Tiotropium Respimat® add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics.

BACKGROUND: Despite currently available therapies and detailed treatment guidelines, many patients with asthma remain symptomatic. Tiotropium delivered by the soft mist inhaler Respimat®, as add-on therapy to medium-dose inhaled corticosteroids (ICS), has been shown to improve lung function and asthma control in patients with symptomatic moderate asthma. OBJECTIVE: To determine whether the efficacy of tiotropium Respimat® in asthma differs by patients' study baseline characteristics. METHODS: Two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group studies (MezzoTinA-asthma®; NCT01172808 and NCT01172821) of once-daily tiotropium Respimat 5 µg and 2.5 µg add-on to ICS were conducted in patients with symptomatic asthma despite treatment with medium-dose ICS with or without additional controllers. Subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, risk of severe asthma exacerbation and Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by patients' baseline characteristics. RESULTS: In this analysis, 523 patients received placebo while 517 and 519 patients received the 5 µg and 2.5 µg dose of tiotropium Respimat, respectively. The magnitude of the improvements in lung function and asthma control, as well as the reduced risk of severe exacerbation with both doses of tiotropium Respimat versus placebo, was independent of a broad range of baseline characteristics. CONCLUSIONS: Once-daily tiotropium Respimat as add-on to ICS is a beneficial treatment option for patients with asthma who remain symptomatic despite at least medium-dose ICS, regardless of baseline characteristics.

Positioning of Long-Acting Muscarinic Antagonists in the Management of Asthma.

Despite a range of efficacious therapies for asthma, including inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA), a significant proportion of patients have poor asthma control and retain a risk of future worsening of their symptoms. Long-acting muscarinic antagonist (LAMA) bronchodilators offer a well-tolerated, efficacious, and cost-effective add-on to a patient's treatment. Of the LAMAs currently under investigation or available for the treatment of asthma, evidence from a comprehensive clinical trial program in adults and children shows that once-daily treatment with tiotropium provides benefits for patients with uncontrolled asthma despite the use of ICS and LABAs. Tiotropium is included in the Global Initiative for Asthma (GINA) strategy document as an add-on therapy option for patients at Step 4 or 5 with a history of asthma exacerbations. Tiotropium Respimat® has demonstrated safety and efficacy in patients with a range of disease severities, ages, and phenotypes. This review describes the evidence for the use of LAMA as add-on therapy for patients with asthma who remain uncontrolled despite the use of ICS and LABA treatments.

Pharmacokinetics of tiotropium administered by Respimat® in asthma patients: Analysis of pooled data from Phase II and III clinical trials.

Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat® inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ss and Cmax,ss. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 µg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 µg once daily or 2.5 µg twice daily via Respimat®). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUCtau,ss) was similar between asthma and COPD, but Cmax,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower Cmax,ss compared to COPD is not considered a concern for tiotropium therapy of asthma.

The asthma-COPD overlap syndrome: how is it defined and what are its clinical implications?

It is increasingly recognized that both asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with a large inter-individual variability with respect to their clinical expression, disease progression, and responsiveness to the available treatments. The introduction of asthma-COPD overlap syndrome (ACOS) may lead to a better clinical characterization and improved treatment of patients with obstructive airways disease. However, it is still in its early phase and several improvements will have to be made. First, a clear definition of ACOS and preferably also its sub-phenotypes, eg, asthma-ACOS and COPD-ACOS, is urgently needed. That would also allow researchers to design clinical studies in well-defined patients. The latter is important since the interpretation of clinical studies performed so far is hampered by the use of many different definitions of ACOS. Second, future studies are needed to investigate the role of state-of-the-art techniques such as computed tomography, genetics, and genomics in the phenotyping of patients with obstructive airways disease, ie, asthma, COPD, and ACOS. Third, longitudinal studies are now needed to better define the clinical implications of ACOS with respect to the long-term outcome and treatment of ACOS and its sub-phenotypes compared to only asthma or COPD.

Achieving asthma control with ICS/LABA: A review of strategies for asthma management and prevention.

Maintenance treatment with an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) is recommended for patients whose asthma is not controlled with a low-to-moderate dose of ICS alone; a separate reliever medication is used on an as-needed basis. The Gaining Optimal Asthma ControL (GOAL) study demonstrated that salmeterol/fluticasone maintenance treatment can improve asthma control and reduce future risk compared with fluticasone alone, although the dose escalation design of this study meant that most patients treated with salmeterol/fluticasone were receiving the highest dose of ICS at the end of the study. Similarly, budesonide/formoterol maintenance therapy improved asthma control and reduced future risk compared with budesonide alone in the Formoterol and Corticosteroids Establishing Therapy (FACET) study. An alternative approach to asthma management is to use an ICS/LABA for both maintenance and reliever therapy. A large body of clinical evidence has shown that the use of budesonide/formoterol in this way improves both current control and reduces future risk compared with ICS/LABA plus as-needed short-acting ß2-agonist (SABA), even when patients receive lower maintenance doses of ICS as part of the maintenance and reliever therapy regimen. In addition, one study has shown that beclometasone/formoterol maintenance and reliever therapy reduces exacerbations more effectively than beclometasone/formoterol plus as-needed SABA. The use of ICS/LABA as both maintenance and reliever therapy ensures that an increase in reliever use in response to worsening symptoms is automatically matched by an increase in ICS.

Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat® Inhaler in Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Combining long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat(®) inhaler. METHODS: This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks. RESULTS: Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments. CONCLUSIONS: Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased. FUNDING: Boehringer Ingelheim. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01040403.

A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV1 profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting ß2-agonist, in patients with chronic obstructive pulmonary disease.

BACKGROUND: This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 µg) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients received olodaterol 2 µg twice daily (BID), 5 µg BID, 5 µg once daily (QD) and 10 µg QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV1 area under the curve from 0 to 12 h (AUC0-12) and area under the curve from 12 to 24 h (AUC12-24) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. RESULTS: 47 patients were treated. All olodaterol doses provided significant increases in FEV1 versus baseline (p < 0.001) and FEV1 time profiles were nearly identical for olodaterol 5 and 10 µg QD. Olodaterol 5 µg QD demonstrated improved FEV1 AUC0-12 and similar AUC12-24 versus 2 µg BID. Olodaterol 5 µg QD showed slightly increased FEV1 AUC0-12 but lower AUC12-24 compared to 5 µg BID. Bronchodilation over 24 h was similar for olodaterol 5 µg QD and BID. All doses were well tolerated. CONCLUSIONS: Olodaterol 5 µg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 µg BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 µg QD or 5 µg BID). TRIAL REGISTRATION: ClinicalTrials.gov: NCT00846768.

Onset of bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomized study.

INTRODUCTION: The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta(2)-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments. METHODS: Adults with mild-to-moderate-severe persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 µg twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 µg b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV(1)] was ≥12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV(1) were assessed at days 0 (baseline) and 84. RESULTS: Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05-2.05]) and 84 (HR = 1.77 [95% CI 1.14-2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96-8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14-42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57-7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65-4.93]; P = 0.011). CONCLUSION: These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma.

Fixed or adjustable maintenance-dose budesonide/formoterol compared with fixed maintenance-dose salmeterol/fluticasone propionate in asthma patients aged >or=16 years: post hoc analysis of a randomized, double-blind/open-label extension, parallel-group study.

BACKGROUND AND OBJECTIVE: Inhaled corticosteroid (ICS)/long-acting beta(2)-agonist (LABA) combinations are the preferred maintenance therapy for adult asthma patients uncontrolled by ICS alone. Supporting data are largely from mixed populations of adolescents and adults, although ICS/LABA combinations are not approved for adolescents in all countries. This analysis evaluates overall asthma control in asthma patients aged >or=16 years receiving ICS/LABA combinations. METHODS: This was a post hoc analysis of asthma patients aged >or=16 years in a randomized, double-blind/open-label extension, parallel-group study. Patients received fixed maintenance-dose budesonide/formoterol (Symbicort Turbuhaler), fixed maintenance-dose salmeterol/fluticasone propionate (Seretide/Advair/Adoair Diskus) or adjustable maintenance-dose budesonide/formoterol. Patients used terbutaline or salbutamol for as-needed reliever medication. The primary efficacy variable was the odds of having a well controlled asthma week during the randomized treatment period. RESULTS: ICS/LABA regimens were well tolerated and efficacious, and the odds for achieving a well controlled asthma week did not differ between groups in this sub-analysis. The number of exacerbations was similar between fixed-dose regimens; however, there were trends toward fewer exacerbations requiring hospitalization/emergency room treatment in the fixed- and adjustable maintenance-dose budesonide/formoterol groups (three and two events, respectively) than in the fixed-dose salmeterol/fluticasone propionate group (eight events). Improvements in forced expiratory volume in 1 second (FEV(1)) were small but significantly greater with fixed-dose budesonide/formoterol versus fixed-dose salmeterol/fluticasone propionate. CONCLUSIONS: This post hoc analysis supports the use of ICS/LABA combinations in adults aged >or=16 years.

Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study.

BACKGROUND: The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear. METHODS: The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a > or = 30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 microg), formoterol (4.5 microg), salbutamol (2 x 100 microg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day. RESULTS: In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1. CONCLUSIONS: A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

[Treatment of asthma during pregnancy]. / Behandeling van astma tijdens de zwangerschap.

Treatment of asthma during pregnancy leads to discussion concerning medication and complications of pregnancy.Insecurity about possible teratogenity leads in the first trimester in 40% of pregnant women to reduction or cessation of asthma medication.This results, in pregnant women with moderate to severe asthma, in an increased consumption of rescue medication and number of exacerbations, and reduced asthma control. Asthma-exacerbations are significantly correlated with low birthweight. Of the majority of asthma medications, consumption during pregnancy has not been shown to cause harmful effects on the foetus. Adequate therapy for maintenance and exacerbations are essential, noting that the treatment in essence should not differ between pregnant and nonpregnant asthmatic women. A preconceptional consultation by a pulmonary physician and gynaecologist could improve care for pregnant women with asthma.

Extent of uncontrolled disease and associated medical costs in severe asthma--a PHARMO study.

OBJECTIVE: Asthma is a major public health problem with considerable economic impact. The highest costs being observed in patients with severe asthma. Furthermore, despite the use of recommended therapies, asthma control can still be poor. Therefore, the objective of this study was to assess the extent of uncontrolled disease and associated medical costs in severe asthma. METHODS: The PHARMO Record Linkage System includes among others drug dispensing and hospitalizations for > or = 2 million subjects in The Netherlands. Severe asthma patients used long-acting beta-agonists and inhaled corticosteroids for over 200 days and short-acting beta-agonists for at least 100 days in 2004. Severe uncontrolled asthma was defined as a hospitalization for asthma or use of multiple short courses of oral corticosteroids assessed in 2004. Reimbursed costs of asthma drugs and hospitalizations were calculated during this year. A matched nested-case control study was performed to identify treatment-related risk factors for uncontrolled disease. Information on clinical diagnosis of (severity of) asthma was not available. RESULTS: About 17% of patients with severe asthma aged 12-49 years (N = 1158) showed lack of control. Excess drug costs for severe uncontrolled asthma with hospitalization mounted up to 700 Euro per patient per year and 300 Euro per patient per year for patients without hospitalization. Including hospital admission costs, excess costs mounted up to over 10,000 Euro per patient per year. Lack of control did not seem to be caused by under-treatment. CONCLUSION: Poor control of severe asthma leads to disproportionately increased direct costs compared to severe controlled asthma, especially when hospital admission is required.

Comparison and optimal use of fixed combinations in the management of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting beta-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient's perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.

Onset of relief of dyspnoea with budesonide/formoterol or salbutamol following methacholine-induced severe bronchoconstriction in adults with asthma: a double-blind, placebo-controlled study.

BACKGROUND: The long-acting beta2-agonist (LABA) formoterol has an onset of effect comparable to that of salbutamol. Consequently, the combination of formoterol and budesonide in one inhaler, approved for maintenance use, can potentially be used for reliever therapy. This study compared the onset of relief from induced bronchospasm with a single dose of budesonide/formoterol versus standard salbutamol therapy in patients with asthma. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study, 32 patients with asthma underwent a methacholine provocation test leading to a fall in forced expiratory volume in 1 second (FEV1) of > or =30% at enrollment (Visit 1) and three subsequent study visits (Visits 2-4). Immediately after each provocation at Visits 2-4, patients received one of three test treatments: one inhalation of budesonide/formoterol 160/4.5 microg (via Turbuhaler), two inhalations of salbutamol 100 microg (via a pressurised metered-dose inhaler [pMDI]) or placebo. All patients received each of the test treatments in a randomised order, after separate methacholine provocations. The effect of treatment on FEV1 and breathlessness (using the Borg scale) was measured at 1, 3, 5, 10, 15, 20, 25 and 30 minutes after test treatment. RESULTS: Following methacholine provocation, Borg score increased from a baseline value of below 0.5 to 3.03, 3.31 and 3.50 before treatment with budesonide/formoterol, salbutamol and placebo, respectively. Budesonide/formoterol and salbutamol reversed methacholine-induced dyspnoea (breathlessness) rapidly. At 1 minute after inhalation, statistically significant decreases in Borg score were observed for budesonide/formoterol and salbutamol (p = 0.0233 and p < 0.0001, respectively, versus placebo), with similar rapid increases in FEV1 (both active treatments p < 0.0001 versus placebo). The median time to 50% recovery in Borg score after methacholine provocation was 3 minutes with budesonide/formoterol, 2 minutes with salbutamol and 10 minutes with placebo. All treatments and procedures were well tolerated. CONCLUSION: Single doses of budesonide/formoterol and salbutamol both provided rapid relief of dyspnoea and reversal of severe airway obstruction in patients with asthma with experimentally induced bronchoconstriction. The perception of relief, as confirmed by objective lung function assessment, provides evidence that budesonide/formoterol can be used as reliever medication in asthma.

The relationship between self-efficacy and self-reported physical functioning in chronic obstructive pulmonary disease and chronic heart failure.

In this study, the authors investigated whether self-reported physical functioning of patients with chronic obstructive pulmonary disease (COPD) and chronic systolic heart failure (CHF) was primarily explained by illness-specific differences related to diagnosis or whether more generic factors also contributed to their physical functioning. Consecutive patients with COPD (n = 56; mean age = 67.8, SD = 8.5) and CHF (n = 65; mean age = 60.0, SD = 10.2)from the outpatient clinics of a university hospital and a general hospital completed a self-report questionnaire, including the Rand-36 Health Survey, Cantril's ladder, the Mastery scale, the Perceived Health Competence Scale, and the Self-efficacy scale. COPD patients scored significantly worse in self-reported physical and psychological functioning and perceived health competence than did patients with CHF Regression analysis revealed that both the diagnosis and the illness severity contributed to self-reported physical functioning, although self-efficacy explained the main part of physical functioning. Therefore, important aims in the treatment of patients with COPD and CHF should be not only improving physical functioning but also enhancing self-efficacy.

Detrimental effects of beta-blockers in COPD: a concern for nonselective beta-blockers.

INTRODUCTION: beta-Blockers are known to worsen FEV(1) and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. OBJECTIVE: To determine the effects of beta-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]), FEV(1), and response to formoterol in patients with COPD. DESIGN: A double-blind, placebo-controlled, randomized, cross-over study. SETTING: An ambulatory, hospital outpatient clinic of pulmonary diseases. PATIENTS: Patients with mild-to-moderate irreversible COPD and AHR. INTERVENTION: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >/= 3 days. On day 4 of treatment, FEV(1) and PC(20) were assessed. Immediately hereafter, formoterol (12 microg) was administered and FEV(1) was measured for up to 30 min. RESULTS: PC(20) was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV(1) deteriorated only after propranolol treatment (2.08 +/- 0.31 L) [mean +/- SD] compared with placebo (2.24 +/- 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV(1) at 3 min, 6.7 +/- 8.9%) but was unaffected by the other beta-blockers (16.9 +/- 9.8%, 22 +/- 11.6%, and 16.9 +/- 9.0% for placebo, metoprolol, and celiprolol, respectively). CONCLUSIONS: Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV(1) and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of beta-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a beta-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV(1), AHR, and response to additional beta(2)-agonists.

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.