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Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug. © 2017 Gallelli et al. Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.

Within the context of the heterogeneous phenotypic stratification of asthmatic population, many patients are characterized by moderate-to-severe eosinophilic asthma, not adequately controlled by relatively high dosages of inhaled and even oral corticosteroids. Therefore, these subjects can obtain significant therapeutic benefits by additional biologic treatments targeting interleukin-5 (IL-5), given the key pathogenic role played by this cytokine in maturation, activation, proliferation, and survival of eosinophils. In particular, reslizumab is a humanized anti-IL-5 monoclonal antibody that has been found to be an effective and safe add-on therapy, capable of decreasing asthma exacerbations and significantly improving disease control and lung function in patients experiencing persistent allergic or nonallergic eosinophilic asthma, despite the regular use of moderate-to-high doses of inhaled corticosteroids. These important therapeutic effects of reslizumab, demonstrated by several controlled clinical trials, have led to the recent approval by US Food and Drug Administration of its use, together with other antiasthma medications, for the maintenance treatment of patients suffering from severe uncontrolled asthma.

Even if severe asthma (SA) accounts for 5–10% of all cases of the disease, it is currently a crucial unmet need, owing its difficult clinical management and its high social costs. For this reason several networks, focused on SA have been organized in some countries, in order to select these patients, to recognize their clinical features, to evaluate their adherence, to classify their biological/clinical phenotypes, to identify their eligibility to the new biologic therapies and to quantify the costs of the disease. Aim of the present paper is to describe the ongoing Italian Severe Asthma Network (SANI). Up today 49 centres have been selected, widespread on the national territory. Sharing the same diagnostic protocol, data regarding patients with SA will be collected and processed in a web platform. After their recruitment, SA patients will be followed in the long term in order to investigate the natural history of the disease. Besides clinical data, the cost/benefit evaluation of the new biologics will be verified as well as the search of peculiar biomarker(s) of the disease.

Continuous spreading of HIV infection may be due to lack of knowledge, especially among young people. It is important to monitor level of knowledge and risk behaviours especially in young people to set up appropriate preventative and informative campaigns.We assessed knowledge of HIV infection and risk factors in a sample of students at the "Magna Graecia" University of Catanzaro, using an anonymous multiple-choice questionnaire.Two-hundred and sixteen medical students attending the first year at "Magna Graecia" University (age: 18-20 years) were prescribed an anonymous multiple-choice questionnaire. Knowledge of HIV infection was scarce in a significant percentage of students. They were often practicing risk behaviours at risk for acquisition of HIV infection and other sexually transmitted infections.This study shows that preventative and informative campaigns are urgently needed in earlier stage of adolescence to avoid acquisition of HIV infection and other sexually transmitted diseases.

Current advances in the knowledge of asthma pathobiology suggest that anticytokine therapies can be potentially useful for the treatment of this complex and heterogeneous airway disease. Recent evidence is accumulating in support of the efficacy of anti-IL-4, anti-IL-5, and anti-IL-13 drugs. Therefore, these new developments are now changing the global scenario of antiasthma therapies, especially with regard to more severe disease. Current findings referring to variability of individual therapeutic responses highlight that the different asthma subtypes need to be well characterized, in order to implement phenotype-targeted treatments which in the near future will hopefully be mainly based on cytokine-directed biologics.

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Bronchial hyperresponsiveness and airway infiltration with eosinophils and T lymphocytes are key features of asthma. In particular, CD4+ T cells are currently believed to play a pivotal role as initiators and coordinators of the asthmatic inflammatory response and, therefore, they represent a crucial target of corticosteroid treatment. The aim of the present investigation is thus to evaluate, in patients with mild asthma, the effects of inhaled corticosteroid therapy on the following parameters: (i) functional state of CD4+ T cells; (ii) airway eosinophilia; (iii) bronchial hyperresponsiveness to methacholine. The study was completed by twenty asthmatic, atopic subjects, subdivided into two groups of ten and treated for 12 weeks with either inhaled budesonide (200 μg twice daily) or terbutaline alone (500 μg twice daily), respectively. Expression of CD4+ T cell activation markers was measured in induced sputum at baseline and after 1, 4, 8 and 12 weeks of treatment by flow cytometry, which showed a down-regulation of HLA-DR and CD25 surface proteins in the budesonide group, compared with the control group; these differences resulted as being statistically significant through weeks 4–12. Budesonide also induced a quick, sharp reduction in the percentage of eosinophils detectable in induced sputum, as well as a more gradual progressive improvement in airway hyperresponsiveness to methacholine. Therefore, in addition to assessing various indices of bronchial inflammation, flow cytometry can be reliably applied to induced sputum in order to monitor, even in mildly symptomatic patients, the effects of anti-asthma treatments on T cell activation.

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Cecilia Calabrese,4 Rosa Terracciano,3 Nicola Lombardo,1 Rosario Maselli11Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, 2Departmentof Medicine and Surgery, University of Salerno, Salerno, 3Department of Health Science, Magna Græcia University of Catanzaro, Catanzaro, 4Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, ItalyAbstract: Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting β2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.Keywords: LAMA, LABA, tiotropium, olodaterol, dual bronchodilation, tiotropium/olodaterol combinations

COPD is a widespread inflammatory respiratory disorder characterized by a progressive, poorly reversible airflow limitation. Currently available therapies are mostly based on those used to treat asthma. However, such compounds are not able to effectively reduce the gradual functional deterioration, as well as the ongoing airway and lung inflammation occurring in COPD patients. Therefore, there is an urgent need to improve the efficacy of the existing drug classes and to develop new treatments, targeting the main cellular and molecular mechanisms underlying disease pathogenesis. These therapeutic strategies will be highlighted in the present review.

Lung cancer is characterized by a high mortality rate probably attributable to early metastasis. Oxidative stress is involved in development and progression of lung cancer, through cellular and molecular mechanisms which at least in part overlap with proinflammatory pathways. Simvastatin is a statin with pleiotropic effects that can also act as an anti-oxidant agent, and these pharmacologic properties may contribute to its potential anti-cancer activity. Therefore, the aim of this study was to evaluate, in the human lung adenocarcinoma cell line GLC-82, the effects of a 24-hour treatment with simvastatin on hydrogen peroxide (H2O2)-induced changes in cell viability, ERK phosphorylation, matrix metalloproteinase (MMP) expression, innate immunity signaling, NF-κB activation and IL-8 secretion. Cell counting was performed after trypan blue staining, cell proliferation was assessed using MTT assay, and apoptosis was evaluated through caspase-3 activation and Tunel assay. Western blotting was used to analyze protein extracts, and IL-8 release into cell culture supernatants was assessed by ELISA. Our results show that simvastatin (30 μM) significantly (P < 0.01) inhibited the proliferative effect of H2O2 (0.5 mM) and its stimulatory actions on ERK1/2 phosphorylation, NF-κB activation and IL-8 production. Furthermore, simvastatin decreased H2O2-mediated induction of the cellular expression of MMP-2 and MMP-9, as well as of several components of the signaling complex activated by innate immune responses, including MyD88, TRAF2, TRAF6 and TRADD. In conclusion, these findings suggest that simvastatin could play a role in prevention and treatment of lung cancer via modulation of important proinflammatory and tumorigenic events promoted by oxidative stress.. © 2014 Gallelli et al.

Bronchodilators are the cornerstone of the treatment of chronic obstructive pulmonary disease (COPD). In particular, the most commonly used drugs are inhaled long-acting agents, including long-acting F2-adrenergic agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs). The combination of a LABA with a LAMA, i.e. of molecules characterized by different mechanisms of action, results in a synergistic enhancement of their clinical and functional effects. Therefore, this combined treatment can be implemented in a number of cases in which disease control is not adequately achieved by a single active agent such as a LABA or a LAMA. Several LABA/LAMA fixed-dose combinations, mainly made up of newly developed compounds, are currently in advanced phases of experimental evaluation. Within such a context, the aim of this review is to outline the pharmacological basis of dual bronchodilation as well as to discuss the results of the main trials carried out using the drug combination consisting of indacaterol and glycopyrronium, a LABA and a LAMA recently introduced in the treatment of COPD. i 2014 S. Karger AG, Basel

Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab.

The most recent guidelines define COPD in a multidimensional way, nevertheless the diagnosis is still linked to the limitation of airflow, usually measured by the reduction in the FEV1/FVC ratio below 70%. However, the severity of obstruction is not directly correlated to symptoms or to invalidity determined by COPD. Thus, besides respiratory function, COPD should be evaluated based on symptoms, frequency and severity of exacerbations, patient’s functional status and health related quality of life (HRQoL). Therapy is mainly aimed at increasing exercise tolerance and reducing dyspnea, with improvement of daily activities and HRQoL. This can be accomplished by a drug-induced reduction of pulmonary hyperinflation and exacerbations frequency and severity. All guidelines recommend bronchodilators as baseline therapy for all stages of COPD, and long-acting inhaled bronchodilators, both beta-2 agonist (LABA) and antimuscarinic (LAMA) drugs, are the most effective in regular treatment in the clinically stable phase. The effectiveness of bronchodilators should be evaluated in terms of functional (relief of bronchial obstruction and pulmonary hyperinflation), symptomatic (exercise tolerance and HRQoL), and clinical improvement (reduction in number or severity of exacerbations), while the absence of a spirometric response is not a reason for interrupting treatment, if there is subjective improvement in symptoms. Because LABA and LAMA act via different mechanisms of action, when administered in combination they can exert additional effects, thus optimizing (i.e. maximizing) sustained bronchodilation in COPD patients with severe airflow limitation, who cannot benefit (or can get only partial benefit) by therapy with a single bronchodilator. Recently, a fixed combination of ultra LABA/LAMA (indacaterol/glycopyrronium) has shown that it is possible to get a stable and persistent bronchodilation, which can help in avoiding undesirable fluctuations of bronchial calibre.

IgE antibodies are crucially involved in mediating, maintaining and amplifying the allergic cascade. The humanized monoclonal anti-IgE antibody omalizumab is currently the only biologic drug approved for asthma treatment. Anti-IgE inhibits allergic responses by binding to serum IgE, thus preventing their interactions with cellular IgE receptors. Omalizumab is also capable of down-regulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both peripheral blood and induced sputum. Randomized clinical trials showed relevant clinical effects of omalizumab including improvements of respiratory symptoms and quality of life. Moreover, a marked reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators was also observed. Omalizumab is relatively well tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for most severe patients with persistent allergic asthma, inadequately controlled by high doses of standard treatments.

Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease.

Objective 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can affect post-translational processes, thus being responsible for decreased farnesylation and geranylgeranylation of intracellular small G proteins such as Ras, Rho and Rac, essential for cell survival and proliferation. In this regard, recent in vitro and in vivo studies suggest a possible role for both statins and farnesyl transferase inhibitors in the treatment of malignancies. Within such a context, the aim of our study was to investigate effects of either simvastatin (at concentrations of 1, 15, and 30 μm) or the farnesyl transferase inhibitor R115777 (at concentrations of 0.1, 1, and 10 μm), on two cultures of human non-small lung cancer cells, adenocarcinoma (GLC-82) and squamous (CALU-1) cell lines. In particular, we evaluated actions of these two drugs on phosphorylation of the ERK1/2 group of mitogen-activated protein kinases and on apoptosis, plus on cell numbers and morphology. Materials and Methods Western blotting was used to detect ERK phosphorylation, and to assess apoptosis by evaluating caspase-3 activation; apoptosis was also further assessed by terminal deoxynucleotidyl-mediated dUTP nick end labelling (TUNEL) assay. Cell counting was performed after trypan blue staining. Results and conclusion In both GLC-82 and CALU-1 cell lines, simvastatin and R115777 significantly reduced ERK phosphorylation; this effect, which reached the greatest intensity after 36 h treatment, was paralleled by a concomitant induction of apoptosis, documented by significant increase in both caspase-3 activation and TUNEL-positive cells, associated with a reduction in cell numbers. Our results thus suggest that simvastatin and R115777 may exert, in susceptible lung cancer cell phenotypes, a pro-apoptotic and anti-proliferative activity, which appears to be mediated by inhibition of the Ras/Raf/MEK/ERK signalling cascade.

Non-typeable Haemophilus influenzae (NTHi) is one of the most frequently involved pathogens in bacterial exacerbations of chronic obstructive pulmonary disease (COPD). In the airways, the main tissue target of NTHi is bronchial epithelium, where this pathogen can further amplify the inflammatory and structural changes induced by proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha). Therefore, the aim of this study is to investigate, in primary cultures of human bronchial epithelial cells, the effects of NTHi on signal transduction pathways, apoptotic events and chemokine production activated by TNF-alpha. Moreover, we also evaluated the effects exerted on such cellular and molecular phenomena by a corticosteroid drug. p38 mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by Western blotting, using an anti-phospho-p38 MAPK monoclonal antibody. Apoptosis was assayed by active caspase-3 expression. Interleukin-8 (IL-8/CXCL8) was detected in cell-free culture supernatants by ELISA. TNF-alpha induced a significant increase in p38 MAPK phosphorylation. NTHi was able to potentiate the stimulatory actions of TNF-alpha on caspase-3 expression and, to a lesser extent, on IL-8 secretion. These effects were significantly (P less than 0.01) inhibited by a pharmacological pre-treatment with budesonide. These results suggest that TNF-alpha is able to stimulate, via activation of p38 MAPK signalling pathway, IL-8 release and airway epithelial cell apoptosis; the latter effect can be markedly potentiated by NTHi. Furthermore, budesonide can be very effective in preventing, through inhibition of p38 MAPK phosphorylation, both structural and proinflammatory changes elicited in bronchial epithelium by TNF-alpha and NTHi.

SummaryAirway smooth muscle (ASM) plays a key role in bronchomotor tone, as well as in structural remodeling of the bronchial wall. Therefore, ASM contraction and proliferation significantly participate in the development and progression of asthma. Many contractile agonists also behave as mitogenic stimuli, thus contributing to frame a hyperresponsive and hyperplastic ASM phenotype. In this review, the molecular mechanisms and signaling pathways involved in excitation–contraction coupling and ASM cell growth will be outlined. Indeed, the recent advances in understanding the basic aspects of ASM biology are disclosing important cellular targets, currently explored for the implementation of new, more effective anti-asthma therapies.

OBJECTIVES: Both interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) are crucially involved in fibrotic events that characterize interstitial lung diseases (ILD). Therefore, the aim of this study was to investigate in primary cultures of normal and fibrotic human lung fibroblasts (HLF), exposed to either IL-6 or TGF-beta1, the effects on phosphorylation of mitogen-activated protein kinases (MAPK) and cell growth of IL-6 signalling inhibition, performed by the IL-6 receptor superantagonist Sant7. MATERIALS AND METHODS: MAPK phosphorylation was detected by Western blotting, HLF viability and proliferation were evaluated using the trypan blue staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, respectively. RESULTS: Sant7, at a concentration of 1 microg/mL, was capable of significantly inhibiting HLF proliferation and MAPK phosphorylation induced by cell exposure to IL-6 (100 ng/mL) or TGF-beta1 (10 ng/mL), whose actions were more evident in fibrotic cells. CONCLUSIONS: These findings suggest that, in HLFs derived from patients with ILDs, the proliferative mechanisms activated by TGF-beta1 are at least in part mediated by an increased release of IL-6, leading to phosphorylation-dependent MAPK activation. Such preliminary findings may thus open new therapeutic perspectives for fibrogenic ILDs, based on inhibition of signal transduction pathways stimulated by the IL-6 receptor.

Inflammation, oxidative stress and apoptosis, which are involved in chronic obstructive pulmonary disease (COPD) pathogenesis, may activate the p38 subgroup of mitogen-activated protein kinases (MAPKs). Therefore, the aim of the present study was to evaluate the expression of the phosphorylated, active form of p38 MAPK (phospho-p38) in the lungs of COPD patients. Surgical specimens were obtained from 18 smokers with COPD at different stages of disease severity, plus nine smoking and eight nonsmoking subjects with normal lung function. Phospho-p38+ cells were quantified by immunohistochemistry in both alveolar spaces and alveolar walls. Moreover, a Western blot analysis of phospho-p38 and total p38alpha isoform expressed by alveolar macrophages was performed. Phospho-p38+ alveolar macrophages and phospho-p38+ cells in alveolar walls were increased in patients with severe and mild/moderate COPD, compared with smoking and nonsmoking controls. Moreover, they were inversely correlated to values of forced expiratory volume in one second (FEV(1)) and FEV(1)/forced vital capacity. Western blot analysis showed that phosphorylated p38, but not the total p38alpha isoform, was specifically increased in alveolar macrophages from COPD patients. Activation of the p38 mitogen-activated protein kinase pathway appears to be involved in the pathogenesis of chronic obstructive pulmonary disease. The present findings suggest that this protein may be a suitable pharmacological target for therapeutic intervention.

Summary Respiratory tract infections caused by both viruses and/or atypical bacteria are involved in the pathogenesis of asthma. In particular, several viruses such as respiratory syncytial virus, rhinovirus and influenza/parainfluenza viruses may favour the expression of the asthmatic phenotype, being also implicated in the induction of disease exacerbations. Within this pathological context, a significant role can also be played by airway bacterial colonizations and infections due to Chlamydiae and Mycoplasms. All these microbial agents probably interfere with complex immunological pathways, thus contributing to induce and exacerbate asthma in genetically predisposed individuals.

Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing interaction with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include improvements in respiratory symptoms and quality of life, paralleled by a reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well-tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma inadequately controlled by high doses of standard inhaled treatments.

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting β2-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.