Respiration 1999;66:495–500
(DOI:10.1159/000029447)

N-Acetylcysteine Reduces the Exacerbation Rate in Patients with Moderate to Severe COPD

Pela R.a · Calcagni A.M.b · Subiaco S.c · Isidori P.d · Tubaldi A.e · Sanguinetti C.M.a
aUnità Operativa di Pneumologia, Presidio Ospedaliero Unificato ASL/Ancona, Regione Marche, Osimo; bAmbulatorio Territoriale di Pneumologia, ASL 11, Fermo; cDivisione di Pneumologia, Ospedale di Jesi, ASL 5, Regione Marche, Jesi; dDivisione di Pneumologia, Azienda Ospedaliera, ‘San Salvatore’, Regione Marche, Pesaro; eDivisione di Pneumologia, Ospedale di Macerata, ASL 9, Regione Marche, Macerata, Italia
email Corresponding Author


 Outline


 goto top of outline Key Words

  • Chronic obstructive pulmonary disease
  • Exacerbations
  • N-actylcysteine
  • Drug dosage

 goto top of outline Abstract

Objective: This study was performed to confirm the efficacy of a 6-month therapy with a formulation of N-acetylcysteine (NAC; 600 mg/day p.o.) on frequency and severity of exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD). Methods: One hundred sixty-nine patients attending five Italian centres were recruited in an open, randomized, controlled study. The patients were randomly allocated to standard therapy plus NAC 600 mg once a day or standard therapy alone over a 6-month period. At baseline, medical history was evaluated, and physical examination was performed; occurrence and severity of exacerbations and side effects of NAC were analyzed after 3 and 6 months. Results: The results showed a decreased number of exacerbations (by 41%) in the group of patients treated with NAC and standard treatment: 46 patients had at least one exacerbation as compared with 63 patients of the group treated with standard therapy alone. Also the number of the patients with two or more exacerbations was lower in the NAC group (26%) than in the standard-therapy group (49%). The number of sick days was less (82) in the NAC group as compared with the standard-therapy group (155). There was a small but significant improvement in FEV1 and MEF50 in the NAC group. NAC once a day was well tolerated. There were no differences in the number of side effects reported in both groups. Conclusions: These data confirm results of previous studies which reported a reduction in the number of exacerbations in patients having moderate to severe COPD treated with the antioxidant NAC. Further, the once-daily formulation is well tolerated and is likely to improve patient compliance with the prescribed regimen.

Copyright © 1999 S. Karger AG, Basel


goto top of outline introduction

Chronic obstructive pulmonary disease (COPD) is a disorder characterized by abnormal expiratory flow tests which do not markedly change during an observation period of several months [1, 2]. The rapid worsening of the lung function over years and the recurrent exacerbations play clearly an important role in the functional status and in the quality of life of patients affected by COPD.

The treatment options are so far quite limited for these patients. First of all, smoking cessation and administration of bronchodilator drugs have a great importance. The target of the COPD therapy could be related to the recent evidence that oxidative stress may be of importance in the pathogenesis and pathophysiology of COPD.

High numbers of neutrophils and macrophages as well as their increased activity lead to an increased production of reactive oxygen-derived species (ROS). ROS can damage the cellular lipid membranes, proteins and enzymes such as α1-protease inhibitor and secretory leukoprotease inhibitor. Patients with stable COPD exhale significantly more hydrogen peroxide (H2O2), a stable ROS, than healthy controls [4]. Apparently, the intracellular and extracellular anti-oxidative defence systems, which protect the lung against ROS, are not sufficient in COPD.

Studies with N-acetylcysteine (NAC) suggest that an improvement in the antioxidant profile of the lung of patients with COPD may reduce the number of exacerbations [5, 6, 7, 8, 9, 10, 11, 12, 13] and perhaps attenuate the accelerated worsening of the lung function [14]. NAC, a cysteine-containing compound, is an antioxidant agent penetrating into the cells, where it is deacetylated to L-cysteine, supporting the biosynthesis of glutathione (GSH). (The GSH redox cycle plays an important role in the antioxidant defence, but, surprisingly, data on the antioxidative effects of GSH in COPD are lacking.) Controlled clinical trials on a wide number of patients suffering from chronic bronchitis with or without airway obstruction showed that a 6-month treatment with NAC (400–600 mg/day p.o.) significantly improved respiratory symptoms and reduced rate and duration of exacerbations as well as the number of sick days [5, 13]. Up to now, the most common dosage of NAC in clinical practice and in clinical studies was 600 mg/day, always divided into two or more daily doses. Now, a once-a-day formulation of NAC of 600 mg is available which is more convenient for the patient.

The aim of this study was to confirm the efficacy of a 6-month daily single-dose therapy with NAC (600 mg/ day p.o.) on frequency and severity of exacerbations in patients suffering from COPD.

 

goto top of outline patients and methods

goto top of outline patients

One hundred sixty-nine patients attending five Italian centres were recruited in an open, randomized, controlled study. Inclusion criteria were: male and female patients aged 45–75 years, diagnosed as having COPD according to the ATS and ERS criteria [1, 2], postbronchodilator forced expiratory volume within 1 s (FEV1) less than 70% of predicted and FEV1 reversibility after administration of 400 μg of salbutamol less than 12% of predicted [15]. At study entry, all patients had to be clinically stable. Exclusion criteria were lung cancer, cardiomyopathy, metabolic disease and/or chronic renal failure or any other severe disease. The local Ethics Committee approved the study.

goto top of outline study design

The patients were randomly allocated to standard therapy plus NAC 600 mg once a day or standard therapy alone over a 6-month period. Standard therapy included β2-agonists, anticholinergics, theophylline and inhaled and/or oral corticosteroids (table 1). Treatment with immunostimulating agents was not allowed during the study period. All the patients were requested to undergo to anti-influenza vaccination.

TAB01

Table 1. Patient data at study entry:baseline characteristics

At baseline, the patients’ medical history was evaluated and physical examination performed. The clinical condition, occurrences and severity of exacerbations and side effects were evaluated after 3 and 6 months.

goto top of outline exacerbations

The exacerbations were classified as the worsening of the clinical profile of the patient with increased cough, dyspnoea and expectoration with mucopurulent sputum, with or without fever requiring medical intervention [1]. If the total score of the following questionnaire amounted to ≥3 points, the occurrence of an exacerbation was confirmed: fever: absent = 0, present = 1; cough: mild = 0, moderate = 1, severe = 2; mucus: unchanged = 0, increased = 1, increased and purulent = 2; dyspnea: unchanged = 0, increased = 1, severely increased = 2.

goto top of outline exacerbation severity score

The exacerbation severity score was obtained by the sum of the scores of each exacerbation (according to the questionnaire) divided by the total number of exacerbations.

goto top of outline patient preference

At the end of the study (6th month), each patient was asked to judge his current health status as compared with baseline by means of the following statements: improved, no change, deteriorated.

goto top of outline lung function measurements

The lung functionality was measured by evaluation of FEV1 and maximal expiratory flow at 50% of forced vital capacity (MEF50) by means of a Volugraph 2000. Data are shown both as absolute values and as percentage of predicted values [15].

goto top of outline statistics analysis

The statistical analysis was performed after 6 months of treatment. The values are expressed as mean ± SD. The baseline differences between the two groups were subjected to an unpaired Student t test. As far as the exacerbation frequency and the exacerbation severity score were concerned, the differences between the two study groups were subjected to a non-parametric Wilcoxon-Mann-Whitney test. The Student t test for paired and unpaired data to analyze the lung function parameters was used. Differences were considered significant at p values <0.05.

 

goto top of outline results

goto top of outline baseline characteristics of the patients

The baseline characteristics of the patients are shown in table 1. The mean duration of COPD was 14 ± 6.7 years in the NAC-treated group and 13 ± 5.9 years in the group with standard therapy. The two study groups did not differ significantly for any of the characteristics. The smoking habits of the patients did not change during the study period.

goto top of outline dropouts and side effects

In the NAC-treated group, 2 patients dropped out: 1 patient was lost to follow-up and 1 patient dropped out due to side effects (epigastric pain and diarrhoea). In the group with standard treatment, 4 patients dropped out: 3 of them were lost to follow-up, and 1 patient died of heart failure. NAC once a day was well tolerated. There were no differences in the number of side effects reported in both groups. Six patients experienced side effects (including the dropouts): 3 in the NAC group (2 patients reported gastric complaints, 1 patient diarrhoea) and 3 in the standard therapy group (1 patient reported gastric complaints, 1 loss of appetite and 1 pyrosis).

goto top of outline exacerbations

The 6-month exacerbation rate is shown in figure 1. The number of exacerbations decreased by 41% in the group of patients treated with NAC on top of standard treatment. In the group treated with standard therapy alone, 63 patients had at least one exacerbation in comparison with 46 patients in the group treated with NAC and standard therapy (p < 0.003; fig. 2).

FIG01

Fig. 1 Total number of exacerbations. Open column: patients with standard therapy; hatched column: patients with NAC on top of standard therapy.

FIG02

Fig. 2. Effect of NAC on top of standard therapy on the proportion of patients with one or more exacerbations. Open columns: patients with standard therapy; hatched columns: patients with NAC on top of standard therapy.

Also the number of the patients with two or more exacerbations was lower in the NAC group (26%) than in the standard-therapy group (49%), but the difference was not statistically significant due to the large variation.

The total number of sick days was significantly less (82) in the NAC group as compared with the standard-therapy group (155; table 2). This reduction, however, did also not reach a statistically significant level due to the large variation.

TAB02

Table 2. Number of sick days during the treatment period

The severity of the exacerbations, represented by the average severity score per exacerbation, is shown in figure 3. There was a small difference in favour of the group of patients treated with NAC and standard therapy as compared with patients treated with standard therapy only. This difference reached statistical significance (p < 0.001).

FIG03

Fig. 3. Effect of NAC on top of standard therapy on the exacerbation severity score. Open column: patients with standard therapy; hatched column: patients with NAC on top of standard therapy.

goto top of outline lung function

The FEV1 and MEF50 values at baseline and after 6 months are shown in table 3. There was a small but significant improvement in FEV1 and MEF50 in the NAC group (p < 0.05 and p < 0.01, respectively). No significant difference between the two groups was observed.

TAB03

Table 3. Effects of standard treatment alone versus NAC on top of standard treatment on lung function parameters

goto top of outline patient preference

Table 4 summarizes the patients’ preference at the end of the trial. In the standard-therapy group, 29% of the patients judged their overall health status improved with respect to the baseline status. In the NAC group, 65% of the patients felt better (p < 0.0001 for the difference between the shifts in both groups).

TAB04

Table 4. Evaluation of the quality of life after the treatment period according to the patient

 

goto top of outline discussion

This study was designed to investigate the efficacy of a 6-month treatment with NAC, 600 mg once a day, on the reduction of number and severity of exacerbations in patients affected by moderate to severe COPD. The patients enrolled into the study were randomized to receive NAC plus standard therapy versus standard therapy alone. With regard to demographic and lung function characteristics, the two groups were well matched. The results show that the number of exacerbations was reduced by 41% in the group of patients treated with NAC plus standard therapy; the exacerbation severity reached a small but significant reduction too. The NAC group showed also a reduced (but non-significant) number of sick days and a small improvement in the lung function parameters. The NAC formulation was well tolerated, and it was well appreciated by the patients.

Although the limit of this study was the open design, the results confirm those obtained in previous studies showing a beneficial effect of NAC on the rate of exacerbations in patients with COPD [5, 13]. The main difference with respect to previous studies, however, is the once a day formulation of NAC 600 mg administered during the study period. Such kind of formulation is likely to improve the patients’ compliance, although this issue was not specifically addressed in this study.

NAC is a cysteine-containing compound that penetrates into the cells, where it is deacetylated to L-cysteine. In this way it supports the biosynthesis of GSH, one of the most important antioxidant systems of the cell. This system protects lung tissue against oxidant-induced damage [16], and can inhibit the epithelial thickening and secretory cell hyperplasia induced by cigarette smoke in rats [17]. In vitro NAC has been shown to inhibit neutrophil and monocyte chemotaxis and oxidative burst responses [18, 19]. In an in vitro study, NAC has been found to protect α1-AT against inactivation induced by HOCl [20].

The efficacy of NAC to reduce the number of respiratory exacerbations may be related to the inhibition of the intrabronchial bacterial growth during the infection-free interval in patients with chronic bronchitis [21]. This mechanism is unknown, but probably it is related to the capacity of NAC to inhibit the adherence of bacteria to the ciliated epithelial cells of the human respiratory tract, as demonstrated in vitro models [21]. Besides, De Flora et al. [22] recently demonstrated that NAC markedly reduces the number and the severity of influenza in patients with chronic (non-pulmonary) diseases.

An important query is whether the reduction of number and severity of exacerbations obtained with NAC administration attenuates the accelerated decline in lung function in patients with moderate to severe COPD in a long-term period. The duration of this study (6 months) is clearly too short to answer this question. In a review by Murphy and Sethi [23] no firm relationship was established between the number of exacerbations and the decline of FEV1 in patients with COPD. However, the reduction in number and severity of exacerbations would attenuate the chemotaxis of inflammatory cells and the release of cytokines during these episodes. This reduction would attenuate the damage of lung airway wall, antiproteases, lung matrix, pulmonary microcirculation and alveolar epithelial cell layer that may contribute to irreversible changes in COPD. Larger and prospective studies are at present undertaken to answer this important question.

In conclusion, the present data confirm results of previous studies which report a reduction in the number of exacerbations in patients with moderate to severe COPD treated with the antioxidant NAC. The once-daily formulation is well tolerated and is likely to improve patient compliance with the prescribed regimen.


 goto top of outline References
  1. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152(suppl):77–120.
  2. Siafakas NM, Vermeire P, Pride NB, et al: Optimal assessment and management of chronic obstructive pulmonary disease. Eur Respir J 1995;8:1398–1420.
  3. Maier KL, Leuschel L, Constabel U: Increased oxidised methionine residues in BAL fluid proteins in acute or chronic bronchitis. Eur Respir J 1992;5:651–658.
  4. Dekhuijzen PNR, Aben KKH, Dekker I, et al: Increased exhalation of hydrogen peroxide in patients with stable and unstable COPD. Am J Respir Crit Care Med 1996;154:813–816.
  5. Grassi C, Morandini GC: A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. Eur J Clin Pharmacol 1976;9:393–396.
  6. Multicenter Study Group: Long-term oral acetylcysteine in chronic bronchitis: A double-blind controlled study. Eur J Clin Respir Dis 1980;61(suppl 111):93:108.
  7. Boman G, Backer U, Larsson S, Melander B, Wahlander L: Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: Report of a trial organised by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis 1983;64:405–415.
  8. Jackson M, Barnes J, Cooksey P: Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: A double-blind placebo-controlled study: J Med Res 1984;198–205.
  9. British Thoracic Society Research Committee: Oral N-acetylcysteine and exacerbation rates with chronic bronchitis and severe airway obstruction. Thorax 1985;40:832–835.
  10. Meister R: Langzeittherapie mit Acetylcystein Retard-Tabletten bei Patienten mit chronischer Bronchitis: Eine doppelblinde placebokontrollierte Studie. Forum Prakt Allg Arzt 1986;25:18–22.
  11. Parr GD, Huitson A: Oral Fabrol (oral N-acetylcysteine) in chronic bronchitis. Br J Dis Chest 1987;81:341–348.
  12. Rasmussen JB, Glennon C: Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. Eur Respir J 1988;1:351–355.
  13. Hansen NCG, Skriver A, Bronsen-Riis L, et al: Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med 1994;88:531–535.
  14. Lundbäck B, Lindström M, Andersson S, Nyström L, Rosenhall L, Stjerberg N: Possible effect of acetylcysteine on lung function. Eur Respir J 1992;5(suppl 15):289.
  15. Quanjer PH: Standardised lung function testing: Report Working Party standardisation of Lung Function tests’ of the European Respiratory Society and the European Community for Coal and Steel. Eur Respir J 1993;6(suppl 16):1–100.
  16. Moldeus P, Cotgreave IA, Berggren M: Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration 1986;50:31–42.
  17. Rogers DF, Jeffery PK: Inhibiton by oral N-acetylcysteine of cigarette smoke-induced ‘bronchitis’ in the rat. Exp Lung Res 1986;10:267–283.
  18. Bridges RB: Protective action of thiols on neutrophil function. Eur J Respir Dis 1985;66(suppl 139):40–48.
  19. Voisin C, Aerts C, Fournier E, Firlik M: Acute effects of tobacco smoke on alveolar macrophages cultured in gas phase. Eur J Respir Dis 1985;66(suppl 139):76–81.
  20. Borregaard N, Jensen HS, Bjerrum OW: Prevention of tissue damage: Inhibition of myeloperoxidase mediated inactivation of alpha 1-proteinase inhibitor by N-acetylcysteine, glutathione, and methionine. Agents Actions 1987;22:255–260.
  21. Riise GC, Larsson S, Larsson P, Jeansson S, Andersson BA: The intrabronchial microbial flora in chronic bronchitis patients: A target for N-acetylcysteine therapy? Eur Respir J 1994;7:94–101.
  22. De Flora S, Grassi C, Carati L: Attenuation of influenza symptomatology and improvement of immunological parameters due to long-term treatment with N-acetylcysteine. Eur Respir J 1997;10:1535–1541.
  23. Murphy TF, Sethi S: Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;146:1067–1083.

 goto top of outline Author Contacts

Prof. C.M. Sanguinetti
Via Leopardi 15
I–60027 Osimo (Italy)
Tel. +39 071 713 030 360 (368 369), Fax +39 071 713 03 76


 goto top of outline Article Information

Received: Received: April 21, 1998
Accepted after revision: February 8, 1999
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 4, Number of References : 23


 goto top of outline Publication Details

Respiration (International Review of Thoracic Diseases)
Founded 1944 as ‘Schweizerische Zeitschrift für Tuberkulose und Pneumonologie’ by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962–1967 as ‘Medicina Thoracalis’

Vol. 66, No. 6, Year 1999 (Cover Date: November-December 1999)

Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025–7931 (print), 1423–0356 (Online)

For additional information: http://www.karger.com/journals/res


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.