Preventive effects of inhaled formoterol and salbutamol on histamine-induced bronchoconstriction--a placebo-controlled study.

The preventive effects of inhaled formoterol (a new beta 2-agonist) and salbutamol aerosols on histamine-induced bronchoconstriction were studied in 12 patients with mild or moderate asthma in a placebo-controlled, double-blind study. Three hours after the administration of 12 micrograms formoterol, 200 micrograms salbutamol (doses with equal bronchodilator effects) or placebo via aerosol, histamine challenge was undertaken, using a dosimetric jet nebulizer with controlled tidal breathing. The noncumulative dose of histamine diphosphate aerosol provoking a 15% fall in FEV1 (PD15) was calculated. The PD15 after inhalation of 12 micrograms formoterol was significantly higher than that after 200 micrograms salbutamol (median values 640 and 310 micrograms, respectively; p < 0.01). For both treatments, the PD15 was significantly higher than that after placebo (median 185 micrograms). The results indicate that the preventive effect against histamine-induced bronchoconstriction at 3 h after drug is significantly better with formoterol than with salbutamol when using inhaled doses with an equal acute bronchodilator effect.     

Formoterol and salbutamol metered aerosols: comparison of a new and an established beta-2-agonist for their bronchodilating efficacy in the treatment of childhood bronchial asthma

In this placebo-controlled, double-blind, single-dose study the new beta-2-agonist formoterol (one puff, 12 micrograms) was intraindividually compared with salbutamol (one puff, 100 micrograms) for onset, magnitude, and duration of bronchodilating efficacy in 15 young asthmatics aged 5 to 14 years with mild to severe asthma. All but one had regular antiasthmatic medication before beginning the study, but none was oral steroid dependent. Both medications produced rapid bronchodilatation within 10 minutes, reflected by a decrease in specific airway resistance (sRaw) with maximum effects at 10 minutes (salbutamol, 51%) and 30 minutes (formoterol, 60%). Significant bronchodilation was present at 10 minutes to 2 hours after inhalation of salbutamol and at 30 minutes to 8 hours after formoterol. Mean percent improvement over baseline was higher for formoterol at all measured times from 30 minutes to 12 hours, when 55% mean decrease in sRaw was still present. The effect of salbutamol was a less than 10% mean decrease in sRaw after 6 hours. The differences in sRaw decrease between the two medications were statistically significant at 4 to 10 hours after inhalation. Neither medication administered as an aerosol caused cardiac side effects. Both had a rapid onset of action and a comparable maximal effect. However, at the doses studied, formoterol produced a larger decrease in sRaw from baseline for longer periods after inhalation than did salbutamol.     

Relief of dyspnoea by beta2-agonists after methacholine-induced bronchoconstriction

Virtually all asthma patients use brorichodilators. Formoterol and salbutamol have a rapid onset of bronchodilating effect, whereas salmeterol acts slower. We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a methacholine-induced bronchoconstriction as a model for an acute asthma attack. Seventeen patients with asthma completed this randomised, double-blind, crossover, double-dummy study. On 4 test days, forced expiratory volume in 1 s (FEV1) and Borg score were recorded and patients were challenged with methacholine until FEV1 fell with > or = 30% of baseline value. Thereafter, formoterol 12 microg via Turbuhaler, salbutamol 50 microg via Turbuhaler, salmeterol 50 microg via Diskhaler, or placebo was inhaled. FEV1 and Borg scores were assessed during the following 60 min. The first sensed improvement of Borg score was significantly (P<0.05) faster achieved with formoterol (geometric mean (Gmean) (range) 1.5 (1-40) min) and salbutamol 1.8 (1-10) min than with salmeterol 4.5 (1-30) min and placebo 3.4 (1-40) min. The Borg score returned significantly faster to the baseline value with formoterol, salbutamol, and salmeterol (Gmean time 13.8 (1-75), 13.4 (1-60), and 18.0 (1-75) min, respectively) than with placebo (33.6 (1-75 min). Formoterol and salbutamol act significantly faster than salmeterol in relieving dyspnoea induced by methacholine-induced bronchoconstriction, in patients with asthma.     

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.     

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 protection against exercise-induced bronchoconstriction by formoterol, salmeterol and terbutaline.

The onset of bronchoprotection as obtained by various beta2-agonists has not been examined in a comparitive study. In this study, the onset of bronchodilation and protection against exercise-induced bronchoconstriction in asthmatics after inhalation of the long-acting beta2-agonists formoterol and salmeterol and the short-acting beta2-agonist terbutaline were measured. Twenty-five subjects with asthma and a history of exercise-induced bronchoconstriction (mean baseline forced expiratory volume in one second (FEV1): 90% predicted; mean fall in FEV1 after exercise: 31% from baseline) were enrolled in this double-blind, double-dummy, placebo-controlled, randomized, four-period crossover study. Exercise challenges were performed on 12 days at either 5, 30, or 60 min after inhalation of a single dose of formoterol (12 microg Turbuhaler), salmeterol (50 microg Diskus), terbutaline (500 microg Turbuhaler) or placebo. Exercise-induced bronchoconstriction (maximum fall in FEV1 or area under the curve) did not differ significantly between terbutaline, formorerol and salmeterol either 5, 30, or 60 min after inhalation of the study medication. In contrast, the onset of bronchodilation was slower after salmeterol compared to terbutaline and formoterol (p<0.05, each), which both showed a similar time course. At all time points between 5 and 60 min, formoterol provided significantly greater bronchodilation than salmeterol (p<0.05). These data indicate that equipotent doses of the bronchodilators salmeterol, formoterol and terbutaline were similarly effective with respect to their short-term protective potency against exercise-induced bronchoconstriction, despite the fact that the time course of bronchodilation was significantly different between the three beta2-agonists.     

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.     

Pulmonary effects of long-term beta 2-blockade in healthy subjects: comparative study of metoprolol OROS

The effects on airway response of metoprolol OROS (oral osmotic) and three other long-acting beta-adrenoceptor blockers were studied. This was a placebo-controlled, randomized, five-period, single-blind, crossover trial in 15 healthy volunteers. Bronchial beta-blockade was estimated as the displacement of the salbutamol bronchodilator response of specific airway conductance (SGAW) measured by whole-body plethysmography. Metoprolol OROS (14/190 mg), slow-release (SR) metoprolol (200 mg), atenolol (100 mg), long-acting (LA) propranolol (160 mg), and placebo were given once daily for 7 days. Inhaled salbutamol was administered at peak drug levels in cumulative doses of 12.5 to 800 micrograms on day 5 and in a single dose of 400 micrograms on day 7. On day 5, salbutamol induced significant increases in SGAW in each treatment group. SGAW increased after the single dose of salbutamol on day 7 in all groups and then declined steadily. The highest values were found after placebo and metoprolol OROS, with smaller increases after SR metoprolol, atenolol, and LA propranolol, the latter showing the smallest increase. Therefore, it would appear that under steady-state conditions, beta 2-bronchial receptors are least blocked by metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol.     

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.     

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.     

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.     

Combined lidocaine and salbutamol inhalation for airway anesthesia markedly protects against reflex bronchoconstriction

BACKGROUND: Lidocaine inhalation, in subjects with bronchial hyperreactivity, attenuates evoked bronchoconstriction but also irritates airways. Whether salbutamol pretreatment can mitigate airway irritation and whether combined treatment offers more protection than treatment with either drug alone is unknown. Therefore, we evaluated the effects of the inhalation of lidocaine, salbutamol, lidocaine and salbutamol combined, and placebo on an inhalational histamine challenge. METHODS: Fifteen patients with mild asthma were selected by a screening procedure (ie, a provocative concentration of a substance [histamine aerosol of < 18 mg/mL] causing a 20% fall in FEV(1) [PC(20)]). On 4 different days after pretreatment with the inhalation of lidocaine (5 mg/kg), inhalation of salbutamol (1.5 mg), combined treatment, or placebo, the histamine challenge was repeated. RESULTS: The baseline FEV(1) after lidocaine inhalation but prior to the histamine challenge decreased by > 5% in 7 of 15 volunteers, with a mean (+/- SD) decrease from 3.82 +/- 0.90 to 3.54 +/- 0.86 L (p = 0.0054). The baseline PC(20) for histamine was 6.4 +/- 4.3 mg/mL. Both lidocaine and salbutamol inhalation significantly increased PC(20) more than twofold (14.9 +/- 13.7 and 16.8 +/- 10.9 mg/mL, respectively; p = 0, 0007) at a lidocaine plasma concentration of 0.7 +/- 0.3 microg/mL. Combined treatment quadrupled the PC(20) to 29.7 +/- 20.3 mg/mL (vs lidocaine, p = 0.002; vs salbutamol, p = 0.003). CONCLUSIONS: Thus, histamine-evoked bronchoconstriction, as a model of reflex bronchoconstriction, can be significantly attenuated by salbutamol or lidocaine inhalation. However, lidocaine inhalation causes significant initial bronchoconstriction. The combined inhalation of salbutamol and lidocaine prevents the initial bronchoconstriction observed with lidocaine alone and offers even more protection to a histamine challenge than either lidocaine or salbutamol alone. Therefore, the combined inhalation of lidocaine and salbutamol can be recommended to mitigate bronchoconstriction when airway instrumentation is required.     

Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma.

Zardaverine is a newly developed selective phosphodiesterase III and IV inhibitor. This study investigates the bronchodilatory properties of zardaverine, administered by inhalation. Twelve patients with reversible bronchial obstruction (increase in forced expiratory volume in one second (change FEV1 % predicted) at least 15% after 200 micrograms salbutamol, median age 31 yrs, range 21-54 years) entered the double-blind, crossover study. Four puffs of either zardaverine (total dose 6 mg) or placebo were inhaled at 15 min intervals. Pulmonary function (specific airway conductance (sGaw) and FEV1 was measured by body plethysmography at regular intervals (5 and 12 min after each puff and, in addition, 30, 60, 120, 180 and 240 min after the last puff). Compared to placebo, sGaw and FEV1 increased significantly during the first hour of repeated inhalations, but not during the entire observation period of almost 5 h. The maximum mean difference between zardaverine and placebo for FEV1 was 0.3 l or 12% and occurred approximately 1 h after inhalation of the first puff. In seven patients FEV1 increased by > 15%. The duration of action varied considerably between patients. Three patients complained of side-effects (headache, drowsiness, vertigo, nausea), and one of these dropped out of the study due to vomiting. We conclude that inhalational administration of zardaverine has a modest and short-lasting bronchodilating activity.     

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.     

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.     

Changes in specific airway resistance after powder inhalation of formoterol or salmeterol in moderate bronchial asthma

Formoterol and salmeterol are two long acting beta 2 agonists available for the treatment of asthma which show differences in onset of action. In a multicentre parallel group study, patients with moderate asthma were investigated by measuring the specific airway resistance (sRaw), a more sensitive parameter than FEV1. A total of 99 patients were randomised for open treatment with either 12 micrograms formoterol delivered via Turbohaler or 50 micrograms salmeterol via Diskus. The patients were between 18 and 66 years of age, had a medium FEV1 of 68.8% (+/- 17.8%) predicted and showed a medium reversibility of 28.8% (+/- 16.5%). The patients response to one inhalation of the study drug was investigated by sRaw measurements 2, 5, 10, 20 and 60 minutes after inhalation of the formulation. Additionally, FEV1 was measured. The results show a significant decrease in specific airway resistance of 29% within the first two minutes in patients who had received 12 micrograms formoterol via Turbohaler. However, patients on salmeterol showed no change (sRaw +/- 1%). This difference is statistically highly significant (p < 0.0001). Furthermore, in 49% of the patients treated with salmeterol an increase in sRaw was seen immediately after inhalation of the drug. This increase was +16.4% in an average of 2 minutes after inhalation. One hour after inhalation the differences between the groups were small and not significant neither between formoterol and salmeterol-treated patients nor within the salmeterol group. In the following week patients were treated with 12 micrograms formoterol Turbohaler b.i.d. or 50 micrograms salmeterol Diskus b.i.d., respectively. A further sRaw measurement was performed 11 +/- 1 hours after the last inhalation of the drug. The results for sRaw and FEV1 show no differences between both study drugs indicating a similar duration of action for both formoterol Turbohaler and Salmeterol Diskus in moderate asthma. No serious adverse events were reported. The adverse event profile observed in both study groups was comparable. Thus, this study shows once again that formoterol delivered via Turbohaler has a more rapid onset of bronchodilating action compared with salmeterol Diskus. Furthermore the inhalation of salmeterol via Diskus in one-half of the patients led to an increase in specific airway resistance within the first minutes after inhalation. It is worth discussing whether an unspecific reaction to the relatively large lactose particles which are components of the salmeterol Diskus formulation are responsible for this observation.     

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.     

Formoterol in the treatment of nocturnal asthma

Formoterol fumarate is a new beta 2-adrenergic agonist with a long lasting effect. The bronchospasmolytic effect of 12 micrograms of formoterol was compared with that of 200 micrograms of albuterol (salbutamol) in a single-center, double-blind, randomized within-patient study. The drugs were given as aerosols by MDI to 16 patients with nocturnal asthma in a stable phase. The inhalations were given at 10 PM and the FEV1 values as parameter were measured before and at 1, 2, 6, 8, 10, and 12 hours afterwards. The FEV1 6 hours after administration of formoterol was significantly higher than that after albuterol (ANCOVA: p = 0.008), and this was still the case 12 hours after the test dose at 10 AM the following morning (ANCOVA: p = 0.009). At 4 AM, the FEV1 fell below the basic starting value after albuterol, whereas it remained at least 10 percent above the formoterol inhalation. Five patients required rescue therapy after albuterol and two after formoterol. We conclude that formoterol in a dose of 12 micrograms via MDI confers good protection against nocturnal asthma; this was only insufficient for some patients with severe asthma, and further studies with higher dosages in these patients are clearly indicated.     

Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma

STUDY OBJECTIVE: To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma. DESIGN: A randomized, double-blind, placebo-controlled, crossover study of the immediate effect of formoterol, 9 microg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction. PATIENTS: Twenty-four 7- to 15-year-old children with persistent asthma. INTERVENTIONS: The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV1 dropped > or = 15% within 5 min after exercise. FEV1 and forced expiratory flows were measured repeatedly until 60 min after dose. RESULTS: Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo (p < 0.001). There was no difference between formoterol and terbutaline in FEV1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of the maximum increase for both. Median times to recovery within 5% of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33). CONCLUSION: Single-dose formoterol, 9 microg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma. Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children.     

Doppler echocardiographic assessment of the effects of inhaled long-acting beta2-agonists on pulmonary artery pressure in COPD patients

Increase in pulmonary artery pressure (PAP), which is common in severe chronic obstructive pulmonary disease (COPD), is a predictor of mortality independent of airflow limitation. beta-agonists might slightly attenuate this increase because they exert a vasodilating effect on pulmonary circulation when systematically administered. We have investigated the acute effects of salmeterol and formoterol on echocardiographic systolic pulmonary artery pressure (sPAP) in 20 patients with COPD and a sPAP greater than 20mmHg at rest. Acute haemodynamic responses to inhaled formoterol or salmeterol were assessed in all patients, in a randomized, double-blind double-dummy fashion. On two consecutive days, patients received, in a randomized order, formoterol 12microg via Turbuhaler plus placebo via Diskus or salmeterol 50microg via Diskus plus placebo via Turbuhaler. Transthoracic Doppler echocardiography measurements of sPAP were made before and 15, 30, 60 and 180min after bronchodilator inhalation. Lung function, pulse oximetry and heart rate were also monitored at the same times. Mean sPAP significantly (p<0.05) decreased in comparison with baseline at 15, 30, and 60min post inhalation but returned towards control levels at 180min after both salmeterol and formoterol. There was no correlation between the maximum increase in FEV(1) and maximum decrease in sPAP either after inhalation of salmeterol (r(2)=0.071) or after that of formoterol (r(2)=0.0006). The increases in FEV(1) in comparison with baseline were always significant (p<0.05) from 15 to 180min post inhalation after either salmeterol or formoterol. Neither pulse oximetry nor heart rate changed in a significant manner (p>0.05). This study demonstrated that salmeterol and formoterol were equally beneficial for pulmonary haemodynamics in patients with COPD. A direct vasodilatation due to the activation of beta-adrenoceptors that are present in pulmonary vessels is a likely mechanism of their action in inducing the decrease in sPAP.