L-carbocisteine can cause cholestasis with vanishing bile duct syndrome in children: A case report.

RATIONALE: Vanishing bile duct syndrome (VBDS) is the acquired progressive destruction and disappearance of intrahepatic interlobular bile ducts in the absence of underlying liver or biliary tract disease, causing chronic cholestasis. Infections, drugs, toxins, malignant diseases, and certain immunological processes are associated with the development of this syndrome. There have been no reports of children developing VBDS as a consequence of the administration of L-carbocisteine. PATIENT CONCERNS: A 9-year-old Japanese girl presented with fever, jaundice, and skin rash. Laboratory investigations revealed elevated levels of serum transaminases, γ-glutamyltransferase, and bilirubin. Histopathological features were consistent with a diagnosis of VBDS. Drug-induced lymphocyte stimulation tests (DLST) were positive for L-carbocisteine. DIAGNOSIS: VBDS caused by L-carbocisteine. INTERVENTIONS: Ursodeoxycholic acid and discontinuation of L-carbocisteine. OUTCOMES: The patient responded to treatment based upon discontinuation of L-carbocisteine and administration of ursodeoxycholic acid. Her transaminase and bilirubin levels were normalized gradually. LESSONS: Physicians should be aware of the fact that L-carbocisteine can cause cholestasis with VBDS in children.

Stereoselective α-Deuteration of Serine, Cysteine, Selenocysteine, and 2,3-Diaminopropanoic Acid Derivatives.

Efficient methodologies for synthesizing enantiopure α-deuterated derivatives of serine, cysteine, selenocysteine, and 2,3-diaminopropanoic acid have been developed. H/D exchange was achieved by deprotonation of a chiral bicyclic serine equivalent followed by selective deuteration. Additionally, diastereoselective additions of thiols, selenols, and amines to a chiral bicyclic dehydroalanine in deuterated alcohols allowed site-selective deuteration at the Cα atom of cysteine, selenocysteine, and 2,3-diaminopropanoic acid derivatives. A deuterated analogue of carbocysteine, a drug for the treatment of bronchiectasis, was synthesized.

Structural and Functional Studies of S-(2-Carboxyethyl)-L-Cysteine and S-(2-Carboxyethyl)-l-Cysteine Sulfoxide.

Insecticidal non-proteinogenic amino acid S-(2-carboxyethyl)-L-cysteine (ß-CEC) and its assumed metabolite, S-(2-carboxyethyl)-l-cysteine sulfoxide (ß-CECO), are present abundantly in a number of plants of the legume family. In humans, these amino acids may occur as a result of exposure to environmental acrylonitrile or acrylamide, and due to consumption of the legumes. The ß-CEC molecule is a homolog of S-carboxymethyl-l-cysteine (carbocisteine, CMC), a clinically employed antioxidant and mucolytic drug. We report here detailed structural data for ß-CEC and ß-CECO, as well as results of in vitro studies evaluating cytotoxicity and the protective potential of the amino acids in renal tubular epithelial cells (RTECs) equipped with reporters for activity of seven stress-responsive transcription factors. In RTECs, ß-CEC and the sulfoxide were not acutely cytotoxic, but activated the antioxidant Nrf2 pathway. ß-CEC, but not the sulfoxide, induced the amino acid stress signaling, which could be moderated by cysteine, methionine, histidine, and tryptophan. ß-CEC enhanced the cytotoxic effects of arsenic, cadmium, lead, and mercury, but inhibited the cytotoxic stress induced by cisplatin, oxaliplatin, and CuO nanoparticles and acted as an antioxidant in a copper-dependent oxidative DNA degradation assay. In these experiments, the structure and activities of ß-CEC closely resembled those of CMC. Our data suggest that ß-CEC may act as a mild activator of the cytoprotective pathways and as a protector from platinum drugs and environmental copper cytotoxicity.

[A CASE OF STEVENS-JOHNSON SYNDROME SUSPECTED BY A COMMON COLD MEDICATION AS CAUSE].

We describe here the case of a 7-year-old male patient with Stevens-Johnson syndrome (SJS), which was suspected to be caused by treatment with tipepidine hibenzate (Asverin®). The day after taking tipepidine hibenzate and L-carbocysteine (Carbocysteine® DS) for relief of a cold, he began presenting with the following symptoms: fever above 38°C, wheezing, and decreased oxygen saturation. Two days later, mucous membrane rashes, such as erosions on the lips, eye mucosa, vulva, and blisters on the trunk appeared, and SJS was thus diagnosed. Because pseudomembrane formation and corneal epithelial defect in the eyes were also observed, steroid pulse therapy was administered early in the course of the disease, and the patient recovered without sequelae.A drug-induced lymphocyte stimulation test performed to determine the cause of the disease was positive for fixed-dose combination therapy with tipepidine hibenzate plus L-carbocysteine and for tipepidine hibenzate alone. It has now been three years since the onset of the disease, and no sequelae have been observed. Although tipepidine hibenzate is a drug frequently used for pediatric patients, it should be administered with caution because of its potential to cause SJS.

Development of a carbocysteine 10% + urea 5% cream for the topical treatment of congenital ichthyosis.

OBJECTIVE: Optimization of a topical formula of N-acetylcysteine and urea for  the topical treatment of ichthyosis. METHOD: We reviewed the chemical structure of the N-acetylcysteine molecule  and its metabolic processes. A search was conducted of possible alternative  molecules with a chemical structure similar to that of N-acetylcysteine that  could have improved organoleptic properties. The following databases were  used: PubChem®, Botplus®, the Drug Information Centre of the Spanish  Agency of Medicines and Medical Devices. The molecule selection criteria were  as follows: structural similarity, same therapeutic group, same mechanism of  action, same authorized indication, absence of unpleasant smell, and being  marketed as raw material in Spain. To complete the pharmaceutical  development and validation of the compound, several tests and controls were  conducted following the emulsion production procedure of the National  Formulary. In order to establish the validity period, we followed the  recommendations of the "Guide to Good Drug Preparation Practices in Hospital  Pharmacy Services". RESULTS: N-acetylcysteine has a free sulfhydryl group, which is responsible for  its smell, and undergoes deacetylation. Its main metabolites are cystine and  cysteamine. The following molecules were assessed: cystine, cysteamine,  carbocisteine, cysteine and methionine. Carbocisteine was selected because it met all the selection criteria. Carbocisteine is  ractically insoluble in water and soluble in mineral acids and alkaline hydroxides solutions. Unlike N-acetylcysteine, it does not have a fetid smell. It reaches its  maximum stability at pH 5.5 to 7.5. The composition of the compound (100 g)  was as follows: carbocisteine (10 g), urea (5 g), glycerine (15 g), water (44  mL), sodium hydroxide (1 g), and Neo PCL® Oil/Water (O/W) (25 g). It has an expiration period of 30 days. The organoleptic characteristics, emulsion type,  and pH remained stable within the established expiration period. The  arbocisteine compound has been incorporated into the group of topical  treatments available for the treatment of patients with ichthyosis in our  hospital. CONCLUSIONS: The carbocisteine molecule is a good therapeutic alternative that  lacks the unpleasant smell of N-acetylcysteine. The  arbocisteine compound developed has been included as topical treatment for  ichthyosis due to its tolerability, acceptability, and effectiveness in the  treatment of patients affected by this genodermatosis.

OBJETIVO: Optimización de una fórmula magistral tópica de N-acetilcisteína y urea para el tratamiento tópico de la ictiosis.Método: Se revisó la estructura química de la molécula de N-acetilcisteína y  sus procesos metabólicos. Se realizó una búsqueda de posibles moléculas  alternativas con una estructura química similar a la N-acetilcisteína que  pudiesen mejorar sus propiedades organolépticas. Bases de datos: PubChem®, Botplus®, Centro de Información de Medicamentos de la  Agencia Española de Medicamentos y Productos Sanitarios. Criterios de  selección de la molécula: similitud estructural, mismo grupo terapéutico,  mismo mecanismo de acción, misma indicación autorizada, ausencia de olor desagradable y estar comercializada como materia prima en España. Para el desarrollo galénico y validación de la fórmula se realizaron varios  ensayos y controles siguiendo el procedimiento de elaboración de emulsiones del Formulario Nacional. Para establecer el periodo de validez se  siguieron las recomendaciones de la "Guía de buenas prácticas de preparación  de medicamentos en los servicios de farmacia hospitalaria". RESULTADOS: La N-acetilcisteína presenta grupo sulfhidrilo libre, responsable del olor, sufre desacetilación y sus principales metabolitos son cistina y cisteamina. Las moléculas evaluadas fueron: cistina, cisteamina, carbocisteína, cisteína y metionina. Se seleccionó la carbocisteína  por  cumplir todos los criterios de selección. La carbocisteína es prácticamente insoluble en agua y soluble en disoluciones de ácidos minerales e hidróxidos  alcalinos. A diferencia de la N-acetilcisteína, carece de olor fétido.Presenta su  máxima estabilidad a pH 5,5-7,5. La composición de la fórmula magistral (100  g): carbocisteína (10 g), urea (5 g), glicerina (15 g), agua (44 ml), hidróxido  sódico (1 g) y Neo PCL® Oil/Water (O/W) (25 g). Periodo de caducidad: 30  días. Los caracteres organolépticos, signo de la emulsión y pH permanecieron  estables durante el periodo de caducidad establecido. La fórmula magistral de  carbocisteína elaborada se ha incorporado al arsenal de tratamientos tópicos  disponibles para los pacientes con ictiosis de nuestro centro. CONCLUSIONES: La molécula de carbocisteína resultó ser una buena alternativa  terapéutica que subsana el olor desagradable de la N-acetilcisteína. La fórmula  magistral de carbocisteína desarrollada fue incluida como tratamiento tópico de  la ictiosis gracias a su tolerabilidad, aceptabilidad y efectividad en el  tratamiento de pacientes afectos de esta genodermatosis.

Combining Powder Formulations of Drugs with Food and Beverages to Improve Palatability.

The taste of medicines can significantly affect patient adherence. Pediatric patients often cannot take powder medicines because of their unpleasant taste. Therefore, patients' parents and health care professionals, including pharmacists, often combine medicines with food or beverages to make them easier for pediatric patients to consume because this can reduce their unpleasant taste. The purpose of this study was to evaluate the palatability of powder formulations of azithromycin and carbocysteine and explore their combination with food or beverages to improve palatability for pediatric patients. We quantitatively evaluated the palatability of powder formulations by performing the gustatory sensation test using the visual analog scale score. The gustatory sensation tests were performed on 16 healthy adult volunteers (age 23.0 ± 2.6 years) and indicated that some food and beverages improved the palatability of the powder formulations of azithromycin and carbocysteine. The results of this study indicate that ice cream improves the palatability of azithromycin, while yogurt improves the palatability of carbocysteine. Moreover, the subjects recommended these same combinations for pediatric patients. This study suggests that some foods and beverages improve the palatability of powder formulations, thereby decreasing the possibility that pediatric patients will refuse medications because of their unpleasant taste.

Use of mucolytics in COPD: A Delphi consensus study.

BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

Airway clearance techniques and use of mucoactive agents for adult critically ill patients with acute respiratory failure: a qualitative study exploring UK physiotherapy practice.

OBJECTIVES: To explore and describe current UK physiotherapy practice relating to airway clearance techniques and mucoactive agents in critically ill adult patients with acute respiratory failure in the intensive care unit. DESIGN: A descriptive, qualitative study using focus group interviews. Focus groups were audio-recorded, independently transcribed, and data analysed thematically. Participants Senior, experienced physiotherapists, clinically active in critical care. RESULTS: Fifteen physiotherapists participated in four interview sessions. Five themes emerged describing airway clearance techniques: 'Repertoire of airway clearance techniques', 'Staffing and skillset', 'Commencing respiratory physiotherapy', 'Technique selection', and 'Determining effectiveness' were themes related to airway clearance techniques. Five themes were also identified in relation to mucoactive agents: 'Use in clinical practice', 'Decision to commence', 'Selection of agent', 'Stopping mucoactive agents', and 'Determining effectiveness'. A summary of key features of standard practice was developed. CONCLUSIONS: Standard UK physiotherapy practice of airway clearance techniques is variable, but patient-centred and targeted to individual need, with adjunctive use of mucoactive agents to enhance and optimise patient management if required. Based on this study, key features of airway clearance techniques have been summarised to help capture standard care, which could be used in future trials involving ACT as part of usual care.

Enhancement of ciliary beat amplitude by carbocisteine in ciliated human nasal epithelial cells.

OBJECTIVE: Carbocisteine (CCis), a mucoactive agent, is used to improve the symptoms of sinonasal diseases. However, the effect of CCis on nasal ciliary beating remains uncertain. We examined the effects of CCis on ciliary beat distance (CBD, an index of amplitude), and ciliary beat frequency (CBF) in ciliated human nasal epithelial cells (cHNECs) in primary culture. METHODS: The cHNECs were prepared from the nasal tissue resected from patients required surgery for chronic sinusitis (CS) or allergic rhinitis (AR). CBD and CBF were measured using videomicroscopy equipped with a high-speed camera. RESULTS: CCis increased CBD by 30%, but not CBF, and decreased intracellular Cl- concentration ([Cl- ]i ) in cHNECs. The CCis' actions were mimicked by the Cl- -free NO3- solution. In contrast, prior treatment of NPPB (20 µM) or CFTR(inh)-172 (1 µM), which increased [Cl- ]i by 20%, decreased CBF by 10% and CBD by 25% and inhibited the CCis' actions. However, prior treatment of T16Ainh-A01 (10 µM) did not inhibit the CCis' actions, although it decreased [Cl- ]i by 10% and CBD by 15%. Thus, CCis stimulates Cl- channels including cystic fibrosis transmembrane conductance regulator (CFTR). Moreover, CCis enhanced the transport of microbeads driven by the beating cilia in cHNECs. The CCis actions were similar in cHNECs from both types of pateints. CONCLUSION: CCis increased CBD by 30% in cHNECs via an [Cl- ]i decrease stimulated by activation of Cl- channels, including CFTR. CCis may stimulate nasal mucociliary clearance by increasing CBD in patients contracting CS or AR. LEVEL OF EVIDENCE: NA. Laryngoscope, 130:E289-E297, 2020.

Phenylalanine 4-monooxygenase: the "sulfoxidation polymorphism".

1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age.2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown.3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.

Late-onset interstitial nephritis in a patient with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe hypersensitivity drug reaction affecting the skin and multiple internal organ systems. We report a 47-year-old man with DIHS/DRESS and comorbidities (fulminant type 1 diabetes mellitus, valsartan-induced photosensitivity, vitiligo and acute interstitial nephritis). Although acute interstitial nephritis usually appears in the early phase, his is a rare case of acute interstitial nephritis more than 2 years after the onset of DIHS/DRESS.

Long-term treatment with clarithromycin and carbocisteine improves lung function in chronic cough patients with chronic rhinosinusitis.

PURPOSE: Chronic cough is a common complaint. Because the pathophysiology of chronic cough is complicated, the management of chronic cough is challenging. To the best of our knowledge, no previous study has examined the effect of macrolide antibiotics in chronic cough patients with chronic rhinosinusitis. The purpose of this study is to determine the changes in lung function for chronic cough patients with chronic rhinosinusitis who are treated by clarithromycin and carbocisteine. MATERIALS AND METHODS: Thirty-two chronic cough patients with chronic rhinosinusitis were recruited. Patients using inhaled corticosteroids and/or a bronchodilator, asthmatic patients, and patients with abnormal findings on auscultation and/or chest X-ray examination were excluded from this study. The patients received low-dose clarithromycin treatment for 3 months. Both before and after the treatment, a computed tomography (CT) scan of the paranasal sinuses, lung function test, peripheral blood test, and sino-nasal outcome test (SNOT-20) were applied. RESULTS: Both the lung function and Lund-MacKay CT scores were improved by the long-duration therapy with macrolide antibiotics. The change in obstructive pulmonary function and the improvement of the CT score in each subject were significantly correlated. SNOT scores also improved after the treatment. CONCLUSIONS: The macrolide antibiotics treatment has beneficial effects on lung function in non-asthmatic chronic cough patients with normal chest X-ray findings. The improvement of chronic rhinosinusitis may have some role in the lung condition. Upper respiratory tract examination and treatment may be useful for the management of chronic cough.

A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis: a protocol for the CLEAR clinical trial.

BACKGROUND: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. METHODS: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care - the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. DISCUSSION: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. TRIAL REGISTRATION: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). SPONSOR: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: v3.0 Final_14052018.

Carbocisteine inhibits the expression of Muc5b in COPD mouse model.

BACKGROUND: Cigarette smoke (CS) results in chronic mucus hypersecretion and airway inflammation, contributing to COPD pathogenesis. Mucin 5B (MUC5B) and mucin 5 AC (MUC5AC) are major mucins implicated in COPD pathogenesis. Carbocisteine can reduce mucus viscosity and elasticity. Although carbocisteine decreased human elastase-induced MUC5AC expression in vitro and reduced MUC5AC expression that alleviated bacteria adhesion and improved mucus clearance in vivo, the roles of carbocisteine in inducing MUC5B expression in COPD remain unclear. METHODS: To investigate the Muc5b/Muc5ac ratio and the gene and protein levels of Muc5b in COPD and carbocisteine intervention models. C57B6J mice were used to develop COPD model by instilling intratracheally with lipopolysaccharide on days 1 and 14 and were exposed to CS for 2 hr twice a day for 12 weeks. Low and high doses of carbocisteine 112.5 and 225 mg/kg/d, respectively, given by gavage administration were applied for the treatment in COPD models for the same duration, and carboxymethylcellulose was used as control. Carbocisteine significantly attenuated inflammation in bronchoalveolar lavage fluid and pulmonary tissue, improved pulmonary function and protected against emphysema. RESULTS: High-dose carbocisteine significantly decreased the overproduction of Muc5b (P<0.01) and Muc5ac (P<0.001), and restored Muc5b/Muc5ac ratio in COPD model group (P<0.001). Moreover, the Muc5b/Muc5ac ratio negatively correlated with pro-inflammatory cytokines such as IL-6 and keratinocyte-derived cytokine, mean linear intercept, functional residual capacity and airway resistance, but positively correlated with dynamic compliance. CONCLUSIONS: These findings suggest that carbocisteine attenuated Muc5b and Muc5ac secretion and restored Muc5b protein levels, which may improve mucus clearance in COPD.

A prospective study of the effects of carbocysteine lysine salt on frequency of exacerbations in COPD patients treated with or without inhaled steroids.

OBJECTIVE: COPD is one of the major causes of morbidity and mortality worldwide and represents one of the most important issues for public health. Frequent exacerbations induce a faster decline in lung function and poorer quality of life, increase mortality, and have a socio-economic impact with a high burden in terms of resources and healthcare costs. The clinical trials evaluated the effect of mucolytics in COPD and showed that the long-term carbocysteine, associated with bronchodilators, anticholinergics, and steroids, reduces the frequency of exacerbations and improves the quality of life. PATIENTS AND METHODS: The aim of this prospective real-life study was to evaluate the long-term impact on exacerbations (at 1 year) in COPD patients treated with carbocysteine lysine salt (single dose of 2.7 g once a day) in addition to background therapy with or without inhaled steroids. RESULTS: In a total of 155 evaluable patients, our study showed that the addition of a single dose of carbocysteine lysine salt to background therapy determines a statistically significant reduction of the average number of exacerbations vs. the number observed in the previous year (from 1.97±0.10 to 1.03±0.11; p<0.01), irrespective of treatment with or without inhaled steroids. In particular, in patients with ≥2 exacerbations in the previous year, the addition of carbocysteine lysine salt resulted in a statistically significant reduction in the exacerbations rate from 69% to 33% and from 58% to 25%, respectively (p<0.01) in patients with or without inhaled steroids. CONCLUSIONS: In summary, our data highlighted the efficacy of long-term administration of a single daily dose of carbocysteine lysine salt (2.7 g/day) in reducing the number and rate of exacerbations in COPD patients, independently from the use of inhaled steroids.

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

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 .