Federico Saibene

Levodropropizine for treating cough in adult and children: a meta-analysis of published studies

BackgroundCough is one of the most common symptoms for which patients seek medical attention from primary care physicians and lung specialists. About 40% of the population at any one time report cough.Cough is associated with significantly impaired health-related quality of life.Levodropropizine is an effective and very well tolerated peripheral antitussive drug. We want to compare it to central cough suppressants efficacy (opioids and non-opioids) that may be associated with side effects limiting their use.MethodsAfter a comprehensive literature search, a meta-analysis of 7 clinical studies of levodropropizine vs. control, including a total of 1,178 patients, was performed with the aim to evaluate the overall comparative efficacy of levodropropizine in the pediatric and adult population.Three electronic databases and reference list were used to search for studies that assessed the efficacy of levodropropizine for treating cough in children and adults using as standardized efficacy parameters the cough frequency and severity, and number of night awakenings as outcome parameters.ResultsThe meta-analysis of all standardized efficacy parameters showed a highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p = 0.0015).The heterogeneity test for the efficacy outcome was not statistically significant (p = 0.0534).Seven studies met out inclusion criteria. A meta-analysis of the eligible ones showed a statistically significant difference in the overall anti-tussive effect of levodropropizine versus control (p = 0.0015).ConclusionsThis analysis indicates that levodropropizine is an effective antitussive drug in children and adults, with statistically significant better overall efficacy outcomes vs. central antitussive drugs (codeine, cloperastine, dextromethorphan) in terms of reducing cough intensity and frequency, and nocturnal awakenings. This result further reinforces the favorable benefit/risk profile of levodropropizine in the management of cough. The efficacy of levodropropizine in the treatment of cough in children and adults is higher than that of the common centrally-acting anti-tussive.

Effects of Carbocysteine and Beclomethasone on Histone Acetylation/Deacetylation Processes in Cigarette Smoke Exposed Bronchial Epithelial Cells.

Histone deacetylase expression/activity may control inflammation, cell senescence, and responses to corticosteroids. Cigarette smoke exposure, increasing oxidative stress, may negatively affect deacetylase expression/activity. The effects of cigarette smoke extracts (CSE), carbocysteine, and beclomethasone dipropionate on chromatin remodeling processes in human bronchial epithelial cells are largely unknown. The present study was aimed to assess the effects of cigarette smoke, carbocysteine, and beclomethasone dipropionate on histone deacetylase 3 (HDAC3) expression/activity, N‐CoR (nuclear receptor corepressor) expression, histone acetyltransferases (HAT) (p300/CBP) expression, p‐CREB and IL‐1 m‐RNA expression, neutrophil chemotaxis. Increased p‐CREB expression was observed in the bronchial epithelium of smokers. CSE increased p‐CREB expression and decreased HDAC3 expression and activity and N‐CoR m‐RNA and protein expression. At the same time, CSE increased the expression of the HAT, p300/CBP. All these events increased acetylation processes within the cells and were associated to increased IL‐1 m‐RNA expression and neutrophil chemotaxis. The incubation of CSE exposed cells with carbocysteine and beclomethasone counteracted the effects of cigarette smoke on HDAC3 and N‐CoR but not on p300/CBP. The increased deacetylation processes due to carbocysteine and beclomethasone dipropionate incubation is associated to reduced p‐CREB, IL‐1 m‐RNA expression, neutrophil chemotaxis. These findings suggest a new role of combination therapy with carbocysteine and beclomethasone dipropionate in restoring deacetylation processes compromised by cigarette smoke exposure. J. Cell. Physiol. 232: 2851–2859, 2017.

Carbocysteine counteracts the effects of cigarette smoke on cell growth and on the SIRT1/FoxO3 axis in bronchial epithelial cells

BACKGROUND Cigarette smoke may accelerate cellular senescence by increasing oxidative stress. Altered proliferation and altered expression of anti-aging factors, including SIRT1 and FoxO3, characterise cellular senescence. The effects of carbocysteine on the SIRT1/FoxO3 axis and on downstream molecular mechanisms in human bronchial epithelial cells exposed to cigarette smoke are largely unknown. AIMS Aim of this study was to explore whether carbocysteine modulated SIRT1/FoxO3 axis, and downstream molecular mechanisms associated to cellular senescence, in a bronchial epithelial cell line (16-HBE) exposed to cigarette smoke. METHODS 16HBE cells were stimulated with/without cigarette smoke extracts (CSE) and carbocysteine. Flow cytometry and clonogenic assay were used to assess cell proliferation; western blot analysis was used for assessing nuclear expression of SIRT1 and FoxO3. The nuclear co-localization of SIRT1 and FoxO3 was assessed by fluorescence microscopy. Beta galactosidase (a senescence marker) and SIRT1 activity were assessed by specific staining and colorimetric assays, respectively. ChiP Assay and flow cytometry were used for assessing survivin gene regulation and protein expression, respectively. RESULTS CSE decreased cell proliferation, the nuclear expression of SIRT1 and FoxO3 and increased beta galactosidase staining. CSE, reduced SIRT1 activity and FoxO3 localization on survivin promoter thus increasing survivin expression. In CSE stimulated bronchial epithelial cells carbocysteine reverted these phenomena by increasing cell proliferation, and SIRT1 and FoxO3 nuclear expression, and by reducing beta galactosidase staining and survivin expression. CONCLUSIONS The study shows for the first time that carbocysteine may revert some senescence processes induced by oxidative stress due to cigarette smoke exposure.

WITHDRAWN: NSAID and Antitussives in Patients With Upper Respiratory Tract Infection-Related Cough: A Good Combination?

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Eur Respir J. 46 (2015) PA3852, http://dx.doi.org/10.1183/13993003.congress-2015.PA3852. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

A Randomized Clinical Trial Comparing the Effects of Antitussive Agents on Respiratory Center Output in Patients With Chronic Cough

BACKGROUND: Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2 rebreathing test in patients with chronic cough of any origin. METHODS: Twenty‐four outpatients (aged 39‐70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO2 for 5 min. Fractional end‐tidal CO2 (Fetco2) and inspiratory minute ventilation (Symboli) were continuously monitored. Changes in breathing pattern variables were also assessed. Symbol. No Caption available. RESULTS: At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P < .01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern. CONCLUSIONS: The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussive agents. TRIAL REGISTRY: European Union Clinical Trials Register (EudraCT No.: 2013‐004735‐68); URL: https://www.clinicaltrialsregister.eu/

Effects of beclomethasone and carbocysteine in histone acetylation/deacetylation processes of bronchial epithelial cells exposed to cigarette smoke

Histone deacetylase expression/activity may control inflammation, cell senescence and responses to corticosteroids. Cigarette smoke exposure, increasing oxidative stress, may negatively affect deacetylase expression/activity. The effects of cigarette smoke extracts (CSE), carbocysteine and beclomethasone on chromatin remodelling processes in human bronchial epithelial cells are largely unknown. The present study was aimed to assess the effects of cigarette smoke, carbocysteine and beclomethasone on histone deacetylase 3 (HDAC3)expression/activity, histone acetyltransferases expression (HAT), pCREB and IL-1 m-RNA expression, neutrophil chemotaxis and p53 protein expression. CSE decreased HDAC3 expression and activity and m-RNA expression of N-CoR (nuclear receptor corepressor). At the same time, CSE increased the expression of the HAT, p300. All these events increased acetylation within the cells thus contributing to increased pCREB expression, IL-1 m-RNA expression, neutrophil chemotaxis and p53 protein expression. The incubation of CSE exposed cells with carbocysteine and beclomethasone counteracted the effects of cigarette smoke on HDAC3 , N-CoR and p300. The increased deacetylation processes due to carbocysteine and beclomethasone incubation is associated to reduced pCREB, IL-1 m-RNA expression, neutrophil chemotaxis and p53 protein expression. These findings suggest a new role of combination therapy with beclomethasone and carbocysteine in restoring deacetylation processes compromised by cigarette smoke exposure. Funded by Consiglio Nazionale delle Ricerche and by Dompe.

Treatment Effect of Combination of Nsaid and Antitussives in Patients With URTI-Related Cough

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Eur Respir J. 46 (2015) PA3852, http://dx.doi.org/10.1183/13993003.congress-2015.PA3852. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Combination of NSAID and Antitussives in Treatment of URTI Related Cough: An Observational Study

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Eur Respir J. 46 (2015) PA3852, http://dx.doi.org/10.1183/13993003.congress-2015.PA3852. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Efficacy of Levodropropizine: 2 Meta-analyses in Pediatric and Adult Population

Cough has an impact on quality of life of children and adults, thus often requiring an empiric treatment with antitussive agents. Levodropropizine is a very well tolerated peripheral drug, while central cough suppressants may be associated with side effects, especially in children. The aim of our 2 metanalysis is to evaluate the overall comparative efficacy of levodropropizine in both children and adults. A first standardized metanalysis of 4 controlled clinical studies of levodropropizine (3 vs central antitussives, 1 vs placebo) included a total of 780 children. A second metanalysis of 7 controlled clinical studies of Levodropropizine (5 vs central drugs, 2 vs placebo) included 2633 patients, both children and adults. First metanalysis of all standardized efficacy parameters (cough frequency, severity, night awakenings,) in children, showed highly statistically significant difference in the overall antitussive efficacy in favor of Levodropropizine vs. controls (p = 0.001). Heterogeneity was not statistically significant (p=0.0619). Second metanalysis in adults and children alsoshowed highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p = 0.0044). Heterogeneity was not statistically significant (p=0.0856). Our two metanalysis indicate that Levodropropizine is an effective antitussive drug both in adults and children, with statistically significant better overall efficacy outcomes vs. central antitussives, in terms of reducing cough intensity, frequency and nocturnal awakenings. These results further reinforce the favorable benefit/risk profile of Levodropropizine in the management of cough in pediatric and adult settings.