Why small particle fixed dose triple therapy? An excursus from COPD pathology to pharmacological treatment evolution

Although bronchodilators are the cornerstone in chronic obstructive pulmonary disease (COPD) therapy, the treatment with a single-agent bronchodilator may not provide adequate symptoms control in COPD. The combination of drugs with different mechanisms of action may be more effective in inducing bronchodilation and preventing exacerbations, with a lower risk of side-effects in comparison with the increase of the dose of a single molecule. Several studies comparing the triple therapy with the association of long-acting ß2 agonist (LABA)/inhaled corticosteroid (ICS) or long-acting muscarinic antagonist (LAMA)/LABA reported improvement of lung function and quality of life. A significant reduction in moderate/severe exacerbations has been observed with a fixed triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) in a single inhaler. The TRILOGY, TRINITY and TRIBUTE studies have provided confirming evidence for a clinical benefit of triple therapy over ICS/LABA combination treatment, LAMA monotherapy and LABA/LAMA combination, with prevention of exacerbations being a key finding. A pooled post hoc analysis of the published clinical studies involving BDP/FF/G fixed combination demonstrated a reduction in fatal events in patients treated with ICS-containing medications, with a trend of statistical significance [hazard ratio = 0.72, 95% confidence interval (CI) 0.50–1.02, p = 0.066], that becomes significant if we consider reduction in fatal events for non-respiratory reasons (hazard ratio = 0.65, 95% CI 0.43–0.97, p = 0.037). In conclusion, a fixed combination of more drugs in a single inhaler can improve long-term adherence to the therapy, reducing the risk of exacerbations and hospital resources utilization. The twice a day administration may provide a better coverage of night, particularly in COPD patients who are highly symptomatic. The inhaled extrafine formulation that allows drug deposition in both large and small – peripheral – airways, is the value added

One-year evolution of symptoms and health status of the copd multi-dimensional phenotypes: Results from the follow-up of the storico observational study

Aim: Describing the 1-year evolution of symptoms and health status in COPD patients enrolled in the STORICO study (observational study on characterization of 24-h symptoms in patients with COPD) classified in multidimensional phenotypes (m-phenotypes). Methods: In our previous study, we performed an exploratory factor analysis to identify clinical and pathophysiological variables having the greatest classificatory properties, followed by a cluster analysis to group patients into m-phenotypes (mild COPD (MC), mild emphysematous (ME), severe bronchitic (SB), severe emphysematous (SE), and severe mixed COPD (SMC)). COPD symptoms were recorded at baseline, 6-, and 12-month follow-up and their evolution was described as frequency of patients with always present, always absent, arising’, ‘no more present symptoms. QoL and quality of sleep were evaluated using the SGRQ and CASIS questionnaires, respectively. Results: We analyzed 379 subjects (144 MC, 71 ME, 96 SB, 14 SE, 54 SMC). M-phenotypes were stable over time in terms of presence of symptoms and health status with selected differences in evolution of symptoms in mild vs severe m-phenotypes. Indeed, 28.1% SB, 50.0% SE and 24.1% SMC vs 0.7% MC and 5.6% ME with night-time symptoms at baseline had no more symptoms at 6-month (p-value night-time symptom evolution MC vs SB, SE, SMC and ME vs SB, SE, SMC <0.0001). All m-phenotypes improved in quality of sleep, more markedly the severe than the mild ones (p-values CASIS score change between baseline and 6-or 12-month in MC, ME vs SB, SE, SMC <0.0001). QoL did not change during observation, irrespectively of m-phenotype. Conclusion: Over 1 year, severe m-phenotypes showed an improvement in night-time symptoms and quality of sleep, but not QoL. Being stable over time, m-phenotypes seem worthy of testing for classificatory and prognostic purposes

Airway remodelling assessed by sputum and high resolution computed tomography in asthma and COPD

It is not known whether sputum elastase, metalloproteinase (MMP)-9 and tissue-inhibitor metalloproteinase (TIMP)-1 are related to structural changes of the airways, as assessed by high-resolution computed tomography (HRCT) scan. The relationships between these markers and the magnitude of structural changes of the airways in asthma and chronic obstructive pulmonary disease (COPD) were assessed. Induced sputum and HRCT scan were performed in 30 asthmatics (14 mild and 16 severe) and in 12 patients with COPD. A greater extent of HRCT scan abnormalities was found in COPD than in severe and mild asthmatics. HRCT scan abnormalities correlated with the degree of airway obstruction in COPD and in severe asthma. HRCT scan abnormalities also correlated with the levels of sputum elastase both in COPD and in severe asthma. HRCT scan abnormalities were associated with sputum MMP-9/TIMP-1 ratio in mild asthma, severe asthma and COPD. In conclusion, this study demonstrates that sputum elastase and the metalloproteinase-9/tissue-inhibitor metalloproteinase-1 ratio are associated with the magnitude of high-resolution computed tomography scan abnormalities of the airways in asthma and chronic obstructive pulmonary disease, and suggests that the levels of these markers reflect the extent of structural changes of the airway

Effect of age and asthma duration upon elastase and alpha1-antitrypsin levels in adult asthmatics

In asthmatic subjects an imbalance between elastase and alpha1-antitrypsin (alpha1-PI) exists. This study aims to evaluate whether ageing per se affects the levels of elastase. Both young and elderly asthmatics with comparable severity and duration of disease, as well as young and elderly healthy subjects, underwent an induced sputum procedure to measure levels of elastase and alpha1-PI. The percentage of sputum neutrophils and eosinophils was higher in young and elderly asthmatics than in young and elderly controls. The levels of both total and active elastase were significantly higher in young and elderly asthmatics than in young and elderly controls, and directly correlated with the percentage of neutrophils. In addition, in both young and elderly asthmatics the levels of total and active elastase were negatively correlated with forced expiratory volume in one second values, but positively correlated with the duration of the disease. This study indicates that ageing per se does not necessarily lead to a progressive elastase/alpha1-antitrypsin imbalance in asthma, and suggests that an important variable in the development of airway remodelling in both young and elderly asthmatics is represented by the duration of the disease

Indacaterol/glycopyrronium/mometasone fixed dose combination for uncontrolled asthma

Introduction: Asthma symptoms can be relieved through a maintenance treatment combining long-acting β2-agonist and inhaled corticosteroids (LABA/ICS). However, for patients with inadequately controlled asthma, the LABA/ICS combination might not be sufficient, and clinical guidelines recommend the administration of inhaled long-acting muscarinic antagonists (LAMA) as an add-on therapy to better control asthma and improve lung function. For nearly two decades, the only LAMA to be approved on the market has been tiotropium. Areas covered: We reviewed recent clinical studies evaluating the safety and efficacy of LABA/LAMA/ICS fixed dose combinations by searching the PubMed database. Molecular mechanisms and clinical data support the use of a once-daily, single-inhaler fixed dose combination of the LABA/LAMA/ICS indacaterol/glycopyrronium/mometasone (IND/GLY/MF), the first therapy combining three agents in a fixed dose approved in Europe for the treatment of uncontrolled asthma. Expert opinion: IND/GLY/MF was superior to both IND/MF and salmeterol/fluticasone, a well-established LABA/ICS combination improving the lung function in uncontrolled asthma. Moreover, IND/GLY/MF, delivered through the Breezhaler inhaler in a single inhalation, is the first inhaled therapy prescribed alongside a digital companion, a sensor and the Propeller app, allowing for improved treatment adherence, reduced rescue inhaler usage and hospitalizations, increased patient satisfaction and asthma control

Effects of exercise training on airway responsiveness and airway cells in healthy subjects

J Appl Physiol. 2010 Aug;109(2):288-94. Epub 2010 Jun 10. Effects of exercise training on airway responsiveness and airway cells in healthy subjects. Scichilone N, Morici G, Zangla D, Chimenti L, Dav\uec E, Reitano S, Patern\uf2 A, Santagata R, Togias A, Bellia V, Bonsignore MR. SourceDept. of Internal Medicine, Div. of Pulmonology (DIBIMIS Univ. of Palermo, "Villa Sofia-Cervello" Hospital, Via Trabucco 180, 90146 Palermo, Italy. [email protected] Abstract Airway responsiveness to methacholine (Mch) in the absence of deep inspirations (DIs) is lower in athletes compared with sedentary individuals. In this prospective study, we tested the hypothesis that a training exercise program reduces the bronchoconstrictive effect of Mch. Ten healthy sedentary subjects (M/F: 3/7; mean + or - SD age: 22 + or - 3 yr) entered a 10-wk indoor rowing exercise program on rowing ergometer and underwent Mch bronchoprovocation in the absence of DIs at baseline, at weeks 5 and 10, as well as 4-6 wk after the training program was completed. Exercise-induced changes on airway cells and markers of airway inflammation were also assessed by sputum induction and venous blood samples. Mean power output during the 1,000 m test was 169 + or - 49 W/stroke at baseline, 174 + or - 49 W/stroke at 5 wk, and 200 + or - 60 W/stroke at 10 wk of training (P < 0.05). The median Mch dose used at baseline was 50 mg/ml (range 25-75 mg/ml) and remained constant per study design. At the pretraining evaluation, the percent reduction in the primary outcome, the inspiratory vital capacity (IVC) after inhalation of Mch in the absence of DIs was 31 +/- 13%; at week 5, the Mch-induced reduction in IVC was 22 + or - 19%, P = 0.01, and it further decreased to 15 + or - 11% at week 10 (P = 0.0008). The percent fall in IVC 4-6 wk after the end of training was 15 + or - 11% (P = 0.87 vs. end of training). Changes in airway cells were not associated with changes in airway responsiveness. Our data show that a course of exercise training can attenuate airway responsiveness against Mch inhaled in the absence of DIs in healthy subjects and suggest that a sedentary lifestyle may favor development of airways hyperresponsiveness. Comment in J Appl Physiol. 2010 Aug;109(2):267-8. PMID:20538849[PubMed - in process

Allergic diseases in the elderly: biological characteristics and main immunological and non-immunological mechanisms

Life expectancy and the number of elderly people are progressively increasing around the world. Together with other pathologies, allergic diseases also show an increasing incidence in geriatric age. This is partly due to the growing emphasis on a more accurate and careful diagnosis of the molecular mechanisms that do not allow to ignore the real pathogenesis of many symptoms until now unknown, and partly to the fact that the allergic people from 20 years ago represent the elderly population now. Moreover, environmental pollution predisposes to the onset of allergic asthma and dermatitis which are the result of internal pathologies more than the expression of allergic manifestations. At the same time the food contamination permits the onset of allergic diseases related to food allergy. In this review we provide the state of the art on the physiological changes in the elderly responsible for allergic diseases, their biological characteristics and the major immunological and extra immunological mechanisms. Much emphasis is given to the management of several diseases in the elderly, including anaphylactic reactions. Moreover, some new features are discussed, such as management of asthma with the support of physical activity and the use of the AIT as prevention of respiratory diseases and for the purpose of a real and long lasting benefit. The mechanisms of adverse reactions to drugs are also discussed, due to their frequency in this age, especially in polytherapy regimens. Study of the modifications of the immune system is also of great importance, as regards to the distribution of the lymphocytes and also the presence of a chronic inflammatory disease related to the production of cytokines, especially in prevision of all the possible therapies to be adopted to allow an active and healthy agin

Inhalation therapy in the next decade : Determinants of adherence to treatment in asthma and COPD

Peer reviewedPublisher PD

Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease:an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN)

Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 μm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician’s considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal