether use of a short-acting bronchodilator provides a protective effect in patients with COPD undergoing bronchoscopy. METHODS: One hundred twenty patients undergoing bronchoscopy were included. Patients with COPD were randomized to receive either 200 mug of salbutamol (n = 40) or placebo (n = 40) before bronchoscopy. Control patients (n = 40) did not receive any inhaled medication. Spirometry was performed before and 2 h after bronchoscopy in all patients. Sedative drug requirements and hemodynamic parameters were recorded. RESULTS: Hemodynamic findings before, during, and after bronchoscopy were similar in patients with COPD randomized to either salbutamol or placebo (p = not significant for all). Compared to prebronchoscopy values, postbronchoscopy percentage of predicted FEV(1) decreased significantly in all three groups: salbutamol (median, - 4.7%; interquartile range [IQR], - 13.3 to 6.6); placebo (median, - 4.8%; IQR, - 19.9 to 8.4); and control subjects (median, - 10.0%; IQR, - 20.2 to - 3.3) [p = 0.023]. The decrease in FEV(1) was similar in all three patient groups (p = 0.432). The relative change in FEV(1) was inversely correlated to the increasing severity of COPD as expressed by Global Initiative for Chronic Obstructive Lung Disease stages (p = 0.01). CONCLUSIONS: Premedication with an inhaled short-acting beta-agonist cannot be recommended in patients with COPD undergoing bronchoscopy.