Role of airway epithelium in viral respiratory infections: Can carbocysteine prevent or mitigate them?

Alterations in airway epithelial homeostasis increase viral respiratory infections risk. Viral infections frequently are associated with chronic obstructive pulmonary disease (COPD) exacerbations, events that dramatically promote disease progression. Mechanism promoting the main respiratory viruses entry and virus-evocated innate and adaptive immune responses have now been elucidated, and an oxidative stress central role in these pathogenic processes has been recognized. Presence of reactive oxygen species in macrophages and other cells allows them to eliminate virus, but its excess alters the balance between innate and adaptive immune responses and proteases/anti-proteases and leads to uncontrolled inflammation, tissue damage, and hypercoagulability. Different upper and lower airway cell types also play a role in viral entry and infection. Carbocysteine is a muco-active drug with anti-oxidant and anti-inflammatory properties used for the management of several chronic respiratory diseases. Although the use of anti-oxidants has been proposed as an effective strategy in COPD exacerbations management, the molecular mechanisms that explain carbocysteine efficacy have not yet been fully clarified. The present review describes the most relevant features of the common respiratory virus pathophysiology with a focus on epithelial cells and oxidative stress role and reports data supporting a putative role of carbocysteine in viral respiratory infections.

[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.

Desarrollo de una crema de carbocisteína10% + urea 5% para el tratamiento tópico de las ictiosis congénitas / Development of a carbocysteine 10% + urea 5% cream for the topical treatment of congenital ichthyosis

Objetivo: Optimización de una fórmula magistral tópica de N-acetilcisteínay urea para el tratamiento tópico de la ictiosis.Método: Se revisó la estructura química de la molécula de N-acetilcisteínay sus procesos metabólicos. Se realizó una búsqueda de posiblesmoléculas alternativas con una estructura química similar a la N-acetilcisteínaque 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 selecciónde la molécula: similitud estructural, mismo grupo terapéutico, mismomecanismo de acción, misma indicación autorizada, ausencia de olordesagradable y estar comercializada como materia prima en España. Parael desarrollo galénico y validación de la fórmula se realizaron varios ensayosy controles siguiendo el procedimiento de elaboración de emulsionesdel Formulario Nacional. Para establecer el periodo de validez se siguieronlas recomendaciones de la “Guía de buenas prácticas de preparación demedicamentos en los servicios de farmacia hospitalaria”.Resultados: La N-acetilcisteína presenta grupo sulfhidrilo libre, responsabledel olor, sufre desacetilación y sus principales metabolitos soncistina 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 prácticamenteinsoluble en agua y soluble en disoluciones de ácidos minerales e hidróxidosalcalinos. A diferencia de la N-acetilcisteína, carece de olor fétido.Presenta su máxima estabilidad a pH 5,5-7,5. La composición de la fórmulamagistral (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.

Objective: Optimization of a topical formula of N-acetylcysteine andurea for the topical treatment of ichthyosis.Method: We reviewed the chemical structure of the N-acetylcysteinemolecule and its metabolic processes. A search was conducted of possiblealternative molecules with a chemical structure similar to that of N-acetylcysteinethat could have improved organoleptic properties. The followingdatabases were used: PubChem®, Botplus®, the Drug Information Centreof the Spanish Agency of Medicines and Medical Devices. The moleculeselection criteria were as follows: structural similarity, same therapeuticgroup, same mechanism of action, same authorized indication, absenceof unpleasant smell, and being marketed as raw material in Spain. To completethe pharmaceutical development and validation of the compound,several tests and controls were conducted following the emulsion productionprocedure of the National Formulary. In order to establish the validityperiod, we followed the recommendations of the “Guide to Good DrugPreparation Practices in Hospital Pharmacy Services”.Results: N-acetylcysteine has a free sulfhydryl group, which is responsiblefor its smell, and undergoes deacetylation. Its main metabolites arecystine and cysteamine. The following molecules were assessed: cystine,cysteamine,carbocisteine, cysteine and methionine. Carbocisteine practicallyinsoluble in water and soluble in mineral acids and alkaline hydroxidessolutions. Unlike N-acetylcysteine, it does not have a fetid smell. It reachesits 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 expirationperiod.

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.

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.

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.

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 .

Inhibitory Effects of S-carboxymethylcystein on Goblet Cell Proliferation in Cultured Epithelium.

BACKGROUND: The influence of S-carboxymethylcystein (S-CMC) on the proliferation ability of goblet cells in nasal polyp epithelium in response to inflammatory stimulation was examined. METHODS: The subjects were patients with chronic paranasal sinusitis. An epithelial cell culture system was established using nasal polyp mucosa excised during endoscopic paranasal sinus surgery. The samples were divided into 4 groups (group a: control group, group b: 10 ng/mL tumor necrosis factor-α (TNF-α) treatment group, group c: 10-7 M S-CMC and 10 ng/mL TNF-α treatment group, group d: 10-5 M S-CMC and 10 ng/mL TNF-α treatment group). The total number of epithelial cells and number of goblet cells were measured under a microscope, and the ratio of goblet cells to the total number of epithelial cells was calculated. RESULTS: In group b, 10 ng/mL of TNF-α significantly increased the number of goblet cells compared with group a, suggesting involvement of TNF-α in goblet cell proliferation. In addition, the number of goblet cells significantly decreased in group d compared with that in group b, and it also decreased in group c compared with that in group b, although the difference was not significant, and the decrease was smaller than that in group d, suggesting that S-CMC inhibited goblet cell proliferation in a concentration-dependent manner. CONCLUSION: TNF-α promoted goblet cell proliferation in nasal polyps, suggesting its influence on nasal polyp formation. As S-CMC inhibited inflammatory stimulation-induced goblet cell proliferation in nasal polyp epithelium, it may be useful for the treatment of sinusitis.

Efficacy of carbocisteine in the treatment of chronic obstructive pulmonary disease and impact on the quality of life.

Aim To investigate the effects of carbocisteine treatment in the reduction of frequency of productive cough episodes, preventing disease progression and improving the quality of life as well as the tolerability of the administered treatment and patient compliance during the study. Methods This observational, non-interventional, multicenter, cohort study included 501 patients with chronic obstructive pulmonary disease (COPD) who were administrated carbocisteine capsules 375 mg and followed up during the next 15 days. The patients were observed at 3 points, baseline and two additional assessments. General clinical condition of patients, along with the spirometry testing at all three points were examined. Thr quality of life was assessed on the 1st and 3rd observation with Leicester Cough Questionnaire. Tolerability and patient compliance were measured throughout the study. Results There was a significant change of forced expiratory volume in 1 second (FEV1) status between the second and third observation (p=0.002). Examination of general symptoms showed a statistically significant reduction in cough by 74.9%, in sputum production by 48.5%, in dyspnea by 29% and in fatigue by 50%. After the administration of carbocisteine the median value of overall quality of life was 3.79 (3.63 - 3.89). Conclusion 375mg carbocisteine capsules were found to be effective and well-tolerated in the treatment of COPD, with a small percentage of reported mild adverse reactions and with a significant improvement of quality of life.

Effect of carbocisteine on patients with COPD: a systematic review and meta-analysis.

BACKGROUND: COPD is the fourth leading cause of death in the world. It is a common, progressive, treatable and preventable disease. The exacerbation of COPD is associated with the peripheral muscle force, forced expiratory volume in 1 second (FEV1), the quality of life and mortality. Many studies indicated that the mucoactive medicines could reduce the exacerbations of COPD. This study summarized the efficacy of carbocisteine as a treatment for COPD. METHODS: We searched the randomized controlled trials (RCTs) following electronic bibliographic databases: MedLine, Embase, Cochrane Library and Web of Science. We additionally searched gray literature database: OpenSIGLE. We also additionally searched the clinical trial registers: ClinicalTrials.gov register and International Clinical Trials Registry Platform Search Portal. We used RCTs to assess the efficacy of the treatments. We included studies of adults (older than 18 years) with COPD. We excluded studies that were published as protocol or written in non-English language (Number 42016047078). FINDINGS: Our findings included data from four studies involving 1,357 patients. There was a decrease in the risk of the rate of total number of exacerbations with carbocisteine compared with placebo (-0.43; 95% confidence interval [CI] -0.57, -0.29, P<0.01). Carbocisteine could also improve the quality of life (-6.29; 95% CI -9.30, -3.27) and reduce the number of patients with at least one exacerbation (0.86; 95% CI 0.78, 0.95) compared with placebo. There was no significant difference in the FEV1 and adverse effects and the rate of hospitalization. INTERPRETATION: Long-term use of carbocisteine (500 mg TID) may be associated with lower exacerbation rates, the smaller number of patients with at least one exacerbation and higher quality of life of patients with COPD.

Impact of Mucolytic Agents on COPD Exacerbations: A Pair-wise and Network Meta-analysis.

Mucolytics are potentially useful for the management of chronic obstructive pulmonary disease (COPD), although there is conflicting advice on their use in different guideline documents. Furthermore, there is paucity of data comparing the efficacy of the different mucolytic agents in reducing the odds of COPD exacerbations. We performed pair-wise and network meta-analyses to evaluate the impact of mucoly-tics in COPD. Randomized clinical trials lasting at least 3 months and investigating the effects of mucolytics on COPD exacerbations were identified from published studies and repository databases. Mucolytics significantly reduced the odds of exacerbation vs. placebo (11 studies analyzed: odds ratio (OR) 0.51, 95% confidence interval (CI) 0.39-0.67; p < 0.001). The most effective drugs were carbocysteine, erdosteine, and N-acetylcysteine 1,200 mg/day (SUCRA 68.0-79.0%), whereas the OR was similar to placebo for ambroxol and N-acetylcysteine 600 mg/day. Only N-acetylcysteine 1,200 mg/day significantly protected against exacerbations vs. placebo (2 studies analyzed: OR 0.56, 95% CI 0.35-0.92; p < 0.05; high quality of evidence). A signal of effectiveness was detected for carbocysteine (2 studies analyzed: OR 0.45, 95% CI 0.20-1.01; p ≥ 0.05; moderate quality of evidence). Specific differences in study designs and patient-related characteristics, such as history of exacerbations and ethnicity, were potential effect modifiers for our statistical models, whereas neither respiratory function nor the use of corticosteroids influenced the analysis. This meta-analysis demonstrates that mucolytics are useful in preventing COPD exacerbations as maintenance add-on therapy to patients with frequent exacerbations. The effectiveness of mucolytics is independent of the severity of airway obstruction and the use of inhaled corticosteroids.

Clinical practice guidelines for the diagnosis and management of otitis media with effusion (OME) in children in Japan, 2015.

OBJECTIVE: To (1) indicate the definition, the disease state, methods of diagnosis, and testing for otitis media with effusion (OME) in childhood (<12 years); and (2) recommend methods of treatment in accordance with the evidence-based consensus reached by the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of OME in Children. METHODS: We produced Clinical Questions (CQs) concerning the treatment of OME and searched the literature published until April 2014 according to each theme including CQ, the definition, the disease state, the method of diagnosis, and examination. The recommendations are based on the results of the literature review and the expert opinion of the Subcommittee. RESULTS: Because children with Down's syndrome and cleft palate are susceptible to OME, we categorized OME into low-risk and high-risk groups (e.g., Down's syndrome and cleft palate), and recommended the appropriate treatment for each group. CONCLUSION: In the clinical management of OME in children, Japanese Clinical Practice Guidelines recommend management not only of OME itself, such as effusion in the middle ear and pathological changes in the tympanic membrane, but also pathological abnormality in surrounding organs, such as infectious or inflammatory diseases.

Efficacy and tolerability of a polysaccharide-resin-honey based cough syrup as compared to carbocysteine syrup for children with colds: a randomized, single-blinded, multicenter study.

BACKGROUND: Available pediatric treatments for acute cough are limited by lack of demonstrated efficacy. The objective of this trial is to compare the effects of a polysaccharide-resin-honey based cough syrup, and carbocysteine syrups on nocturnal and daytime cough associated with childhood upper respiratory tract infections (URIs). METHODS: Using a single-blind randomization design, the study recruited children from 4 general pediatric community clinics. Participants included 150 children aged 2 to 5 years with an URI, nocturnal and daytime cough and illness duration of ≤7 days. To be eligible, children had to be free of medication on the day before presentation. A survey was administered to parents on 4 consecutive days beginning from the day of presentation in clinic. Children received the study preparation on the first evening and then 3 times per day for 3 further days. Main outcome measures were cough frequency, cough severity, bothersome nature of cough, and quality of sleep for both child and parent. RESULTS: Both preparations were well tolerated and cough improved over the study period. After one night and on all survey days, there was a significantly better result for polysaccharide-resin-honey (P<0.05) for all the main outcome measures. The trend of improvement over the 4 days was steeper for polysaccharide-resin-honey (P<0.05) with regards to all cough parameters. CONCLUSIONS: Both polysaccharide-resin-honey and carbocysteine cough syrups were well tolerated in children over 2 years of age. The polysaccharide-resin-honey syrup was associated with a more rapid and greater improvement in all clinical cough symptoms measured, beginning from the first night of therapy. Both nocturnal and daytime cough improved, as did sleep quality for both children and parents.

Effect of CArbocisteine in Prevention of exaceRbation of chronic obstructive pulmonary disease (CAPRI study): An observational study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic and progressive lung disease characterized by irreversible airflow obstruction, airway inflammation, oxidative stress and, often, mucus hypersecretion. The aim of this study is to determine if carbocisteine, a mucolytic and antioxidant agent, administered daily for 12 months, can reduce exacerbation frequency in COPD patients. METHODS: This observational study was conducted in Naples (population approximately 1000,000), Italy. It included 85 out-patients (mean age of 67.8 ± 8.6 years) followed by Clinic of Respiratory Diseases of the University Federico II. Every patient underwent spirometry demonstrating airflow obstruction not fully reversible according to ERS/ATS criteria for COPD diagnosis (Tiffenau index less than 70% after administration of salbutamol, a beta2 agonist drug). Patients enrolled had diagnosed COPD since 2 years and suffered at least one exacerbation in the previous year. None of the patients had been treated with carbocisteine or other mucolytic agent for a longer period of time than 7 days and no more than 4 times in the previous year to the enrollment. All of them assumed daily 2.7 g of carbocisteine lysine salt for a year in addition to their basic therapy. RESULTS: The comparison of exacerbation frequency between the previous year (T0) and the end of study treatment (T12), documents a statistically significant reduction of exacerbations(number of exacerbations at T0: 2 [1,3] vs number of exacerbations at T12: 1 [1,2]; p < 0.001).Quality of life was also reported and showed a statistically significant improvement at the end of the study (p < 0.001).We did not find correlation between reducing exacerbation frequency and exposure to cigarette smoking, passive smoking exposure in childhood, the use of inhaled steroids, the level of education of our patients and the GOLD stadium. INTERPRETATION: Daily administration of a mucolytic drug such as carbocisteine for prolonged periods in addition to the bronchodilator therapy can be considered a good strategy for reducing exacerbation frequency in COPD.

Antioxidant Carbocysteine Treatment in Obstructive Sleep Apnea Syndrome: A Randomized Clinical Trial.

OBJECTIVE: This study aimed to examine the effects of carbocysteine in OSAS patients. METHODS: A total of 40 patients with moderate to severe obstructive sleep apnea syndrome (OSAS) were randomly divided into two groups. One group was treated with 1500 mg carbocysteine daily, and the other was treated with continuous positive airway pressure (CPAP) at night. Before treatment and after 6 weeks of treatment, all patients underwent polysomnography and completed questionnaires. Treatment compliance was compared between the two groups. Plasma was collected for various biochemical analyses. Endothelial function was assessed with ultrasound in the carbocysteine group. RESULTS: The proportion of patients who fulfilled the criteria for good compliance was higher in the carbocysteine group (n = 17) than in the CPAP group (n = 11; 100% vs. 64.7%). Compared with baseline values, the carbocysteine group showed significant improvement in their Epworth Sleepiness Scale score (10.18 ± 4.28 vs. 6.82 ± 3.66; P ≤ 0.01), apnea-hypopnea index (55.34 ± 25.03 vs. 47.56 ± 27.32; P ≤ 0.01), time and percentage of 90% oxygen desaturation (12.66 (2.81; 50.01) vs. 8.9 (1.41; 39.71); P ≤ 0.01), and lowest oxygen saturation level (65.88 ± 14.86 vs. 70.41 ± 14.34; P ≤ 0.01). Similar changes were also observed in the CPAP group. The CPAP group also showed a decreased oxygen desaturation index and a significant increase in the mean oxygen saturation after treatment, but these increases were not observed in the carbocysteine group. Snoring volume parameters, such as the power spectral density, were significantly reduced in both groups after the treatments. The plasma malondialdehyde level decreased and the superoxide dismutase and nitric oxide levels increased in both groups. The endothelin-1 level decreased in the CPAP group but did not significantly change in the carbocysteine group. Ultrasonography showed that the intima-media thickness decreased (0.71 ± 0.15 vs. 0.66 ± 0.15; P ≤ 0.05) but that flow-mediated dilation did not significantly change in the carbocysteine group. CONCLUSIONS: Oral carbocysteine slightly improves sleep disorders by attenuating oxidative stress in patients with moderate to severe OSAS. Carbocysteine may have a role in the treatment of OSAS patients with poor compliance with CPAP treatment. However, the efficiency and feasibility of carbocysteine treatment for OSAS needs further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02015598.

Clinical effects of clarithromycin on persistent inflammation following Haemophilus influenzae-positive acute otitis media.

CONCLUSION: Additional treatment with clarithromycin (CAM) reduced persistent middle ear inflammation after acute otitis media (AOM) caused by Haemophilus influenzae in children. CAM is a treatment option for persistent inflammation following AOM and to prevent continuing otitis media with effusion. OBJECTIVE: We conducted a clinical study to evaluate a new method of treatment for persistent inflammation after AOM in children. METHODS: H. influenzae-infected children with AOM were treated acutely with antimicrobial agents, after which those still demonstrating effusion of the middle ear cavity received additional treatment with carbocysteine (S-CMC) alone or S-CMC combined with clarithromycin (CAM) for 1 week. The two regimens were compared in terms of clinical effects. RESULTS: After the initial acute treatment, many patients still showed abnormal otoscopic findings. At the completion of additional treatment, there were no significant differences between the two treatment groups. However, 1 week after completion of additional treatment, the prevalence of a diminished light reflex was significantly lower in the CAM + S-CMC group than in the S-CMC group (p = 0.017). The prevalence of redness of the tympanic membrane also tended to be lower in the combined treatment group than in those receiving a single drug (p = 0.097).

Sistema GRADE: metodología para la realización de recomendaciones para la práctica clínica / GRADE: Methodology for formulating and grading recommendations in clinical practice

Las guías de práctica clínica proporcionan recomendaciones sobre los beneficios y desventajas de diferentes intervenciones disponibles en la asistencia sanitaria. Su adecuado desarrollo e implementación permitirían reducir la variabilidad en la práctica clínica, así como mejorar su calidad y su seguridad. El sistema GRADE es una herramienta que permite evaluar la calidad de la evidencia y graduar la fuerza de las recomendaciones en el contexto de desarrollo de guías de práctica clínica, revisiones sistemáticas o evaluación de tecnologías sanitarias. El objetivo de este artículo es describir las principales características del sistema GRADE a través de ejemplos relevantes en el contexto de la atención primaria

Clinical practice guidelines (CPG) provide recommendations on the benefits and harms of different healthcare interventions. Proper CPG development and implementation can potentially reduce variability in clinical practice while improving its quality and safety. The GRADE system is used to assess the quality of evidence and to grade the strength of recommendations in the context of the development of CPGs, systematic reviews or health technology assessments. The aim of this article is to describe the main characteristics of the GRADE system through relevant examples in the context of primary care