The secrets of men since born: Il Machiavelli di Lord Acton

Lord Acton was one of the most eminent intellectuals of the Victorian age. His political thought aimed at reconciling his Catholic faith with liberal prin-ciples. Although he has never written a book, his essays expressed an histo-riography that has exerted great influence in the study of history, the most known example of which is the Cambridge Modern History, conceived by Lord Acton himself. This article aims at showing that his interpretation of Ma-chiavelli, expressed in the introduction to the famous edition of the Prince edited by Arthur Burd, is a precious testimony of the widespread circulation of Machiavellian thought in Europe

Association between reduced bronchodilatory effect of deep inspiration and loss of alveolar attachments

BACKGROUND: We have previously shown that the bronchodilatory effect of deep inspiration is attenuated in individuals with COPD. This study was designed to investigate whether the impairment in this effect is associated with loss of alveolar attachments. METHODS: We measured deep inspiration (DI)-induced bronchodilation in 15 individuals with and without COPD (67 ± 2.2 yrs of age, mean ± SEM) undergoing lobar resection for peripheral pulmonary nodule. Prior to surgery, we measured TLCO and determined the bronchodilatory effect of deep inspiration after constricting the airways with methacholine. The number of destroyed alveolar attachments, as well as airway wall area and airway smooth muscle area, were determined in tumor-free, peripheral lung tissue. RESULTS: The bronchodilatory effect of deep inspiration correlated inversely with the % destroyed attachments (r = -0.51, p = 0.05) and directly with the airway smooth muscle area (r = 0.59, p = 0.03), but not with the total wall area (r = 0.39, p = 0.15). CONCLUSION: We postulate that attenuation of airway stretch due to loss of alveolar attachments contributes to the loss of the bronchodilatory effect of lung inflation in COPD

Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations.

Drugs for asthma and other chronic obstructive diseases of the lungs should be preferably delivered by the inhalation route to match therapeutic effects with low systemic exposure. Inhaled drugs are delivered to the lungs via different devices, mainly metered dose inhalers and dry powder inhalers, each characterized by specific inhaler technique and instructions for use. The patient-device interaction is part of the prescribed therapy and can have a relevant impact on adherence and clinical outcomes. The most suitable device should be considered for each patient to assure the correct drug intake and adherence to the prescribed therapy. The development of new drugs/devices in the past decades improved the compliance with inhaler and possibly drug delivery to the bronchi. The present review focuses on the recently developed beclomethasone/formoterol extrafine fixed combination and technical aspects of drug delivery to the lungs in patient's perspective

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

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

Predicting Lung Deposition of Extrafine Inhaled Corticosteroid-Containing Fixed Combinations in Patients with Chronic Obstructive Pulmonary Disease Using Functional Respiratory Imaging: An in Silico Study

Background: Functional respiratory imaging (FRI) is a computational fluid dynamics-based technique using three-dimensional models of human lungs and formulation profiles to simulate aerosol deposition. Methods: FRI was used to evaluate lung deposition of extrafine beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) and extrafine BDP/FF delivered through pressurized metered dose inhalers and to compare results with reference gamma scintigraphy data. FRI combined high-resolution computed tomography scans of 20 patients with moderate-to-severe chronic obstructive pulmonary disease (mean forced expiratory volume in 1 second 42% predicted) with in silico computational flow simulations, and incorporated drug delivery parameters to calculate aerosol airway deposition. Inhalation was simulated using profiles obtained from real-life measurements. Results: Total lung deposition (proportion deposited in intrathoracic region) was similarly high for both products, with mean ± standard deviation (SD) values of 31.0% ± 5.7% and 28.1% ± 5.2% (relative to nominal dose) for BDP/FF/GB and BDP/FF, respectively. Pairwise comparison of the deposition of BDP and FF gave a mean intrathoracic BDP/FF/GB:BDP/FF deposition ratio of 1.10 (p = 0.0405). Mean intrathoracic, central and peripheral deposition ratios for BDP were 1.09 (95% confidence interval [CI]: 1.05-1.14), 0.92 (95% CI: 0.89-0.96), and 1.20 (95% CI: 1.15-1.26), respectively, and for FF were 1.11 (95% CI: 1.07-1.15), 0.94 (95% CI: 0.91-0.98), and 1.21 (95% CI: 1.15-1.27), within the bioequivalence range (0.80-1.25) for intrathoracic and central regions, and slightly exceeding the upper boundary in the peripheral region. Mean ± SD central:peripheral deposition (C:P) was 0.48 ± 0.13 for BDP/FF/GB and 0.62 ± 0.17 for BDP/FF, indicating a higher proportion of drug deposition in the small airways than in the large airways. Conclusion: FRI demonstrated similar deposition patterns for extrafine BDP/FF/GB and BDP/FF, with both having a high lung deposition. Moreover, the deposition patterns of BDP and FF were similar in both products. Furthermore, the C:P ratios of both products indicated a high peripheral deposition, supporting small airway targeting and delivery of these two extrafine fixed combinations, with a small difference in ratios potentially due to mass median aerodynamic diameters

Clinical evolution and quality of life in clinically based copd chronic bronchitic and emphysematous phenotypes: Results from the 1-year follow-up of the storico italian observational study

Introduction: Understanding clinical evolution of chronic obstructive pulmonary disease (COPD) is crucial for improving disease management. Materials and Methods: STORICO (NCT03105999), an Italian, multicenter, non-inter-ventional, observational study conducted in 40 pulmonology centers, aimed to describe the 1-year clinical evolution and health status of clinicallbased phenotypes. Baseline and follow-up data of COPD subjects with a chronic bronchitis (CB) or emphysema (EM) phenotype were collected. The frequency of COPD symptoms during the 24 hours (gathered via the night-time, morning and day-time symptoms of COPD questionnaire) and the anxiety and depression levels (via the HADS Scale) were recorded at each visit. Results: A total of 261 CB and 159 EM patients were analyzed. CB patients with ≥1 night-time symptom seemed to be more frequent (51.7%, 41.8% and 41.4% at baseline, 6-month and 12-month follow-up, respectively) than EM (37.7%, 32.1% and 30.2% at study visits) even if no statistical differences were observed at time points between phenotypes (chi-square test p-values presence/absence of night-time symptoms in CB vs EM at study visits >0.0007). In the first 6 months, the frequency of patients with ≥1 night-time symptom decreased of 9.9% in CB and of 5.6% in EM. A clinically relevant decline of DLCO % predicted over 1 year in EM was observed, the mean (SD) being 61.5 (20.8) % at baseline and 59.1 (17.4) % at 12-month follow-up. EM had higher levels of anxiety and depression than CB (median (25th-75th percentile) HADS total score in CB: 7.0 (4.0–13.0) and 7.0 (3.0–12.0), in EM: 9.0 (3.0–14.0) and 9.5 (3.0–14.0) both at baseline and at 6-month follow-up, respectively), considering 1.17 as minimally clinical important difference (MCID) for the total score. Conclusion: EM patients, evaluated in a real-world setting, seem to suffer from a worse clinical condition and health status compared to CB patients, appearing to have “more treatable” traits

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

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