Formoterol Turbuhaler 4.5 microg (delivered dose) has a rapid onset and 12-h duration of bronchodilation

Clinical trials show that formoterol (Oxis) Turbuhaler 4.5 microg delivered dose (6 microg metered dose) has a rapid onset of bronchodilation similar to that of salbutamol and a 12-h duration of action. Maximum increase in FEV(1) and duration of bronchodilation are dose-dependent, the 4.5 microg dose being the lowest dose tested giving both effects.Clinical studies investigating onset of bronchodilation show a significant increase in specific airway conductance occurring within 1 min after inhalation of formoterol Turbuhaler 4.5 microg. When measured from 3-20 min after inhalation, formoterol Turbuhaler 4.5 microg showed similar increases in FEV(1) to salbutamol administered via pMDI. No difference in onset of bronchodilation was observed between the formoterol Turbuhaler 4.5 and 9 microg doses.Single-dose studies and studies of 1-12 weeks' duration show that formoterol Turbuhaler 4.5 microg produces a significant and clinically important mean bronchodilating effect for > or =12 h after inhalation. In the cited studies no significant differences in duration of bronchodilation were observed between the formoterol Turbuhaler 4.5 and 9 microg doses.Conclusion: clinical data show that formoterol Turbuhaler 4.5 microg is an effective dose in patients with asthma, with a rapid onset of bronchodilation and a duration of at least 12 h.     

Relative therapeutic index between inhaled formoterol and salbutamol in asthma patients

A double-blind, randomized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol. Pre-drug administration FEV1 (mean 2.08 l) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutamol. Patients inhaled single doses of formoterol (Oxis) (4.5,18 and 54 microg, delivered doses) via Turbuhaler, salbutamol (Ventolin) (200 and 1800 microg) via pressurized metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. Relative local (maximum FEV1) and systemic (minimum S-K+) dose potencies, and their ratio, the relative therapeutic index, were estimated using a non-linear mixed effect model. The drug effects were well tolerated and dose dependent. A log-linear approximation was used to describe the bronchodilatory effect, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index between formoterol 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol; this trend was not statistically significant.     

Formoterol Turbuhaler as reliever medication in patients with acute asthma.

The aim of this study was to compare the efficacy and safety of formoterol versus salbutamol as reliever medication in patients presenting at an emergency dept with acute asthma. A randomised, double-blind, double-dummy, parallel group study was performed in four Australian emergency treatment centres. The study included a total of 78 adult patients (mean baseline forced expiratory volume in one second (FEV1) 1.83 L; 59% predicted) with acute asthma. Based on the expected dose equivalence of formoterol Turbuhaler 4.5 microg (delivered dose) and salbutamol pressurised metered-dose inhaler 200 microg (metered dose), patients received a total of formoterol Turbuhaler 36 microg (delivered) or salbutamol pressurised metered-dose inhaler with spacer 1,600 microg (metered), divided into two equal doses at 0 and 30 min. FEV1, peak expiratory flow and systemic beta2-agonist effects were monitored for 4 h. The primary variable was FEV1% pred at 45 min. At 45 min, mean increases in FEV1 expressed in % pred were 6.6% and 9.3%, respectively, with a small adjusted mean difference in favour of salbutamol (3.0%, 95% confidence interval -2.0-8.0). Transient increases in systemic beta2-agonist effects occurred predominantly with salbutamol, although no significant treatment differences were observed. Eight patients discontinued due to adverse events. In this study of patients presenting at emergency depts with acute asthma, formoterol Turbuhaler 36 microg was well tolerated and, as rescue therapy, had an efficacy that was not different from that of salbutamol pressurised metered-dose inhaler with spacer 1,600 microg in the number of patients studied.     

Formoterol (OXIS) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma

Formoterol has a similar onset of effect to salbutamol but a prolonged duration of action. However, the relative efficacy of the two drugs in acute severe asthma is not known. This double-blind, double-dummy study compared the safety and efficacy of the maximum recommended daily dose of formoterol and a predicted equivalent dose of salbutamol in 88 patients presenting to the emergency department with acute severe asthma. Patients were randomized to formoterol 54 microg via Turbuhaler or salbutamol 2400 microg via pressurized metered dose inhaler (pMDI) plus spacer in three equal doses over 1 h. Following the full dose, mean FEV1 at 75 min increased by 37% for formoterol and 28% for salbutamol (P = 0.18). The maximum increase in FEV1 over 4 h was significantly greater with formoterol compared with salbutamol (51% vs. 36%, respectively P < 0.05) and formoterol was as effective as salbutamol at improving symptoms and wellbeing. Both treatments were well tolerated. Formoterol caused a greater decrease in serum potassium (difference -0.2 mmol/l). In severe acute asthma, bronchodilator therapy with high-dose (54 microg) formoterol Turbuhaler provided equally rapid improvements in lung function of greater magnitude over 4 h than high-dose (2400 microg) salbutamol pMDI plus spacer.     

Oxis (formoterol given by Turbuhaler) showed as rapid an onset of action as salbutamol given by a pMDI

Thirty-six adult patients (16 women) with mild to moderate asthma with a mean baseline forced expiratory volume in 1 sec (FEV1) of 73.8% (46-106%) of predicted normal value and mean reversibility of 24.2% (14.6-47.1%) were included in this double-blind, double-dummy, randomized, placebo-controlled and cross-over study. The patients inhaled single doses 4.5 or 9 microg of formoterol (Oxis) via Turbuhaler salbutamol (Ventolin) 100 or 200 microg from a pressurized metered dose inhaler (pMDI) or placebo at five randomized visits. Efficacy was measured by FEV1 pre-dose and then 1, 3, 5, 7, 10, 15, 20, 25 and 30 min after inhalation of the study drug. The primary variable of efficacy was the FEV1-value 3 min after dose intake. No statistically significant differences were found between active treatments. All active treatments gave a higher bronchodilating effect at 3 min than placebo: 10.0, 11.4% for salbutamol 100 and 200 microg and 11.7, 11.8% for formoterol 4.5 and 9 microg (P<0.001 in all cases). There was a correlation between the measured response at 3 min and the subjective experience of the patients. The relative difference vs. placebo remained throughout the study period for all active treatments except for low dose salbutamol. All treatments were well tolerated. In conclusion, formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at recommended doses.     

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.     

The efficacy of a new salbutamol metered-dose powder inhaler in comparison with two other inhaler devices

An open cross-over and randomized study was carried out in order to compare the efficacy and safety of inhaled salbutamol delivered from a new 50 microg dose(-1) metered-dose dry powder inhaler Taifun, and a commercially available 50 microg dose(-1) dry powder inhaler Turbuhaler, and a conventional 100 microg dose(-1) pressurized metered-dose inhaler with a spacer (pMDI+S). Twenty-one patients, aged 21-70 years, with stable asthma and with demonstrated reversibility upon inhalation of salbutamol were included in the study. On three separate study days, the patients received a total dose of 400 microg of salbutamol from the dry powder inhalers and a dose of 800 microg from the pMDI+S in a cumulative fashion: 1,1, 2 and 4 doses at 30 min intervals. The percent change in forced expiratory volume in 1 sec (FEV1), was used as the primary efficacy variable. Salbutamol inhaled via the Taifun produced greater bronchodilation than the other devices. The difference in percent change in FEV1 between the Taifun and the other devices was statistically significant at the two first dose levels, but diminished towards the higher doses when the plateau of the dose-response curve was reached. The estimated relative dose potency of the Taifun was approximately 1.9- and 2.8-fold compared to the Turbuhaler and the pMDI+S, respectively. The Taifun caused a slight, but clinically insignificant, decrease in serum potassium concentration. There were no significant changes in the other safety parameters (blood pressure, heart rate and electrocardiogram recordings) with any of the used devices. In conclusion, this study indicates that salbutamol inhaled via the Taifun is more potentthan salbutamol inhaled from the other devices tested. In practise, a smaller total dose of salbutamol from theTaifun is needed to produce a similar bronchodilatory response. All treatments were equally well tolerated.     

Single-dose comparison of formoterol (Oxis) Turbuhaler 6 microg and formoterol Aerolizer 12 microg in moderate to severe asthma: a randomised,crossover study

Formoterol inhaled via Turbuhaler (Oxis) or Aerolizer (Foradil) produces fast and long-lasting bronchodilation in asthmatic patients. While formoterol Turbuhaler provides sustained efficacy for > or =12h at a metered dose of 6 microg (delivered dose 4.5 microg), the recommended metered dose for formoterol Aerolizer is 12 microg (delivered dose unknown). This difference may be attributable to improved lung deposition with the Turbuhaler. This open, randomised, crossover study compared the effects of a single metered dose of formoterol Turbuhaler 6 microg and formoterol Aerolizer 12 microg in 16 patients with stable moderate-to-severe asthma. Pulmonary function, assessed by measuring specific airway conductance (sGaw), was determined at intervals of < or =8h post-inhalation of each drug on separate study days. Both inhalers increased sGaw at all time points. There were no significant differences between the two formulations in onset of activity, maximum effect, duration of effect or area under the response curve. Furthermore, both treatments were well tolerated with no differences in adverse events, blood pressure or heart rate; thus the formoterol Turbuhaler may, therefore, have an improved therapeutic index. This pilot study indicates that the same clinical effect can be achieved with half the metered dose (6 microg) of formoterol Turbuhaler compared with formoterol Aerolizer (12 microg).     

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.     

Efficacy of formoterol Turbuhaler in the emergency treatment of patients with obstructive airway diseases

Dry powder devices are rarely used in the emergency room (ER) treatment of acute and severe bronchoconstriction due to hesitations with respect to clinical efficacy. This study investigated the effects of two inhalers with formoterol in patients visiting the ER Department for acute and severe dyspnoea, mainly exacerbations of chronic obstructive pulmonary disease. Two doses of 12mug formoterol were given at enrolment, either via Turbuhaler or via pressurised metered dose inhaler, connected to a spacer device (pMDI+S) in a double-blind way and parallel design. Another two doses of 12 microg formoterol were given after 30 min. Forced expiratory volume in the 1s (FEV(1)) and Borg dyspnoea score were assessed until 60 min. The study was designed to test non-inferiority in effects on FEV(1). Seventy-seven patients were enrolled with a mean age of 66 years and a FEV(1) of 1.03 L (39% of predicted). The effects of the two treatments were almost identical. The mean improvement in FEV(1) at 60 min after formoterol Turbuhaler was 94% of the improvement after formoterol pMDI+S. A statistically significant non-inferiority was shown (p=0.037) at 60 min (primary endpoint) as well as at 5 and 30 min (secondary endpoints, p=0.0043 and 0.013, respectively). Improvements in the Borg dyspnoea score and other lung-function parameters did not differ significantly between the two devices. In conclusion, formoterol Turbuhaler was equally effective as formoterol pMDI+S in the treatment of acute bronchoconstriction within the ER.     

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.     

Efficacy and safety of formoterol delivered through the Novolizer, a novel dry powder inhaler (DPI) compared with a standard DPI in patients with moderate to severe asthma

BACKGROUND & OBJECTIVE: Because of environmental concerns CFC-containing pressurised metered dose inhalers (pMDI) had to be replaced by dry powder inhalers (DPI). The Novolizer, a novel DPI has previously been shown to be as effective as the Turbuhaler in delivering budesonide. The objective of this study was to show non-inferiority of inhaled formoterol therapy delivered through the Novolizer compared to formoterol delivered through the Aerolizer in patients suffering from moderate to severe asthma. METHODS: In this double-blind, double-dummy, multicentre study 392 patients were randomised and received a dose of 12 microg formoterol twice daily for 4 weeks either through the Aerolizer or the Novolizer. FEV1 after 4 weeks of treatment was the primary variable. Secondary variables were FVC, PEF, consumption of short-acting; 2 adrenoceptor agonists, asthma symptoms, tolerability and safety. RESULTS: After 4 weeks of treatment, the mean trough FEV1 (95% CI) was 2.34 L (2.24-2.45) for the Novolizer and 2.31 L (2.21-2.41) for the Aerolizer. Non-inferiority was proven (p<0.0001, pre-defined; of 0.25 L). All secondary variables (incl. PEF) confirmed these findings. Treatment with both devices was safe and well tolerated. CONCLUSION: Inhalation of 12 microg formoterol twice daily via Novolizer was shown to be equally therapeutically effective compared to the inhalation via Aerolizer in the treatment of moderate to severe persistent asthma. Treatment via both inhalers was safe and well tolerated.     

Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients

RATIONALE: Formoterol is approved as asthma rescue medication in many countries. The exact duration of the airway vs. systemic effects of formoterol compared with another rescue medication, salbutamol, has not been evaluated. OBJECTIVE: To assess the duration of airway bronchodilatory effects vs. systemic effects of inhaled formoterol and salbutamol in asthmatic patients. METHODS: Twenty-six patients with stable and reversible asthma were given single doses of formoterol dry-powder inhaler (OxisTurbuhaler) 2x9 microg (lower dose; LD) and 6x9 microg (higher dose; HD), salbutamol (VentolinDiskhaler) 3x400 microg (LD) and 9x400 microg (HD), and placebo in a randomized, double-blind, crossover trial. Airway and systemic effects were assessed by forced expiratory volume in 1s (FEV1), serum potassium, blood pressure, corrected QT-interval (QTc), and palpitation and tremor scores. Time with clinically relevant bronchodilation (FEV1 increase 12%) without clinically relevant markers of systemic effects (serum potassium suppression 0.2 mmol/L, QTc-prolongation 20 ms, or heart rate increase 8 beats per minute) was evaluated. RESULTS: Bronchodilation was maintained for 24h with both formoterol doses and for 7-11h with salbutamol. Maximum bronchodilation and systemic effects were similar after formoterol and salbutamol, except for statistically significantly larger maximum heart rate and palpitation and tremor scores after salbutamol. Systemic responses were similarly brief for formoterol and salbutamol (7 h). CONCLUSIONS: The airway effects of inhaled formoterol are of long duration, whereas the systemic effects are of a similarly short duration as salbutamol. Thus, the time with clinically relevant bronchodilation without systemic effects is substantially longer after formoterol than after salbutamol.     

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.     

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.     

Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma

This study compared the efficacy and safety of budesonide/formoterol (Symbicort) Turbuhaler)) with salbutamol pressurized metered-dose inhaler (pMDI) with spacer for relief of acute bronchoconstriction in patients with asthma. In this randomized, double-blind, parallel-group study, patients (n = 104 allocated to treatment; n = 103 received treatment; mean age 45 years) seeking medical attention for acute asthma (mean FEV(1) 43% of predicted) received two doses repeated at t = -5 and 0 min of either budesonide/formoterol (320/9 microg, two inhalations) or salbutamol (100 microg x eight inhalations); total doses 1280/36 microg and 1600 microg, respectively. All patients received prednisolone 60 mg at 90 min and FEV(1) was assessed over 3h. FEV(1) 90 min after dosing (primary variable) increased compared with pre-dose FEV(1) by an average of 30% and 32% for budesonide/formoterol and salbutamol, respectively (P = 0.66), with similar increases at all timepoints from 3 to 180 min for both groups. Mean pulse rate over 3h was significantly higher in the salbutamol group versus the budesonide/formoterol group (92 vs. 88 bpm; P < 0.01). No treatment differences were seen for other vital signs, including ECG. High-dose budesonide/formoterol was effective and well tolerated for the treatment of acute asthma, with rapid onset of efficacy and a safety profile over 3h similar to high-dose salbutamol.     

Safety of formoterol Turbuhaler at cumulative dose of 90 microg in patients with acute bronchial obstruction.

This study compared the safety of formoterol (Oxis Turbuhaler; 90 microg delivered dose; 120 microg metered dose) with terbutaline (Bricanyl Turbuhaler; 10 mg), in patients with acute bronchoconstriction. Forty-eight patients (31 females) with a mean age of 45 yrs, were randomized into two parallel groups (double-blind design). Mean baseline forced expiratory volume in one second (FEV1) was 0.98 L (33% of predicted normal). Study drugs were administered on six occasions during 3 h (formoterol 4.5 microg or terbutaline 0.5 mg x inhalation(-1), 20 inhalations). Patients received intravenous prednisolone after 1.5 h and oxygen during the first 3 h. Pulse rate, serum potassium, 12-lead electrocardiogram (ECG), Holter ECG, arterial blood gases and FEV1 were assessed during 12 h after the first dose. Four patients (one formoterol, three terbutaline) discontinued. The 12-h mean values of serum potassium decreased from 4.02 to 3.89 mmol x L(-1) for formoterol and from 4.22 to 3.76 mmol x L(-1) for terbutaline. Mean 12-h pulse rate was significantly (p<0.01) higher in the terbutaline group (101.7 beats per minute (bpm)) than in the formoterol group (93.5 bpm). No individual patient value was considered clinically important or alarming. FEV1 improved in both groups but with no statistically significant difference between treatments. Oxis Turbuhaler (90 microg) was at least as safe and well tolerated as terbutaline (10 mg) [corrected] in patients with acute bronchoconstriction.     

Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction.

The onset of the bronchodilating effect of formoterol (12 microg by Turbuhaler) was compared with that of salbutamol (50 microg by Turbuhaler), salmeterol (50 microg by Diskhaler) and placebo in methacholine-induced severe bronchoconstriction. Seventeen subjects with mild-to-moderate asthma completed this randomized, double blind, cross-over, double-dummy study. On four study days, baseline forced expiratory volume in one second (FEV1) was recorded and the subjects were challenged with methacholine until FEV1 fell by at least 30%. Immediately thereafter, the study drugs were inhaled and lung function was assessed for 60 min. The geometric mean time for FEV1 to return to 85% of baseline was 7.2 min with formoterol, 6.5 min with salbutamol, 14.1 min with salmeterol and 34.7 min with placebo (p=0.0001, overall ANOVA). The difference between formoterol and salmeterol was statistically significant (p=0.01); there was no difference between formoterol and salbutamol (p=0.69). In conclusion, formoterol reversed methacholine-induced severe bronchoconstriction as rapidly as salbutamol and more rapidly than salmeterol. Classifying beta2-agonists as "fast"- and "slow"- acting may be supplemental to "short"- and "long"-acting.     

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.     

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.