Long-acting Β2-adrenoceptor Agonist Research Articles

Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis.

Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as “biological asthma risk genes.” Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, IL6R is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment.

Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies.

Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC).Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma.Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium-dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk 0.61-0.80) and increasing trough forced expiratory volume in 1 s (from +33 to +114 mL). Triple combination therapies including HD ICS were superior (p<0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns.This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

Correction to "Long-Acting β2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR".

Correction to "Long-Acting β2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR".

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study

Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 μg, 150 μg) or medium-dose MF-IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. Novartis Pharmaceuticals.

Pharmacology and Therapeutics of Bronchodilators Revisited.

Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of β 2-adrenoceptors (β 2-ARs) on airway smooth muscle with β 2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting β 2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.

Fluticasone propionate/salmeterol (Wixela® Inhub®) dry-powder inhaler in asthma and COPD: a profile of its use in the USA

Wixela® Inhub® is the first therapeutically equivalent, substitutable generic version of Advair Diskus® (fluticasone propionate/salmeterol) approved for the treatment of asthma and chronic obstructive pulmonary disease (COPD) in the USA. Wixela Inhub combines the inhaled corticosteroid fluticasone propionate and the long-acting β2-adrenoceptor agonist salmeterol in a single dry-powder inhaler. Each drug has a different mechanism of action, targeting different and complementary aspects of the pathophysiology of asthma and COPD. The in vitro performance of Wixela Inhub is comparable to that of Advair Diskus at all dosage strengths (100/50 μg, 250/50 μg, and 500/50 μg) and all flow rates. Wixela Inhub has pharmacokinetic and pulmonary therapeutic bioequivalence to Advair Diskus, which has well-established efficacy, tolerability, and safety profiles. The Wixela Inhub device is robust and easy to use without instruction. All three dosage strengths of Wixela Inhub will be offered at a wholesale acquisition cost of up to 70% less than Advair Diskus and the authorized generic equivalent.

Fluticasone propionate/formoterol fumarate in children aged ≥ 5 years with asthma: a profile of its use

The fluticasone propionate/formoterol fumarate (hereafter fluticasone/formoterol) 50/5 µg pressurized metered-dose inhaler (pMDI) [Flutiform®] is a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting β2-adrenoceptor agonist (LABA) for the regular treatment of asthma where regular use of an ICS and a LABA combination product is appropriate. In the EU, the fluticasone/formoterol 50/5 µg pMDI is recommended for use in adults, adolescents and children aged ≥ 5 years, with the latter being a recent expansion of the indicated population and the focus of this review. Fluticasone/formoterol 50/5 µg, administered as two actuations (i.e. 100/10 µg) twice daily, provided benefit over fluticasone propionate 100 µg twice daily and was noninferior to fluticasone/salmeterol 100/50 µg twice daily, in improving lung function in patients aged 5 to < 12 or 4–12 years in randomized trials. Fluticasone/formoterol was generally similar to each of these comparator pMDI regimens in terms of asthma exacerbation rates and patient-reported measures and was generally well tolerated, with no evidence of clinically meaningful systemic adverse effects over up to 36 weeks of treatment. Longer-term data would be of interest.

Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients.

The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (LAMA) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/LAMA combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with olodaterol 5 μg is the best combination option: tiotropium/olodaterol 5/5 μg has the same efficacy profile of tiotropium/olodaterol 5/2 μg, and it is less effective than tiotropium/olodaterol 5/10 μg. Furthermore, tiotropium/olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the LAMA.

Efficacy and cardiovascular safety profile of dual bronchodilation therapy in chronic obstructive pulmonary disease: A bidimensional comparative analysis across fixed-dose combinations

Despite several long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) are currently approved for the treatment of chronic obstructive pulmonary disease (COPD), there are limited findings concerning the direct comparison across the different LABA/LAMA FDCs. The aim of this study was to compare the efficacy/safety profile of approved LABA/LAMA FDCs in COPD. A network meta-analysis was performed by linking the efficacy (forced expiratory volume in 1 s, St’ George Respiratory Questionnaire, transitional dyspnea index) and safety (cardiovascular serious adverse events) outcomes resulting from randomized controlled trials that directly compared LABA/LAMA FDCs with placebo and/or each other. The Surface Under the Cumulative Ranking Curve Analysis (SUCRA) was performed for each single outcome (SUCRA: 1 = best, 0 = worst). The combined efficacy/safety profile was reported via the novel Improved Bidimensional SUCRA score (IBiS: the higher the value the better the treatment). Data obtained from 12,136 COPD patients (79.50% LABA/LAMA FDCs vs. placebo; 20.50% direct comparison between different LABA/LAMA FDCs) were extracted from 22 studies published between 2013 and 2019. The IBiS score showed the following rank of efficacy/safety profile: tiotropium/olodaterol 5/5 μg (area 66.83%) » glycopyrronium/indacaterol 15.6/27.5 μg (area 40.43%) > umeclidinium/vilanterol 62.5/25 μg (area 30.48%) ≈ aclidinium/formoterol 400/12 μg (area 28.44%) > glycopyrronium/indacaterol 50/110 μg (area 19.95%) > glycopyrronium/formoterol 14.4/9.6 μg (area 11.50%). Each available LABA/LAMA FDC has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD. Head-to-head studies aimed to assess the impact of different LABA/LAMA FDCs on the risk of COPD exacerbation are needed to further improve the information provided by this quantitative synthesis.

The once-daily fixed-dose combination of olodaterol and tiotropium in the management of COPD: current evidence and future prospects.

Long-acting bronchodilators are the cornerstone of pharmacologic treatment of chronic obstructive pulmonary disease (COPD). Spiolto® or Stiolto® is a fixed-dose combination (FDC) containing two long-acting bronchodilators, the long-acting muscarinic receptor antagonist tiotropium (TIO) and the long-acting β2-adrenoceptor agonist olodaterol (OLO), formulated in the Respimat® Soft Mist™ inhaler. A total of 13 large, multicentre studies of up to 52 weeks’ duration have documented its efficacy in more than 15,000 patients with COPD. TIO/OLO 5/5 µg FDC significantly increases pulmonary function compared with placebo and its respective constituent mono-components TIO 5 µg and OLO 5 µg. TIO/OLO 5/5 µg also results in statistically and clinically significant improvements in patient-reported outcomes, such as dyspnoea, use of rescue medication, and health status. Addition of OLO 5 µg to TIO 5 µg reduces the rate of moderate-to-severe exacerbations by approximately 10%. Compared with placebo and TIO 5 µg, TIO/OLO 5/5 µg significantly improves exercise capacity (e.g. endurance time) and physical activity, the latter increase being reached by a unique combination behavioural modification intervention, dual bronchodilatation and exercise training. Overall, the likelihood for patients to experience a clinically significant benefit is higher with TIO/OLO 5/5 µg than with its constituent mono-components, which usually yield smaller improvements which do not always reach statistical significance, compared with baseline or placebo. This supports the early introduction of TIO/OLO 5/5 µg in the management of patients with symptomatic COPD.

Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting β2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan.

BackgroundA large body of evidence suggests that long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) combinations induce a strong synergistic bronchodilatory effect in human isolated airways. Moreover, a recent post hoc analysis demonstrated clinical synergism between LABAs and LAMAs, which induces a synergistic improvement not only in lung function but also in dyspnea in COPD patients.AimThe aim of this study is to examine the baseline factors related to improvement in lung function or clinical symptoms that results from the administration of LAMA or LAMA/LABA and to compare the differences in improvement in lung function or clinical symptoms between LAMA and LAMA/LABA.MethodsAmong 829 patients with COPD who were treated with LAMA or LAMA/LABA in our hospital, 112 patients (aged 40–89 years) matched the criteria. Of these 112 patients, 71 received LAMA (LAMA group) and 41 received LAMA/LABA (LAMA/LABA group) as the initial treatment. Various examination results such as lung function test values, symptom change, and frequency of exacerbations were compared between the two groups.ResultsCompared with the monotherapy, the combination therapy significantly improved the FEV1, inspiratory capacity (IC), and total COPD assessment test (CAT) scores. Comparing the improvement in each domain of the CAT produced by the combination therapy with that of the monotherapy, larger improvements were found for the domains of going out and sleeping. The frequency of exacerbations during the 24 weeks was significantly lower in the combination therapy group than in the LAMA monotherapy group (P=0.034). Although no relationship was found between improvement in FEV1 and any pretreatment factors in the LAMA/LABA group, the improvement in the CAT score was strongly related to the baseline CAT score, smoking index, and air trapping index (P-value <1×10−4).ConclusionIn this study of clinical practice, we found that LAMA/LABA combination therapy improved the clinical symptoms of COPD and IC and that the effects of the combination therapy were consistent with those observed in previous clinical trials.

Olodaterol for the treatment of chronic obstructive pulmonary disease: a narrative review

ABSTRACTIntroduction: Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy.Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD.Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death.LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea.

A Single Institution Retrospective Study of the Clinical Efficacy of Tiotropium Respimat in Never-Smoking Elderly Asthmatics with Irreversible Airflow Limitation.

In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium RespimatⓇ (Tio-Res) in symptomatic, never-smoking, elderly asthmatics with irreversible airflow limitation despite the use of high-dose inhaled corticosteroids (ICS) plus long-acting β2-adrenoceptor agonists (LABA). The Asthma Control Test™ (ACT), pulmonary function tests, morning and evening peak flow (mPEF, ePEF, respectively, evaluated with an ASSESS® peak flow meter), and respiratory impedance (assessed with MostGraph®) were measured before and after a minimum of one year of Tio-Res 5 µg/day administration. Sixteen symptomatic, never-smoking asthmatics, aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA, were analyzed. All patients were female (mean age, 81.6 years). Tio-Res led to statistically significant improvements in the total ACT score (19.9 to 23.6), FVC and FEV1 (1.97 to 2.14 L and 1.13 to 1.23 L, respectively), and mPEF and ePEF (229.9 to 253.8 L/min and 259.8 to 277.4 L/min, respectively). Tio-Res also resulted in statistically significant improvements in respiratory resistance at 5 Hz (R5), respiratory resistance at 20 Hz (R20), R5-R20, low-frequency reactant indices at 5 Hz (X5), resonant frequency (Fres) and low-frequency reactance area (ALX). Our retrospective study suggests that Tio-Res improves symptoms, pulmonary function, and respiratory impedance in symptomatic asthmatics aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA.

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects of β2-Adrenoceptor Agonists.

The contribution of gene expression changes to the adverse and therapeutic effects of β2-adrenoceptor agonists in asthma was investigated using human airway epithelial cells as a therapeutically relevant target. Operational model-fitting established that the long-acting β2-adrenoceptor agonists (LABA) indacaterol, salmeterol, formoterol, and picumeterol were full agonists on BEAS-2B cells transfected with a cAMP-response element reporter but differed in efficacy (indacaterol ≥ formoterol > salmeterol ≥ picumeterol). The transcriptomic signature of indacaterol in BEAS-2B cells identified 180, 368, 252, and 10 genes that were differentially expressed (>1.5- to <0.67-fold) after 1-, 2-, 6-, and 18-hour of exposure, respectively. Many upregulated genes (e.g., AREG, BDNF, CCL20, CXCL2, EDN1, IL6, IL15, IL20) encode proteins with proinflammatory activity and are annotated by several, enriched gene ontology (GO) terms, including cellular response to interleukin-1, cytokine activity, and positive regulation of neutrophil chemotaxis The general enriched GO term extracellular space was also associated with indacaterol-induced genes, and many of those, including CRISPLD2, DMBT1, GAS1, and SOCS3, have putative anti-inflammatory, antibacterial, and/or antiviral activity. Numerous indacaterol-regulated genes were also induced or repressed in BEAS-2B cells and human primary bronchial epithelial cells by the low efficacy LABA salmeterol, indicating that this genomic effect was neither unique to indacaterol nor restricted to the BEAS-2B airway epithelial cell line. Collectively, these data suggest that the consequences of inhaling a β2-adrenoceptor agonist may be complex and involve widespread changes in gene expression. We propose that this genomic effect represents a generally unappreciated mechanism that may contribute to the adverse and therapeutic actions of β2-adrenoceptor agonists in asthma.

Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects.

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting β2-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients’ daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.

Abediterol (LAS100977), an inhaled long-acting β2-adrenoceptor agonist, has a fast association rate and long residence time at receptor

This study describes the association rate and residence time of abediterol, a novel long-acting β2-adrenoceptor agonist (LABA) in Phase II development for treatment of asthma and COPD, in comparison with indacaterol, olodaterol, vilanterol and salmeterol, for both human β1- and β2-adrenoceptors.Abediterol association and dissociation rates were monitored directly by using its tritiated form. Moreover, association was determined indirectly using experimental Ki and koff obtained from assays performed with unlabelled compound. Dissociation was also studied indirectly by measuring the association rate of 3H-CGP12177 to beta adrenoceptors previously occupied by unlabelled compounds.Abediterol shows a fast association for the β2-adrenoceptor (kon 1.4 × 107 ± 1.8 × 106M−1min−1) while its dissociation rate is between 30 and 64 times slower than that of the reference LABA compounds tested, with a residence time of 91.3 ± 13.3min (measured directly) and 185.5 ± 7.5min (measured indirectly). Abediterol shows kinetic selectivity for the β2- over the β1-adrenoceptor, with a dissociation rate from the β1-adrenoceptor similar to the other LABA compounds tested.In conclusion, abediterol is a potent LABA with a fast association rate and a long residence time at β2-adrenoceptors. These data are in agreement with the onset and duration of action of abediterol shown in humans.

Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD.

Inhaled corticosteroids (ICSs) treatment combined with long-acting β2-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia. There are indications that this association is stronger for fluticasone propionate than for budesonide. We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy. Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%–78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide. We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs. These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid.

Budesonide/formoterol Easyhaler®: a guide to its use in asthma and chronic obstructive pulmonary disease

Budesonide/formoterol Easyhaler® is an easy-to-use, convenient, effective and well tolerated option for the treatment of patients with asthma or chronic obstructive pulmonary disease (COPD). This device-metered dry powder inhaler (DPI) contains both the inhaled corticosteroid budesonide and the long-acting β2-adrenoceptor agonist formoterol. The use of the budesonide/formoterol in a single inhaler is well established as an effective and well tolerated option for the treatment of asthma and COPD. Budesonide/formoterol Easyhaler® is therapeutically equivalent to budesonide/formoterol Turbuhaler®, and is indicated for use as maintenance therapy in adults, adolescents and children aged ≥6 years with asthma, maintenance and reliever therapy in adults with asthma and for the symptomatic treatment of adults with severe COPD and a history of repeated exacerbations.

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

The GTPase-accelerating protein, regulator of G-protein signalling 2 (RGS2) reduces signalling from G-protein-coupled receptors (GPCRs) that signal via Gαq. In humans, RGS2 expression is up-regulated by inhaled corticosteroids (ICSs) and long-acting β2-adrenoceptor agonists (LABAs) such that synergy is produced in combination. This may contribute to the superior clinical efficacy of ICS/LABA therapy in asthma relative to ICS alone. In a murine model of house dust mite (HDM)-induced airways inflammation, three weeks of intranasal HDM (25 μg, 3×/week) reduced lung function and induced granulocytic airways inflammation. Compared to wild type animals, Rgs2-/- mice showed airways hyperresponsiveness (increased airways resistance and reduced compliance). While HDM increased pulmonary inflammation observed on hematoxylin and eosin-stained sections, there was no difference between wild type and Rgs2-/- animals. HDM-induced mucus hypersecretion was also unaffected by RGS2 deficiency. However, inflammatory cell counts in the bronchoalveolar lavage fluid of Rgs2-/- animals were significantly increased (57%) compared to wild type animals and this correlated with increased granulocyte (neutrophil and eosinophil) numbers. Likewise, cytokine and chemokine (IL4, IL17, IL5, LIF, IL6, CSF3, CXCLl, CXCL10 and CXCL11) release was increased by HDM exposure. Compared to wild type, Rgs2-/- animals showed a trend towards increased expression for many cytokines/chemokines, with CCL3, CCL11, CXCL9 and CXCL10 being significantly enhanced. As RGS2 expression was unaffected by HDM exposure, these data indicate that RGS2 exerts tonic bronchoprotection in HDM-induced airways inflammation. Modest anti-inflammatory and anti-remodelling roles for RGS2 are also suggested. If translatable to humans, therapies that maximize RGS2 expression may prove advantageous.

Long-acting β2-agonists promote glucocorticoid-mediated repression of NF-κB by enhancing expression of the feedback regulator TNFAIP3.

Glucocorticoids, or corticosteroids, are effective treatments for many chronic inflammatory diseases, and in mild/moderate asthma, long-acting β2-adrenoceptor agonists (LABAs) enhance the efficacy of inhaled corticosteroids (ICSs) more than increasing the ICS dose. In human bronchial epithelial, BEAS-2B, cells, expression of TNFα-induced protein-3 (TNFAIP3), or A20, a dual-ubiquitin ligase that provides feedback inhibition of NF-κB, was induced by budesonide, an ICS, and formoterol, a LABA, and was further enhanced by budesonide-formoterol combination. The proinflammatory cytokine TNF induced TNFAIP3 and TNF expression. Whereas subsequent budesonide treatment enhanced TNF-induced TNFAIP3 and reduced TNF expression, formoterol amplified these differential effects. In primary human airway smooth muscle cells, TNFAIP3 expression was induced by TNF. This was largely unaffected by budesonide but was acutely enhanced by budesonide-formoterol combination. In BEAS-2B cells, TNF recruited RELA, the main NF-κB transactivating subunit, to a 3' region of the TNF gene. RELA binding was reduced by budesonide, was further reduced by formoterol cotreatment, and was associated with reduced RNA polymerase II recruitment to the TNF gene. This is consistent with reduced TNF expression. TNFAIP3 knockdown enhanced TNF expression in the presence of TNF, TNF plus budesonide, and TNF plus budesonide-formoterol combination and confirms feedback inhibition. A luciferase reporter containing the TNF 3' RELA binding region recapitulated TNF inducibility and was inhibited by an IκB kinase inhibitor and TNFAIP3 overexpression. Repression of reporter activity by budesonide was increased by formoterol and involved TNFAIP3. Thus LABAs may improve the anti-inflammatory properties of ICSs by augmenting TNFAIP3 expression to negatively regulate NF-κB.