Background: Carbocysteine is a mucoregulatory agent with anti-inflammatory properties used in chronic respiratory and otorhinolaryngological diseases. However, clinical evidence across indications remains heterogeneous. Methods: A systematic review and meta-analysis were conducted to assess the efficacy of oral carbocysteine in stable chronic conditions. PubMed, Cochrane Library, and ClinicalTrials.gov were searched up to February 2025. Eligible randomized controlled trials compared carbocysteine with placebo or standard treatments. Outcomes were meta-analyzed when reported in at least two studies. Results: Twenty RCTs were included. In COPD, a meta-analysis of incidence rates showed a pooled rate ratio of 0.48 (95% CI: 0.32 - 0.72; p < 0.001), reflecting a 52% reduction in exacerbations with carbocysteine. The mean number of exacerbations also declined significantly (SMD ？3.39; 95% CI: ？6.36 to ？0.42; p < 0.001), alongside improvements in QoL (SMD ？1.45; 95% CI: ？2.43 to ？0.48; p < 0.001). In otitis media with effusion, carbocysteine reduced effusion persistence and improved audiometric outcomes. In chronic bronchitis, benefits were observed in sputum viscosity and mucociliary clearance. Meta-analysis was not feasible in other conditions due to data limitations. Conclusions: Carbocysteine demonstrates consistent clinical benefits in COPD and otitis media with effusion. Further high-quality trials are warranted in other chronic indications.
References
[1]
Shen, Y., Huang, S., Kang, J., Lin, J., Lai, K., Sun, Y., et al. (2018) Management of Airway Mucus Hypersecretion in Chronic Airway Inflammatory Disease: Chinese Expert Consensus (English Edition). International Journal of Chronic Obstructive Pulmonary Disease, 13, 399-407. https://doi.org/10.2147/copd.s144312
[2]
Kim, Y. and Yoo, K.H. (2022) Mucus Plugs and Small Airway Dysfunction: An Important Concept in Airway Disease Pathophysiology. Allergy, Asthma & Immunology Research, 14, 151-152. https://doi.org/10.4168/aair.2022.14.2.151
[3]
Tarrant, B.J., Le Maitre, C., Romero, L., Steward, R., Button, B.M., Thompson, B.R., et al. (2017) Mucoactive Agents for Chronic, Non-Cystic Fibrosis Lung Disease: A Systematic Review and Meta-Analysis. Respirology, 22, 1084-1092. https://doi.org/10.1111/resp.13047
[4]
Ishibashi, Y., Takayama, G., Inouye, Y. and Taniguchi, A. (2010) Carbocisteine Normalizes the Viscous Property of Mucus through Regulation of Fucosylated and Sialylated Sugar Chain on Airway Mucins. European Journal of Pharmacology, 641, 226-228. https://doi.org/10.1016/j.ejphar.2010.05.045
[5]
Pace, E., Cerveri, I., Lacedonia, D., Paone, G., Sanduzzi Zamparelli, A., Sorbo, R., et al. (2022) Clinical Efficacy of Carbocysteine in COPD: Beyond the Mucolytic Action. Pharmaceutics, 14, Article No. 1261. https://doi.org/10.3390/pharmaceutics14061261
[6]
Paone, G., Lanata, L., Saibene, F., et al. (2019) A Prospective Study of the Effects of Carbocysteine Lysine Salt on Frequency of Exacerbations in COPD Patients Treated with or without Inhaled Steroids. European Review for Medical and Pharmacological Sciences, 23, 6727-6735.
[7]
Chalumeau, M. and Duijvestijn, Y.C. (2013) Acetylcysteine and Carbocysteine for Acute Upper and Lower Respiratory Tract Infections in Paediatric Patients without Chronic Broncho-Pulmonary Disease. Cochrane Database of Systematic Reviews, No. 5, CD003124. https://doi.org/10.1002/14651858.cd003124.pub4
[8]
Rogliani, P., Matera, M.G., Page, C., Puxeddu, E., Cazzola, M. and Calzetta, L. (2019) Efficacy and Safety Profile of Mucolytic/Antioxidant Agents in Chronic Obstructive Pulmonary Disease: A Comparative Analysis across Erdosteine, Carbocysteine, and N-Acetylcysteine. Respiratory Research, 20, Article No. 104. https://doi.org/10.1186/s12931-019-1078-y
[9]
Allegra, L., Cordaro, C.I. and Grassi, C. (1996) Prevention of Acute Exacerbations of Chronic Obstructive Bronchitis with Carbocysteine Lysine Salt Monohydrate: A Multicenter, Double-Blind, Placebo-Controlled Trial. Respiration, 63, 174-180.
[10]
Blaive, B., Lapalus, P. and Lemoigne, F. (1978) Étude clinique comparée de deux fluidifiants bronchiques: La S-carboxyméthyl-cystéine et la létostéine. La Semaine des hopitaux de Paris, 54, 983-986.
[11]
Distefano, S.M., Palermo, F., Crimi, N., et al. (1988) Evaluation of the Activity of the Carbocysteine-Sobrerol Combination on Mucus Spinnability. International Journal of Pharmaceutical and Clinical Research, 8, 31-35.
[12]
Edwards, G.F., Steel, A.E., Scott, J.K. and Jordan, J.W. (1976) S-carboxymethylcysteine in the Fluidification of Sputum and Treatment of Chronic Airway Obstruction. Chest, 70, 506-513. https://doi.org/10.1378/chest.70.4.506
[13]
Puchelle, E., Aug, F. and Polu, J.M. (1978) Effect of the Mucoregulator S-Carboxy-Methyl-Cysteine in Patients with Chronic Bronchitis. European Journal of Clinical Pharmacology, 14, 177-184. https://doi.org/10.1007/bf02089957
[14]
Tatsumi, K. and Fukuchi, Y. (2007) Carbocisteine Improves Quality of Life in Patients with Chronic Obstructive Pulmonary Disease. Journal of the American Geriatrics Society, 55, 1884-1886. https://doi.org/10.1111/j.1532-5415.2007.01373.x
[15]
Yasuda, H., Yamaya, M., Sasaki, T., Inoue, D., Nakayama, K., Tomita, N., et al. (2006) Carbocisteine Reduces Frequency of Common Colds and Exacerbations in Patients with Chronic Obstructive Pulmonary Disease. Journal of the American Geriatrics Society, 54, 378-380. https://doi.org/10.1111/j.1532-5415.2005.00592_9.x
[16]
Zheng, J., Kang, J., Huang, S., Chen, P., Yao, W., Yang, L., et al. (2008) Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE Study): A Randomised Placebo-Controlled Study. The Lancet, 371, 2013-2018. https://doi.org/10.1016/s0140-6736(08)60869-7
[17]
Braga, P.C., Allegra, L., Rampoldi, C., Ornaghi, A. and Beghi, G. (1990) Long-Lasting Effects on Rheology and Clearance of Bronchial Mucus after Short-Term Administration of High Doses of Carbocysteine-Lysine to Patients with Chronic Bronchitis. Respiration, 57, 353-358. https://doi.org/10.1159/000195871
[18]
Wierzbicka, M. and Wójcik, R.A. (1981) Zastosowanie Mukodyny w leczeniu przewlekłego zapa-lenia oskrzeli. Pneumonologia Polska, 49, 369-374.
[19]
Grillage, M. and Barnard-Jones, K. (1985) Long-Term Oral Carbocisteine Therapy in Patients with Chronic Bronchitis. A Double Blind Trial with Placebo Control. International Journal of Clinical Practice, 39, 395-398. https://doi.org/10.1111/j.1742-1241.1985.tb07868.x
[20]
Caramia, G., Gagliardini, R., Ruffini, E., Osimani, P. and Nobilini, A. (1995) The Management of Cystic Fibrosis with Carbocysteine Lysine Salt: Single-Blind Comparative Study with Ambroxol Hydrochloride. Journal of International Medical Research, 23, 284-293. https://doi.org/10.1177/030006059502300409
[21]
Wu, K., Su, X., Li, G. and Zhang, N. (2016) Antioxidant Carbocysteine Treatment in Obstructive Sleep Apnea Syndrome: A Randomized Clinical Trial. PLOS ONE, 11, e0148519. https://doi.org/10.1371/journal.pone.0148519
[22]
Commins, D.J., Koay, B.C., Bates, G.J., Moore, R.A., Sleeman, K., Mitchell, B., et al. (2000) The Role of Mucodyner in Reducing the Need for Surgery in Patients with Persistent Otitis Media with Effusion. Clinical Otolaryngology and Allied Sciences, 25, 274-279. https://doi.org/10.1046/j.1365-2273.2000.00365.x
[23]
Karpova, E.P. and Burlakova, K.Y. (2018) Possibilities of Treatment of Inflammatory Pathology of the Nasopharynx in Children with Chronic Adenoiditis and Otitis Media with Effusion. VestnikOtorinolaringologii, 83, 40-43. https://doi.org/10.17116/otorino20188306140
[24]
Khan, J.A., Marcus, P. and Cummings, S.W. (1981) S-Carboxymethylcysteine in Otitis Media with Effusion: A Double-Blind Study. The Journal of Laryngology & Otology, 95, 995-1001. https://doi.org/10.1017/s002221510009174x
[25]
Kumazawa, T. and Ushiro, K. (1988) Clinical Evaluation of S-CMC Syrup Applied in the Treatment of Otitis Media with Effusion: Double Blind Comparative Test with Placebo. Acta Oto-Laryngologica, 105, 56-62. https://doi.org/10.3109/00016488809125103
[26]
Lesser, T.H.J., Clayton, M.I. and Skinner, D. (1986) Efficacy of Medical Treatment as an Adjunct to Surgery in the Treatment of Secretory Otitis Media. The Journal of Laryngology & Otology, 100, 1347-1350. https://doi.org/10.1017/s0022215100101124
[27]
Ramsden, R.T., Moffat, D.A., Gibson, W.P.R. and Jay, M.M. (1977) S-carboxymethylcysteine in the Treatment of Glue Ear: A Double Blind Trial. The Journal of Laryngology & Otology, 91, 847-851. https://doi.org/10.1017/s0022215100084462
[28]
Renou, G. and Benzakein, J. (1986) Traitement médical de l’otite séromuqueuse: Étude en double aveugle versus placebo de la carbocystéine. Thérapie, 41, 327-330.
[29]
Decramer, M. and Janssens, W. (2010) Mucoactive Therapy in COPD. European Respiratory Review, 19, 134-140. https://doi.org/10.1183/09059180.00003610
[30]
Ohnishi, H., Tanimoto, T., Inaba, R. and Eitoku, M. (2024) Efficacy and Safety of Mucolytics in Patients with Stable Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis. Respiratory Investigation, 62, 1168-1175. https://doi.org/10.1016/j.resinv.2024.10.004
[31]
Zeng, Z., Yang, D., Huang, X. and Xiao, Z. (2017) Effect of Carbocisteine on Patients with COPD: A Systematic Review and Meta-Analysis. International Journal of Chronic Obstructive Pulmonary Disease, 12, 2277-2283. https://doi.org/10.2147/copd.s140603
[32]
Bianco, A., Conte, S., Mariniello, D., Allocca, V., Matera, M., D’Agnano, V., et al. (2022) Mucolytic and Antioxidant Properties of Carbocysteine as a Strategy in COVID-19 Therapy. Life, 12, Article No. 1824. https://doi.org/10.3390/life12111824
[33]
Wedzicha, J.A., Calverley, P.M.A., Albert, R.K., Anzueto, A., Criner, G.J., Hurst, J.R., et al. (2017) Prevention of COPD Exacerbations: A European Respiratory Society/American Thoracic Society Guideline. European Respiratory Journal, 50, Article ID: 1602265. https://doi.org/10.1183/13993003.02265-2016
[34]
Sun, L., Tang, L., Xu, Y., Wang, S., Li, Y. and Kang, J. (2010) The Effect and Mechanism of Action of Carbocysteine on Airway Bacterial Load in Rats Chronically Exposed to Cigarette Smoke. Respirology, 15, 1064-1071. https://doi.org/10.1111/j.1440-1843.2010.01816.x
[35]
Yao, H. and Rahman, I. (2012) Role of Histone Deacetylase 2 in Epigenetics and Cellular Senescence: Implications in Lung Inflammaging and COPD. American Journal of Physiology-Lung Cellular and Molecular Physiology, 303, L557-L566. https://doi.org/10.1152/ajplung.00175.2012
[36]
Pace, E., Ferraro, M., Siena, L., Scafidi, V., Gerbino, S., Di Vincenzo, S., et al. (2013) Carbocysteine Regulates Innate Immune Responses and Senescence Processes in Cigarette Smoke Stimulated Bronchial Epithelial Cells. Toxicology Letters, 223, 198-204. https://doi.org/10.1016/j.toxlet.2013.09.013
[37]
Pace, E., Ferraro, M., Vincenzo, S., et al. (2013) Comparative Anti-Oxidant Effects of Carbocysteine and Fluticasone Propionate in Cigarette Smoke Stimulated Airway Epithelial Cells. European Respiratory Journal, 18, 733-743.
[38]
Ferraro, M., Di Vincenzo, S., Sangiorgi, C., Leto Barone, S., Gangemi, S., Lanata, L., et al. (2022) Carbocysteine Modifies Circulating miR-21, IL-8, sRAGE and fAGEs Levels in Mild Acute Exacerbated COPD Patients: A Pilot Study. Pharmaceuticals, 15, Article No. 218. https://doi.org/10.3390/ph15020218
[39]
Saibene, F., Paone, G., Lanata, L., Puglisi, G., Moscatelli, B. and Delli Colli, R. (2016) Effect of Carbocysteine Lysine Salt on Frequency of Exacerbations in COPD Patient Treated with or without Inhaled Steroids. European Respiratory Journal, 48, PA544. https://doi.org/10.1183/13993003.congress-2016.pa544
[40]
Pace, E., Vincenzo, S., Gerbino, S., et al. (2014) Carbocysteine Reverts the Effects of Cigarette Smoke on the Growth and on the Senescence of Bronchial Epithelial Cells. European Respiratory Journal, 44, 3244.
[41]
Pace, E., Di Vincenzo, S., Ferraro, M., Bruno, A., Dino, P., Bonsignore, M.R., et al. (2016) Carbocysteine Counteracts the Effects of Cigarette Smoke on Cell Growth and on the SIRT1/FoxO3 Axis in Bronchial Epithelial Cells. Experimental Gerontology, 81, 119-128. https://doi.org/10.1016/j.exger.2016.05.013
[42]
Sarker, R.S.J., Conlon, T.M., Morrone, C., Srivastava, B., Konyalilar, N., Verleden, S.E., et al. (2019) CARM1 Regulates Senescence during Airway Epithelial Cell Injury in COPD Pathogenesis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 317, L602-L614. https://doi.org/10.1152/ajplung.00441.2018
[43]
Pace, E., Di Vincenzo, S., Ferraro, M., Lanata, L. and Scaglione, F. (2024) Role of Airway Epithelium in Viral Respiratory Infections: Can Carbocysteine Prevent or Mitigate Them? Immunology, 172, 329-342. https://doi.org/10.1111/imm.13762
[44]
Macciò, A., Madeddu, C., Panzone, F. and Mantovani, G. (2009) Carbocysteine: Clinical Experience and New Perspectives in the Treatment of Chronic Inflammatory Diseases. Expert Opinion on Pharmacotherapy, 10, 693-703. https://doi.org/10.1517/14656560902758343
[45]
Minov, J., Stoleski, S., Petrova, T., Vasilevska, K., Mijakoski, D. and Karadzinska-Bislimovska, J. (2019) Effects of a Long-Term Use of Carbocysteine on Frequency and Duration of Exacerbations in Patients with Bronchiectasis. Open Access Macedonian Journal of Medical Sciences, 7, 4030-4035. https://doi.org/10.3889/oamjms.2019.697
[46]
Tam, J., Nash, E.F., Ratjen, F., Tullis, E. and Stephenson, A. (2013) Nebulized and Oral Thiol Derivatives for Pulmonary Disease in Cystic Fibrosis. Cochrane Database of Systematic Reviews, No. 7, CD007168. https://doi.org/10.1002/14651858.cd007168.pub3
[47]
Cintra, F., Tufik, S., D’Almeida, V., Calegare, B.F.A., de Paola, A., Oliveira, W., et al. (2011) Cysteine: A Potential Biomarker for Obstructive Sleep Apnea. Chest, 139, 246-252. https://doi.org/10.1378/chest.10-0667
[48]
Monneret, D., Tamisier, R., Ducros, V., Garrel, C., Levy, P., Baguet, J.P., et al. (2012) The Impact of Obstructive Sleep Apnea on Homocysteine and Carotid Remodeling in Metabolic Syndrome. Respiratory Physiology & Neurobiology, 180, 298-304. https://doi.org/10.1016/j.resp.2011.12.009
[49]
Iino, Y., Yoshida, N., Kato, T., Kakizaki, K., Miyazawa, T. and Kakuta, H. (2015) Clinical Effects of Clarithromycin on Persistent Inflammation Following Haemophilus Influenzae-Positive Acute Otitis Media. Acta Oto-Laryngologica, 135, 217-225. https://doi.org/10.3109/00016489.2014.975893
[50]
Osman, M., Mohammed, M., Elsherief, W. and Abdelmaksoud, A. (2016) Role of Medical Management in Otitis Media with Effusion. Journal of Current Medical Research and Practice, 1, 24-27. https://doi.org/10.4103/2357-0121.192541
[51]
Al-Salim, S., Tempero, R.M., Johnson, H. and Merchant, G.R. (2021) Audiologic Profiles of Children with Otitis Media with Effusion. Ear & Hearing, 42, 1195-1207. https://doi.org/10.1097/aud.0000000000001038
