Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis: Cochrane systematic review
Assessed as up to date: 2013/06/13
Cystic fibrosis is an inherited condition resulting in thickened, sticky respiratory secretions. Respiratory failure, due to recurrent pulmonary infection and inflammation, is the most common cause of mortality. Muco-active therapies (e.g. dornase alfa and nebulized hypertonic saline) may decrease sputum viscosity, increase airway clearance of sputum, reduce infection and inflammation and improve lung function. Thiol derivatives, either oral or nebulized, have shown benefit in other respiratory diseases. Their mode of action is likely to differ according to the route of administration. There are several thiol derivatives, and it is unclear which of these may be beneficial in cystic fibrosis.Objectives
To evaluate the efficacy and safety of nebulized and oral thiol derivatives in people with cystic fibrosis.Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, hand searches of relevant journals, abstract books and conference proceedings.
Most recent search: 13 June 2013.
We also conducted a PubMed search on 26 February 2013 for relevant published articles.Selection criteria
Randomized and quasi-randomized controlled trials comparing nebulized or oral thiol derivatives to placebo or another thiol derivative in people with cystic fibrosis.Data collection and analysis
The authors independently assessed trials for inclusion, analysed risk of bias and extracted data.Main results
Searches identified 23 trials; nine trials (255 participants) are included, of these seven trials are more than 10 years old. Three trials of nebulized thiol derivatives were identified (one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and another compared glutathione to 4% hypertonic saline). Although generally well-tolerated with no significant adverse effects, there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.
Six trials of oral thiol derivatives were identified. Three trials compared N-acetylcysteine to placebo; one compared N-acetylcysteine, ambroxol and placebo; one compared carbocysteine to ambroxol; and one compared low and high-dose N-acetylcysteine. Oral thiol derivatives were generally well-tolerated with no significant adverse effects, however there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.Authors' conclusions
We found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.
Tam Julian, Nash Edward F, Ratjen Felix, Tullis Elizabeth, Stephenson Anne
Compounds which can break down the structure of mucus for lung disease in cystic fibrosis
Cystic fibrosis is a genetic disorder which mainly affects the lungs. Chest infections recur in people with cystic fibrosis due to a build up of thick sputum (phlegm) in the air passages. Several treatments, including thiol derivatives, aim to loosen this sputum and so improve lung function and reduce the frequency of chest infections. Thiol derivatives may be either nebulized (breathed in) or oral (by mouth). They have been shown to help in other lung conditions, such as chronic obstructive pulmonary disease. This review aims to find out if there is enough evidence to recommend the use of nebulized or oral thiol derivatives for people with cystic fibrosis. We included nine trials; three assessed the effect of nebulized thiol derivatives. Of the nebulized trials, one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and the other compared glutathione to 4% hypertonic saline. Nebulized thiol derivatives were generally well-tolerated with no major adverse effects. However they showed no significant improvements in any of our outcome measures.
Six included trials assessed the effects of oral thiol derivatives.Three of these trials compared oral N-acetylcysteine to placebo; one compared oral N-acetylcysteine, oral ambroxol and placebo; and one compared oral carbocysteine and oral ambroxol (no placebo). None of the trials showed an overall significant benefit in any of the outcome measures of this review. Oral thiol derivatives were generally well-tolerated with no major adverse effects.
In summary, the trials included in the review did not provide any evidence that nebulized or oral thiol derivatives were either beneficial or harmful to people with cystic fibrosis. Further research investigating the effects of thiol derivatives in people with cystic fibrosis is required before their use can be recommended.
Implications for practice
From this review of eligible trials, we have not been able to identify any evidence to recommend the use of nebulized thiol derivatives in people with CF. We have also not been able to find any evidence to recommend the use of oral thiol derivatives in the management of CF lung disease.
Implications for research
Despite the paucity of literature on the effectiveness of thiol derivatives in CF, these are still potentially useful drugs for further trial because thickened mucous, leading to chronic infection and inflammation and respiratory failure is still the most common cause of early death in CF. Therapies aimed at improving sputum clearance and therefore reducing pulmonary infection and inflammation are sorely needed. The other effective mucolytic therapies that are available for pulmonary disease in CF are unable to be tolerated by some people due to side effects (mainly bronchospasm) and can also be prohibitively expensive (in the case of dornase alfa). Thiol derivatives are relatively inexpensive, and, especially when administered orally, are well-tolerated. Further trials are required to investigate the potential beneficial effects of both nebulized and oral thiol derivatives in CF lung disease.
Well-designed randomized placebo-controlled double-blind trials of people with CF over six years of age are required to adequately assess the potential benefit of these medications. Pulmonary function testing cannot be reliably done in individuals under the age of six years. A wide range of disease severities and age groups should be included in these trials and in sufficient numbers so that data on these subgroups can be analyzed separately. It is not clear from the literature if mucolytic therapy is helpful in early disease to prevent decline in lung function or whether it is more advantageous later in the disease course when mucous production is increased. Enrolling participants with a wide range of disease severity may help to elucidate this. As mucolytic therapy takes time to exert its effect, the duration of the trials should be no less than four months, with six months of follow-up to evaluate the long-term effects of therapy with thiol derivatives. Pulmonary function (specifically FEV1 and FVC), would be reasonable primary endpoints, while other secondary endpoints such as markers of inflammation, the need for both IV and oral antibiotics therapy, the number of days in hospital, QoL, the acquisition of new respiratory pathogens, and radiologic improvement would be key in assessing the efficacy of these medications. Additionally, lung clearance index (LCI) should be considered as an endpoint, since this technique is a sensitive method of assessing the small airway disease that could theoretically be altered by thiol derivatives in CF individuals (Davies 2008). Mortality, although an important hard endpoint, would not be recommended as an outcome measure as it is unlikely changes in mortality would be detected in a 4- to 12-month trial given the median survival in CF at present.Get full text at The Cochrane Library
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