The pulmonary and extra-pulmonary effects of high-dose formoterol in COPD: a comparison with salbutamol

OBJECTIVES: Formoterol, a beta(2) agonist with a rapid onset of effect and long duration of action, can be used as maintenance and reliever medication for asthma and COPD. We compared the pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol in patients with COPD to assess efficacy and safety. METHODOLOGY: In a randomized, double-blind, cross-over study, 12 patients with moderate to severe COPD inhaled, via Turbuhaler, 10 doses of formoterol (total metered dose, 120 microg, equivalent to a 90- microg delivered dose), salbutamol (total metered dose 2000 microg) or placebo at 2-min intervals on separate days. The effects on lung function (FEV(1) and PEF), heart rate, blood pressure, oxygen saturation, corrected QT interval (QTc), T-wave height and plasma potassium were assessed before each dose, 15 min after each dose, and at half-hourly intervals for 3 h following the final dose. RESULTS: Inhalation of formoterol or salbutamol resulted in significant improvement in lung function (measured 30 min after the last dose) when compared with placebo. There were no clinically important or statistically significant changes in heart rate, QTc, T-wave height, plasma potassium, oxygen saturation, or systolic and diastolic blood pressures with formoterol or salbutamol. One patient developed ventricular trigeminy after both formoterol and salbutamol. She had had ventricular ectopics on her screening electrocardiogram. CONCLUSION: Formoterol and salbutamol both produced significant improvement in lung function and were similarly well tolerated in high doses, as might be taken by a patient for relief of COPD symptoms.     

Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease

Formoterol is a long-acting beta2-agonist with a rapid onset of effect in patients with chronic obstructive pulmonary disease (COPD), making it potentially suitable for both maintenance and as-needed bronchodilator treatment. To evaluate the efficacy and tolerability of maintenance formoterol in patients with COPD and to compare the effects of additional formoterol as needed with terbutaline. In this 6-month, double-blind study, 657 patients with COPD (40 years, forced expiratory volume in 1s [FEV1] 40-70% predicted normal) were randomized to formoterol 9 microg twice daily (bid) plus terbutaline 0.5 mg as needed (FORM bid), formoterol 9 microg bid plus formoterol 4.5 microg as needed (FORM bid+prn), or placebo bid plus terbutaline 0.5 mg as needed (placebo), all administered via Turbuhaler. Primary efficacy variables were FEV1 and the sum of breathlessness and chest tightness scores combined symptom score. Formoterol significantly (P<0.01) increased FEV(1) compared with placebo: FORM bid 6.5% (95% CI: 2.5, 10.7%); FORM bid+prn 11.8% (95% CI: 7.7, 16.2%). Combined symptom score decreased significantly in both formoterol groups compared with placebo: FORM bid -0.27 (95% CI: -0.49, -0.06; P=0.012); FORM bid+prn -0.32 (95% CI: -0.53, -0.11; P=0.0026). Similar significant (P<0.05) improvements were seen in both formoterol groups for morning peak expiratory flow, cough and sleep scores, and reliever use. In this study, formoterol 9 microg bid via Turbuhaler as maintenance therapy, with either formoterol or terbutaline as rescue medication, provided sustained improvements in lung function and COPD symptoms. Both formoterol regimens were well tolerated with no differences in adverse events or electrocardiogram profiles.     

Onset of action of single doses of formoterol administered via Turbuhaler in patients with stable COPD

We studied 16 patients with stable COPD in a double blind, double dummy, placebo-controlled, within patient study to see if formoterol could be used as a rescue drug. We compared the of onset of bronchodilation obtained with formoterol 12 microg (metered dose corresponding to 9 microg delivered dose) and formoterol 24 microg (metered dose corresponding to 18 microg delivered dose), both delivered via Turbuhaler, with that of salbutamol 400 microg and salbutamol 800 microg delivered via pressurized metered-dose inhaler (pMDI). Patients inhaled single doses of placebo, formoterol and salbutamol on five separate days. FEV1 was measured in baseline condition and 3, 6, 9, 12, 15, 18, 21, 24, 30, 40, 50, and 60 min after inhalation of each treatment. We examined two separate criteria for deciding if a response was greater than that expected by a random variation of the measurement: (1) a rise in FEV1 of at least 15% from the baseline value; (2) an absolute increase in FEV1 of at least 200 ml. Formoterol 12 microg (15.2 min; 95% CI 9.5-21.0) and formoterol 24 microg (15.1 min; 95% CI 8.9-21.2) caused a rise in FEV1 of at least 15% from the baseline value almost rapidly as salbutamol 400 microg (13.6 min; 95% CI 7.1-20.1) and salbutamol 800 microg (14.5 min; 95% CI 7.1-21.9). No significant difference (P=0.982) in onset of action was seen between the four active treatments. According to Criterion 2, the mean time to 200 ml increase in FEV1 was 11.1 min (95% CI: 7.0-15.2) after salbutamol 400 microg, 13.0 min (95% CI: 7.9-18.1) after salbutamol 800 microg, 14.7 min (95% CI: 7.1-22.4) after formoterol 12 microg, and 12.7 min (95% CI: 7.4-18.0) after formoterol 24 microg. Again, there was no significant difference (P= 0.817) between the four active treatments. Formoterol Turbuhaler 12 microg and 24 microg caused bronchodilation as rapidly as salbutamol 400 microg and 800 microg given via pMDI.     

Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD

Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes more severe, the therapeutic option is to add salbutamol, but not salmeterol, as needed to cause rapid relief of bronchospasm. Unfortunately the most effective dosage of beta2-agonists may increase above that recommended during acute exacerbations. In this study, we compared the acute effects of higher than customary doses of salmeterol and salbutamol in 20 patients with acute exacerbation of COPD. A dose-response curve to salmeterol pMDI, 25 microg/puff or salbutamol pMDI, 100 microg/puff, was constructed using 1, 1, and 2 puff' i.e., a total cumulative dose of 100 microg salmeterol or 400 microg salbutamol on 2 consecutive days. After baseline measurements, dose increments were given at 30-min intervals with measurements being made 25 min after each dose. Hear rate (HR) and pulse-oximetry (SpO2) measurements were then taken. Both salmeterol and salbutamol induced a larg and significant (P < 0.05) dose-dependent increase in FEV1 [mean differences from baseline (L) = after 100 microg salmeterol 0.174 (95% CI: 0.112 to 0.237); after 400 microg salbutamol: 0.165 (95% CI: 0.080 to 0.249)], in IC [mean differences from baseline (L) = after 100 microg salmeterol: 0.332 (95% CI: 0.165 to 0.499); after 400 microg salbutamol: 0.281 (95% CI: 0.107 to 0.456)] (Fig. 2), and in FVC mean differences from baseline (L) = after 100 microg salmeterol: 0.224 (95% CI: 0.117 to 0.331); after 400 microg salbutamol: 0.242 (95% CI: 0.090 to 0.395)]. There was no significant difference between the FEV1 values (P=0.418), the ICvalues (P=0.585), and the FVCvalue (P=0.610) after 100 microg salmeterol and 400 microg salbutamol. HR [mean differences from baseline (beats/min) = after 100 microg salmeterol: 3.15 (95% CI: -0.65 to 6.96); after 400 microg salbutamol: 2.30 (95% CI: -0.91 to 5.51)] and SpO2 [mean differences from baseline (%) = after 100 microg salmeterol: -0.20 (95% CI: -1.00 to 0.60); after 400 microg salbutamol: -0.11 (95% CI: -1.00 to 0.79)] did not change significantly from baseline (P > 0.05). These data indicate that salmeterol is effective and safe in the treatment of acute exacerbation of COPD and support its use in this clinical condition.     

Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD

Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect. An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD. In this study, we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol. A total of 20 patients with stable COPD were randomized. Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler. Serial measurements of FEV(1) were performed over 60 min. Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0-15 min) than formoterol alone. Also the change in FEV(1) 15 min after inhalation of formoterol/budesonide combination (0.197 l; 95% CI: to 0.142-0.252) was greater than that induced by formoterol alone (0.147 l; 95% CI: to 0.092-0.201). The mean increases in FEV(1) were always higher after budesonide/formoterol than formoterol alone, although both treatments induced a significant improvement over baseline at each explored time point. Even the FEV(1)-AUC(0-60 min) after formoterol/budesonide was significantly larger than that after formoterol. Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner. This study indicates that the addition of budesonide influences the fast onset of action of formoterol, but does not induce systemic effects, in patients with stable COPD.     

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.     

Efficacy and safety of formoterol Turbuhaler when added to inhaled corticosteroid treatment in children with asthma

This double-blind, placebo-controlled, randomized, parallel-group, multicenter study was conducted in 302 children aged 6-11 years with asthma not optimally treated with inhaled corticosteroids alone. Patients continued with their existing dose of inhaled corticosteroids and in addition received placebo, formoterol 4.5 microg or formoterol 9 microg b.i.d., for 12 weeks (all delivered via Turbuhaler). Terbutaline was available as reliever medication. The primary efficacy variable was change from baseline in morning peak expiratory flow (PEF); secondary efficacy variables included forced expiratory volume in 1 sec (FEV(1)), serial PEF measured over 12 hr, evening PEF, asthma symptom score, and quality of life. Compared with placebo, formoterol 4.5 microg and 9 microg improved morning PEF by 8 l/min (P = 0.035) and 11 l/min (P = 0.0045), respectively. Evening PEF and FEV(1) were also significantly increased compared with placebo, with no statistically significant difference between formoterol doses. Lung-function improvements compared with placebo were greater in the middle of the day. Twelve-hour average serial PEF after 3 months increased by 24 l/min (95% CI, 9, 39 l/min) in the formoterol 9-microg group, and by 14 l/min (95% CI, 0, 29 l/min) in the formoterol 4.5-microg group. The incidence of severe exacerbations in both formoterol groups was numerically lower than in the placebo group, indicating that formoterol may have the potential to improve exacerbation control in children. Both formoterol doses were well-tolerated, and tolerance to the drug's bronchodilator effect was not observed. Formoterol provided sustained improvements in lung function and was well-tolerated in children with asthma suboptimally treated with inhaled corticosteroids alone.     

Onset of action following formoterol Turbuhaler and salbutamol pMDI in reversible chronic airway obstruction

Short-acting beta(2)-agonists are currently recommended for symptom relief in asthma and the treatment of mild, acute exacerbations in COPD. However, formoterol has as fast an onset of action as salbutamol with the additional benefit of longer-lasting bronchodilation (approximately 12 h). Furthermore, systemic side effects observed with formoterol are of a similar duration but less pronounced than with short-acting beta(2)-agonists. In this double-blind, randomized, cross-over study, 20 adult patients with reversible chronic airway obstruction (intrinsic asthma or COPD) inhaled single doses of formoterol 9 microg or salbutamol 100 microg (group A) or formoterol 18 microg or salbutamol 200 microg (group B). FEV(1) was measured prior to and 5, 10, 15, 20, 25 and 30 min following inhalation of study drug. No significant differences in FEV(1) values were observed between group A (P=0.704) or group B (P=0.270) at baseline, or at 5 (Group A: P=0.340; Group B: P=0.559) and 15 min (Group A: P=0.526; Group B: P=0.818) post dose. No adverse events were reported during the study. Formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at the recommended doses.     

Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study.

The aim of this study was to compare the effects of formoterol, ipratropium bromide and a placebo on walking distance, lung function, symptoms and quality of life (QoL) in chronic obstructive pulmonary disease (COPD) patients. A total of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe nonreversible COPD participated in this randomised, double-blind, parallel-group study. After a 2-week placebo run-in, patients were randomised to formoterol Turbuhaler 18 microg b.i.d. (delivered dose), ipratropium bromide 80 microg t.i.d. via a pressurised metered dose inhaler, or placebo for 12 weeks. Inhaled short-acting beta2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose. The primary variable was walking distance in the shuttle walking test (SWT). Baseline mean SWT distance was 325 m, mean forced expiratory volume in one second (FEV1) was 40% predicted. Clinically significant improvements in SWT (>30 m) were seen in 41, 38 and 30% of formoterol, ipratropium and placebo patients, respectively (not significant). Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium and placebo groups, respectively. Both active treatments significantly improved FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea score compared with placebo. Formoterol reduced relief medication use compared with placebo. Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms, without significant improvements in the shuttle walking test.     

Evidence of the rapid protective effect of formoterol dry-powder inhalation against exercise-induced bronchospasm in athletes with asthma

BACKGROUND: Although formoterol, a new long-acting beta(2)-adrenergic agonist, has a rapid bronchodilating action, no studies have previously examined whether it can provide equally rapid protection against exercise-induced bronchospasm (EIB). Aim: The aim of the study was to assess the effect of inhaled formoterol against EIB 15 min and 4 h after administration in asthmatic athletes. METHODS: The protective effect of a formoterol (12 microg) dry-powder inhalation was evaluated in 14 EIB-positive asthmatic athletes (13 males, mean age 16.8 years), in a double-blind, placebo-controlled, two-period cross-over study. On each treatment day, the subjects underwent two cycloergometric exercise tests 15 min and 4 h after receiving formoterol or placebo. RESULTS: Formoterol induced significant bronchodilation in comparison with placebo both 15 min and 4 h after administration (p = 0.007 and p = 0.004); placebo treatment had no effect on EIB, the maximum percent fall in FEV(1) after exercise being 29.3 +/- 14.3% and 22.9 +/- 13. 7% at 15 min and 4 h, respectively. Formoterol offered good protection against EIB in 12 athletes (86%) who experienced a decrease in FEV(1) after exercise <10% both 15 min and 4 h after administration. The mean maximum percent fall in FEV(1) after formoterol was 5.9+/-7.2% at 15 min (p < 0.0001), and 5.8 +/- 6.9% at 4 h (p < 0.0001). There was no statistically significant difference in resting heart rate before and after medication with placebo or formoterol, nor was the heart rate at the end of exercise significantly different on the 2 treatment days. No side effect was observed in either group. CONCLUSIONS: This study demonstrates that formoterol dry powder inhalation is effective in protecting asthmatic athletes as early as 15 min after dosing. Furthermore, the data confirm the long duration of its protective effect and the absence of any significant adverse effects after acute administration.     

Bronchodilator response to formoterol Turbuhaler in patients with COPD under regular treatment with formoterol Turbuhaler

Formoterol Turbuhaler has been suggested for as-needed use in asthmatic patients. We investigated whether regular treatment with formoterol would modify the dose-response curves to formoterol in patients with partially reversible COPD. In this randomised, double-blind, cross-over study taking place over four non-consecutive days 16 outpatients with moderate to severe COPD, who were under regular treatment with formoterol Turbuhaler (18 microg in two daily doses) from at least 4 months, inhaled a conventional dose of formoterol Turbuhaler 9 microg or placebo. Two hours later, a FEV(1) value was established, following which a dose-response curve to formoterol (4.5 microg/inhalation) or placebo was constructed using four inhalations (1+1+2)--total cumulative delivered dose of 18 microg formoterol--with the following sequences: (1) formoterol pre-treatment + formoterol 18 microg, (2) formoterol pre-treatment + placebo, (3) placebo pre-treatment + formoterol 18 microg, (4) placebo pre-treatment + placebo. Formoterol 9 microg induced significant (P < 0.0001) bronchodilation at 2 h after inhalation (best mean increase in FEV(1): 0.170 L). Afterwards, dose-dependent increases in FEV(1) occurred with formoterol (maximum mean increase from 2-h value with formoterol: 0.072 after formoterol pre-treatment, and 0.201 L after placebo pre-treatment). Both maximum values of bronchodilation after the last inhalation of formoterol were statistically different (P < 0.001) from 2-h levels. These results show that dose-dependent bronchodilatation of formoterol is maintained despite regular treatment.     

Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype

PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta(2)-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta(2)-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta(2)-agonist (inhaled formoterol, 12 microg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype.SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV(1)]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment.RESULTS: Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo.CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta(2)-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.     

Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial.

The aim of this study was to investigate formoterol, an inhaled long-acting beta2-agonist, in patients with chronic obstructive pulmonary disease (COPD). Six-hundred and ninety-two COPD patients, mean baseline forced expiratory volume in one second (FEV1) 54%, FEV1/forced vital capacity 75% of predicted, reversibility 6.4% pred, were treated with formoterol (4.5, 9 or 18 microg b.i.d.) or placebo via Turbuhaler for 12 weeks. Symptoms were recorded daily. Spirometry and the incremental shuttle walking test (SWT) were performed at clinic visits. Compared with placebo, 18 microg b.i.d. formoterol reduced the mean total symptom score by 13% and increased the percentage of nights without awakenings by 15%. Formoterol (9 and 18 microg b.i.d.) significantly reduced symptom scores for breathlessness (-7% and -9%, respectively) and chest tightness (-11% and -8%, respectively), reduced the need for rescue medication (-25% and -18%, respectively), and increased symptom-free days (71% and 86%, respectively). FEV1 improved significantly after all three doses of formoterol (versus placebo). No differences were found between groups in SWT walking distance. No unexpected adverse events were seen. In conclusion, 9 and 18 microg b.i.d. formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients. Formoterol improved lung function at a dose of 4.5 microg b.i.d. and higher.     

A bolus of inhaled budesonide rapidly reverses airway subsensitivity and beta2-adrenoceptor down-regulation after regular inhaled formoterol

BACKGROUND: Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid. METHODS: Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/- SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 microg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 microg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta2-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol. RESULTS: There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte 02-adrenoceptor density (geometric mean Bmax: fmol/10(6) cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80). CONCLUSION: We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction.     

Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.

Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 microg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 microg, budesonide 400 microg, formoterol 9 microg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (-7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.     

Influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in COPD

We examined the influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in patients with partially reversible stable COPD. Twenty outpatients inhaled one or two puffs of formoterol (12 microg puff(-1)), or placebo. Two hours after inhalation, a dose-response curve to inhaled oxitropium bromide (100 microg puff(-1)) or placebo was constructed using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg oxitropium bromide. Doses were given at 20-min intervals and measurements made 15 min after each dose. On six separate days, all patients received one of the following: (1) formoterol 12 microg + oxitropium bromide 600 microg, (2) formoterol 12 microg + placebo, (3) formoterol 24 microg + oxitropium bromide 600 microg, (4) formoterol 24 microg + placebo, (5) placebo + oxitropium bromide 600 microg, or (6) placebo + placebo. Both formoterol 12 microg and 24 microg induced a good bronchodilation (formoterol 12 microg, 0.19-0.20 l; formoterol 24 microg 0.22-0.24 l). The dose-response curve of oxitropium, but not placebo, showed an evident increase in FEV1, with a further significant increase of respectively 0.087 l and 0.082 l after the formoterol 12 microg and formoterol 24 microg pre-treatment. This study shows that improved pulmonary function in patients with stable COPD may be achieved by adding oxitropium 400-600 microg to formoterol. There is not much difference in bronchodilation between combining oxitropium with formoterol 12 microg or 24 microg. In any case, formoterol 24 microg alone seems sufficient to achieve the same bronchodilation induced by oxitropium 600 microg alone in most patients.     

A single high dose of formoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD

Several clinical trials have shown that the inhaled beta2-agonists with long-acting properties, formoterol and salmeterol, may be effective in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, there is a great deal of controversy regarding the timing and optimal dose of inhaled beta2-agonists in this pathologic condition. In this double-blind, randomised, crossover study, we have compared the bronchodilating effect and the safety of inhaled formoterol administered via Turbuhaler using either a cumulative dose regimen or the equivalent single dose in 16 patients with acute exacerbations of COPD. On the two consecutive days, the patients received, in a randomised order, each of the following active dose regimens: (A): 9 + 9 + 18 microg of formoterol via Turbuhaler (36 microg cumulative delivered dose) or (B): 36 + 0 + 0 microg of formoterol via Turbuhaler. The three doses on each treatment day were administered at 30-mm intervals, with measurements being made 5 and 30 min after each dose. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO2) and pulse rate. Both the high dose and the cumulative one induced a significant bronchodilation expressed as change in FEV1. The difference between the two regimens was significant (P=0.0332) only 60 min after the first inhalation. The trend of FVC and IC was similar to that of FEV1. All treatment regimens were well tolerated and no adverse events were reported. Neither the administration ofthe high dose nor that of the cumulative one modified heart rate in a significant manner. Also they did not influence SpO2. This study indicates that a single high dose offormoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD.     

Effects of formoterol on exercise tolerance in severely disabled patients with COPD

OBJECTIVE: We wished to evaluate the effects of inhaled formoterol, a long-acting beta(2)-adrenergic agonist, on exercise tolerance and dynamic hyperinflation (DH) in severely disabled chronic obstructive pulmonary disease (COPD) patients. DESIGN: In a two-period, crossover study, 21 patients with advanced COPD (FEV(1)=38.8+/-11.7% predicted, 16 patients GOLD stages III-IV) were randomly allocated to receive inhaled formoterol fumarate 12 microg twice daily for 14 days followed by placebo for 14 days, or vice versa. Patients performed constant work-rate cardiopulmonary exercise tests to the limit of tolerance (Tlim) on a cycle ergometer: inspiratory capacity (IC) was obtained at rest and each minute during exercise. Baseline and transitional dyspnoea indices (BDI and TDI) were also recorded. RESULTS: Eighteen patients completed both treatment periods. Formoterol treatment was associated with an estimated increase of 130 s in Tlim compared with placebo (P=0.052): this corresponded to a 37.8% improvement over placebo (P=0.012). Enhanced exercise tolerance after bronchodilator was associated with diminished DH marked by higher inspiratory reserve and tidal volumes at isotime and exercise cessation (P<0.05). There was no significant difference between formoterol and placebo on exercise dyspnoea ratings; however, all domains of the TDI improved (P相似文献   

Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism

BACKGROUND: Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors, with formoterol being a full agonist. The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40% of patients and is known to predispose to agonist-induced downregulation and desensitization. OBJECTIVES: To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction (the primary end point) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism. METHODS: Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were randomized to completion (mean [SEM] age, 35.8 [3.2] years; mean FEV(1), 76.9 [2. 5]% predicted). Patients received three different treatments for 1 week in randomized, double-blind, crossover fashion, with a 1-week washout period between treatments: formoterol, 12 microg bid; salmeterol, 50 microg bid; and placebo. For each of the randomized treatment periods, there were three separate methacholine challenges: baseline after washout, 12 h after the first dose, and 12 h after the last dose. RESULTS: Both salmeterol and formoterol exhibited significantly (p < 0.05) greater bronchoprotection than placebo for their effects after single or repeated dosing, although there was no significant difference between the two drugs. The geometric mean fold protection vs placebo (95% confidence interval [CI]) for the first dose was 1.6-fold (95% CI, 1.1 to 2.2) for salmeterol and 1.9-fold (95% CI, 1.1 to 3.2) for formoterol, and for last dose was 1.6-fold (95% CI, 1.2 to 2.3) for salmeterol and 1. 9-fold (95% CI, 1.2 to 2.8) for formoterol. Salmeterol and formoterol produced significant (p < 0.05) increases in FEV(1) and forced expiratory flow after 25 to 75% of vital capacity has been expelled, after the first but not the last dose compared to placebo, while there were significant (p < 0.05) improvements in domiciliary peak flows during treatment with both drugs. CONCLUSION: Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect.     

Clinically equivalent bronchodilatation achieved with formoterol delivered via Easyhaler and Aerolizer

BACKGROUND: User-friendly devices for the delivery of asthma drugs are needed to enhance treatment compliance. Formoterol inhalation powder has been developed to Easyhaler multidose powder inhaler to enable the treatment of all asthma severities with the same device. OBJECTIVES: This double-blind, double-dummy, single- dose, placebo-controlled, cross-over study aimed to demonstrate the non-inferiority of the bronchodilating effect of formoterol 12 microg delivered via Easyhaler versus via Aerolizer. In addition, dose responses following placebo, 12-microg and 48-microg doses of formoterol via Easyhaler were compared. Furthermore, onset and duration of action, and safety of formoterol inhaled using the two inhalers were compared. METHODS: Sixty-seven adult asthmatic subjects showing >or=15% increase in forced expiratory volume in 1 s (FEV(1)) after short-acting sympathomimetic inhalation were enrolled and completed the study. The study comprised screening and 4 treatment days, with each subject inhaling a single 12-mug dose of formoterol via Easyhaler, a 12-microg dose via Aerolizer, a 48-microg dose via Easyhaler or placebo. Repeat spirometry and vital sign measurements were performed for 12 h during treatment days. The primary efficacy variable was the area under the flow volume curve (AUC(0-12)) of FEV(1). Secondary efficacy variables comprised maximum FEV(1 )(FEV(1max)), forced vital capacity (FVC), and the need of rescue medication during the treatment days. Safety was evaluated by determining blood pressure, heart rate and the number of adverse events (AEs). RESULTS: Results showed the non-inferiority of the bronchodilating effect of 12 microg formoterol via Easyhaler compared to Aerolizer. The Easyhaler-Aerolizer ratio for AUC(0-12) of FEV(1 )was 0.991 (95% confidence interval from 0.969 to 1.013). No statistically significant differences emerged for secondary efficacy variables. A statistically significant dose response was seen following placebo, 12- and 48-microg doses in FEV(1). No safety differences emerged for the 12-microg dose inhaled via Easyhaler or Aerolizer, but the incidence of AEs was higher following formoterol 48 microg and placebo treatments. CONCLUSIONS: Formoterol delivered via Easyhaler was therapeutically equivalent to Aerolizerat the 12-microg dose. The 48-microg dose via Easyhaler demonstrated statistically significantly greater bronchodilation but showed an increased occurrence of AEs.