Doses Of Formoterol Research Articles

Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil®AerolizerTM) with salbutamol (VentodiskTM)

Formoterol fumarate is a β2-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 μ g delivered via the AerolizerTMdry powder inhaler device (double-blind), or salbutamol 400μ g delivered via 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 FEV1from 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 FEV1increase above predose baseline from 0 to 30 min (AUC0−30 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.

Formoterol used as needed—clinical effectiveness

A number of studies have already demonstrated the clinical effectiveness of formoterol when used as maintenance therapy in patients requiring both a β 2-agonist with a long duration of action and a regular inhaled corticosteroid. However, formoterol has a unique mechanism of action that gives it both fast- and long-acting properties. Hence the question arises as to whether formoterol can also be used as first-line reliever medication in addition to maintenance therapy. Compared with terbutaline, formoterol used as needed in steroid-treated mild to moderate asthma has superior efficacy, not only significantly improving peak flow, but also the exacerbation rate. In moderate to severe asthma, formoterol used as needed has demonstrated efficacy comparable with salbutamol and terbutaline in improving symptoms and lung function. Single doses of formoterol have also been shown to result in protection against exercise-induced bronchoconstriction for periods up to 12 h. Furthermore, bronchoprotection was maintained following repeated dosing, although further research is needed to confirm the duration of protection achieved with frequent and regular use. Initial research also suggests that formoterol is as effective and well tolerated as terbutaline in the treatment of acute asthma attacks. The evidence presented supports the use of formoterol on an as-needed basis for effective asthma control.

Open-label, uncontrolled clinical study of formoterol, a selective beta 2-receptor agonist, in patients with bronchial asthma and asthmatic bronchitis

Background: Formoterol, a selective beta 2-receptor agonist, has been shown to be effective and well tolerated in Japanese patients with bronchial asthma. Objective: The purpose of this open-label, uncontrolled clinical study was to investigate the short-term and long-term efficacy and tolerability of formoterol in Chinese patients with bronchial asthma and asthmatic bronchitis. Methods: Patients with mild or moderate bronchial asthma or asthmatic bronchitis were enrolled. After a 2-week placebo run-in period, a subgroup of patients were orally administered a single dose of formoterol 40 μg, and clinical signs and pulmonary expiratory function were assessed 0.5, 1, 2, 4, 6, and 8 hours after administration. In the long-term phase of the study, a second subgroup of patients were orally administered formoterol 40 μg twice daily for 14 days. Clinical signs, pulmonary function, laboratory test results, and adverse events before and after treatment were compared. Results: A total of 157 patients were enrolled. Thirty patients were included in the short-term phase of the study and 127 in the long-term phase. Thirty minutes after single-dose administration of formoterol, improvements were observed in clinical signs such as wheezing and coughing and in pulmonary expiratory function (PEF); these effects peaked 4 hours after administration of formoterol and lasted for 8 hours. In the long-term phase of the study, 120 of 127 patients (94%) completed the study; 4 patients voluntarily discontinued treatment during the observation period because of adverse events, and 3 patients discontinued hospital visits at 1, 2, and 2 weeks after drug administration, respectively, because of personal reasons. Clinical signs such as wheezing and coughing improved after 14 days of treatment, with ∼82% of patients demonstrating at least moderate improvement. Mean PEF increased significantly compared with baseline (from 3.47 ± 1.70 to 4.97 ± 2.10 L/sec; P < 0.01), as did mean forced expiratory volume in 1 second (from 1.68 ± 0.59 to 2.23 ± 0.83 L; P < 0.01). After 14 days of treatment, the daily variation rate of PEF had decreased significantly from 26.40% ± 7.80% to 10.38% ± 7.56% ( P < 0.01). Fifteen patients (12.1%) experienced adverse events; the most common adverse events were palpitations ( 7 124 [5.6%]) and tremors in the hands ( 7 124 [5.6%]); all adverse events were transient and mild. Conclusion: Oral formoterol was well tolerated and effective in this sample of patients with bronchial asthma and asthmatic bronchitis, with a quick onset and long-lasting beta-agonistic effects. Oral formoterol may have clinical utility in the long-term treatment of these respiratory disorders.

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 μg (metered dose corresponding to 9 μg delivered dose) and formoterol 24 μg (metered dose corresponding to 18 μg delivered dose), both delivered via Turbuhaler, with that of salbutamol 400 μg and salbutamol 800 μg delivered via pressurized metered-dose inhaler (pMDI). Patients inhaled single doses of placebo, formoterol and salbutamol on five separate days. FEV1was 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 FEV1of at least 15% from the baseline value; (2) an absolute increase in FEV1of at least 200 ml. Formoterol 12 μg (15.2 min; 95% CI 9.5–21.0) and formoterol 24 μg (15.1 min; 95% CI 8.9–21.2) caused a rise in FEV1of at least 15% from the baseline value almost rapidly as salbutamol 400 μg (13.6 min; 95% CI 7.1–20.1) and salbutamol 800 μg (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 FEV1was 11.1 min (95% CI: 7.0–15.2) after salbutamol 400 μg, 13.0 min (95% CI: 7.9–18.1) after salbutamol 800 μg, 14.7 min (95% CI: 7.1–22.4) after formoterol 12 μg, and 12.7 min (95% CI: 7.4–18.0) after formoterol 24 μg. Again, there was no significant difference (P= 0.817) between the four active treatments. Formoterol Turbuhaler 12 μg and 24 μg caused bronchodilation as rapidly as salbutamol 400 μg and 800 μg given via pMDI.

A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler

Formoterol is a beta2-adrenergic agent which, when inhaled, produces rapid and long-lasting bronchodilatation. The aim of this study was to compare the efficacy, safety, and tolerability of formoterol powder for inhalation delivered via the Aerolizer device with placebo and with albuterol delivered via metered-dose inhaler in patients with mild to moderate persistent asthma. In a multicenter, double-blind, parallel-group study, 541 patients were randomized at 26 trial sites to receive either formoterol, 12 microg twice daily; formoterol, 24 microg twice daily; albuterol, 180 microg four times daily; or a placebo for 12 weeks. The effects of each treatment on lung function, asthma symptoms, and frequency of rescue albuterol use were evaluated. Adverse effects and clinical laboratory parameters were also evaluated. The bronchodilatory effects of formoterol were rapid in onset and persisted for 12 hours. Both formoterol doses were more effective than placebo and albuterol for objective measures of lung function. Morning and evening peak expiratory flow rates were more improved with formoterol, and formoterol provided significantly greater improvements in asthma symptom scores compared with both albuterol and placebo. Overall, patients taking formoterol used significantly less rescue medication than did those taking albuterol or placebo. Nocturnal awakenings occurred less often with formoterol than with placebo or albuterol. The therapeutic effects of formoterol were maintained over the entire 12 weeks of treatment. Adverse events were similar for all treatment groups, and clinical laboratory data were unremarkable. Rapid-onset, long-acting formoterol, administered via the Aerolizer inhaler, is an effective and safe treatment for patients with mild to moderate persistent asthma.

Long-acting beta2 agonists in the management of stable chronic obstructive pulmonary disease.

Long-acting beta2 agonist bronchodilators (e.g. formoterol, salmeterol) are a new interesting therapeutic option for patients with chronic obstructive pulmonary disease (COPD). In the short term, both salmeterol and formoterol appear to be more effective than short-acting beta2 agonists, and in patients with stable COPD they are more effective than anticholinergic agents and theophylline. Regular treatment of patients with COPD with long-acting beta2 agonists can induce an improvement in the respiratory function and certain aspects of quality of life. Moreover, salmeterol seems to be better than ipratropium and theophylline in improving lung function at the recommended doses after a long term treatment. Use of combination therapy of a long-acting inhaled beta2 agonist and an anticholinergic agent or theophylline in patients with COPD has not been sufficiently studied. Combination of usual doses of ipratropium or oxitropium with usual doses of salmeterol or formoterol does not appear to improve pulmonary function, but this lack of improvement with the combination should not, in itself, prevent implementation of further therapeutic steps in patients responsive to an anticholinergic agent and/or salmeterol or formoterol administered singly. Neither formoterol nor salmeterol elicit significant cardiovascular effects in healthy individuals and patients with reversible airway obstruction. However, adverse cardiac events might occur in patients with COPD with pre-existing cardiac arrhythmias and hypoxaemia if they use long-acting 12 agonists, although the recommended single dose of salmeterol 50 microg or formoterol 12 microg ensures a relatively higher safety margin than formoterol 24 microg. The bronchodilatory effect of long-acting beta2 agonists seems to be fairly stable after regular treatment with these bronchodilators. Moreover, pre-treatment with a conventional dose of formoterol or salmeterol does not preclude the possibility of inducing further bronchodilation with salbutamol in patients with partially reversible COPD. All these findings support the use of long-acting beta2 agonist bronchodilators as first-line bronchodilator therapy for the long term treatment of airflow obstruction in patients with COPD. However, since physicians must always choose a drug that is highly efficacious, well tolerated and inexpensive, the cost-effectiveness analysis in relation to other bronchodilators will determine the proper place of long-acting beta2 agonists in the long term therapy of stable COPD.

Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects

BACKGROUNDThe main adverse effects of inhaled long acting β2 agonists relate to their systemic activity. The systemic effects seen over eight hours after inhalation of three doses of salmeterol and...

Non-Pulmonary Effects Induced by the Addition of Formoterol to Budesonide Therapy in Patients with Mild or Moderate Persistent Asthma

Objective: The present study was designed to assess the non-pulmonary effects of a 2-week treatment with the addition of formoterol to budesonide therapy in 10 patients with mild or moderate asthma. Methods: Each patient was invited to perform a screening visit which included spirometry before and after inhalation of 12 μg formoterol with a metered dose inhaler (MDI), measurement of arterial blood pressure, baseline electrocardiography and 24-hour Holter monitoring, and a test for evaluating upper limb tremor. Patients then began bronchodilating therapy with 12 μg formoterol MDI and 400 μg budesonide Turbuhaler b.i.d. Each patient was also given a peak flowmeter and a diary in which he had to record the morning and evening values measured before taking inhaled drugs. Two weeks later, the patients repeated the same examinations; the diary card was returned 2 months after the beginning of the study. Results: Adding formoterol to budesonide therapy caused a significant improvement in lung function, but neither induced any statistically significant effect on mean heart rate, nor altered the circadian rhythm of autonomic regulation nor elicited significant alterations in cardiac morphology. However, the evaluation of upper limb tremor revealed a statistically significant increase (p = 0.02). Conclusions: This study shows that adding the recommended dose of formoterol to an inhaled corticosteroid therapy does not induce significant cardiac undesirable effects, although tremor, surely due to stimulation of β₂ receptors of the skeletal muscles, may sometimes be a limiting effect.

Comparison of the Relative Efficacy of Formoterol and Salmeterol in Asthmatic Patients

Studies performed on airway smooth muscle in vitro have indicated that salmeterol is a partial agonist on the beta2-receptor in comparison to formoterol. In the present study we evaluated whether these pharmacological differences between salmeterol and formoterol also are applicable to asthmatic patients. The protective effects by increasing cumulative doses of formoterol (12, 60, 120 micrograms) and salmeterol (50, 250, 500 micrograms) on methacholine-induced bronchoconstriction were evaluated in a double-blind, crossover, placebo-controlled design. Patients were regularly treated with salbutamol 200 micrograms twice daily during the study period, to avoid variability in beta2-adrenoceptor tolerance. S-potassium, heart rate corrected Q-T interval (Q-Tc), and tremor score were followed as measures of systemic effects. Formoterol dose-dependently protected against methacholine responsiveness (4.6 doubling doses after 120 micrograms). Salmeterol, however, showed a flatter dose-response curve, and a significantly weaker maximal protective effect (2.8 doubling doses after 250 micrograms). Formoterol caused a significantly higher tremor score and a larger drop in S-potassium than salmeterol at the highest doses. These data show that salmeterol is a partial agonist on the beta2-receptor in relation to formoterol in human airways in vivo. Further studies are required to document the clinical consequences of this finding, for example in severe asthmatic patients.

A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and β2-Adrenoceptor Down-regulation After Regular Inhaled Formoterol

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. 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. 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). 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.

β2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy

The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting β2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12μg once daily, 6μg twice daily or 24μg twice daily) or terbutaline (500μg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 ;s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without β2-agonist, and at 1 ;h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and β2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as μg of methacholine, geometric means±S.E.M.): formoterol, 12μg once daily, 99±42μg; formoterol, 6μg twice daily, 107±44μg; formoterol, 24μg twice daily, 108±45μg; terbutaline, 500μg four times daily, 88±37μg. All patients receiving formoterol, 24μg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12μg once daily or 6μg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean±S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66±11%; Het-16, 53±8%; Arg-16, 69±18%; Glu-27, 68±12%; Het-27, 58±8%; Gln-27, 52±12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting β2-agonist exposure irrespective of β2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.

β 2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy

The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting beta2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12 microg once daily, 6 microg twice daily or 24 microg twice daily) or terbutaline (500 microg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without beta2-agonist, and at 1 h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and beta2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as microg of methacholine, geometric means+/-S. E.M.): formoterol, 12 microg once daily, 99+/-42 microg; formoterol, 6 microg twice daily, 107+/-44 microg; formoterol, 24 microg twice daily, 108+/-45 microg; terbutaline, 500 microg four times daily, 88+/-37 microg. All patients receiving formoterol, 24 microg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12 microg once daily or 6 microg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean+/-S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66+/-11%; Het-16, 53+/-8%; Arg-16, 69+/-18%; Glu-27, 68+/-12%; Het-27, 58+/-8%; Gln-27, 52+/-12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting beta2-agonist exposure irrespective of beta2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.

A comparison of the onset of action of salbutamol and formoterol in reversing methacholine-induced bronchoconstriction

This single-centre, randomized, double-blind, double-dummy four-way cross-over study in 24 moderately severe asthmatic patients compared the speed of onset of recommended doses of salbutamol (200 μg) and formoterol (12 μg) delivered by metered-dose inhaler in reversing the bronchoconstriction induced by a cumulative dose of methacholine to produce a 20% decrease (PD 20) in forced expiratory volume in 1 s (FEV 1). Specific airway conductance ( SG aw) and airway resistance ( R aw) were measured in baseline condition, immediately after challenge and 0·5, 1·5, 3, 5, 10, 15, 30, 60 min and every hour up to 4 h after inhalation of the trial drug. FEV 1 was measured in baseline condition, after challenge and 15, 30 and 60 min and then every 30 min up to 4 h after inhalation of the study drug. The primary efficacy parameter was the change in SG aw. Salbutamol produced a two-fold increase in SG aw within 4 min and a maximum increase after 79·3 min. Formoterol produced a two-fold increase in SG aw after 5 min and a maximum increase after 119·6 min. Changes in SG aw were slightly, but consistently, higher during the first 2 h after inhalation of salbutamol, both in absolute values and as a percentage of the maximum response. Differences were significant at 10, 15 and 30 min time points. There was no significant difference between the maximum values of SG aw after the two drugs. Changes in R aw and FEV 1 reflected the differences in SG aw. It was concluded that in methacholine-induced bronchoconstriction both formoterol and salbutamol have a very fast onset of action, achieving prechallenge values of SG aw within 3 min, salbutamol being slightly faster than formoterol.

Onset and duration of action of single doses of formoterol inhaled via turbuhaler ®

The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler ® in patients with moderate asthma. Thirty-one patients (five women) with a mean forced expiratory volume in 1 s (FEV 1) of 1·97 ± 0·54 1 and a mean reversibility of 31 ± 14% of baseline were included in this double-blind, randomized, placebo-controlled and cross-over study. The patients inhaled single doses of placebo, i.e. 6, 12, 24, or 48 μg formoterol fumarate, on 5 separate days. Serial measurements of specific airways conductance ( SG aw) and FEV 1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50% increase in SG aw within 1–4 min after administration of all active treatments. The maximum increase in FEV 1 over placebo was dose-dependent: 12% (6 μg), 18% (12 μg), 19% (24 μg), and 26% (48 μg) ( P<0·001). Twelve hours after administration of 6, 12, 24, and 48 μg formoterol, the mean increase in FEV 1 was still 7%, 15%, 18% and 27%, respectively, above the value following placebo. Headache was the most frequently reported adverse event in all treatments including placebo. After inhalation of 48 μg, three patients experienced mild tremor lasting for less than 1 h; likewise, one patient experienced the same event for 3 h after placebo. Formoterol administered via Turbuhaler ® gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated.

Cardiac Effects of Formoterol and Salmeterol in Patients Suffering from COPD with Preexisting Cardiac Arrhythmias and Hypoxemia

There are several reports of documented adverse cardiac effects during treatment with beta-agonists. Since one should be aware that this may be a problem in patients with preexisting cardiac disorders, we have conducted a randomized, single-blind, balanced, crossover, placebo-controlled study to assess the cardiac effects of two single doses of formoterol (12 microg and 24 microg) and one single dose of salmeterol (50 microg) in 12 patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia (PaO2<60 mm Hg). Each patient was evaluated at a screening visit that included spirometry, blood gas analysis, plasma potassium measurement, and 12-lead ECG. In following nonconsecutive days, all patients underwent Holter monitoring 24 h during each of the four treatments. Holter monitoring was started soon before drug administration in the morning. Plasma potassium level was measured before drug inhalation, at 2-h intervals for 6 h, and at 9, 12, and 24 h following administration. None of our patients took rescue medication during the 24-h period. Holter monitoring showed a heart rate higher after formoterol, 24 microg, than after formoterol, 12 microg, and salmeterol, 50 microg, and supraventricular or ventricular premature beats more often after formoterol, 24 microg. Formoterol, 24 microg, significantly reduced plasma potassium level for 9 h when compared with placebo, whereas formoterol, 12 microg, was different after 2 h and salmeterol, 50 microg, from 4 to 6 h. The results of this study suggest that if a COPD patient is suffering from preexisting cardiac arrhythmias and hypoxemia, long-acting beta-agonists may have adverse effects on the myocardium, although the recommended single dose of salmeterol and formoterol, 12 microg, allows a higher safety margin than formoterol, 24 microg.

Efficacy and tolerability of formoterol in elderly patients with reversible obstructive airways disease

This study has compared the efficacy and tolerability of formoterol (FORADIL) dry powder and salbutamol in elderly patients with reversible obstructive airways disease (ROAD). A total of 262 elderly outpatients with clinically stable ROAD participated in a multicentre, double-blind, parallel study. Patients were randomized in equal numbers to receive formoterol 12 μg b.i.d. formoterol 24 μg b.i.d. or salbutamol 400 μg q.i.d. for a 3 month period. All study drugs were inhaled through an Aeroliser ™ device. Daily morning and evening peak expiratory flow (PEF) values, symptom scores and additional bronchodilator use were recorded by the patients throughout the study. Clinic assessment which included spirometry and PEF measurements was made at 4, 8 and 12 weeks. Morning and evening PEF values were significantly higher with both doses of formoterol compared with salbutamol. This difference was statistically significant both for the overall study period and during the week preceding each of the clinic visits (4, 8 and 12 weeks). There was no significant difference for the two doses of formoterol with respect to PEF values. The FEV 1 and FVC values between the three treatment groups were similar. The daily use of rescue medication was significantly lower for the formoterol 24 μg group compared with the salbutamol group. The percentage of patients rating the therapeutic effect as ‘very good’ was significantly higher for formoterol: 41% on 12 μg; 34% on 24 μg; 19% on salbutamol. All treatments were well tolerated. This study demonstrates that formoterol 12 μg and 24 μg b.i.d. by dry powder inhalation are equally effective and are both significantly superior to salbutamol 400 μg q.i.d. in the treatment of ROAD in the elderly.

Hypokalaemia in Healthy Volunteers after Single and Multiple Doses of Formoterol or Salbutamol

A specific beta(2)-adrenoceptor-mediated effect, hypokalaemia, was studied in healthy volunteers after single as well as multiple dosages of the long-acting agonist formoterol and the short-acting agent salbutamol. The purpose of the study was to test with simple methodologies if rapidly induced tachyphylaxis for this well known systemic effect can be shown and if it will then be more pronounced for the long-acting compound. Hypokalaemia induced by inhalation of, respectively, 72microg formoterol and 1200microg of salbutamol was studied before and after 1 week of medication. Potassium-time curves were described by a biexponential equation and also analysed with a deconvolution technique. Both drugs induced a statistically significant hypokalaemia, the duration of this effect being considerably shorter for salbutamol than for formoterol (p < 0.05 with both methods of analysis). After multiple doses for 1 week, both maximal hypokalaemia and the area under the curve of the hypokalaemic effect had decreased after inhalation of formoterol (p < 0.05) but not after inhalation of salbutamol.It was concluded that plasma potassium as an effect measurement can be used to study in a simple but reproducible way differences of pharmacological interest between various beta(2)-adrenoceptor agonists.

Association between β 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics

In-vitro studies have suggested that polymorphisms of the beta 2-adrenoceptor may influence the desensitisation induced by beta 2-agonists. We investigated the influence of beta 2-AR polymorphism on the development of bronchodilator desensitisation in asthma patients. We carried out an analysis of 22 moderately severe stable asthmatics, mean age 38 years, FEV1 63% of predicted and FEF25-75 38% of predicted, who received a median inhaled corticosteroid dose of 1000 micrograms/day. Patients were randomly assigned inhaled placebo or inhaled formoterol 24 micrograms bid for 4 weeks each in a crossover study. Bronchodilator dose-response curves were made at the end of each treatment period by use of cumulative doses of formoterol (6-108 micrograms) with FEV1 and FEF25-75 measured 30 min after each dose, and up to 6 h after the last dose. We calculated the degree of bronchodilator desensitisation by comparing the dose-response (for maximum and 6 h) after placebo with that after formoterol, and expressed this degree as a percentage of placebo response. Patients were divided into groups according to genotype at codon 16: homozygous Arg 16 (n = 4), heterozygous Arg 16/Gly 16 (n = 8), and homozygous Gly 16 (n = 10). At codon 27: homozygous Gln 27 (n = 5), heterozygous Gln 27/Glu 27 (n = 11), and homozygous Glu 27 (n = 6). We found a significantly (p < 0.05) greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16 for maximal FEV1 response: -8% (Arg 16) vs 46% (Gly 16); and for maximal FEF25-75 response: -32% (Arg 16) vs 74% (Gly 16; 95% CI 15-92% and 49-164%, respectively). Bronchodilator responses at 6 h were also significantly (p < 0.05) different for FEV1 and FEF25-75 when Arg 16 and Gly 16 were compared and values for heterozygous Arg 16/Gly 16 were intermediate. There was significantly greater desensitisation with Glu 27 than with Gln 27 for maximal FEF25-75 response: -7% (Gln 27) vs 68% (Glu 27), p = 0.05; and for 6 h FEF25-75 response: 43% (Gln 27) vs 93% (Glu 27), p < 0.05 (95% CI 2-147% and 5-94%, respectively). All patients who were homozygous Glu 27 were also homozygous Gly 16. We have found preliminary evidence that beta 2-adrenoceptor polymorphism is associated with altered beta 2-adrenoceptor expression in asthma patients. The homozygous Gly-16 form was significantly more prone to bronchodilator desensitisation than Arg 16, with the influence of Gly 16 dominating over any putative protective effects of Glu 27.

Characterization of tolerance to the anti-leakage effect of formoterol in rat airways

These experiments addressed the question of whether the anti-plasma leakage action of β 2-adrenoceptor agonists in rat airways is subject to tolerance. Pathogen-free F344 rats were pretreated with the highly selective, long-acting β 2-adrenoceptor agonist, formoterol (0, 0.1, 1, 10 μg/kg, i.p.) for 7 days; 24 h later the effectiveness of acute doses of formoterol (0, 0.1, 1, 10 μg/kg, i.v.) was tested against substance P-induced plasma leakage. The anti-leakage effect of formoterol was not subject to tolerance with the low or intermediate pretreatment dose. Pretreatment with 10 μg/kg formoterol reduced the effectiveness of the 1 μg/kg acute dose but not the 10 μg/kg acute dose. We conclude that tolerance to the anti-leakage effect of formoterol can occur, but airway vessels are likely to retain functionally coupled receptors even after high dose pretreatment.

Clinical Experience over Five Years of Daily Therapy with Formoterol in Patients with Bronchial Asthma

This study investigated regular treatment with the long-acting β2-agonist formoterol over 5 years in patients with predominantly moderate to severe bronchial asthma. It was an open, prospective, surveillance study in 54 randomly selected asthmatics that considered concomitant medication, pulmonary function, exacerbations and the patients’ subjective condition. The objective findings were compared with the corresponding data for the previous 12 months. Five follow-up examinations were carried out for 5 consecutive years. The mean number of 12µg puffs of formoterol inhaled per day over 5 years was 2.5, 2.5, 2.6, 2.5 and 2.2, for each consecutive year. The number of patients who used an electric nebuliser fell from 41 (pretrial period) to 6, 4, 3, 1 and 1, consecutively over the 5-year period (p < 0.001). The total number of patients using theophylline fell from 31 to 9 in the first year, and dropped to 4 at the end of the trial (p < 0.001). The percentage of patients on inhaled corticosteroids remained more or less constant (72 vs 75%). The mean daily use of beclomethasone dipropionate decreased from 2.8 to 1.9 puffs daily after 1 year and remained at this level (p < 0.05). During the pretrial period, 27 patients had exacerbations necessitating treatment with systemic corticosteroids. This number fell to 12, 5, 11, 6 and 9 over the consecutive years, and the mean number of interventions decreased from 1.6 to 0.2 at the end of the trial (p < 0.001). Over 5 years of treatment, the mean decrease in forced expiratory volume in the first second (FEV1) was 0.11 ±0.52L and the mean reversibility fell by 0.001 ± 0.36L, indicating a high stability of lung function. Adverse effects occurred in 19 of 66 patients (29%). Two patients died. Neither of the deaths was judged to be related to the therapy with formoterol. In conclusion, regular therapy with formoterol appears to be very useful; there was a significant reduction in concomitant use of asthma drugs, with well-preserved pulmonary function, better subjective condition and less need for corticosteroid intervention treatment. No increase in the formoterol dose was observed, indicating no clinically relevant development of tolerance. Furthermore, no patient had to be withdrawn because of adverse effects.