Long-acting Β2-adrenergic Agonist Research Articles

Long-Acting β2 Adrenergic Receptor Agonist Ameliorates Imiquimod-Induced Psoriasis-Like Skin Lesion by Regulating Keratinocyte Proliferation and Apoptosis.

Psoriasis is a chronic inflammatory disease that affects approximately 1%–5% of the population worldwide. Considering frequent relapse, adverse drug reactions, and large costs of treatment, it is urgent to identify new medications for psoriasis. Keratinocytes play an essential role during psoriasis development, and they express high levels of β2-Adrenergic receptor (β2-AR), which increases intracellular cAMP levels when activated. Increased level of cAMP is associated with the inhibition of epidermal cell proliferation. In the present study, we observed the effect of salmeterol, a long-acting β2-AR agonist, on the proliferation and apoptosis of keratinocytes as well as imiquimod-induced psoriasis-like skin lesions in mice. As phosphodiesterase 4 (PDE4) inhibitors increases intracellular cAMP concentration by inhibiting its inactivation, we further explored the synergetic effect of a PDE4 inhibitor and salmeterol on psoriasis-like skin lesions in mice. Our results indicated that salmeterol effectively inhibited the proliferation of HaCaT cells induced by TNF-α and serum, and this effect was accompanied by significantly increased apoptosis and CREB phosphorylation, which were reversed by the PKA inhibitor, H89. Salmeterol ameliorated imiquimod-induced psoriasis-like skin lesions in mice, but salmeterol combined with a PDE4 inhibitor had no synergetic effect in improving skin lesions in mice. Of note, the synergistic effects of anti-proliferation and induction of apoptosis in HaCaT cells appeared by inhibiting ERK signaling. In summary, salmeterol, a long-acting β2-AR agonist, alleviates the severity of psoriasis via inhibiting the proliferation and promoting apoptosis of keratinocytes, partially by activating the cAMP/PKA signaling pathway.

Impact of immunotherapy with autologous activated T-lymphocytes on clinical parameters and quality of life in patients with allergic bronchial asthma

Aim. To assess the impact of autologous activated T-lymphocyte immunotherapy on clinical parameters and quality of life in patients with allergic bronchial asthma (BA) in comparison with patients with allergic BA who received standard therapy.Materials and methods. A non-randomized, pilot study included 19 patients with allergic BA of moderate severity (7 men and 12 women aged 23–61 years, average age – 38.5 ± 4.3 years) who received the T-cell vaccine (n = 12) and standard therapy with inhaled glucocorticoids, short- and long-acting β2-adrenergic agonists (n = 7). After signing an informed consent, the patients were subcutaneously injected with autologous activated T-lymphocytes with a frequency of 4 injections 1 time / week, and then 6 injections 1 time / month. The research methods included asthma control measurement according to the ACQ-5 questionnaire and quality of life assessment according to the AQLQ(S) questionnaire. Clinical data were collected during lung function tests and by measuring the total immunoglobulin E (IgE) level.Results. In the course of the study, the immunotherapy was well tolerated, no systemic adverse reactions were noted. The treatment approach in the patients who received the T-cell vaccine resulted in significant improvement of asthma control parameters (according to the ACQ-5 questionnaire) and parameters of the patients’ quality of life (according to the AQLQ(S) questionnaire) within all 4 categories. Besides, their lung function improved by the end of treatment, and the total IgE level decreased. No significant changes in these parameters were observed during the follow-up in patients who received standard therapy. The study was conducted before immunotherapy, after 2 months (after 5 injections), and after 7 months (after 10 injections).Conclusion. Evaluation of the impact of immunotherapy with autologous activated T-lymphocytes on the clinical parameters and quality of life in patients with BA indicates effectiveness of treatment in patients with allergic BA.

The role and place of bronchodilative and anti-inflammatory therapy for chronic obstructive pulmonary disease in patients with newly detected respiratory tuberculosis

Introduction. The relevance of the problem of managing patients with concomitant infectious and non-infectious pathology is beyond doubt, a third of patients suffering from tuberculosis have COPD as a comorbidity, which re-quires adequate therapy to improve the prognosis of the patient’s treatment as a whole. Objective: to evaluate the effectiveness of various options for bronchodilatory and anti-inflammatory therapy in patients with newly diag-nosed pulmonary tuberculosis secondary to COPD. Ma-terials and methods. A simple prospective comparative study included 210 patients divided into 3 groups: 124 pa-tients with TB+COPD; 46 patients with drug-susceptible TB (TB DS)+COPD; 40 patients with multidrug-resistant TB+COPD. The selection of treatment regimens was car-ried out with an assessment of the best efficiency, includ-ing inhaled glucocorticosteroid in combination with a long-acting β2-adrenergic agonist (IGCS/LABA) into the treatment regimens in the intensive phase of the course of TB. Duration of the follow-up is 6–9 months with assess-ment of X-ray pattern, bacterial shedding and smear neg-ativity as criteria for curing TB. Results. In patients with TB+COPD, the best effect of minimizing the severity of broncho-obstructive syndrome (reduction of dyspnea ac-cording to mMRC and CAT test) was obtained during ther-apy with a combination drug (long-acting anticholinergic drug and long-acting β2-agonist (LAAC/LABA) with good tolerance. In patients with TB DS+COPD, positive dynam-ics in the reduction of the severity of cough, dyspnea, CAT test was obtained in the ICS group in comparison with patients taking short-acting anticholinergic drugs (SDA). For patients with MDR+TB COPD, ICS/LABA showed the optimal effect on the severity of COPD symptoms. Against the background of taking IGCS/LABA in both groups, there was an increase in the number of patients achiev-ing smear negativity, cessation of bacterial shedding and closure of decay cavities, in comparison with the CAAC group, without any side effects. Conclusion. Adequate correction of broncho-obstructive syndrome in patients with COPD, including the use of bronchodilators (LABA) and anti-inflammatory drugs (IGCS) in the intensive phase of treatment of newly diagnosed pulmonary TB due to the main and additional effects of drugs, can improve the effectiveness of tuberculosis therapy

Pediatric asthma: The REGAP consensus

Asthma is one of the main chronic diseases in childhood, due to its high prevalence and its social and health costs. This document is a summary of a consensus guideline approved by 6 Spanish pediatric societies related to asthma and endorsed by the Spanish Pediatric Association. Asthma is easily identifiable by clinical criteria in most patients. Spirometry and other tests are helpful for diagnosis, especially in atypical cases. Asthma exacerbation is a frequent manifestation of the disease and must be identified and treated promptly. When asthma symptoms are frequent and the quality of life is affected, maintenance treatment must be instituted to achieve control of the disease. Low-dose inhaled corticosteroids are effective and safe for long-term use. Education of the patient with asthma is essential for good control. The main reason for poor asthma control is non-compliance with treatment, either due to its erratic and insufficient administration, or due to poor application technique of inhaled drugs. If control is not obtained despite adequate treatment, the diagnosis must be reconsidered, as well as the factors or comorbidities that make control difficult. Other drugs can be added to avoid high doses of inhaled corticosteroids, notably montelukast or long-acting β2 adrenergic agonists. Severe or difficult-to-control asthma, which does not respond to the usual treatments, should be managed in specialized units.

Asma en pediatría: consenso REGAP

Asthma is one of the main chronic diseases in childhood, due to its high prevalence and its social and health costs. This document is a summary of a consensus guideline approved by 6 Spanish pediatric societies related to asthma and endorsed by the Spanish Pediatric Association. Asthma is easily identifiable by clinical criteria in most patients. Spirometry and other tests are helpful for diagnosis, especially in atypical cases. Asthma exacerbation is a frequent manifestation of the disease and must be identified and treated promptly. When asthma symptoms are frequent and the quality of life is affected, maintenance treatment must be instituted to achieve control of the disease. Low-dose inhaled corticosteroids are effective and safe for long-term use. Education of the patient with asthma is essential for good control. The main reason for poor asthma control is non-compliance with treatment, either due to its erratic and insufficient administration, or due to poor application technique of inhaled drugs. If control is not obtained despite adequate treatment, the diagnosis must be reconsidered, as well as the factors or comorbidities that make control difficult. Other drugs can be added to avoid high doses of inhaled corticosteroids, notably montelukast or long-acting β2 adrenergic agonists. Severe or difficult-to-control asthma, which does not respond to the usual treatments, should be managed in specialized units.

Once-daily fluticasone furoate/vilanterol combination versus twice-daily budesonide/formoterol combination in the treatment of controlled stable asthma: a randomized crossover trial.

IntroductionFluticasone furoate (FF)/vilanterol (VI) dry powder inhaler (DPI) is the only once-daily maintenance inhaled corticosteroid (ICS)/long-acting β2 adrenergic agonist (LABA) combination for asthma. We aimed to compare the clinical effects of once-daily FF/VI and twice-daily budesonide (BUD)/formoterol (FM) DPI in patients with controlled stable asthma.MethodsWe performed a randomized crossover trial in which stable asthmatic patients controlled on ICS/LABA received 8 weeks of FF/VI (100/25 μg 1 puff once-daily) or BUD/FM (160/4.5 μg 2 puffs twice-daily) DPI treatment. After a 4–8-week washout period, patients received another crossover treatment for 8 weeks. We assessed pulmonary function, the 5-item version asthma control questionnaire (ACQ5), the asthma control test (ACT), and fractional exhaled nitric oxide (FeNO) at baseline and after 8 weeks of treatment (week 8). As the primary outcome was change in force expiratory volume in 1 s (FEV1) between baseline and week 8, we evaluated the incidence of asthma exacerbation and adherence barrier questionnaire (Ask-12) at week 8.ResultsTwenty-three patients were initially enrolled in this study; however, one patient had to be excluded. The FF/VI DPI treatment group showed a similar magnitude of change in FEV1 between baseline and week 8 as the BUD/FM DPI treatment group. In addition, there were no significant differences in pulmonary function tests, ACQ5 scores, ACT scores, and FeNO between baseline and week 8 in both groups. Although the incidence of exacerbation did not differ between groups, the Ask-12 score in the FF/VI DPI group was significantly lower than that in the BUD/FM DPI group.ConclusionsThe present study indicates that once-daily FF/VI DPI is not inferior to twice-daily BUD/FM DPI in clinical effect and more likely to improve inconvenience and forgetfulness in inhalation adherence barriers for stable asthma control therapy. Once-daily FF/VI DPI may be an effective alternative for asthma maintenance treatment.

Mitochondrial biogenesis induced by the β2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury

Podocytes have limited ability to recover from injury. Here, we demonstrate that increased mitochondrial biogenesis, to meet the metabolic and energy demand of a cell, accelerates podocyte recovery from injury. Analysis of events induced during podocyte injury and recovery showed marked upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a transcriptional co-activator of mitochondrial biogenesis, and key components of the mitochondrial electron transport chain. To evaluate our hypothesis that increasing mitochondrial biogenesis enhanced podocyte recovery from injury, we treated injured podocytes with formoterol, a potent, specific, and long-acting β2-adrenergic receptor agonist that induces mitochondrial biogenesis invitro and invivo. Formoterol increased mitochondrial biogenesis and restored mitochondrial morphology and the injury-induced changes to the organization of the actin cytoskeleton in podocytes. Importantly, β2-adrenergic receptors were found to be present on podocyte membranes. Their knockdown attenuated formoterol-induced mitochondrial biogenesis. To determine the potential clinical relevance of these findings, mouse models of acute nephrotoxic serum nephritis and chronic (Adriamycin [doxorubicin]) glomerulopathy were used. Mice were treated with formoterol post-injury when glomerular dysfunction was established. Strikingly, formoterol accelerated the recovery of glomerular function by reducing proteinuria and ameliorating kidney pathology. Furthermore, formoterol treatment reduced cellular apoptosis and increased the expression of the mitochondrial biogenesis marker PGC-1α and multiple electron transport chain proteins. Thus, our results support β2-adrenergic receptors as novel therapeutic targets and formoterol as a therapeutic compound for treating podocytopathies.

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250μg of fluticasone twice daily for 2weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P=.62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P=.81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P=.86) and 0.8 for placebo (P=.15; P=.31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P=.43) and 1.02 for placebo (P=.84; P=.44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.

The Cholinergic Pathways in Inflammation: A Potential Pharmacotherapeutic Target for COPD.

In COPD, the activity of the cholinergic system is increased, which is one of the reasons for the airflow limitation caused by the contraction of airway smooth muscles. Therefore, blocking the contractive actions with anticholinergics is a useful therapeutic intervention to reduce the airflow limitation. In addition to the effects of bronchoconstriction and mucus secretion, accumulating evidence from animal models of COPD suggest acetylcholine has a role in inflammation. Experiments using muscarinic M3-receptor deficient mice or M3 selective antagonists revealed that M3-receptors on parenchymal cells, but not on hematopoietic cells, are involved in the pro-inflammatory effect of acetylcholine. Recently, combinations of long-acting β2 adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have become available for COPD treatment. These dual long-acting bronchodilators may have synergistic anti-inflammatory effects because stimulation of β2 adrenergic receptors induces inhibitory effects in inflammatory cells via a different signaling pathway from that by antagonizing M3-receptor, though these anti-inflammatory effects have not been clearly demonstrated in COPD patients. In contrast to the pro-inflammatory effects by ACh via muscarinic receptors, it has been demonstrated that the cholinergic anti-inflammatory pathway, which involves the parasympathetic nervous systems, regulates excessive inflammatory responses to protect organs during tissue injury and infection. Stimulation of acetylcholine via the α7 nicotinic acetylcholine receptor (α7nAChR) exerts inhibitory effects on leukocytes including macrophages and type 2 innate lymphoid cells. Although it remains unclear whether the inhibitory effects of acetylcholine via α7nAChR in inflammatory cells can regulate inflammation in COPD, neuroimmune interactions including the cholinergic anti-inflammatory pathway might serve as potential therapeutic targets.

Real-world Clinical Characteristics, Treatment Patterns, and Exacerbations in US Patients With Asthma Newly Treated With Omalizumab

PurposeThe objective of this study was to examine patient characteristics, treatment patterns, and exacerbations among patients with asthma newly treated with omalizumab. MethodsData for this study were obtained from administrative claims and medical records. The index date was the date of the first claim for omalizumab. All patients had ≥12 months of continuous health plan eligibility before and after the index date. Demographic and clinical characteristics were obtained 12 months before the index date. Treatment patterns of asthma medications, including omalizumab, and asthma exacerbations were evaluated in the preindex and postindex periods. FindingsThe study included 1564 patients. Asthma-related medication use decreased from the preindex to the postindex periods (oral corticosteroids, 83.3%–66.4%, P < 0.001; inhaled corticosteroids [ICSs], 33.1%–26.8%, P < 0.001; long-acting β2-adrenergic agonists [LABAs], 6.6%–5.2%, P = 0.009; ICS-LABA combination, 69.3%–64.3%, P < 0.001; leukotriene modifiers, 67.8%–59.7%, P < 0.001). The proportion of patients with any asthma exacerbations decreased by 33.6% (66.6%–44.2%, P < 0.001). Notably, the relative decreases in hospitalization and emergency department exacerbations were 79.3% and 72.2%, respectively. A total of 930 patients (59.5%) discontinued omalizumab treatment during the entire postindex period (maximum, 3400 days [approximately 9 years]), with 353 (38.0%) restarting omalizumab treatment. ImplicationsIn this real-world analysis, patients newly initiating omalizumab therapy for allergic asthma used fewer concomitant asthma medications, while experiencing significant reductions in asthma exacerbations, especially hospitalization- and emergency department–specific exacerbations, from pre– to post–omalizumab treatment initiation periods.

Fluticasone furoate/umeclidinium/vilanterol dry-powder inhaler in COPD: a profile of its use in the EU

Fluticasone furoate/umeclidinium/vilanterol (TrelegyTM), an orally inhaled dry powder formulation administered via the Ellipta® device, is the first fixed-dose, single-inhalation, once-daily triple therapy approved for the treatment of chronic obstructive pulmonary disease (COPD). It combines three major classes of COPD medications, namely an inhaled corticosteroid (fluticasone furoate), a long-acting muscarinic antagonist (umeclidinium) and a long-acting β2-adrenergic agonist (vilanterol), in a single inhaler. The triple therapy is effective and well tolerated in patients with advanced COPD. In the FULFIL trial, furoate/umeclidinium/vilanterol provided significant and sustained improvements in lung function and health-related quality of life, as well as reducing the risk of COPD exacerbation and improving other patient-reported outcomes, relative to twice-daily budesonide/formoterol. In a non-inferiority trial, fluticasone furoate/umeclidinium/vilanterol administered using a single Ellipta® inhaler was noninferior to the same nominal dosages of furoate/vilanterol + umeclidinium administered using two Ellipta® inhalers with respect to changes in lung function, with comparable between-treatment improvements in other endpoints. Fluticasone furoate/umeclidinium/vilanterol offers the convenience of a single-inhalation once-daily treatment, which may potentially reduce inhalation errors and improve treatment adherence in some patients.

Salmeterol, a Long-Acting β2-Adrenergic Receptor Agonist, Inhibits Macrophage Activation by Lipopolysaccharide From Porphyromonas gingivalis.

Salmeterol is a long-acting β2-adrenergic receptor agonist used to treat chronic obstructive pulmonary disease. The authors of the current study previously showed that preincubation of primary microglial-enriched cells with salmeterol could inhibit the inflammatory response induced by Escherichia coli lipopolysaccharide (LPS), a Toll-like receptor (TLR)-4 agonist. In this study, the authors sought to determine if salmeterol had a similar inhibitory effect on the inflammatory response of the murine macrophage cell line RAW264.7 and human monocyte THP-1 to LPS from Porphyromonas gingivalis (PgLPS), an oral microbe implicated in the pathogenesis of periodontal disease. RAW264.7 and THP-1 cells were pretreated with salmeterol, followed by PgLPS, and monitored for production of inflammatory mediators by enzyme-linked immunosorbent assay. The nitric oxide concentration and nuclear factor-kappa B (NF-κB) activity were measured by Griess method and secretory alkaline phosphatase reporter activity assay, respectively. Reverse-transcriptase polymerase chain reaction and immunoblot analysis were used to measure messenger RNA and protein levels. Nuclear translocation of NF-κB was detected by immunofluorescence. Pretreatment with salmeterol significantly inhibited production of proinflammatory mediators by RAW264.7 and THP-1 cells. Salmeterol downregulated PgLPS-mediated phosphorylation of the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase but not p38 mitogen-activated protein kinases (MAPKs). Salmeterol also attenuated activation of NF-κB via inhibition of nuclear translocation of p65-NFκB, the transcriptional activity of NF-κB and IκBα phosphorylation. Salmeterol can significantly inhibit activation of macrophage-mediated inflammation by PgLPS, suggesting that use of salmeterol may be an effective treatment in inhibiting or lessening the inflammatory response mediated through TLR pathway activation.

Exacerbations in COPD patients treated with Inhaled Corticosteroids/Long-acting β2 agonists combinations, switching to another combination drugs or inhaler device: A “real – world” study

This study investigates the effects of switching to different devices of the same active substance or between different active substances, in patients with Chronic Obstructive Pulmonary Disease (COPD) treated with Inhaled Corticosteroids (ICS) plus Long-acting β2-adrenergic agonists (LABAs) in terms of incidence of exacerbations. A retrospective cohort analysis, based on administrative databases of 3 Italian Local Health Units, was conducted. Patients with at least one prescription of a fixed dose combination of ICS/LABA from 1 January 2009 to 31 December 2011 were included. The index-date was defined as the earliest date within the inclusion period in which the patient had the first switch of drug or device (switchers) or the first prescription of ICS/LABA for patients continuing with the same treatment (non-switchers). Patients were observed until 31 December 2012. Propensity score matching was performed to check for cofounding effects. COPD exacerbations were defined as COPD-related hospitalization and prescription of corticosteroids and antibiotics. Number of: hospitalizations for COPD, oral corticosteroids and antibiotics prescriptions were analyzed using Poisson regression models. After matching, 1,759 patients per arm were analyzed. No statistically significant difference was found between study groups’. Incidence Rate Ratio in favor of non-switcher patients, as compared to switcher patients, was 1.41 (95% CI: 1.10–1.80) for number of hospitalizations, 1.05 (95% CI: 1.11–1.09) and 1.02 (95% CI: 0.96–1.09) for number of oral corticosteroids and antibiotics prescriptions, respectively. Our findings showed that switching to different devices of the same active substance or among different active substances in COPD patients treated with a fixed dose combination of ICS/LABA can lead to an higher likelihood of exacerbation COPD related rates than those who did not switch. Considering the study’s limitations, further studies are needed in order to confirm and enhance the generalizability of our findings.

How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease. Several studies have documented that long-acting bronchodilators can reduce exacerbation rate and/or severity, and others have shown that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroid combinations in patients at low and high risk for these events. In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single long-acting bronchodilators or LABA/inhaled corticosteroids in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary clearance, and symptom severity may all contribute to decreasing exacerbations. Although preclinical studies suggest LABAs and LAMAs have antiinflammatory effects, such effects have not been demonstrated yet in patients with chronic obstructive pulmonary disease.

Combined inhaled corticosteroid and long-acting β2-adrenergic agonist therapy for noncystic fibrosis bronchiectasis with airflow limitation

Combined inhaled corticosteroid and long-acting β2-adrenergic agonist therapy for noncystic fibrosis bronchiectasis with airflow limitation

The burden of chronic obstructive pulmonary disease associated with maintenance monotherapy in the UK.

BackgroundThis study characterized a cohort of chronic obstructive pulmonary disease (COPD) patients on maintenance bronchodilator monotherapy for ≥6 months to establish their disease burden, measured by health care utilization.MethodsData were extracted from the UK Clinical Practice Research Datalink and linked to Hospital Episode Statistics. The monotherapy period spanned the first prescription of a long-acting β2-adrenergic agonist or a long-acting muscarinic antagonist until the end of the study (December 31, 2013) or until step up to dual/triple therapy, for example, addition of another long-acting bronchodilator, an inhaled corticosteroid, or both. A minimum of four consecutive prescriptions and 6 months on continuous monotherapy were required. Patients <50 years old at first COPD diagnosis or with another significant respiratory disease before starting monotherapy were excluded. Disease burden was evaluated by measuring patients’ rate of face-to-face interactions with a health care professional (HCP), COPD-related exacerbations, hospitalizations, and referrals.ResultsA cohort of 8,811 COPD patients (95% Global initiative for chronic Obstructive Lung Disease stage A/B) on maintenance monotherapy was identified between 2002 and 2013; 45% of these patients were still on monotherapy by the end of the study. Median time from first COPD diagnosis to first monotherapy prescription was 56 days, while the median time on maintenance bronchodilator monotherapy was 2 years. The median number of prescriptions was 14. On average, patients had 15 HCP interactions per year, and one in ten patients experienced a COPD exacerbation (N=8,811). One in 50 patients were hospitalized for COPD per year (n=4,848).ConclusionThe average monotherapy-treated patient had a higher than average HCP interaction rate. We also identified a large cohort of patients who were stepped up to triple therapy despite a low rate of exacerbations. The use of the new class of long-acting muscarinic antagonist/long-acting β2-adrenergic agonist fixed-dose combinations may provide a useful step-up treatment option in such monotherapy patients, before the use of inhaled corticosteroids.

Combined inhaled corticosteroid and long-acting β2-adrenergic agonist therapy for noncystic fibrosis bronchiectasis with airflow limitation: An observational study.

There is presently no clear evidence on the effect of combined treatment for non-cystic fibrosis (non-CF) bronchiectasis with inhaled corticosteroid (ICS) and long-acting β2-adrenergic agonist (LABA). The objective of this study is to assess the efficacy and safety of salmeterol-fluticasone combined inhaled therapy for non-CF bronchiectasis with airflow limitation. An observational study was performed in 120 non-CF bronchiectasis patients diagnosed by high-resolution computed tomography (HRCT) scanning of the chest. Patients received either routine therapy or salmeterol-fluticasone (100/500 μg daily) combined inhaled therapy on the basis of routine therapy. Clinical symptoms, health-related quality of life (HRQL), lung function, short-acting β2-adrenergic agonist (SABA) use, and safety were monitored throughout the study. OF the 120 subjects, 60 received combined inhaled therapy and 60 received routine therapy. Compared to the control group, the combined inhaled therapy group showed significant improvement in their clinical symptom scores (-2.21 vs. -0.31, P = 0.002) and a reduction in number of weekly SABA usage (-4.2 vs. 0.1, P < 0.01). In addition, patients in the inhaled therapy group achieved a significant improvement in HRQL based on mMRC (-1.51 vs. -0.31, P < 0.005) and SGRQ (-7.83 vs. -2.16, P < 0.01) scoring accompanied with no severe adverse events. There were fewer exacerbation frequencies in the combined inhaled therapy group over the 12 months of treatment compared to the control group (1 [0-2] vs. 2 [1-4], P = 0.017). Furthermore, stratified analysis indicated that combined inhaled therapy partially improve lung function for patients for whom it is severely impaired and those with pseudomonas aeruginosa isolated. Our results show that salmeterol-fluticasone combined inhaled therapy should be effective and safe for non-CF bronchiectasis patients especially for those patients with poor lung function or pseudomonas aeruginosa isolated.

Step-down treatment from medium-dosage of budesonide/formoterol in controlled asthma

BackgroundThe stepping down of asthma treatment can be considered when asthma symptoms have been well controlled with inhaled corticosteroids (ICSs)/long-acting β2 adrenergic agonists (LABAs). However, few data are available comparing the efficacy between two step-down strategies, to reduce ICS/LABA dose or to withdraw LABA continuing ICS, in well-controlled asthmatics. MethodsThis was a prospective multicentre randomized, two-arm, controlled study. Ninety-one asthmatic patients controlled by budesonide/formoterol combination (BFC) 320/9 μg twice daily were assigned to 2 stepping-down treatments as follows: the BFC group; BUD/FM 160/4.5 μg twice daily, and the ICS group; ICS (budesonide 400 μg twice daily or equivalent dose of ICS) without LABA, and followed for 12 weeks. The primary outcome was the incidence of asthma exacerbations. Asthma control, pulmonary function tests, and fraction of exhaled nitric oxide (FeNO) were evaluated at the beginning and end of the period. ResultsThe incidence of exacerbations was 16.3% in the BFC groups and 12.5% in the ICS group, which were not different between the groups (p = 0.766). No significant differences were found in QOL score and FeNO between 0 week and 12 week in the both group. FEV1 and FEV1 percentage of the predicted value were lower at week 12 than at week 0 in the ICS group, but not in the BFC group. ConclusionsThe two step-down strategies for 12 weeks have equal acceptability in well-controlled asthmatics treated with medium-dose of BFC, however, withdrawal of LABA may have potential risk to deteriorate FEV1. Clinical trial registrationThis study was registered to UMIN-CTR (http://www.umin.ac.jp/ctr/), UMIN000010333.

Effect of formoterol, a long-acting β2-adrenergic agonist, on muscle strength and power output, metabolism, and fatigue during maximal sprinting in men.

The aim was to investigate the effect of the long-acting β2-adrenergic agonist formoterol on muscle strength and power output, muscle metabolism, and phosphorylation of CaMKII Thr(287) and FXYD1 during maximal sprinting. In a double-blind crossover study, 13 males [V̇o2 max: 45.0 ± 0.2 (means ± SE) ml·min(-1)·kg(-1)] performed a 30-s cycle ergometer sprint after inhalation of either 54 μg of formoterol (FOR) or placebo (PLA). Before and after the sprint, muscle biopsies were collected from vastus lateralis and maximal voluntary contraction (MVC), and contractile properties of quadriceps were measured. Oxygen uptake was measured during the sprint. During the sprint, peak power, mean power, and end power were 4.6 ± 0.8, 3.9 ± 1.1, and 9.5 ± 3.2% higher (P < 0.05) in FOR than in PLA, respectively. Net rates of glycogenolysis and glycolysis were 45.7 ± 21.0 and 28.5 ± 13.4% higher (P < 0.05) in FOR than in PLA, respectively, and the decrease in ATP content was lower (P < 0.05) in FOR than in PLA (3.7 ± 1.5 vs. 8.0 ± 1.6 mmol/kg dry weight). There was no difference in breakdown of phosphocreatine and oxygen uptake between treatments. Before and after the sprint, MVC and peak twitch force were higher (P < 0.05) in FOR than in PLA. No differences were observed in phosphorylation of CaMKII Thr(287) and FXYD1 between treatments before the sprint, whereas phosphorylation of CaMKII Thr(287) and FXYD1 was greater (P < 0.05) in FOR than in PLA after the sprint. In conclusion, formoterol-induced enhancement in power output during maximal sprinting is associated with increased rates of glycogenolysis and glycolysis that may counteract development of fatigue.

Combinación a dosis fija de fluticasona propionato/formoterol fumarato para el tratamiento del asma: una revisión de la farmacología, eficacia y tolerabilidad

The fixed-dose combination fluticasone propionate/formoterol (FPF) is a novel combination of a widely known and used inhaled glucocorticoid (IGC) and a long-acting β2-adrenergic agonist (LABA), available for the first time in a single device. This fixed-dose combination of FPF has a demonstrated efficacy and safety profile in clinical trials compared with its individual components and other fixed-dose combinations of IGC/LABA and is indicated for the treatment of persistent asthma in adults and adolescents. FPF is available in a wide range of doses that can adequately cover the therapeutic steps recommended by treatment guidelines, constituting a fixed-dose combination of GCI/LABA that is effective, rapid, well tolerated and with a reasonable acquisition cost. Various assessment agencies of the Spanish Autonomous Communities consider this combination to be an appropriate alternative therapy for asthma in the primary care setting.