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      Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine

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          Abstract

          Background

          To date there are no head-to-head studies comparing different mucolytic/antioxidant agents. Considering the inconsistent evidence resulting from the pivotal studies on mucolytic/antioxidant agents tested in chronic obstructive pulmonary disease (COPD), and the recent publication of Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD (RESTORE) study, we have performed a meta-analysis to compare the efficacy and safety of erdosteine 600 mg/day, carbocysteine 1500 mg/day, and N-acetylcysteine (NAC) 1200 mg/day in COPD.

          Methods

          A pairwise and network meta-analyses were performed to assess the efficacy of erdosteine, carbocysteine, and NAC on acute exacerbation of COPD (AECOPD), duration of AECOPD, and hospitalization. The frequency of adverse events (AEs) was also investigated.

          Results

          Data obtained from 2753 COPD patients were extracted from 7 RCTs published between 2004 and 2017. In the pairwise meta-analysis mucolytic/antioxidant agents significantly reduced the risk of AECOPD (RR 0.74 95%CI 0.68–0.80). The network meta-analysis provided the following rank of effectiveness: erdosteine>carbocysteine>NAC. Only erdosteine reduced the risk of experiencing at least one AECOPD ( P < 0.01) and the risk of hospitalization due to AECOPD ( P < 0.05). Erdosteine and NAC both significantly reduced the duration of AECOPD (P < 0.01). The AEs induced by erdosteine, carbocysteine, and NAC were mild in severity and generally well tolerated. The quality of evidence of this quantitative synthesis is moderate.

          Conclusions

          The overall efficacy/safety profile of erdosteine is superior to that of both carbocysteine and NAC. Future head-to-head studies performed on the same COPD populations are needed to definitely confirm the results of this meta-analysis.

          Trial registration

          CRD42016053762.

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          Most cited references 21

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          Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.

          Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD. We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233. 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated. Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.
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            High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study.

            The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD. The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease-a Double-blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George's Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year. Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8±0.74 years; %FEV1 53.9±2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P=.037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P=.019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P=.196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported. In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD. ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.
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              Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis.

              In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤ 600 mg per day) and high (> 600 mg per day) doses of NAC. The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n = 1933; placebo or controls n = 2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66-0.84; p < 0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68-0.82; p = 0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89-0.97; p = 0.40; high doses relative risk 1.11, 95% CI 0.89-1.39; p = 0.58). The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥ 1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient.
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                Author and article information

                Contributors
                +39 06 7259 6666 , paola.rogliani@uniroma2.it
                mariagabriella.matera@unicampania.it
                clive.page@kcl.ac.uk
                ermanno.puxeddu@uniroma2.it
                mario.cazzola@uniroma2.it
                luigino.calzetta@uniroma2.it
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                27 May 2019
                27 May 2019
                2019
                : 20
                Affiliations
                [1 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Unit of Respiratory Medicine, Department of Experimental Medicine, , University of Rome “Tor Vergata”, ; Via Montpellier 1, 00133 Rome, Italy
                [2 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Unit of Pharmacology, Department of Experimental Medicine, , University of Campania “Luigi Vanvitelli”, ; Naples, Italy
                [3 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, , King’s College London, ; London, UK
                Article
                1078
                10.1186/s12931-019-1078-y
                6537173
                31133026
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Edmond Pharma Srl
                Award ID: NA
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Respiratory medicine

                copd, erdosteine, carbocysteine, n-acetylcysteine, meta-analysis

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