C. Califano

Formoterol as dry powder oral inhalation compared with salbutamol metered-dose inhaler in acute exacerbations of chronic obstructive pulmonary disease

BACKGROUND Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patients existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. OBJECTIVE The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). METHODS A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. RESULTS Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. CONCLUSIONS In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol.

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.

Long-Acting β2-Agonists in the Treatment of Acute Exacerbations of COPD

AbstractObjective: To evaluate the acute bronchodilating effect of cumulative doses of formoterol administered via Turbuhaler™ or salmeterol administered via pressurised metered-dose inhaler (pMDI) in patients with mild acute exacerbations of chronic obstructive pulmonary disease (COPD) to determine if these drugs might be used in this condition. Design: This was a randomised, double-blind, double-dummy, crossover study taking place over two consecutive days. Patients and setting: 30 patients attending our outpatient clinics with mild acute exacerbations of COPD (Anthonisen exacerbation type I or II), and who were willing to participate, were recruited. Interventions: A dose-response curve to salmeterol pMDI (25 μg/inhalation) or formoterol Turbuhaler™ (12 μg/inhalation) was constructed using one inhalation, one inhalation, and two inhalations, i.e. a total cumulative dose of metered salmeterol 100μg or formoterol 48μg on two consecutive days. After baseline measurements, dose increments were given at 30-minute intervals with measurements being made 25 minutes after each dose. Oral bronchodilators were not permitted during the study. Short-acting inhaled β2-agonists were permitted soon after each test when required. All patients received treatment with an oral antibiotic (amoxicillin/clavulanic acid or levofloxacin) and an inhaled steroid (budesonide 400μg or fluticasone 250μg twice daily). Main outcome measures: The highest forced vital capacity (FVC), inspiratory capacity (IC) and forced expiratory volume in one second (FEV1) values obtained from one or other of the curves were kept for analysis. We also measured oxygen saturation by pulse oximetry (SpO2) and heart rate (HR). The maximum FEV1 value during the dose-response curve to formoterol or salmeterol was chosen as the primary outcome variable to compare the two treatments. Results: Both formoterol and salmeterol induced a large and significant (p < 0.001) dose-dependent increase in FEV1, FVC and IC. There was no significant difference between the FEV1 values (p = 0.081), the FVC values (p = 0.085) and the IC values (p = 0.111) after formoterol 48μg or salmeterol 100μg. Neither HR nor SpO2 changed significantly (p > 0.05). Conclusions: Our results suggest that cumulative doses of long-acting β2-agonists may improve lung function in patients with mild acute exacerbations of COPD although we cannot advocate their use in the initial therapy of an acute exacerbation because much fundamental information is still lacking.

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.

Long-Acting ??2-Agonists in the Treatment of Acute Exacerbations of COPD

AbstractObjective: To evaluate the acute bronchodilating effect of cumulative doses of formoterol administered via Turbuhaler™ or salmeterol administered via pressurised metered-dose inhaler (pMDI) in patients with mild acute exacerbations of chronic obstructive pulmonary disease (COPD) to determine if these drugs might be used in this condition. Design: This was a randomised, double-blind, double-dummy, crossover study taking place over two consecutive days. Patients and setting: 30 patients attending our outpatient clinics with mild acute exacerbations of COPD (Anthonisen exacerbation type I or II), and who were willing to participate, were recruited. Interventions: A dose-response curve to salmeterol pMDI (25 μg/inhalation) or formoterol Turbuhaler™ (12 μg/inhalation) was constructed using one inhalation, one inhalation, and two inhalations, i.e. a total cumulative dose of metered salmeterol 100μg or formoterol 48μg on two consecutive days. After baseline measurements, dose increments were given at 30-minute intervals with measurements being made 25 minutes after each dose. Oral bronchodilators were not permitted during the study. Short-acting inhaled β2-agonists were permitted soon after each test when required. All patients received treatment with an oral antibiotic (amoxicillin/clavulanic acid or levofloxacin) and an inhaled steroid (budesonide 400μg or fluticasone 250μg twice daily). Main outcome measures: The highest forced vital capacity (FVC), inspiratory capacity (IC) and forced expiratory volume in one second (FEV1) values obtained from one or other of the curves were kept for analysis. We also measured oxygen saturation by pulse oximetry (SpO2) and heart rate (HR). The maximum FEV1 value during the dose-response curve to formoterol or salmeterol was chosen as the primary outcome variable to compare the two treatments. Results: Both formoterol and salmeterol induced a large and significant (p < 0.001) dose-dependent increase in FEV1, FVC and IC. There was no significant difference between the FEV1 values (p = 0.081), the FVC values (p = 0.085) and the IC values (p = 0.111) after formoterol 48μg or salmeterol 100μg. Neither HR nor SpO2 changed significantly (p > 0.05). Conclusions: Our results suggest that cumulative doses of long-acting β2-agonists may improve lung function in patients with mild acute exacerbations of COPD although we cannot advocate their use in the initial therapy of an acute exacerbation because much fundamental information is still lacking.

Long-Acting β 2 -Agonists in the Treatment of Acute Exacerbations of COPD

AbstractObjective: To evaluate the acute bronchodilating effect of cumulative doses of formoterol administered via Turbuhaler™ or salmeterol administered via pressurised metered-dose inhaler (pMDI) in patients with mild acute exacerbations of chronic obstructive pulmonary disease (COPD) to determine if these drugs might be used in this condition. Design: This was a randomised, double-blind, double-dummy, crossover study taking place over two consecutive days. Patients and setting: 30 patients attending our outpatient clinics with mild acute exacerbations of COPD (Anthonisen exacerbation type I or II), and who were willing to participate, were recruited. Interventions: A dose-response curve to salmeterol pMDI (25 μg/inhalation) or formoterol Turbuhaler™ (12 μg/inhalation) was constructed using one inhalation, one inhalation, and two inhalations, i.e. a total cumulative dose of metered salmeterol 100μg or formoterol 48μg on two consecutive days. After baseline measurements, dose increments were given at 30-minute intervals with measurements being made 25 minutes after each dose. Oral bronchodilators were not permitted during the study. Short-acting inhaled β2-agonists were permitted soon after each test when required. All patients received treatment with an oral antibiotic (amoxicillin/clavulanic acid or levofloxacin) and an inhaled steroid (budesonide 400μg or fluticasone 250μg twice daily). Main outcome measures: The highest forced vital capacity (FVC), inspiratory capacity (IC) and forced expiratory volume in one second (FEV1) values obtained from one or other of the curves were kept for analysis. We also measured oxygen saturation by pulse oximetry (SpO2) and heart rate (HR). The maximum FEV1 value during the dose-response curve to formoterol or salmeterol was chosen as the primary outcome variable to compare the two treatments. Results: Both formoterol and salmeterol induced a large and significant (p < 0.001) dose-dependent increase in FEV1, FVC and IC. There was no significant difference between the FEV1 values (p = 0.081), the FVC values (p = 0.085) and the IC values (p = 0.111) after formoterol 48μg or salmeterol 100μg. Neither HR nor SpO2 changed significantly (p > 0.05). Conclusions: Our results suggest that cumulative doses of long-acting β2-agonists may improve lung function in patients with mild acute exacerbations of COPD although we cannot advocate their use in the initial therapy of an acute exacerbation because much fundamental information is still lacking.