Efficacy of salmeterol and magnesium isoglycyrrhizinate combination treatment in rats with chronic obstructive pulmonary disease.

The most classic treatment recommended in the current chronic obstructive pulmonary disease (COPD) guidelines is glucocorticoid and ß2 receptor agonist combination, such as salmeterol xinafoate and fluticasone propionate (Sal/Flu), causing many adverse reactions due to hormones. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating chronic inflammation, contributing to its structure is similar to steroidal anti-inflammatory drugs. In this study, we successfully established COPD rat model by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction, as characterized by lung function decline. We discovered that salmeterol xinafoate/MgIG combination could alleviated lung inflammation infiltration, airway wall thickness (AWT) and the secretion of bronchial mucin MUC5AC of COPD rats more than salmeterol xinafoate, MgIG, or salmeterol xinafoate and fluticasone propionate treatment did, as well as reduced inflammatory cells (white blood cells, neutrophils and lymphocytes) accumulation in bronchoalveolar lavage fluid and decreased TNF-α, IL-6 and IL-1ß production in the serum of COPD rats. Finally, we found that Moreover, the mechanism involved might be related to the suppression of JAK/STAT signaling pathway. Overall, our studies suggested that MgIG might be a potential alternative adjuvant drug for fluticasone propionate for the clinical treatment of patients with COPD.

Comparative Efficacy of Umeclidinium/Vilanterol Versus Other Bronchodilators for the Treatment of Chronic Obstructive Pulmonary Disease: A Network Meta-Analysis.

INTRODUCTION: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD. METHODS: A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented. RESULTS: The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 µg, glycopyrronium 50 µg, glycopyrronium 18 µg, tiotropium 18 µg and salmeterol 50 µg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation. CONCLUSION: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

Bronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting ß₂-agonists (LABAs), which can be used on their own or combined (LAMA/LABAs). Only a few clinical trials have compared different LAMA/LABA combinations with each other, so it is unclear which LAMA/LABA combination provides the greatest benefits for patients.In this study, we used network meta-analysis to compare a LAMA/LABA combination medicine called umeclidinium and vilanterol (UMEC/VI) with other LAMAs and LABAs used alone or in combination to treat patients with COPD. Network meta-analysis is a way of comparing two or more medicines by analysing data from many studies. We systematically searched for evidence from clinical trials in adult patients with COPD that were at least 8 weeks long and that compared LAMA/LABA combinations with a LAMA, a LABA, or another LAMA/LABA combination. We analysed data from 49 clinical trials that met these criteria.We found that patients treated with UMEC/VI had better lung function than patients treated with alternative LAMA/LABA combinations or bronchodilators used on their own. Patients treated with UMEC/VI had better quality of life than those receiving some other treatments, but not all. All the medicines we compared had similar side effects.Our results suggest that treating patients with COPD with UMEC/VI might improve their lung function and quality of life more than alternative bronchodilators.

A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.

Understanding the mechanism of SARS-CoV-2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID-19. These were deduced from the gene expression signature of SARS-CoV-2-infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral-host interactome. We also identified immuno-modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID-19 patients, based on the transcriptome of ACE2-overexpressing A549 cells. Experiments with Vero-E6 cells infected by SARS-CoV-2, as well as independent syncytia formation assays for probing ACE2/SARS-CoV-2 spike protein-mediated cell fusion using HEK293T and Calu-3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero-E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID-19.

Physiological Temperature Changes Fine-Tune ß 2- Adrenergic Receptor-Induced Cytosolic cAMP Accumulation.

Norepinephrine (NE) controls many vital body functions by activating adrenergic receptors (ARs). Average core body temperature (CBT) in mice is 37°C. Of note, CBT fluctuates between 36 and 38°C within 24 hours, but little is known about the effects of CBT changes on the pharmacodynamics of NE. Here, we used Peltier element-controlled incubators and challenged murine hypothalamic mHypoA -2/10 cells with temperature changes of ±1°C. We observed enhanced NE-induced activation of a cAMP-dependent luciferase reporter at 36 compared with 38°C. mRNA analysis and subtype specific antagonists revealed that NE activates ß 2- and ß 3-AR in mHypoA-2/10 cells. Agonist binding to the ß 2-AR was temperature insensitive, but measurements of cytosolic cAMP accumulation revealed an increase in efficacy of 45% ± 27% for NE and of 62% ± 33% for the ß 2-AR-selective agonist salmeterol at 36°C. When monitoring NE-promoted cAMP efflux, we observed an increase in the absolute efflux at 36°C. However, the ratio of exported to cytosolic accumulated cAMP is higher at 38°C. We also stimulated cells with NE at 37°C and measured cAMP degradation at 36 and 38°C afterward. We observed increased cAMP degradation at 38°C, indicating enhanced phosphodiesterase activity at higher temperatures. In line with these data, NE-induced activation of the thyreoliberin promoter was found to be enhanced at 36°C. Overall, we show that physiologic temperature changes fine-tune NE-induced cAMP signaling in hypothalamic cells via ß 2-AR by modulating cAMP degradation and the ratio of intra- and extracellular cAMP. SIGNIFICANCE STATEMENT: Increasing cytosolic cAMP levels by activation of G protein-coupled receptors (GPCR) such as the ß 2-adrenergic receptor (AR) is essential for many body functions. Changes in core body temperature are fundamental and universal factors of mammalian life. This study provides the first data linking physiologically relevant temperature fluctuations to ß 2-AR-induced cAMP signaling, highlighting a so far unappreciated role of body temperature as a modulator of the prototypic class A GPCR.

[Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease].

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease / 中国中药杂志

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

Real-world effectiveness of umeclidinium/vilanterol versus fluticasone propionate/salmeterol as initial maintenance therapy for chronic obstructive pulmonary disease (COPD): a retrospective cohort study.

Background and objective: Retrospective claims data in patients with chronic obstructive pulmonary disease (COPD) initiating maintenance therapy with inhaled fixed-dose combinations of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) versus inhaled corticosteroid (ICS)/LABA have not been reported. Methods: Retrospective observational study in a COPD-diagnosed population of commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years from a US health insurer database. Patients initiated umeclidinium/vilanterol (UMEC/VI [62.5/25 µg]) or fluticasone propionate/salmeterol (FP/SAL [250/50 µg]) between April 1, 2014 and August 31, 2016 (index date) and had 12 months continuous enrollment pre- and post-index. Exclusion criteria included an asthma diagnosis in the pre-index period/index date; ICS-, LABA-, or LAMA-containing therapy during the pre-index period; or pharmacy fills for both UMEC/VI and FP/SAL, multiple-inhaler triple therapy, a non-index therapy, or COPD exacerbation on the index date. Adherence (proportion of days covered [PDC] ≥80%) was modeled using weighted logistic regression following inverse probability of treatment weighting (IPTW). Weighted Kaplan-Meier and Cox proportional hazards regression following IPTW were performed for incidence of COPD exacerbation and escalation to multiple-inhaler triple therapy. Results: The study population included 5306 patients (1386 initiating UMEC/VI and 3920 initiating FP/SAL). Adjusted odds of adherence were 2.00 times greater among UMEC/VI than FP/SAL initiators (95% confidence interval [CI]: 1.62─2.46; P<0.001). The adjusted hazard ratio (HR) for first exacerbation was 0.87 (95% CI: 0.74-1.01; P=0.067) among UMEC/VI versus FP/SAL initiators. UMEC/VI initiators had 35% lower adjusted risk of escalation to multiple-inhaler triple therapy (HR 0.65; 95% CI: 0.47-0.89; P=0.008) versus FP/SAL. On-treatment, UMEC/VI initiators had an adjusted 30% reduced risk of a first moderate/severe COPD exacerbation (HR 0.70; 95% CI: 0.54-0.90; P=0.006). Conclusion: Patients with COPD initiating UMEC/VI had higher adherence and longer time before escalation to multiple-inhaler triple therapy than FP/SAL initiators.

A retrospective study of Yiqibushenhuoxue decoction for the treatment of chronic obstructive pulmonary disease.

This retrospective study aimed to investigate the effect and safety of Yiqibushenhuoxue decoction (YQBSHXD) for the treatment of chronic obstructive pulmonary disease (COPD).This study involved 120 cases of patients with COPD. These cases were assigned to an intervention group and a control group equally, 60 subjects each group. Patients in both groups underwent Salmeterol. In addition, the cases in the intervention group also received YQBSHXD. All cases received a total of 12 weeks treatment. The primary outcome of lung function was measured by forced expiratory volume in 1 second (FEV1), and FEV1/forced vital capacity (FVC). The secondary outcomes included severity of dyspnea on exertion, evaluated by 6-minute walk test (6MWT) with measurement of 6-minute walk distance (6MWD); and quality of life, assessed by the St. George's Respiratory Questionnaire (SGRQ). In addition, adverse events (AEs) were also recorded in this study. All outcome measurements were assessed before and after 12-week treatment.After 12-week treatment, cases in the intervention group underwent YQBSHXD did not show better outcome in lung function improvement, measured by the FEV1 (P = .11), and FEV1/FVC (P = .15), compared with those in the control group. However, YQBSHXD may help to alleviate the severity of dyspnea on exertion, as measured by 6MWD (P = .03), and to improve the quality of life, as assessed by the SGRQ (P < .01). Additionally, no significant differences in AEs were detected between the 2 groups.The results of this study showed that YQBSHXD may help to manage COPD after 12-week treatment, although the lung function has not been improved.

Characteristics and health care resource use of subjects with COPD in the year before initiating LAMA monotherapy or LAMA+LABA combination therapy: A U.S. database study.

PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting ß2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations. RESULTS: Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean±SD: 0.63±1.13 vs. 0.66±1.28), but the number of prescriptions was higher (mean±SD: 42.9±23.2 vs. 30.5±27.2). The LAMA+LABA cohort had higher short-acting inhaled ß2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean±SD: $3,320.40±4085.9 vs. $1,226.20±3602.9), although emergency department ($11.00±66.8 vs. $30.70±259.2) and outpatient visit ($39.60±163.1 vs. $41.70±424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts. CONCLUSION: In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment.

When Two Drugs Are Better than Three: Re-Modulating the Therapeutic Plan of a Chronic Obstructive Pulmonary Disease Patient.

We present the case of a 77-year-old man diagnosed with chronic obstructive pulmonary disease (COPD) stage D with emphysema phenotype and treated with triple therapy (salmeterol, fluticasone propionate, and tiotropium) for 1 year without relevant improvements in exertional dyspnea and disease impact. After switching to combination therapy with a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (indacaterol/glycopyrronium), we observed, in a 3-month period, a substantial reduction of the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) scores. Moreover, the patient reported a reduction of dynamic hyperinflation and an improvement of ventilatory response to exercise.

[Role of ICS/LABA on COPD treatment].

In the treatment of chronic obstructive pulmonary disease (COPD), bronchodilators such as long acting muscarinic antagonist (LAMA) and long acting ß agonist(LABA) play key roles for improving respiratory function and symptoms, and reducing risk of exacerbation. However, inhaled corticosteroid (ICS), a key medicine for bronchial asthma, is limitedly used in COPD treatment. Japanese Respiratory Society recommends to use ICS for severe COPD patients who have been frequently exacerbated, because previous clinical studies indicated that ICS reduces exacerbation in moderate to severe COPD patients. Asthma sometimes overlaps with COPD, and symptoms of those patients are not well controlled by the bronchodilation therapy alone. Therefore, ICS/LABA or ICS/LAMA should be prescribed to those overlapped patients. Concentration of exhaled nitrogen oxide and percentage of peripheral eosinophil may be good biomarkers for discriminating the COPD patients who have good response to ICS treatment.

Chinese Herbal Medicine and Salmeterol and Fluticasone Propionate for Chronic Obstructive Pulmonary Disease: Systematic Review and Network Meta-Analysis.

Among Chinese populations worldwide, Chinese herbal medicines (CHMs) are often used as an adjunct to pharmacotherapy in managing chronic obstructive pulmonary disease (COPD). However, the relative performance among different CHM is unknown.The aim of this study was to evaluate comparative effectiveness of different CHM when used with salmeterol and fluticasone propionate (SFP), compared with SFP alone.This study is a systematic review of randomized controlled trials (RCTs) with network meta-analyses (NMAs).Eight electronic databases were searched. Data from RCTs were extracted for random effect pairwise meta-analyses. Pooled relative risk (RR) with 95% confidence interval (CI) was used to quantify the impact of CHM and SFP on forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) scoring, and 6-Minute Walk Test (6MWT). NMA was used to explore the most effective CHM when used with SFP.Eleven RCTs (n = 925) assessing 11 different CHM were included. Result from pairwise meta-analyses indicated favorable, clinically relevant benefit of CHM and SFP on FEV1 [7 studies, pooled weighted mean difference (WMD) = 0.20 L, 95% CI: 0.06-0.34 L], SGRQ scoring (5 studies, pooled WMD = -4.99, 95% CI: -7.73 to -2.24), and 6MWT (3 studies, pooled WMD = 32.84 m, 95% CI: 18.26-47.42). Results from NMA showed no differences on the comparative effectiveness among CHM formulations for improving FEV1. For SGRQ, NMA suggested that Runfeijianpibushen decoction and Renshenbufei pills performed best. Use of CHM on top of SFP can provide clinically relevant benefit for COPD patients on FEV1 and SGRQ. Additional use of Runfeijianpibushen decoction and Renshenbufei pills showed better effect on improving SGRQ.Use of CHM and SFP may provide clinically relevant benefit for COPD patients on FEV1, SGRQ, and 6MWT. Use of different CHM formulae included in this NMA showed similar effect for increasing FEV1, while the additional use of Runfeijianpibushen formula and Renshenbufei Pills showed better effect on improving SGRQ. Well conducted, adequately powered trials are needed to confirm their effectiveness in the future.

ß2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. ß2-Adrenergic receptor agonists (ß2-agonists) activate PKA, and we hypothesized that ß2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting ß2-agonist salbutamol or the long-acting ß2-agonist salmeterol prior to stimulation with HDE. ß2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of ß2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure.

Budesonide/salmeterol in fixed-dose combination for the treatment of asthma.

Fixed dose combinations (FDC) of inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) are well established in asthma treatment. The budesonide/salmeterol (B/S) FDC is now about to reach the market. It is provided as powder in hard capsules of two strengths: 120/20µg and 240/20µg when expressed as delivered doses, equivalent to 150/25µg and 300/25µg when expressed as nominal doses. Its development involved 9 pharmacokinetic (320 subjects), 3 phase II (123 subjects) and 4 phase III (1206 patients with different asthma severity) studies. Delivery is effectuated via low resistance inhaler device, Axahaler®, generating also fine particles targeting the small airways. B/S safety, assessed in 1401 subjects, did not outline novel concerns specific for this FDC. In conclusion, the B/S dry powder FDC can be used for asthma treatment in adults not adequately controlled on ICS alone, or to maintain control of ICS/LABA treated patients, in whom switching to alternative FDC is indicated.

Glicopirrônio para o tratamento da síndrome de Swyer-James-Macleod / Glycopyrronium for the treatment of Swyer-James-Macleod syndrome

CONTEXTO: A Síndrome de Swyer-James-Macleod (SSJM) ou síndrome pulmonar hiperlucente unilateral é uma rara bronquiolite constritiva com obstrução do fluxo de ar e uma diminuição do número e diâmetro dos vasos pulmonares periféricas ipsilaterais. Esta síndrome é caracterizada por hiperlucência unilateral na radiografia de tórax, sendo que a tomografia computadorizada fornece informações adicionais úteis. A doença geralmente se apresenta com dispnéia, diminuição da tolerância ao exercício, tosse, hemoptise, e infecções pulmonares recorrentes. SSJM pode ser confundida com asma ou embolia pulmonar devido a sintomas semelhantes e podem resultar em terapia inapropriada. ). Pode se manifestar de duas formas: assintomática, sendo a maioria diagnosticada na fase adulta, quando o paciente se submete a exames radiológicos de rotina, e a forma sintomática, que é mais encontrada em crianças. Segundo a Classificação Internacional de Doenças 10 (CID-10) é classificada como um tipo de enfisema (J43) dentro do grupo de doenças respiratórias crônicas das vias inferiores. TECNOLOGIA: Glicopirrônio (Seebri®). PERGUNTA: Glicopirrônio é eficaz e seguro para o tratamento da síndrome de Swyer-James-Macleod? EVIDÊNCIAS: Não foram encontrados estudos específicos que avaliassem o uso de glicopirrônio para o tratamento da Síndrome de Swyer-James-Macleod. Foram selecionadas três revisões sistemáticas que avaliaram glicopirrônio para DPOC. No primeiro estudo foi demonstrado que glicopirrônio apresenta resultados semelhantes a outros antagonistas muscarínicos de longa duração (LAMA), como o tiotrópio, para os desfechos de eficácia e qualidade de vida. No segundo estudo, verificou-se que o uso de glicopirrônio em associação com um agonista ß2 de longa duração (indacaterol) é mais eficaz do que o uso desses medicamentos em monoterapia e mais seguro quando comparado a esquemas que utilizam corticoides, quando em monoterapia ou associado a indacaterol. Por fim, o último estudo demonstrou por meio de comparações indiretas que antagonistas muscarínicos apresentam eficácia comparável, especialmente em 12 semanas, a dos agonistas ß2 de longa duração. CONCLUSÕES: A SSJM é uma condição rara e o seu tratamento ainda não é bem estabelecido na literatura. Broncodilatadores são utilizados para tratar os sintomas da doença, dentre os quais está o glicopirrônio. Os resultados das revisões sistemáticas demonstraram que glicopirrônio não apresenta diferenças estatisticamentes significantes para tiotrópio e outros LAMA e para agonistas ß2 de longa duração (LABA), incluindo salmeterol e formoterol que estão disponíveis no SUS para DPOC e asma. Entretanto, o uso associado de glicopirrônio a um agonista ß2 de longa duração (indacaterol) demonstrou melhores resultados do que a monoterapia. Como limitação, ressalta-se que os pacientes avaliados não eram portadores de SSJM, mas de DPOC em geral.

Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease.

BACKGROUND: Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear. OBJECTIVES: To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015. SELECTION CRITERIA: We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. MAIN RESULTS: This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies). AUTHORS' CONCLUSIONS: The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis.

BACKGROUND: Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers. METHODS: A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework. RESULTS: A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 µg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: -14.2, 42.3]), SGRQ total score (0.18 [-1.28, 1.63]), TDI focal score (-0.30 [-0.73, 0.13]), and rescue medication use (0.02 [-0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [-25.3, 159.4]), SGRQ total score (-0.11 [-1.84, 1.61]), and TDI focal score (0.58 [-0.33, 1.50]); and compared with formoterol plus TIO 18 µg on SGRQ total score (-0.68 [-1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks. CONCLUSION: UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial.

BACKGROUND: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting ß2 agonist (LABA). METHODS: This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone. RESULTS: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively. CONCLUSIONS: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP. TRIAL REGISTRATION NUMBER: NCT01513460.

[Efficacy on chronic obstructive pulmonary disease at stable stage treated with cutting method and western medication].

OBJECTIVE: To compare the difference in clinical efficacy on chronic obstructive pulmonary disease (COPD) at stable stage in the patients among the combined therapy of cutting method and western medication (combined therapy), simple cutting method and simple western medication. METHODS: One hundred and twenty cases of COPD were randomized into three groups, 40 cases in each one. In the cutting method group, for excessive phlegm pattern/syndrome, Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1) and Yuji (LU 10) were selected as the main acupoints, and Lieque (LU 7) and Pianli (LI 6) were as the supplementary acupoints. For the pattern/syndrome of failure to consolidate kidney primary, Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4) and Yuji (LU 10) were selected as main acupoints, and Jueyinshu (BL 14) and Zusanli (ST 36) were as the supplementary acupoint. Three acupoints were selected alternatively in each treatment and the cutting method was applied once every 10 days. Three treatments made one session. Two sessions of treatment were required. In the western medication group, salbutamol sulfate aerosol, one press (200 µg/press) was used each night, as well as salmeterol xinafoate and fluticasone propionate powder for inhalation, one inhalation each night. The treatment of 1 month made one session. Two sessions were required. In the combined therapy group, the cutting method and western medication were applied in combination. The results of clinical symptom score, lung function test, arterial blood gas analysis, degree of inflation as well as clinical efficacy were observed before and after treatment in each group. RESULTS: Except the degree of lung inflation, the clinical symptom score, indices of lung function test, partial pressure of arterial blood gas (PaO2) and partial pressure of carbon dioxide (PaCO2) were all obviously improved after treatment as compared with those before treatment in each group (all P<0.05). They were apparently improved after treatment in the combined therapy group and the cutting method group as compared with those in the western medication group (all P<0.05). The total effective rate was 77.5% (31/40) in the combined therapy group and was 75.0% (30/40) in the cutting method group, both better than 60.0% (24/40) in the western medication group (both P<0.05). CONCLUSION: The simple cutting method based on syndrome differentiation and the combined therapy with western medication achieve the superior efficacy on COPD at stable stage as compared with the simple western medication. The effect mechanism is possibly related to the improvement of bronchial airway function through constant acupoint stimulation.

Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and ß2-adrenoceptor agonist properties.

The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and ß2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hß2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hß2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hß1- and hß3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC50 = 50.2 nM), BA (EC50=24.6 nM), and MABA (EC50 = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 = 33.9 µg/ml), BA (ED50 = 14.1 µg/ml), and MABA (ED50 = 6.4 µg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic ß2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.