S-Carboxymethylcysteine in the Fluidification of Sputum and Treatment of Chronic Airway Obstruction

doi:10.1378/chest.70.4.506

Chest

Volume 70, Issue 4, October 1976, Pages 506-513

https://doi.org/10.1378/chest.70.4.506 Get rights and content

The clinical results and changes in sputum found in both a short-term inpatient trial and a subsequent long-term outpatient investigation (three-month double-blind controlled study) of 82 patients with chronic bronchitis treated with a new mucolytic agent, S-carboxymethylcysteine (Mucodyne), are reported. Fluidification of sputum with reduction in certain measurements of the viscosity of morning sputum aliquots, associated with improvement in the ability to cough up bronchial secretions, significant increase in sputum volume output, and improvement in ventilation (as estimated by the forced expiratory volume in one second), were observed in both trials as dose-related responses, with an increase in the ease of expectoration and a reduction in cough frequency and dyspnea. Therapy with 5-carboxymethylcysteine was well tolerated, and there were no serious adverse effects, either immediate or delayed. We suggest that the effect of the drug in fluidifying sputum may be due to a mucoregulatory mechanism which reverses the sputum macromolecular disturbances seen in chronic bronchitis.

Section snippets

Materials and Methods

Following a pilot study of inpatients,¹² a two-phase inpatient and outpatient trial was organized. Those bronchitic patients in remission who did not require continued routine therapy, who attended similarly developed medical chest units at Killingbeck Hospital, Leeds Chest Clinic, Pinderfields General Hospital, and Pontefract General Infirmary, and who produced about 25 to 50 ml of nonpurulent sputum daily, were invited to take part in a clinical therapeutic trial. For admission to the trial,

Clinical Results

Some 87 patients from three medical centers in the West Riding section of Yorkshire were admitted to the two-part studies; and of these, 85 completed the phase 1 inpatient study, and 82 completed the three-month follow-up phase 2 regimen. The phase 1 records of 13 patients from one medical center were lost in transit to the organizing medical center; hence, the records of only 72 inpatients but 82 out-patients are available for analysis. These details and those of the randomized allocation of

Discussion

The diverse nature of mucolytic agents as a group is a reflection of the chemical heterogeneity of sputum. Reid¹³ has suggested that freshly collected purulent sputum is more viscous than mucoid, whether obtained from the same patient or from different patients with the same bronchial disease. Certainly purulent sputum is largely composed of DNA fibers, which would not be expected to respond to disulfide-splitting agents, of which S-carboxymethylcysteine is one. Denton¹⁴ has shown that the

Acknowledgments

We are grateful to Mrs. Elizabeth Collins for her assistance and advice concerning the statistical analyses employed in these studies, to the nursing and medical staff of the various chest units involved in the day-to-day management of the patients, and to the patients themselves for their constant and sustained cooperation. Our thanks are also due to Messrs. Berk Pharmaceuticals Ltd. for making the S-carboxymethylcysteine (Mucodyne) and the placebo syrup available.

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N-Acetylcysteine Rinse for Thick Secretion and Mucositis of Head and Neck Chemoradiotherapy (Alliance MC13C2): A Double-Blind Randomized Clinical Trial
2019, Mayo Clinic Proceedings
To determine whether N-acetylcysteine rinse was safe and could improve thickened secretions and dry mouth during and after radiotherapy.
We designed a prospective pilot double-blind, placebo-controlled randomized clinical trial (Alliance MC13C2). Adult patients (age ≥18 years) were enrolled if they underwent chemoradiotherapy (≥60 Gy). Patients initiated testing rinse within 3 days of starting radiotherapy. With swish-and-spit, they received 10% N-acetylcysteine (2500 mg daily) or placebo rinse solution 5 times daily during radiotherapy and 2 weeks postradiotherapy. The primary aim was to evaluate N-acetylcysteine in improvement of saliva viscosity with the Groningen Radiotherapy-Induced Xerostomia questionnaire. Secondary aims included evaluating xerostomia improvement by the same questionnaire and with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck-35 Questions survey and adverse-event profiles. The type I error rate was 20%.
Thirty-two patients undergoing chemoradiotherapy were enrolled. Baseline characteristics were balanced for placebo (n=17) and N-acetylcysteine (n=15). N-acetylcysteine was better for improving sticky saliva (area under curve, P=.12). Scores of multiple secondary end points favored N-acetylcysteine, including sticky saliva daytime (P=.04), daytime and total xerostomia (both P=.02), pain (P=.18), and trouble with social eating (P=.15). Repeated measures models confirmed the findings. Taste was a major dissatisifer for N-acetylcysteine rinse; however, both testing rinses were safe and well tolerated overall.
Our pilot data showed that N-acetylcysteine rinse was safe and provided strong evidence of potential efficacy for improving thickened saliva and xerostomia by patient-reported outcome. A confirmatory phase 3 trial is required.
clinicaltrials.gov Identifier: NCT02123511
Antioxidant pharmacological therapies for COPD
2012, Current Opinion in Pharmacology
Citation Excerpt :
Carbocysteine could also reduce the frequency of common colds and associated exacerbations in COPD patients, a property that has been attributed to its ability to decrease ICAM-1 expression in the respiratory tract [26]. Clinical studies of carbocysteine in COPD patients are now available (Table 2) [17••,26–34]. The PEACE study investigated the effect of treatment of 709 Chinese COPD subjects for three years with carbocysteine (250 mg t.d.s) and found that COPD patients treated with carbocysteine experienced fewer numbers of exacerbations per year [17••].
Increased oxidative stress occurs in the lungs and systemically in COPD, which plays a role in many of the pathogenic mechanisms in COPD. Hence, targeting local lung and systemic oxidative stress with agents that modulate the antioxidants/redox system or boost endogenous antioxidants would be a useful therapeutic approach in COPD. Thiol antioxidants (N-acetyl-l-cysteine [NAC] and N-acystelyn, carbocysteine, erdosteine, and fudosteine) have been used to increase lung thiol content. Modulation of cigarette smoke (CS) induced oxidative stress and its consequent cellular changes have also been reported to be effected by synthetic molecules, such as spin traps (α-phenyl-N-tert-butyl nitrone), catalytic antioxidants (superoxide dismutase [ECSOD] mimetics), porphyrins, and lipid peroxidation and protein carbonylation blockers/inhibitors (edaravone and lazaroids/tirilazad). Preclinical and clinical trials have shown that these antioxidants can reduce oxidative stress, affect redox and glutathione biosynthesis genes, and proinflammatory gene expression. In this review the approaches to enhance lung antioxidants in COPD and the potential beneficial effects of antioxidant therapy on the course of the disease are discussed.
Pharmacological antioxidant strategies as therapeutic interventions for COPD
2012, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
Reduction in frequency of common colds including infections and associated exacerbations in COPD patients on treatment with carbocysteine have been attributed to its ability to decrease ICAM-1 expression in the respiratory tract [147]. There are reports regarding the clinical use of carbocysteine to treat COPD patients with mixed results on alterations in lung function and exacerbation rate (Table 3) [122,147–155]. Importantly, the PEACE study involving 709 Chinese COPD subjects, has examined the effect of over three year period of treatment with carbocysteine (250 mg t.d.s) focusing on the rate of COPD exacerbations.
Cigarette/tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress are intimately associated with the progression and exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, targeting systemic and local oxidative stress with antioxidants/redox modulating agents, or boosting the endogenous levels of antioxidants are likely to have beneficial effects in the treatment/management of COPD. Various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine), have been reported to modulate various cellular and biochemical aspects of COPD. These antioxidants have been found to scavenge and detoxify free radicals and oxidants, regulate of glutathione biosynthesis, control nuclear factor-kappaB (NF-kappaB) activation, and hence inhibiting inflammatory gene expression. Synthetic molecules, such as specific spin traps like α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, iNOS and myeloperoxidase inhibitors, lipid peroxidation inhibitors/blockers edaravone, and lazaroids/tirilazad have also been shown to have beneficial effects by inhibiting cigarette smoke-induced inflammatory responses and other carbonyl/oxidative stress-induced cellular alterations. A variety of oxidants, free radicals, and carbonyls/aldehydes are implicated in the pathogenesis of COPD, it is therefore, possible that therapeutic administration or supplementation of multiple antioxidants and/or boosting the endogenous levels of antioxidants will be beneficial in the treatment of COPD. This review discusses various novel pharmacological approaches adopted to enhance lung antioxidant levels, and various emerging beneficial and/or prophylactic effects of antioxidant therapeutics in halting or intervening the progression of COPD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines
2006, Chest
Citation Excerpt :
Carbocysteine was inactive in one study21 to alter the clearance of secretions or cough frequency in a small population of patients with chronic bronchitis and with or without radiologic evidence of emphysema. Another larger study22 of patients with chronic bronchitis producing at least 25 mL of sputum daily showed significant reductions in objective measures of sputum viscosity after carbocysteine treatment. There were no significant changes in the subjective indexes of cough frequency or severity, but patients reported significantly better ease of expectoration while receiving therapy with carbocysteine.
Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis.
Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.”
Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further.
These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.
Phenylalanine hydroxylase: Possible involvement in the S-oxidation of S-carboxymethyl-L-cysteine
2004, Analytical Biochemistry
Activated phenylalanine 4-monooxygenase, phenylalanine hydroxylase (PAH), is known to be involved in the S-oxidation of a number of sulfide compounds. One of these compounds, S-carboxymethyl-l-cysteine (SCMC), is currently used for the treatment of chronic obstructive pulmonary disease and otitis media with effusion as a mucolytic agent, and the S-oxides are the major metabolites found in urine. However, the enzyme catalyzing the S-oxidation of SCMC has yet to be identified. Here we report on the role of nonactivated phenylalanine 4-monooxygenase activity in rat liver cytosol in the S-oxidation of SCMC. Linearity of the enzyme assays was seen for both time (0–16 min) and cytosolic protein concentration (0.1–0.5 mg/ml). The calculated K_m and V_max values for the formation of SCMC (S) S-oxide were 3.92 ± 0.15 mM and 1.10 ± 0.12 nmol SCMC (S) S-oxide formed/mg protein/min, respectively. The calculated K_m and V_max values for the formation of SCMC (R) S-oxide were 9.18 ± 1.13 mM and 0.46 ± 0.11 nmol SCMC (R) S-oxide formed/mg protein/min, respectively. These results indicate that in the female Wistar rat, nonactivated PAH showed a stereospecific preference for the formation of the (S) S-oxide metabolite of SCMC against the (R) S-oxide metabolite of SCMC.
Exhaled Interleukine-6 and 8-isoprostane in chronic obstructive pulmonary disease: Effect of carbocysteine lysine salt monohydrate (SCMC-Lys)
2004, European Journal of Pharmacology
Chronic obstructive pulmonary disease (COPD) is characterized by an airways inflammation and by an enhanced generation of reactive oxygen species. The aim of our study was to assess the inflammation and the oxidative stress in airways of COPD patients with acute exacerbation of disease and in stability. Furthermore, we investigated the anti-inflammatory and antioxidant effects of 6 months treatment with carbocysteine lysine salt monohydrate (SCMC-Lys) in COPD. We studied 30 mild acute COPD, 10 mild stable COPD and 15 healthy subjects. 8-isoprostane and Interleukine-6 were measured in their breath condensate through immunoassay. Significantly higher concentrations of exhaled 8-isoprostane and Interleukine-6 were found in acute COPD patients compared to stable COPD and healthy controls (21.8±5.1 vs. 13.2±2.0 vs. 4.7±1.8 pg/ml and 7.4±0.9 vs. 5.8±0.2 vs. 2.7±0.6 pg/ml, p<0.0001). COPD patients treated with SCMC-Lys showed a marked reduction of exhaled 8-isoprostane and Interleukine-6 (8.9±1.5 and 4.6±0.8 pg/ml, p<0.0001). These findings suggest that there is an increase of 8-isoprostane and Interleukine-6 concentrations in the breath condensate of COPD patients compared to healthy controls especially during acute exacerbations of the disease. Moreover, we showed an anti-inflammatory and antioxidant effect of short-term administration of SCMC-Lys in COPD, suggesting the importance of a further placebo-controlled study that should evaluate the effects of this drug.

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: Supported in part by a grant from Messrs. Berk Pharmaceuticals Ltd., Surrey, England.

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Chest

Clinical InvestigationsS-Carboxymethylcysteine in the Fluidification of Sputum and Treatment of Chronic Airway Obstruction

Section snippets

Materials and Methods

Clinical Results

Discussion

Acknowledgments

Lancet

J Allergy

Lancet

Measurement of sputum viscosity in a cone-plate viscometer: 1. Characteristics of sputum viscosity

Am Rev Respir Dis

Measurement of sputum viscosity in a cone-plate viscometer: 2. An evaluation of mucolytic agents in vitro

Am Rev Respir Dis

Rheological assessment of mucolytic agents on sputum of chronic bronchitics

Thorax

Expectorant action of bromhexine in chronic obstructive bronchitis

Br Med J

Clinical trial of bromhexine in severe chronic bronchitics during winter

Thorax

A controlled trial of the effects of bromhexine on the symptoms of out-patients with chronic bronchitis

Br J Dis Chest

The in vitro reduction in viscosity of human tracheobronchial secretions by acetyl-cysteine

Am Rev Respir Dis

Clinical Investigations
S-Carboxymethylcysteine in the Fluidification of Sputum and Treatment of Chronic Airway Obstruction