High Dose N--Acetylcysteine in Patients With Exacerbations of Chronic Obstructive Pulmonary Disease

R. Zuin; A. Palamidese; R. Negrin; L. Catozzo; A. Scarda; M. Balbinot

Disclosures

Clin Drug Invest. 2005;25(6):401-408. 

In This Article

Abstract and Introduction

Objective: To investigate the efficacy and tolerability of high-dose N-acetylcysteine (NAC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (COPD).
Design and Patients: Randomised, double-blind, double-dummy, placebo-controlled study in 123 patients experiencing an acute exacerbation of COPD.
Interventions: NAC 1200 mg/day, 600 mg/day or placebo administered once daily for 10 days.
Main Outcome Measures: The primary objective was to assess the proportion of patients with normalised C-reactive protein (CRP) levels. Also assessed were effects on interleukin (IL)-8 levels, lung function and symptoms.
Results: Both NAC 600 and 1200 mg/day were associated with a significantly higher proportion of patients achieving normalised CRP levels compared with placebo (52% and 90% vs 19% of patients; p = 0.01); however, NAC 1200 mg/day was superior to NAC 600 mg/day (p = 0.002). Furthermore, treatment with NAC 1200 mg/day was more efficacious than NAC 600 mg/day in reducing IL-8 levels and difficulty of expectoration, while the two active regimens had similar beneficial effects on lung function and other clinical outcomes (cough intensity and frequency, and lung auscultation). Treatments were well tolerated with one adverse event reported in NAC 1200 mg/day recipients and two reported in placebo recipients.
Conclusion: Treatment with NAC 1200 mg/day improved biological markers and clinical outcomes in patients with COPD exacerbations. It is speculated that the effect of NAC on inflammatory markers may be due to both mucolytic and antioxidant properties.

Chronic obstructive pulmonary disease (COPD) is characterised by irreversible or only partially reversible airway obstruction with episodes of symptom exacerbation that are believed to contribute to the progression of the disease and progressive loss of lung function.[1,2] Bacterial or viral infections appear to be responsible for exacerbations by causing an influx of inflammatory cells, such as activated neutrophils and macrophages responsible for the release of elastase and myeloperoxidase,[3] in the bronchial mucosa.[4] Release of elastase and mye- loperoxidase may lead to production of oxygen free radicals,[3] which have pro-inflammatory properties[5] and inhibit a-1 antitrypsin, the most important inhibitor of elastase.[6] A role for oxygen free radicals in the pathogenesis of COPD has been confirmed in a recent study showing a large increase in exhaled hydrogen peroxide during exacerbations.[5] Thus, it seems reasonable to assume that treatment of exacerbations of COPD with drugs possessing antioxidant properties may lead to reductions in markers of airway inflammation and improve clinical outcomes.

Data suggest that N-acetylcysteine (NAC) at dosages of 400-1200 mg/day may reduce symptoms, exacerbation rates and lung function decline in COPD patients, although not all studies have yielded consistent results.[7,8,9] These effects were originally attributed to the ability of NAC to reduce mucus viscosity and facilitate expectoration. However, other studies have shown that NAC has anti-inflammatory and antioxidant properties.[10,11,12,13] In vitro, NAC inhibits neutrophil chemotaxis, interleukin (IL)-8 secretion, and other pro-inflammatory mediators such as the transcription nuclear factor (NF)-?B, which is directly correlated with the production of the systemic inflammatory marker C-reactive protein (CRP).[14]

CRP levels are elevated during exacerbations of COPD and significantly reduced with treatment; thus, they can be used to monitor clinical improvement.[15,16] IL-8 has also been shown to be significantly elevated during exacerbations of COPD.[17]

The aim of this study was to evaluate the efficacy of high-dose NAC (1200 mg/day) in patients with an acute exacerbation of COPD. Since the degree of anti-inflammatory effect of NAC is associated directly with CRP and IL-8 secretion, the anti-inflammatory effect of NAC was inferred from changes in CRP and IL-8, while clinical efficacy was assessed by changes in lung function, symptoms and physical examination. Tolerability was also evaluated by standard clinical and laboratory tests.

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