Comment

N-acetylcysteine in COPD may be beneficial, but for whom?

The airway smooth muscle (ASM) surrounding the airways is dysfunctional in both asthma and chronic obstructive pulmonary disease (COPD), exhibiting; increased contraction, increased mass, increased inflammatory mediator release and decreased corticosteroid responsiveness. Due to this dysfunction, ASM is a key contributor to symptoms in patients that remain symptomatic despite optimal provision of currently available treatments.

There is a significant body of research investigating the effects of oxidative stress/ROS on ASM behaviour, falling into the following categories; cigarette smoke and associated compounds, air pollutants, aero-allergens, asthma and COPD relevant mediators, and the anti-oxidant Nrf2/HO-1 signalling pathway. However, despite a number of recent reviews addressing the role of oxidative stress/ROS in asthma and COPD, the potential contribution of oxidative stress/ROS-related ASM dysfunction to asthma and COPD pathophysiology has not been comprehensively reviewed.

We provide a thorough review of studies that have used primary airway, bronchial or tracheal smooth muscle cells to investigate the role of oxidative stress/ROS in ASM dysfunction and consider how they could contribute to the pathophysiology of asthma and COPD. We summarise the current state of play with regards to clinical trials/development of agents targeting oxidative stress and associated limitations, and the adverse effects of oxidative stress on the efficacy of current therapies, with reference to ASM related studies where appropriate. We also identify limitations in the current knowledge of the role of oxidative stress/ROS in ASM dysfunction and identify areas for future research.

There is currently no consensus on the treatment sequence in chronic obstructive pulmonary disease (COPD), although it is recognized that early diagnosis is of paramount importance to start treatment in the early stages of the disease. Although it is fairly consensual that initial treatment should be with an inhaled short-acting beta agonist, a short-acting muscarinic antagonist, a long-acting beta-agonist or a long-acting muscarinic antagonist. As the disease progresses, several therapeutic options are available, and which to choose at each disease stage remains controversial. When and in which patients to use dual bronchodilation? When to use inhaled corticosteroids? And triple therapy? Are the existing non-inhaled therapies, such as mucolytic agents, antibiotics, phosphodiesterase-4 inhibitors, methylxanthines and immunostimulating agents, useful? If so, which patients would benefit? Should co-morbitities be taken into account when choosing COPD therapy for a patient?

This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients. We also propose a treatment algorithm in the hope that it will help physicians to decide the best approach for their patients. The authors conclude that, at present, a full consensus on optimal treatment sequence in COPD cannot be found, mainly due to disease heterogeneity and lack of biomarkers to guide treatment. For the time being, and although some therapeutic approaches are consensual, treatment of COPD should be patient-oriented.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased airway and systemic inflammation. There is evidence that erdosteine accelerates recovery from AECOPD by reducing airway inflammation.

To investigate the dose-dependent antioxidant/anti-inflammatory activity of erdosteine in COPD patients.

In this single-centre, double blind, double dummy study, patients with mild-to-moderate COPD (GOLD stage II–III), were randomised to receive either placebo or two dosages of oral erdosteine (300 mg tid or 300 mg bid + 1 capsule of indistinguishable placebo) for 28 days in addition to their standard treatment. Primary variables were plasma reactive oxygen species (ROS) and 8-isoprostane levels, while secondary variable was lung function (FEV1; FEV1/FVC; FEV1 short-term reversibility), all assessed in baseline; every two weeks during the study, and one week after the end of the study.

Baseline demographic characteristics, plasma ROS and 8-isoprostane levels and lung function were not significantly different in the 24 eligible patients (14 males, aged 38–75 years). At 2 weeks, there was a dose-dependent decrease in ROS in the erdosteine groups. By week 4 there were significant differences in ROS levels compared to baseline between patients receiving 900 mg/day (p < 0.003) and those receiving 600 mg/day (p < 0.04). This effect continued in the follow-up week (p < 0.021). Erdosteine also lowered 8-isoprostane plasma levels after 4 weeks (p < 0.01), and this effect lasted over the post-treatment week. Moreover, % FEV1 reversibility after salbutamol 400 mcg obtained after a 4 -week treatment of erdosteine 900 mg/day was significantly higher than that obtained after 600 mg/day (p < 0.01). Erdosteine was well tolerated and no treatment-related adverse event was reported.

Results confirm the antioxidant dose- and time-dependent activity of erdosteine, and support the utility of including erdosteine it in the therapeutic strategy for the prevention and treatment of oxidative stress-induced inflammation, which frequently leads to AECOPD occurrence.