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      Multifaceted Beneficial Effects of Erdosteine: More than a Mucolytic Agent

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          Abstract

          Erdosteine is a drug approved for the treatment of acute and chronic pulmonary diseases, originally developed as a mucolytic agent. It belongs to the thiol-based family of drugs that are known to also possess potentially important antioxidant and anti-inflammatory properties, and exhibit antibacterial activity against a variety of medically important bacterial species. Erdosteine is a prodrug that is metabolized to the ring-opening compound metabolite M1 (MET 1), which has mucolytic properties. Experimental studies have documented that erdosteine prevents or reduces lung tissue damage induced by oxidative stress and, in particular, that Met 1 also regulates reactive oxygen species production. The RESTORE study, which has been the only trial that investigated the effects of a thiol-based drug in chronic obstructive pulmonary disease (COPD) frequent exacerbators, documented that erdosteine significantly reduces the risk of acute exacerbations of COPD (AECOPDs), shortens their course, and also decreases the risk of hospitalization from COPD. The preventive action of erdosteine on AECOPDs was not affected by the presence or absence of inhaled corticosteroids (ICSs) or blood eosinophil count. These findings clearly contrast with the Global Initiative for Chronic Obstructive Lung Disease strategy’s approach to use erdosteine only in those COPD patients not treated simultaneously with an ICS. Furthermore, they support the possibility of using erdosteine in a step-down approach that in COPD is characterized by the withdrawal of the ICS.

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          Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.

          Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83–0.95); serum CXCL10, 0.83 (95% CI, 0.70–0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78–0.93), respectively. The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.
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            Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases.

            Reactive oxygen species (ROS) are products of normal cellular metabolism and are known to act as second messengers. Under physiological conditions, ROS participate in maintenance of cellular 'redox homeostasis' in order to protect cells against oxidative stress. In addition, regulation of redox state is important for cell activation, viability, proliferation, and organ function. However, overproduction of ROS, most frequently due to excessive stimulation of either reduced nicotinamide adenine dinucleotide phosphate (NADPH) by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) or the mitochondrial electron transport chain and xanthine oxidase, results in oxidative stress. Oxidative stress is a deleterious process that leads to airway and lung damage and consequently to several respiratory inflammatory diseases/injuries, including acute respiratory distress syndrome (ARDS), asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Many of the known inflammatory target proteins, such as matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and cytosolic phospholipase A(2) (cPLA(2)), are associated with NADPH oxidase activation and ROS overproduction in response to pro-inflammatory mediators. Thus, oxidative stress regulates both key inflammatory signal transduction pathways and target proteins involved in airway and lung inflammation. In this review, we discuss mechanisms of NADPH oxidase/ROS in the expression of inflammatory target proteins involved in airway and lung diseases. Knowledge of the mechanisms of ROS regulation could lead to the pharmacological manipulation of antioxidants in airway and lung inflammation and injury. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians.

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                Author and article information

                Contributors
                mario.cazzola@uniroma2.it
                Journal
                Drugs
                Drugs
                Drugs
                Springer International Publishing (Cham )
                0012-6667
                1179-1950
                6 October 2020
                6 October 2020
                2020
                : 80
                : 17
                : 1799-1809
                Affiliations
                [1 ]GRID grid.6530.0, ISNI 0000 0001 2300 0941, Unit of Respiratory Medicine, Department of Experimental Medicine, , University of Rome “Tor Vergata”, ; Rome, Italy
                [2 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, , King’s College London, ; London, UK
                [3 ]GRID grid.10383.39, ISNI 0000 0004 1758 0937, Unit of Respiratory Disease and Lung Function, Department Medicine and Surgery, , University of Parma, ; Parma, Italy
                [4 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Unit of Pharmacology, Department of Experimental Medicine, , University of Campania “Luigi Vanvitelli”, ; Naples, Italy
                Author information
                http://orcid.org/0000-0003-4895-9707
                Article
                1412
                10.1007/s40265-020-01412-x
                7647991
                33025535
                e7dfa9cf-f305-4fcf-9d29-53bac9e551ff
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Funding
                Funded by: Università degli Studi di Roma Tor Vergata
                Categories
                Review Article
                Custom metadata
                © Springer Nature Switzerland AG 2020

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