Characterization of N-acetylcysteine and ambroxol in anti-oxidant therapy

Our plain-English summary of Characterization of N-acetylcysteine and ambroxol in anti-oxidant therapy, by A. Gillissen, D. Nowak (Respiratory Medicine, 1998).

The study

• Authors: A. Gillissen, D. Nowak
• Journal: Respiratory Medicine
• Published: 1998;92(4):609-23
• Type of article: Review
• Cited by: 213 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.

In plain English

This article is a narrative review, not a new study. The authors summarized published laboratory, animal and human research on two mucus-thinning drugs, N-acetylcysteine (NAC) and ambroxol, as possible antioxidant treatments for lung diseases. Asbestos was discussed briefly, as one source of oxidant stress in the lung. The review described asbestos fibres such as crocidolite as having an iron content of up to 28%. It cited reports that asbestos fibres trigger cytokine release and that inhaled crocidolite enhanced antioxidant activity in rat lungs, and it mentioned the proposal that oxygen radicals are linked to asbestos-related tumours. It did not report any study of NAC or ambroxol in asbestos-exposed people. Among the cited human studies, oral NAC failed to raise glutathione or cysteine in lung fluid or tissue of patients with chronic obstructive pulmonary disease. In one acute lung injury trial, one-month mortality was 22% with NAC (32 patients) and 35% with placebo (29 patients), and the review stated that mortality was not significantly reduced. The authors cautioned that several NAC results showed only biochemical changes. They concluded that numerous measures indicate the potential usefulness of this approach.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review (published as a 'Topical Review') of earlier cell culture, animal and human studies
• Who was studied: No population of its own. The review drew on published cell culture and animal experiments and on human studies, mainly in patients with ARDS, IPF or COPD and in healthy volunteers.
• Exposure: The drugs N-acetylcysteine (NAC) and ambroxol as antioxidant therapy. Asbestos fibres (crocidolite given as an example) were discussed briefly as one source of oxidant stress in the lung.
• Main results:
  • The review stated that asbestos fibres and silica trigger release of cytokines (for example TNF), which stimulates inflammatory cells to produce oxidants. This comes from cited literature, not new data.
  • Citing other studies, the review stated that inhaled crocidolite enhances antioxidant activity in rat lungs. It also stated that alveolar macrophages have been seen to undergo lipid peroxidation that can be blocked by antioxidants.
  • Citing other studies, the review stated that asbestos fibres cause an increase in manganese superoxide dismutase (MnSOD) mRNA levels.
  • The review noted that oxygen radicals are associated with an increased incidence of malignancies, as has been proposed for asbestos-related tumours.
  • In a cited study of COPD patients given oral NAC, neither GSH nor cysteine levels rose in lung lavage fluid, epithelial lining fluid or lung tissue.
  • The review described the effect of NAC in enhancing lung antioxidant defence in healthy volunteers as marginal.
  • In a cited trial of intravenous NAC in patients with mild-to-moderate acute lung injury, one-month mortality was 22% in the NAC group (n=32) and 35% in the placebo group (n=29). The review stated that survival (mortality) was not significantly reduced by this therapy.
  • In a cited double-blind multicentre trial of 252 patients given intravenous ambroxol before upper abdominal surgery, atelectasis occurred in 10.6% of the ambroxol group and 23.9% of the placebo group (p less than 0.05).
• The authors' conclusion: The authors concluded that numerous physiological and biochemical measures for both substances indicate the potential usefulness of this therapeutic approach.
• Limitations the authors state:
  • The authors stated that the IPF results do not establish clinical efficacy of NAC, because only biochemical changes were shown. They said this still has to be shown in long-term studies.
  • The authors stated that it is difficult to attribute treatment success to the antioxidant effect of NAC alone, because NAC also has mucolytic properties.
  • The authors stated that only a few human studies of ambroxol's antioxidant effect had been published.

Topics

Medical terms in this study, explained in our Lexicon: Idiopathic, Pulmonary Fibrosis, Fibrosis, Glutathione (GSH), Cytokine.

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