Duration of action of inhaled terbutaline at two different doses and of albuterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in asthmatic subjects

Although several studies have examined the duration of the bronchodilator effect of several inhaled beta-2-adrenergic agents, the duration of the blocking effect on bronchial hyperresponsiveness, another key feature of asthma, has seldom been studied. We investigated this problem in eight adult asthmatic subjects who underwent hyperventilation tests with dry cold air on 4 different days. On the first day, five hyperventilation tests with assessment of the level of ventilation causing a 20% fall in FEV1 (PD20) were obtained to evaluate the within-day variability of the test. On the three other visits, after a baseline hyperventilation test, albuterol 200 micrograms, terbutaline 500 micrograms, and terbutaline 1,500 micrograms were administered in a double-blind, randomized way. Hyperventilation tests were carried out 1, 2, 4, and 6 h later. The blocking effect on the treatment days, as assessed by the differences in PD20 for each test compared with baseline PD20 for that day, was corrected for the within-day variability of the control day. There was a significant bronchodilator effect 1 h after administering the drug; it was equivalent for albuterol 200 micrograms (25.6 +/- 14.7%) and terbutaline 1,500 micrograms (21.7 +/- 13.5%) and significantly less for terbutaline 500 micrograms (14.1 +/- 10.0%). Complete or partial blockade on bronchial responsiveness was obtained in the majority (six to seven of eight) of the subjects 1 h after inhaling the bronchodilator, with progressive reduction in the effect later on. Four subjects still showed a blocking effect 6 h after terbutaline 1,500 micrograms was administered, one subject after terbutaline 500 micrograms, and no subjects after albuterol (chi square = 6.6, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration

BACKGROUND: There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists. OBJECTIVES: The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol, and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid. MATERIALS AND METHODS: Twelve patients (mean [SD] age, 43 [15] years; FEV(1), 57 [17] % predicted) with stable, moderate to severe persistent asthma who were all taking inhaled corticosteroids were evaluated in a randomized, placebo-controlled, double-blind, double-dummy, crossover study. Patients received treatments each for 2 weeks followed by a bolus (IV/inhaled) of corticosteroid or placebo: (1) placebo inhaler bid + bolus placebo; (2) formoterol Turbuhaler 24 microg metered dosage bid (delivered dosage 18 microg bid) + placebo; (3) formoterol 24 microg bid + bolus IV hydrocortisone, 200 mg; or (4) formoterol 24 microg bid + bolus inhaled budesonide, 1,600 microg. Bronchodilator response to repeated puffs of albuterol (200 to 1,600 microg) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid. The study was powered at the 80% level to detect a 20% difference in area under curve between 20 and 80 min (AUC) for FEV(1) response to albuterol as change from baseline (primary end point). RESULTS: There was significant subsensitivity (p = 0.01) of the mean albuterol FEV(1) response (as AUC, L x s) after formoterol alone (737) as compared to placebo (1,453) along with partial reversal by steroid administration: formoterol + hydrocortisone (1, 050), and formoterol + budesonide (942). There was a similar pattern of subsensitivity (p = 0.03) for the mean albuterol forced expiratory flow between 25% and 75% of vital capacity response (as AUC, L): placebo (2,149), formoterol alone (1,002), formoterol + hydrocortisone (1,402), and formoterol + budesonide (1,271). CONCLUSION: Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol, which was partially reversed by a bolus dose of systemic or inhaled corticosteroid.     

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.     

Prophylaxis of exercise-induced asthma with inhaled formoterol, a long-acting beta 2-adrenergic agonist

The prophylaxis of exercise-induced asthma with inhaled formoterol (12 micrograms) was compared with inhaled salbutamol (200 micrograms) and placebo in 12 patients with atopic asthma. Both drugs produced equal bronchodilation 2 and 4 h after administration. Both drugs protected equally against exercise-induced bronchoconstriction 2 h after administration; at 4 h, formoterol gave undiminished protection from that seen at 2 h while salbutamol was no more effective than placebo.     

Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma.

Short-acting beta2-agonists provide greater protection against bronchoconstriction induced by adenosine 5'-monophosphate (AMP) than by direct-acting bronchoconstrictors such as histamine and methacholine. AMP is thought to cause bronchoconstriction via release of mediators from mast cells, which suggests that these drugs stabilize mast cells in vivo. This in vivo property has not yet been demonstrated for long-acting beta2-agonists. We undertook a double-blind, randomized, placebo-controlled, cross-over study to investigate the effects of a single dose of formoterol inhaled via Turbuhaler (12 micrograms) and of albuterol inhaled via Turbuhaler (200 micrograms) on airway responsiveness to AMP and histamine in 16 subjects with mild atopic asthma. Albuterol reduced airway responsiveness to AMP and histamine by 4.1 +/- 0.5 and 3.5 +/- 0.4 doubling doses, respectively. In contrast, formoterol caused a greater protective effect against AMP than against histamine challenge, decreasing airway responsiveness by 6.0 +/- 0.8 and 4.2 +/- 0.4 doubling doses, respectively (p < 0.05). Thus, the long-acting beta2-agonist formoterol appears to have a mast cell-stabilizing effect in vivo in mild asthma.     

Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma.

Tolerance to the bronchoprotective effects by long-acting beta2-agonists (LAB) in patients with asthma is not prevented by inhaled corticosteroids (ICS). This study examined whether oral prednisolone can restore the bronchoprotective effects of formoterol in 24 patients with persistent asthma already treated with ICS (at least 800 microg budesonide x day(-1) or equivalent) and LAB, using a parallel-group design. During a 2-week run-in period and during the study, patients used formoterol 12 microg twice daily by Turbuhaler, instead of their own LAB. At baseline and at the end of 7-days treatment with oral placebo or prednisolone (30 mg x day(-1)), provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20 histamine) was measured on two separate days after randomized single-dose inhalation of placebo (postP) or formoterol (postF). In addition, PC20postF was measured 24 h after starting oral treatment. The protective effect by formoterol at baseline and during treatment was calculated as the difference between the logs of PC20postP and PC20postF. The mean+/-SEM in doubling dose (DD) bronchoprotective effect at baseline was 0.8+/-0.4 DD in the placebo group and 1.0+/-0.4 DD in the prednisolone group. At the end of the treatment period, the protective effect changed to 1.0+/-0.5 DD and 0.8+/-0.6 DD in the placebo and prednisolone treated groups, respectively. This change was not different between the groups (p > 0.4). In conclusion, the bronchoprotective effect by formoterol is not influenced by 1 week prednisolone treatment in patients with asthma who are using regular inhaled corticosteroids and long-acting beta2-agonists. These findings indicate that tolerance to long-acting beta2-agonists cannot be restored by oral steroid therapy.     

Theophylline minimally inhibits bronchoconstriction induced by dry cold air inhalation in asthmatic subjects

The aim of this study was to evaluate the effect of a sustained-release theophylline preparation on bronchial responsiveness to cold dry air inhalation in asthmatic subjects. Sixteen adult subjects with asthma in a clinical steady state underwent 3 isocapnic cold air challenges on 3 consecutive days at a time when they had not received oral theophylline medication over the past 3 days. The dose of cold air causing a 20% (PD20) fall in FEV1 was obtained from each subject's dose-response curve. Subjects were then administered active or placebo sustained-release theophylline preparations according to a double-blind, randomized, two-treatment crossover design. Medication was given for a minimum of 3 consecutive days. PD20 was reassessed on 4 different days, 3 to 4 h after receiving active or placebo medication (two visits for each medication). We found a significant bronchodilator effect of theophylline as compared to the placebo (mean +/- SD differences in changes of FEV1 of 8.8 +/- 1.9%). We also documented a significant blocking effect of the active medication as opposed to the placebo on PD20 (p = 0.01). This difference (mean = 0.18 on the loge scale) was statistically beyond the intraindividual between-day variability observed on the 3 control days (p less than 0.001) but was physiologically minimal. This blocking effect was also partially related to changes in airway caliber. We conclude that theophylline showed a blocking effect on bronchial responsiveness to dry cold air, which was physiologically minimal and was partially related to changes in airway caliber.     

The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma

It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Formoterol: a review of its use in chronic obstructive pulmonary disease

Inhaled formoterol is a long-acting selective beta2-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours. Statistically significant and clinically relevant (>120 ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV1) versus time curve (AUC FEV1)] were observed with inhaled formoterol 12 microg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD). The bronchodilator efficacy of formoterol 12 microg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40 microg four times daily in a 12-week trial. Improvement in AUC FEV1 with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12 microg twice daily plus ipratropium bromide 40 microg four times daily was significantly more effective than albuterol (salbutamol) 200 microg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial. Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12 microg twice daily was similar to that with placebo and inhaled ipratropium bromide 40 microg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range. In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.     

Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma.

The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD4 receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD4 receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta 2-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV1 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV1) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV1 above baseline, 20 min after the start of the MK-571 infusion, was 22 +/- 3.9% compared with 1.3 +/- 2.3% for placebo (mean +/- SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Formoterol

Abstract

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours.Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV₁) versus time curve (AUC FEV₁)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD).The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV₁ with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial.Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range.In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.

Pharmacodynamic Properties

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist (β₂-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial.Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV₁) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV₁. Mean peak FEV₁ was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg.Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily.All β₂-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β₂ receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO₂ (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients.

Pharmacokinetic Properties

The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L.Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38).Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers.Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals.

Therapeutic Efficacy

Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines.The bronchodilator effect [measured as normalized area under the FEV₁ versus time curve (AUC FEV₁)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p < 0.001) and health-related quality of life [all three subsections of the St. George’s Respiratory Questionnaire (SGRQ); p ≤ 0.036], and significant reductions were reported for the use of rescue medication (p ≤ 0.014) and the percentage of ‘bad days’ (days with at least two individual symptom scores of ≥2 and/or a reduction in PEF from baseline of >20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ.Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC_12h FEV₁ (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV₁ values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV₁).In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD.The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV₁ to 6 hours (p< 0.0001), peak postmedication FEV₁ (p < 0.0001) and AUC FEV₁ (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy.

Tolerability

Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo.Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial.There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials.

Dosage and Administration

Formoterol, inhaled orally using an Aerolizer?1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg.Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.

     

A study of the duration of the bronchodilator effect of 12 micrograms and 24 micrograms of inhaled formoterol and 200 micrograms inhaled salbutamol in asthma

Formoterol is a new catecholamine analogue for which a longer duration of action is claimed. We studied the bronchodilator action of 12 micrograms and 24 micrograms of inhaled formoterol compared to 200 micrograms of inhaled salbutamol and placebo, in seven patients (mean age 59.3 yr) with moderate asthma. The adjusted mean peak rise in FEV1 was +0.331 each for salbutamol, 12 micrograms formoterol and 24 micrograms formoterol, all being significantly greater than that of placebo (+0.161; P less than 0.01). The duration of action was calculated in two ways. When calculating the time for the group mean FEV1 to return to baseline, the values were: for placebo, 3.1 h; salbutamol, 4.2 h; 12 micrograms formoterol, 6.8 h; and 24 micrograms formoterol, 11.2 h. When taking the times for each treatment at which individual FEV1 values returned to baseline and then calculating the adjusted mean time for each treatment group, the durations of action were: placebo, 3.5 h; salbutamol, 3.9 h; 12 micrograms formoterol, 5.9 h; and 24 micrograms formoterol, 8.1 h (24 micrograms formoterol compared to placebo, P = 0.02 and to 200 micrograms salbutamol, P = 0.03). The second method of calculation is nearer to a patient's approach in treating their asthma (i.e. taking an extra dose when needed), and may be a more realistic method of assessing duration of action. Formoterol is an effective bronchodilator, and the 24 micrograms dose should be assessed in the treatment of nocturnal asthma. In this group of older asthmatics with a degree of fixed airflow obstruction, we suggest that doses should be taken 8 hourly.     

Effects of formoterol (Oxis Turbuhaler) and ipratropium on exercise capacity in patients with COPD

Although long-acting inhaled beta 2-agonists improve various outcome measures in COPD, no double-blind study has yet shown a significant effect of these drugs on exercise capacity. In a randomized, double-blind, placebo-controlled, crossover study, patients received formoterol (4, 5, 9, or 18 micrograms b.i.d. via Turbuhaler), ipratropium bromide (80 micrograms t.i.d. via pMDI with spacer), or placebo for 1 week. Main endpoint was time to exhaustion (TTE) in an incremental cycle ergometer test. Secondary endpoints were Borg dyspnoea score during exercise, lung function, and adverse events. Thirty-four patients with COPD were included, mean age 64.8 years, FEV1 55.6% predicted, reversibility 6.1% predicted. All doses of formoterol, and ipratropium significantly improved TTE, FEV1, FEF25-75%, FRC, IVC, RV and sGAW compared with placebo. A negative dose-response relationship was observed with formoterol. Ipratropium increased time to exhaustion more compared with formoterol, 18 micrograms, but not with formoterol, 4.5 and 9 micrograms. No changes in Borg score were found. There was no difference in the adverse event profile between treatments. In conclusion, 1 week of treatment with formoterol and ipratropium significantly improved exercise capacity and lung function compared with placebo. However, a negative dose-response relation for formoterol was unexpected and needs further investigation.     

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

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

Comparison of the Bronchodilating Effects of Formoterol and Albuterol Delivered by Hydrofluoroalkane Pressurized Metered-Dose Inhaler

Objective

To compare the onset of bronchodilation with a new formoterol hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) with albuterol (salbutamol) HFA pMDI.

Patients and methods

Thirty patients with stable mild or moderate asthma (23 using inhaled corticosteroids, mean FEV₁ 82% of predicted, ≥15% reversibility to terbutaline 1mg after 30 minutes) received formoterol HFA (Oxis®) 2 × 4.5µg, albuterol HFA (Ventoline® Evohaler®) 2 × l00µg, or placebo at three separate visits in this randomized, double-blind, double-dummy, three-way crossover study. FEV₁ was measured before and 3, 10, 20, 30 and 60 minutes after inhalation. Change in FEV₁ at 3 minutes after inhalation was the primary variable.

Results

Mean baseline FEV₁ was stable on all study days (range 2.92–2.94L). FEV₁ values at 3 minutes were: formoterol 3.22L (8% increase), albuterol 3.23L (9% increase) and placebo 2.99L (both p < 0.001 vs placebo). Maximum FEV₁ increased similarly with formoterol and albuterol, with no differences observed between the active treatments at any time point. Patients rated treatment effective at 3 minutes in 15 of 30, 19 of 30 and 7 of 30 cases with formoterol, albuterol and placebo, respectively. All treatments were well tolerated.

Conclusion

In stable, mild, or moderate asthma, formoterol 9µg and albuterol 200µg, both by HFA pMDI, provided equally rapid and effective bronchodilation.

     

Inhalation of 0.30 ppm nitrogen dioxide potentiates exercise-induced bronchospasm in asthmatics

Epidemiologic studies support an association among elevated levels of nitrogen dioxide (NO2), increased respiratory symptoms, and alterations in lung function. To determine if low level NO2 inhalation potentiates exercise-induced bronchospasm, 15 asthmatic subjects, defined by airway constriction with cold air provocation, inhaled 0.30 ppm (560 micrograms/m3) NO2 for 30 min. All asthmatics inhaled either air or 0.30 ppm NO2 via a mouthpiece for 20 min at rest followed by 10 min of exercise on a bicycle ergometer at a workload of 300 kpm/min, producing a 3-fold or greater increase in minute ventilation. Our studies showed 72 +/- 2 (SE)% deposition of inhaled NO2 at rest and 87 +/- 1% deposition with exercise (p less than 0.001). Nitrogen dioxide inhalation at rest resulted in no significant change in pulmonary function. Nitrogen dioxide inhalation plus exercise compared to control (air) exposure plus exercise produced significantly greater reductions in FEV (p less than 0.01) and partial expiratory flow rates at 60% of total lung capacity (p less than 0.05). One hour after completion of NO2 exposure and exercise, pulmonary function had returned to baseline values. To determine if NO2 exposure caused increased reactivity to a known bronchoconstrictor, asthmatic subjects inhaled cold air (range: -11 +/- 2 degrees C) at 3 successive rates of isocapnic ventilation. The response to cold air was expressed as the respiratory heat exchange required to reduce the FEV by 10% (PD10RHE). Prior NO2 exposure potentiated the fall in FEV, PD10RHE, and specific airway conductance (p less than 0.05) after isocapnic cold air hyperventilation, compared to the control exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic inhalation of nebulized levalbuterol does not increase mucociliary clearance in healthy subjects

Acute inhalations of beta 2-adrenergic receptor agonists increase mucociliary clearance (MCC). Less is known about the effect of long-term inhalations of these agents on MCC, or cough clearance (CC). We hypothesized that chronic inhalations of nebulized levalbuterol, the R-isomer of albuterol, would enhance MCC and/or CC in healthy subjects, compared to albuterol or placebo. This was a randomized, double-blind, placebo-controlled trial in ten healthy, adult subjects who inhaled nebulized levalbuterol (1.25mg), albuterol (2.5mg), or placebo for 7 days, three times daily. MCC and CC were measured 6-7h after the last dose of drug on the 7th day of treatment. These were quantified from gamma camera images of the lungs following inhalation of an aerosol containing the isotope (99m)technetium. Levalbuterol did not improve MCC or CC. MCC averaged (+/-SD) 12.3+/-8.3%, 9.2+/-4.7% and 10.0+/-9.6% with placebo, albuterol and levalbuterol, respectively. CC averaged 3.9+/-6.8%, 4.9+/-4.3% and 3.8+/-6.4% with placebo, albuterol and levalbuterol, respectively. These results indicate that chronic inhalations of nebulized levalbuterol for 1 week do not increase MCC or CC in healthy subjects, compared to albuterol or placebo.     

A controlled trial of long-term bronchodilator therapy in cystic fibrosis

To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness, we first performed methacholine challenges to determine responsiveness, then entered 27 patients (16 methacholine responders and 11 nonresponders) into a two-month double-blind crossover trial of albuterol, 90 micrograms by inhalation four times a day vs placebo. Among the responders, daily PEFR measures improved significantly more during treatment with albuterol (12 +/- 32 L/min) than with placebo (-0.4 +/- 19 L/min; p less than 0.05). In addition, a clinically important level of improvement in PEFR (15 percent increase) was reached significantly more frequently in the responders. Methacholine nonresponders had no change in PEFR on either albuterol or placebo. Daily symptom scores as well as spirometry measurements at biweekly visits did not show significant changes. We conclude that long-term therapy with inhaled albuterol improves lung function in CF patients, but only in those with bronchial hyperresponsiveness as demonstrated by methacholine challenge.     

Efficacy of a heat exchanger mask in cold exercise-induced asthma

STUDY OBJECTIVES: To determine the efficacy of a novel mask device in limiting cold air exercise-induced decline in lung function in subjects with a history of exercise-induced asthma (EIA). SETTING: In spite of appropriate medical therapy, many asthma patients are limited in cold weather activities. DESIGN: In study 1, 13 asthmatic subjects performed two randomized, single-blind treadmill exercise tests while breathing cold air (- 25 to - 15 degrees C) through a placebo or active heat exchanger mask. In study 2, five subjects with EIA performed three treadmill exercise tests while breathing cold air: one test using the heat exchanger mask, one test without the mask but with albuterol pretreatment, and one test with neither the mask nor albuterol pretreatment (unprotected exercise). For all studies, spirometry was performed before and at 5, 15, and 30 min after exercise challenge. PATIENTS: For both studies, a total of 15 subjects with a history of asthma symptoms during cold air exercise were recruited. RESULTS: In study 1, the mean decrease (+/- SE) in FEV1 was 19 +/- 4.9% with placebo, and 4.3 +/- 1.6% with the active device (p = 0.0002). The mean decrease in maximum mid-expiratory flow (FEF(25-75)) was 31 +/- 5.7% with placebo and 4.7 +/- 1.7% with the active device (p = 0.0002). In study 2, the mean decrease in FEV1 was 6.3 +/- 3.9%, 11 +/- 3.7%, and 28 +/- 10% for the heat exchanger mask, albuterol pretreatment, and unprotected exercises, respectively (p = 0.4375 for mask vs albuterol, p = 0.0625 for mask vs unprotected exercise). The mean decrease in FEF(25-75) was 10 +/- 4.8%, 23 +/- 6.0%, and 36 +/- 11%, respectively (p = 0.0625 for mask vs albuterol, p = 0.0625 for mask vs unprotected exercise). CONCLUSIONS: This heat exchanger mask blocks cold exercise-induced decline in lung function at least as effectively as albuterol pretreatment.     

Effect of albuterol on maximal exercise capacity in cystic fibrosis

BACKGROUND: Inhaled, short-acting beta-adrenergic agonists (SAbetaAs) are widely prescribed in cystic fibrosis (CF) subjects, despite a lack of convincing data for efficacy and the potential for these agents to result in airway instability. We tested the hypothesis that inhaled albuterol would improve maximal exercise performance in CF subjects with airflow obstruction, as a result of acute bronchodilation. METHODS: Randomized, double-blind, placebo-controlled crossover study of the effect of inhaled albuterol on maximal exercise performance in 20 stable adult CF patients (mean +/- SD age, 23.3 +/- 6.1 years; FEV(1), 57.65 +/- 17.13% of predicted). RESULTS: Ventilatory limitation to exercise was demonstrated in 16 subjects (80%). Significant bronchodilation occurred with exercise alone (end-exercise FEV(1), 2.24 +/- 0.8 L; vs preexercise FEV(1), 2.09 +/- 0.77 L; p < 0.0001), but albuterol resulted in significantly greater exercise-induced bronchodilation than placebo (change in FEV(1), 0.3 +/- 0.15 L vs 0.15 +/- 0.11 L; 95% confidence interval [CI], + 0.07 to + 0.23; p < 0.001). However, there was no difference in maximal workload achieved (albuterol, 158 +/- 46 W; vs placebo, 158 +/- 45 W; 95% CI, - 4.41 to + 4.71; p = 0.95), nor any other measure of exercise performance including maximal oxygen uptake. CONCLUSIONS: Despite causing significant acute bronchodilation, inhaled albuterol did not improve maximal exercise performance in ventilatory-limited CF adults, adding to the body of literature that fails to show any clinical benefit of SAbetaAs in CF subjects. The current results provide further evidence to question the widespread use of these agents, although the potential for adrenergic beta-agonists to instead improve submaximal exercise performance merits further investigation.