European Review for Medical and Pharmacological Sciences 2019; 23: 6727-6735 A prospective study of the effects of carbocysteine lysine salt on frequency of exacerbations in COPD patients treated with or without inhaled steroids G. PAONE1, L. LANATA2, F. SAIBENE2, S. TOTI3, P. PALERMO4, C. GRAZIANI3, M.C. FLORE5, M. RAMACCIA3, G. PUGLISI3 1Department of Cardiovascular, Respiratory, Nephrological, Anesthesiologic and Geriatric Sciences, Sapienza University of Rome, Italy 2Dompé Farmaceutici S.p.A. Medical Affairs Department, Milan, Italy 3Department of Respiratory Diseases S. Camillo-Forlanini Hospital, Rome, Italy 4San Marco Hospital, Latina, Italy 5IRCCS Fondazione Policlinico Universitario A Gemelli - Università Cattolica del Sacro Cuore, UOC Pneumologia, Rome, Italy Abstract. – OBJECTIVE: COPD is one of the tion of a single daily dose of carbocysteine ly- major causes of morbidity and mortality world- sine salt (2.7 g/day) in reducing the number and wide and represents one of the most import- rate of exacerbations in COPD patients, inde- ant issues for public health. Frequent exacer- pendently from the use of inhaled steroids. bations induce a faster decline in lung function and poorer quality of life, increase mortality, and Key Words: have a socio-economic impact with a high bur- COPD, Exacerbations, Mucolytics, Carbocysteine, den in terms of resources and healthcare costs. Steroids. The clinical trials evaluated the effect of muco- lytics in COPD and showed that the long-term carbocysteine, associated with bronchodilators, anticholinergics, and steroids, reduces the fre- Introduction quency of exacerbations and improves the qual- ity of life. PATIENTS AND METHODS: The aim of this Chronic Obstructive Pulmonary Disease prospective real-life study was to evaluate the (COPD) is a progressive lung disease charac- long-term impact on exacerbations (at 1 year) terized by persistent respiratory symptoms and in COPD patients treated with carbocysteine ly- airflow limitation due to airway and alveolar sine salt (single dose of 2.7 g once a day) in ad- abnormalities. COPD pathogenesis seems based dition to background therapy with or without in- haled steroids. on the innate and adaptive inflammatory re- RESULTS: In a total of 155 evaluable patients, sponse to continued exposures to risk factors, our study showed that the addition of a sin- especially cigarette smoking. The inflammatory gle dose of carbocysteine lysine salt to back- response causes damage with consequent lung ground therapy determines a statistically signif- remodeling and irreversible airflow wall thick- icant reduction of the average number of exac- ening1,2. Moreover, oxidative stress may play an erbations vs. the number observed in the previ- important role in COPD pathogenesis. In fact, ous year (from 1.97±0.10 to 1.03±0.11; p<0.01), ir- respective of treatment with or without inhaled oxidative stress biomarkers are increased in steroids. In particular, in patients with ≥2 exac- exhaled breath condensate, sputum, and blood erbations in the previous year, the addition of samples of COPD patients1. The most common carbocysteine lysine salt resulted in a statisti- respiratory symptoms include dyspnea, cough, cally significant reduction in the exacerbations and/or sputum production1. COPD is currently rate from 69% to 33% and from 58% to 25%, re- the fourth leading cause of death and morbidity spectively (p<0.01) in patients with or without in- haled steroids. in the world and is predicted to become the third CONCLUSIONS: In summary, our data high- cause of death by 2020 due to continuous expo- 3,4 lighted the efficacy of long-term administra- sure to risk factors . The estimated number of Corresponding Author: Federico Saibene, MD; e-mail: [email protected] 6727 G. Paone, L. Lanata, F. Saibene, S. Toti, P. Palermo, C. Graziani, M.C. Flore, M. Ramaccia, G. Puglisi patients in 2010 was 384 million1,5. Viegi et al6 balance between sialomucins and fucomucins evaluated that the prevalence of COPD in Italy contributing to the viscoelastic properties of is approximately 11%, using the spirometric mucus, along with a capability to reduce neutro- criteria of the European Respiratory Society phil infiltration into the airway lumen and IL8. (ERS). COPD has a huge economic impact since Furthermore, carbocysteine lysine salt reduces new and more expensive drugs have begun to be exhaled IL6- and 8-isoprostane in COPD15-18. used7. COPD is characterized by periods of acute Carbocysteine action on inflammation levels worsening of airway function and respiratory and oxidative stress may play an important role symptoms, also known as exacerbations, that in reducing COPD exacerbations19. Carbocyste- result in additional therapy1,8. This condition is ine was effective in suppressing inflammation usually associated with inflammation commonly in human alveolar epithelial cells upon stim- triggered by viral or bacterial infections9,10 and ulation with TNF-α in vitro. These effects are a key aspect of the treatment of COPD should intimately associated with the inhibition of the be exacerbation prevention. Frequent exacerba- NF-κB and ERK1/2 MAPK signaling pathways, tions induce a faster decline in lung function, suggesting that carbocysteine may have a con- poorer quality of life and increased mortality; siderable therapeutic potential for the preven- in addition, these episodes have a socio-eco- tion and management of airway inflammation nomic impact with very high healthcare costs11. in COPD20. Carbocysteine may also modulate Therefore, treatments that reduce the frequency airways inflammation by decreasing virus-in- and duration of acute exacerbations will provide duced cytokine production and inhibiting bacte- benefits for both individual patients and health- rial adherence to epithelial cells21,22. The aim of care systems12. From 2006, several Cochrane our study was to evaluate the long-term effect reviews that evaluated the efficacy of drugs in (1 year) of carbocysteine lysine salt on COPD the prevention of exacerbations have been pub- exacerbations in addition to background therapy lished. The use of mucolytic agents has led to a with or without inhaled steroids in the Cauca- statistically significant reduction in exacerbation sian population. frequency and a decrease in the number of dis- ability days12. Clinical studies have been carried out to evaluate the effect of mucolytic agents on Patients and Methods the prevention and the reduction of exacerbation episodes. Zheng et al13 in the PEACE Study, This is an observational prospective real-life a randomized placebo-controlled study carried study in COPD patients treated with a single dai- out in China on 709 patients, showed that long- ly dose of carbocysteine lysine salt (2.7 g/day) in term use (12 months) of carbocysteine, asso- addition to background therapy with or without ciated with a bronchodilator, anticholinergics, associated inhaled steroids. COPD exacerbations and steroids therapy, reduced the frequency of were defined according to Anthonisen criteria 23: exacerbations and improved the quality of life. at least 2 days’ persistence of 2 major symptoms More recently, in an observational study on a (worsening of dyspnea, increase in sputum puru- Caucasian population (CAPRI study), Esposito lence, or volume, or both), and any major symp- et al14 demonstrated that the daily administration tom plus more than one minor symptom (upper of carbocysteine lysine salt for 12 months sig- airway infection, unexplained fever, increase of nificantly reduces the number of exacerbations wheezing). Patients on systemic steroids or with (p<0.001), in a manner completely independent respiratory diseases other than COPD or system- from the use of inhaled corticosteroids. Car- ic diseases involving lungs or diffuse bilateral bocysteine (S-carboxymethyl L-cysteine also bronchiectasis were excluded from the study. available in the lysinate form, SCMC-Lys) is a At baseline, our study population was stratified thiol derivative of the amino acid L-cysteine. It by the number of COPD exacerbations during is conventionally used as a mucolytic agent be- the previous years (<2 or ≥2 exacerbations). Pa- cause of its effectiveness in normalizing mucus; tients received carbocysteine lysine salt 2.7 g/day however, it should be more properly defined as (Fluifort®) for 12 months together with baseline a mucoactive agent or mucoregulator because therapy with or without inhaled steroids. The of its effect in normalizing mucus properties. patients were evaluated at baseline and after 12 Carbocysteine has antioxidant and anti-inflam- months when pulmonary function tests and phys- matory properties and has shown to restore the ical examinations were performed. The study was 6728 Effects of carbocysteine lysine salt w/wo inhaled steroids in COPD exacerbations Table I. Gender. Female Male Total Treatment No. % No. % No. % p-value Carbocysteine lysine salt (no inhaled steroids) 32 40.5 47 59.5 79 100.0 0.9999 (N.S.) Carbocysteine lysine salt + inhaled steroids 15 41.7 21 58.3 36 100.0 Total 47 40.9 68 59.1 115 100.0 – approved by the local Ethics Committee (#144 and 36 (31.3%) with carbocysteine lysine salt plus August 2011) and all patients gave their written inhaled steroids; 68 were males (59.1%) and 47 informed consent. females (40.9%) with an average age of 70.4 years (SD 9.6). Demographic characteristics tabulated Statistical Analysis by treatment group are reported in Table I and Age was analyzed using ANOVA performing Table II. multiple comparisons between groups and, where Over one year of treatment with carbocyste- applicable, within groups. Gender was analyzed ine lysine salt, the number of patients with <2 by the Chi square test with Yates correction. The exacerbations increased to 72.2% from 38.3% in changes in the mean number of exacerbations the previous year, whereas the number of more between time assessments (at baseline and after severely affected patients with ≥2 exacerbations 12 months) were analyzed using the t-test for dropped from 61.7% to 27.8% (p<0.01) (Figure paired data. McNemar test was used to compare 1).