Long-acting Β2-adrenergic Agonist Research Articles

Torsade de pointes associated with the combination of solifenacin and clenbuterol for urinary incontinence

A 79-year-old woman undergoing medical treatment with solifenacin and clenbuterol for urinary incontinence was admitted to our hospital because of recurrent syncope. Her syncope appeared one month after the doses of clenbuterol were increased. Torsade de pointes (TdP) was evident on her Holter electrocardiogram at the time when she developed syncope. Ultimately, a cardioverter-defibrillator with dual chamber pacing capability was implanted. To our knowledge, this is the first report of TdP associated with the combination of solifenacin and clenbuterol for urinary incontinence.<Learning objective: Urinary incontinence increases with age. Muscarinic receptor antagonists are considered the mainstay of pharmacologic treatment for this condition. Some patients might be treated with a combination of a bladder selective muscarinic receptor antagonist solifenacin and a long-acting β2 adrenergic agonist clenbuterol. However, this combination therapy may cause torsade de pointes with syncope.>

Disconnect between sputum neutrophils and other measures of airway inflammation in asthma

To the Editor: Asthma heterogeneity has been described by the nature and intensity of granulocytic infiltration into the airways [1, 2]. Sputum, endobronchial biopsies and bronchoalveolar lavage (BAL) sample different anatomical regions of the airways. Few studies have directly compared the inflammatory cell infiltrates in these regions within a large cohort of moderate–severe asthma patients using standard techniques. In the BOBCAT (Bronchoscopic exploratory research study Of Biomarkers in Corticosteroid-refractory AsThma) study, we sampled multiple airway compartments concurrently, enabling us to evaluate relationships between granulocytic infiltrates within and between compartments in a large cohort of moderate–severe adult asthma patients. This prospective multicentre observational study was conducted in four visits over a 4–6 week period, as described previously [3]. The patients included had moderate–severe persistent asthma (forced expiratory volume in 1 s (FEV1) 40–80% predicted and Asthma Control Questionnaire (ACQ) [4] score >1.5) and, within the past 5 years, evidence of >12% post-bronchodilator reversibility or a provocative concentration of methacholine causing a 20% decline in FEV1 ≤8 mg·mL−1 despite high-dose inhaled corticosteroid (ICS) (≥1000 μg·day−1 fluticasone propionate equivalent) with or without long-acting β2-adrenergic agonist therapy. Key exclusion criteria included initiation or increase in systemic steroid use 30 days prior to screening, chronic or recent (within the past 30 days) use of immunosuppressive therapies, or other active lung disease. Patients had a prior established diagnosis of moderate–severe asthma for ≥6 months prior to screening while receiving a stable dose regimen (>6 weeks) of a high-dose ICS. Allowed concomitant medications included leukotriene receptor antagonists and oral corticosteroids. 78 patients with confirmed moderate–severe asthma were enrolled at 18 sites; 67 (86%) completed the study. All patients had persistently impaired …

Abstracts from The Aerosol Society Drug Delivery to the Lungs 22Edinburgh International Conference CentreEdinburgh, Scotland, UKDecember 7–9, 2011

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.

An evaluation of asthma medication utilization for risk evaluation and mitigation strategies (REMS) in the United States: 2005–2011

Purpose: The purpose of this study was to assess drug utilization patterns of fluticasone propionate (FP)/salmeterol (SAL) combination (FSC) and SAL over the 7-year period of 2005–2011 in patients with asthma as part of the Risk Evaluation and Mitigation Strategies (REMS). Methods: A descriptive, retrospective observational study utilizing national pharmacy data and employer-based claims data to characterize drug utilization patterns. Results: For patients with asthma, the total number of FSC and SAL dispensings and users of FSC and SAL has declined between 2005 and 2011. During this period, FSC and SAL dispensing for asthma decreased 24% and 76%, respectively, with a more pronounced decline between 2010 and 2011 relative to other years. The total number of patients with asthma who were dispensed FSC has decreased by 10% among adults and by 40% in children and adolescents. While SAL-containing medications decreased, dispensing of FP monotherapy increased 39% during the same 7-year period. The number of patients dispensed FP for asthma has increased 47% in children 4–11 years of age, 72% in adolescents 12–17 years of age, and 6% in adults. SAL use without a controller was infrequent and decreasing, reported by 1.7% and 0.5% of patients with asthma in 2005 and 2011, respectively. Conclusions: In patients with asthma, use of FSC and SAL decreased between 2005 and 2011, while the use of FP increased. Use of SAL monotherapy was infrequent and declined during the study period. The data suggest that the substantial communication activities have encouraged appropriate prescribing of long-acting β2-adrenergic agonist (LABA).

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice. We studied the status of β adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis. We found significant atrophy of dentate gyrus and failure of β adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting β2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice. Our data suggest that targeting β2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar β2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome.

Fluticasone–vilanterol combination approved for COPD

FDA on May 10 announced the approval of the Breo Ellipta inhaler, which contains the new long-acting β2-adrenergic agonist (LABA) vilanterol in combination with fluticasone furoate, for use in adults with chronic obstructive pulmonary disease (COPD). The product, from GlaxoSmithKline and

Reaching Beyond Disparity: Safely Improving Asthma Control in the At-Risk African-American Population

In the United States, substantial racial disparities exist in asthma prevalence, etiology, morbidity and mortality, particularly between African Americans and white Americans. African-American patients with asthma have inadequate access to appropriate healthcare, insufficient asthma management guidance from their physicians and poor adherence to asthma medications-all factors that may contribute to disproportionate morbidity. Historically, African Americans have been under-represented in clinical asthma studies, and a paucity of data exists surrounding asthma treatment response. One controversial study from 2006 suggests an increased safety risk with the use of long-acting beta2-adrenergic agonists (LABAs) in African Americans. More recently, several studies have evaluated the use of LABAs in combination with an ICS in African-American populations. This article reviews the existing data on asthma treatment outcomes, with particular emphasis on the recently published short- and long-term studies of ICS/LABA products conducted in African-American populations with moderate-to-severe asthma. Overall, evidence suggests that if African-American patients with asthma are provided with access to well-trained physicians, appropriate asthma management and effective medications, existing disparities in asthma control between African-American and white populations may be overcome.

Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate-to-severe asthma

The inhaled corticosteroid, fluticasone propionate, and the long-acting β(2)-adrenergic agonist, formoterol fumarate, are both highly effective treatments for bronchial asthma. This study (NCT00393952/EudraCT number: 2006-005989-39) compared the efficacy and safety of fluticasone/formoterol combination therapy (flutiform(®); 250/10μg) administered twice daily (b.i.d.) via a single aerosol inhaler, with the individual components (fluticasone 250μg b.i.d.; formoterol 10μg b.i.d.), in adult and adolescent patients with moderate-to-severe asthma. This was a 12-week, double-blind, randomised, parallel-group, multicentre, placebocontrolled phase 3 study. The co-primary efficacy endpoints were: i) the mean change in the forced expiratory volume in the first second (FEV(1)) from morning pre-dose at baseline to pre-dose at week 12 (fluticasone/formoterol 250/10μg vs. formoterol), ii) the mean change in FEV(1) from morning pre-dose at baseline to 2h post-dose at week 12 (fluticasone/formoterol 250/10μg vs. fluticasone), and iii) the number of patients who discontinued prematurely due to lack of treatment efficacy (fluticasone/formoterol 250/10μg vs. placebo). The secondary endpoints included measures of lung function, disease control, and asthma symptoms. Safety was assessed based on adverse events, vital signs, and clinical laboratory evaluations. Overall, 395 (70.9%) patients completed the study. Fluticasone/formoterol 250/10μg b.i.d. was superior to the individual components and placebo for all three co-primary endpoints and demonstrated numerically greater improvements for multiple secondary efficacy analyses. Fluticasone/formoterol combination therapy had a good safety profile over the 12 weeks. Fluticasone/formoterol combination therapy will provide clinicians with an efficacious alternative treatment option for patients with moderate-to-severe asthma.

Lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone

Salmeterol, a long-acting β2-adrenergic receptor agonist used for the treatment of asthma and chronic obstructive pulmonary disease, has an adverse effects profile that is similar to that of salbutamol and other β2-agonists. We report a sympathomimetic syndrome with metabolic acidosis and hyperlactatemia after intentional inhalation of salmeterol in a suicide attempt. A 16-year-old female patient was admitted to the emergency department approximately 2 hours after having inhaled 60 puffs of a combination of salmeterol xinafoate 25 μg and fluticasone propionate 50 μg. She presented in an anxious state with complaints of palpitations and chest pain. The electrocardiogram demonstrated sinus tachycardia and ST-segment depression in the inferior and anterolateral leads. Laboratory findings showed hypokalemia, hypophosphatemia, and lactic acidosis. Cardiac troponin I and creatine kinase MB remained within the normal range. Treatment was supportive and included intravenous fluids and cautious potassium supplementation. The next day, electrocardiographic and laboratory findings returned to normal. We hypothesize that stimulation of β2-adrenergic receptors by inhalation of salmeterol caused this patient's lactic acidosis. This observation is consistent with the hypothesis that the hyperlactatemia observed during asthma attacks is due in part to the administration of high doses of β2-agonists. Salmeterol overdose by inhalation appears to be sufficient to cause lactic acidosis.

Age and Risks of FDA-Approved Long-Acting β2-adrenergic Receptor Agonists

AW McMahon, MS Levenson, BW McEvoy, AD Mosholder, D Murphy. Pediatrics. 2011;128(5):e1147–1154 This meta-analysis investigated the relationship between adverse asthma-related events and long-acting β2-adrenergic receptor antagonists (LABAs) among different age groups. Previous studies have suggested a correlation between increased risk and LABA use that seems most pronounced among children. The meta-analysis included 110 trials with 60 954 patients, 9807 of whom were children between the ages of 4 and 18 years. All trials included were randomized controlled trials of LABAs for the treatment of asthma. Only Food and Drug Administration (FDA)-approved LABA products …

The Influence of Treatment with Formoterol, Formoterol with Tiotropium, Formoterol with Inhaled Glucocorticosteroid and Tiotropium on Lung Functions, Tolerance of Exercise and Simple, Morning Everyday Activities in Patients with Chronic Obstructive Pulmonary Disease (COPD)

Bronchodilators - long-acting b2-adrenergic agonists (formoterol and salmeterol) and a long-acting antimuscarinic drug (tiotropium), are the main drugs applied in symptomatic treatment of COPD. In patients with COPD, dyspnea is frequently associated with simple everyday activities. Two questionnaires have been published recently as a means of assessing the patients' ability to perform morning activities and symptoms. Dynamic hyperinflation is the pathophysiological disorder responsible for dyspnea and decreased exercise tolerance in COPD. Formoterol is faster than salmeterol in diminishing air-trapping. It has been shown that treatment with formoterol and tiotropium in COPD patients improves FEV(1), FVC, IC, symptoms score and quality of life in comparison with tiotropium applied alone. Among LABA and inhaled glucocorticosteroids combinations, those containing formoterol have a more beneficial effect on the ability to perform simple morning activities (budesonide/formoterol was better than fluticasone/salmeterol). Beclomethasone/formoterol - 400/24 mcg/die, in comparison with fluticasone/salmeterol - 500/100 mcg/die significantly reduced air-trapping and dyspnea in COPD patients. The comparison of budesonide/formoterol - 400/12 mcg 2 x die with beclomethasone/ /formoterol - 200/12 mcg 2 x die has shown similar influence of both combinations on FEV(1), dyspnea, 6-minute walk test, symptoms score and quality of life. The addition of budesonide and formoterol combination to tiotropium gives further benefits: reduces number of exacerbations, improves FEV1, symptoms score and performance of simple morning routines. Doctors should pay more attention to symptoms and limitations in simple activities in the morning and adequately adjust the treatment.

Effect of β2-adrenergic receptor gene (ADRB2) 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response

BackgroundEvidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR) of the β2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.MethodsIn 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed.ResultsPoly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype.ConclusionsThe extensive sequence diversity present in the poly-C repeat region of the ADRB2 3′UTR did not predict therapeutic response to ICS/LABA therapy.

Acute Effects of Salmeterol and Fluticasone Propionate Alone and in Combination on Airway Blood Flow in Patients With Asthma

The airway contains airway smooth muscle and airway vascular smooth muscle. The acute effects of inhaled long-acting β(2)-adrenergic agonists (LABAs) alone, or in combination with an inhaled glucocorticoid (ICS), on airway smooth muscle tone in asthma are known; however, to the best of our knowledge, their effect on airway vascular smooth muscle tone has not been investigated previously. The objective of this study was to investigate the immediate effects of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma. Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 μg), fluticasone propionate (250 μg), salmeterol/fluticasone propionate (50/250 μg), or placebo; Qaw was measured before and serially for 240 min after drug administration. Mean Qaw increased after salmeterol and salmeterol/fluticasone propionate, with peaks at 60 min of 34% and 40%, respectively, and returned to baseline by 240 min after inhalation. Fluticasone propionate alone caused a transient decrease in mean Qaw. The maximal changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone propionate, and -19% for fluticasone propionate (P < .05 vs placebo for all). The LABA salmeterol has an acute vasodilator action on the airway of subjects with stable asthma. The addition of fluticasone propionate, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone propionate potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway. ClinicalTrials.gov; No.: NCT01231230; URL: www.clinicaltrials.gov.

Age and Risks of FDA-Approved Long-Acting β2-Adrenergic Receptor Agonists

Age and Risks of FDA-Approved Long-Acting β2-Adrenergic Receptor Agonists

Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma

Omalizumab is a humanized monoclonal anti-IgE antibody approved in 2005 by the European Medicine Agency (EMA) for the treatment of severe persistent allergic asthma, which remains inadequately controlled despite optimal therapy with high doses of inhaled corticosteroids and long-acting β₂-adrenergic agonists. Within this context, the present observational study refers to 16 patients currently treated with omalizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti- IgE therapy was started in the period included between March 2007 and February 2010, thus lasting at least 10 months. After 40 weeks of add-on treatment with omalizumab, very relevant decreases were detected, in comparison with pre-treatment mean (± standard deviation) values, in monthly exacerbation numbers (from 1.1 ± 0.6 to 0.2 ± 0.4; p < 0.01) and oral corticosteroid consumption (from 22.6 ± 5.0 to 1.2 ± 2.9 mg/day of prednisone; p < 0.01). These changes were associated with stable improvements in lung function, expressed as increases of both FEV1 (from 53.6 ± 14.6% to 77.0 ± 14.9% of predicted values; p < 0.01) and FEV1/FVC ratio (from 56.3 ± 9.5% to 65.8 ± 9.2%; p < 0.01). Moreover, in 5 patients who persistently had increased numbers of eosinophils (mean ± SD: 15.9 ± 8.0% of total WBC count; absolute number: 1,588.0 ± 956.9/μl) despite a long-lasting therapy with inhaled and systemic corticosteroids, the peripheral counts of these cells decreased down to near normal levels (mean ± SD: 6.3 ± 2.3% of total WBC count; absolute number: 462.0 ± 262.3/μl) after 16 weeks of treatment with omalizumab. Therefore, this descriptive evaluation confirms the efficacy of add-on omalizumab therapy in selected patients with exacerbation-prone, chronic allergic uncontrolled asthma, requiring a continuous intake of oral corticosteroids.

Budesonide/Formoterol Pressurized Metered-Dose Inhaler versus Budesonide: A Randomized Controlled Trial in Black Patients with Asthma

Objective. Concerns exist that responses to long-acting β2-adrenergic agonists in black patients may differ from the general population. The efficacy and safety of budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (BUD DPI) were evaluated in adolescent and adult black asthma patients. Methods. This 12-week, randomized, double-blind, multicenter, phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma, previously receiving medium- to high-dose inhaled corticosteroid. After 2 weeks on BUD 90 μg × 2 inhalations twice daily (bid), symptomatic patients were randomized to BUD/FM 160/4.5 μg × 2 inhalations bid or BUD 180 μg × 2 inhalations bid. Results. Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean (primary variable) was greater with BUD/FM versus BUD (0.16 vs. 0.07 L; p = .008); this effect was also observed at weeks 2, 6, and end of treatment (p ≤ .032). Greater improvements (p < .001) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks (morning: 25.34 vs. 7.53 L/minute, respectively; evening: 21.61 vs. 7.67 L/minute, respectively); greater improvements in daily asthma symptom score and rescue medication use were also observed (p ≤ .039). Both treatments were well tolerated, with similar safety profiles. Conclusions. In this population of black asthma patients, BUD/FM pMDI resulted in greater improvements in pulmonary function and asthma control versus BUD DPI, with similar safety profiles.

Age and Risks of FDA-Approved Long-Acting β2-Adrenergic Receptor Agonists

To determine the risk, by age group, of serious asthma-related events with long-acting β(2)-adrenergic receptor agonists marketed in the United States for asthma. The US Food and Drug Administration performed a meta-analysis of controlled clinical trials comparing the risk of LABA use with no LABA use for patients 4 to 11, 12 to 17, 18 to 64, and older than 64 years old. The effects of age on a composite of asthma-related deaths, intubations, and hospitalizations (asthma composite index) and the effects of concomitant inhaled corticosteroid (ICS) use were analyzed. One hundred ten trials with 60 954 patients were included in the meta-analysis. The composite event incidence difference for all ages was 6.3 events per 1000 patient-years (95% confidence interval [CI]: 2.2-10.3) for using LABAs compared with not using LABAs. The largest incidence difference was observed for the 4- to 11-year age group (30.4 events per 1000 patient-years [95% CI: 5.7-55.1]). Differences according to age were statistically significant (P = .020). Results for the subgroup of patients with concomitant ICS use (n = 36 210) were similar to the overall results; with assigned ICSs (n = 15 192), the incidence difference was 0.4 events per 1000 patient-years (95% CI: -3.8 to 4.6), and there was no statistically significant difference according to age group. The excess of serious asthma-related events attributable to LABAs was greatest among children. Additional data are needed to assess risks of LABA use for children with simultaneous ICS use.

Bronchodilator Combination Therapy for the Treatment of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and its prevalence is rising worldwide. Bronchodilators remain the cornerstone of COPD treatment, especially inhaled β2-adrenergic receptor agonists and inhaled anticholinergics. Long-acting bronchodilators are considered more effective and convenient than short-acting bronchodilators for the maintenance treatment in patients with moderate to very severe COPD. There are currently 3 long-acting inhaled bronchodilators available in the United States: the β2-adrenergic receptor agonists formoterol and salmeterol, and the anticholinergic, tiotropium. All 3 long-acting bronchodilators have been shown to be effective and well tolerated for the management of patients with stable COPD in clinical studies. The combination of β2-adrenergic receptor agonists and anticholinergics has been shown to provide superior bronchodilatory effect than either agent alone, possibly because of different mechanisms of action of these agents. The current treatment guidelines recommend the use of one or more long-acting bronchodilators for patients with moderate to severe stable COPD who remain symptomatic with single-agent bronchodilator therapy. The objective of this article is to review clinical data on combined bronchodilator therapy with β2-adrenergic receptor agonists and anticholinergics in patients with COPD.

Assessment of Bronchodilator Responsiveness after Methacholine-Induced Bronchoconstriction

Spirometry is the only objective clinical tool available to physicians in the outpatient setting. Patient history is often unreliable and physical examinations are normal when the child doesn't show symptoms. For that reason, spirometry is currently considered essential for asthma diagnosis, severity stratification, and monitoring asthma control in children ≥5 years.1 Bronchodilator responsiveness (BDR), which is an improvement of forced expiratory volume in 1 second after inhalation of β2-agonists, has traditionally been the definition of asthma2 and has recently been reported to reflect biomarkers of eosinophilic inflammation,3,4 bronchial hyperreactivity,5,6 and airway remodeling.7 BDR has also been regarded as a good predictor of response to therapy,8 a marker for long-term prognosis,5,9 and an important component in defining asthma phenotypes.10,11 Since BDR is usually measured by changes in airflow before and after administration of β2-agonists, it is influenced by the baseline airway tone. If the airways at baseline were fully dilated by asthma treatment, airflow would barely increase. Moreover, asthmatic children usually show prebronchodilator spirometry within the normal range, regardless of their symptom-based severity of asthma control.12 Consequently, impaired β-adrenergic responsiveness, which plays a role in the pathogenesis of asthma, is rarely evident, especially when the children are taking controller medications. In 1999, Hancox et al.13 first introduced the 'challenge-rescue' technique to assess BDR. They measured BDR after bronchoconstriction induced by methacholine, because β2-receptor responsiveness was easier to demonstrate under conditions of increased bronchomotor tone. The challenge-rescue model has been widely used14,15 because it has consistently provided evidence of bronchodilator tolerance, whereas previous studies of stable asthma have not. Moreover, it has obvious clinical relevance; asthmatics usually take β-agonists to relieve symptoms caused by bronchoconstriction.16 Despite the usefulness of this approach, some problems exist in terms of data interpretation. BDR to salbutamol is confounded by spontaneous recovery from the bronchoconstricting effects of methacholine. Although spontaneous recovery for 15 minutes after bronchoconstriction is rare,13 other factors that facilitate recovery from bronchoconstriction may be displayed as an enhanced responsiveness to bronchodilators. On the other hand, geometric factors, such as airway mucus plugging and mucosal edema, might not be discerned from bronchodilator tolerance. Therefore, care must be taken when analyzing BDR data obtained from the challenge-rescue technique. In the present issue of Allergy, Asthma, & Immunology Research, Bauer et al.17 assessed BDR using the challenge-rescue technique and evaluated the clinical factors that may affect BDR in children with mild to moderate asthma. Though the interpretation of the data is complicated, the results provide interesting information. Asthmatic patients with atopy and/or eosinophilia displayed higher BDR as compared with that of non-atopic and/or non-eosinophilic patients, which provides indirect evidence that BDR may be a marker for inflammation. While admitting that bronchoconstriction induced by methacholine may not exactly reflect clinical exacerbation of asthma, the results raise the possibility that more frequent or severe asthma attacks would occur in non-atopic and/or non-eosinophilic children with asthma. Another interesting finding is that no apparent differences were observed among the medication subgroups. Since inhaled long-acting β2 adrenergic agonists or corticosteroids were discontinued seven days prior to testing in this study, it is likely that tolerance to β-agonists would no longer be a concern when medications are withheld for more than seven days. Assessment of BDR following induced bronchoconstriction may be a useful tool for evaluating impaired β-adrenergic responsiveness, which plays a key role in the pathogenesis of asthma. Further studies are needed to extend the application of BDR assessment to determine management options in asthmatic patients.

Treatment of Persistent Asthma With Symbicort® (Budesonide/Formoterol Inhalation Aerosol): An Inhaled Corticosteroid and Long-Acting β2-Adrenergic Agonist in One Pressurized Metered-Dose Inhaler

Objective. Budesonide/formoterol inhalation aerosol (Symbicort® AstraZeneca, Wilmington, Delaware) is an inhaled corticosteroid (ICS) and long-acting β2-adrenergic agonist (LABA) combination administered twice daily via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) approved in the United States for the long-term maintenance treatment of persistent asthma in patients ≥12 years of age whose asthma cannot be controlled by an ICS alone. The objective was to review efficacy, safety, and pharmacogenetic data on budesonide/formoterol pMDI in the treatment of persistent asthma. Methods. The authors searched PubMed and respiratory meeting databases to identify asthma studies of budesonide/formoterol pMDI. Studies involving traditional and patient-reported outcomes, safety, tolerability, or pharmacogenetics were included. Results. In two 12-week pivotal trials in adolescents and adults, treatment with budesonide/formoterol pMDI 160/4.5 μg × 2 inhalations (320/9 μg) twice daily for moderate to severe persistent asthma or 80/4.5 μg × 2 inhalations (160/9 μg) twice daily for mild to moderate persistent asthma, demonstrated greater efficacy and similar tolerability compared with placebo and the same nominal dose of its monocomponents. Comparisons with formoterol dry powder inhaler (DPI) for predose forced expiratory volume in one second (FEV1) and with budesonide pMDI for 12-hour mean postdose FEV1 demonstrated the anti-inflammatory and bronchodilatory contributions of budesonide and formoterol, respectively. Evaluations of patient-reported outcomes, including asthma-specific quality of life and treatment satisfaction, further supported the clinical benefits of budesonide/formoterol pMDI. In a 52-week tolerability study of patients aged ≥12 years, budesonide/formoterol pMDI was delivered at up to double the maximum dose (640/18 μg twice daily) and demonstrated a safety profile similar to that of budesonide (640 μg twice daily), with no unexpected pattern of abnormalities. Additional studies reported that budesonide/formoterol pMDI 320/9 μg twice daily and fluticasone propionate/salmeterol DPI 250/50 μg twice daily have similar efficacy and tolerability, with significantly more patients achieving ≥15% improvement in FEV1 within 15 minutes with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI. Moreover, inheritance of the Gly16Arg polymorphism of the β2-adrenergic receptor does not appear to affect clinical outcomes with budesonide/formoterol pMDI. Conclusion. Budesonide/formoterol pMDI administered twice daily is effective and generally well tolerated in patients whose asthma is not well controlled on ICS alone.