Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis
ABSTRACT BACKGROUND: Progressive lung damage causes most deaths in cystic fibrosis (CF). Non-steroidal anti-inflammatory drugs (NSAIDs) may prevent progressive pulmonary deterioration and morbidity in CF. OBJECTIVES: To assess the effectiveness of treatment with NSAIDs in CF. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of NSAIDs.Latest search of the Group's Trials Register: 15 May 2013. SELECTION CRITERIA: Randomized controlled trials comparing oral NSAIDs, at any dose for at least two months, to placebo in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for the review. MAIN RESULTS: The searches identified eight trials; five are included (334 participants aged five to 39 years; maximum follow up of four years). Three trials compared ibuprofen to placebo (two from the same centre with some of the same participants); one trial assessed piroxicam versus placebo, a fifth trial compared cycloxygenase-2 inhibitor nimesulide and clarithromycin. The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a significantly lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV1) mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42); forced vital capacity (FVC) MD 1.27 (95% CI 0.26 to 2.28); forced expiratory flow (25-75%) MD 1.80 (95% CI 0.15 to 3.45). The post-hoc analysis of data from two trials split by age showed a statistically significant slower rate of annual decline of % predicted FEV1 and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) and MD 1.32% (95% CI 0.04 to 2.60) respectively. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. AUTHORS' CONCLUSIONS: High-dose ibuprofen can slow the progression of lung disease in people with CF, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with CF.
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ABSTRACT: Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene nearly 12 years ago, cystic fibrosis (CF) has become one of the most intensively investigated monogenetic disorders considered approachable by gene therapy. This has resulted in over 20 clinical trials currently under way, concluded or awaiting approval. Despite the initial promise of gene therapy for CF, and the demonstration of successful gene transfer to the nose and airways of individuals, it has not so far been as effective as initially projected. Here we discuss the rationale behind CF gene therapy and dissect the vast array of literature representing the work that ultimately brought about the current phase I/II clinical trials. In the context of human trials, we review the limitations of current vector systems for CF gene therapy. We come to the conclusion that at present none of the application methods and vector systems are able to achieve the level and persistence of CFTR gene expression in the affected epithelia of CF patients that is required for therapeutic success. We also outline the challenges that must be overcome and describe some of the novel approaches to be taken in order to attain the curative therapy that was originally envisaged for this disease.BioDrugs 02/2001; 15(9):615-34. DOI:10.2165/00063030-200115090-00006 · 2.12 Impact Factor
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ABSTRACT: In the decade since the gene for cystic fibrosis (CF) was discovered, research into potential therapeutic interventions has progressed on a number of different fronts. The vast majority of morbidity and mortality in CF results from inflammation and infection of the airways. Direct delivery of antibacterials to the airway secretions via a nebuliser is an attractive therapeutic option, and a novel formulation of tobramycin designed for such a purpose has been demonstrated to improve spirometry and decrease the need for intravenous antibacterials. In addition, early clinical trials are studying the effects of small peptides with antibiotic properties (defensins) delivered directly to the airways. Inflammation, whether secondary to infection or an independent feature of CF, leads to progressive bronchiectasis. Anti-inflammatories such as prednisone and possibly ibuprofen have been shown to decrease the rate of respiratory decline in patients with CF but have tolerability profiles that limit clinical usefulness. Macrolides also have anti-inflammatory properties and clinical trials are now ongoing to assess the efficacy of these agents in CF. Multiple agents, including uridine triphosphate (UTP), genistein, phenylbutyrate and CPX (cyclopentyl dipropylxanthine), have been demonstrated in cell culture to at least partially correct the primary defect of ion transport related to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). No agent of this class has yet demonstrated clinical effectiveness, but several are in preclinical and early clinical trials. Finally, gene therapy that allows for the incorporation and expression of wild-type CFTR in respiratory epithelial cells would be definitive therapy for CF. However, multiple barriers to delivery and expression need to be overcome. With research proceeding on these multiple fronts, new therapies for pulmonary complications promise to continue to increase the life expectancy of individuals with CF.Drugs 02/2001; 61(10):1379-85. DOI:10.2165/00003495-200161100-00001 · 4.13 Impact Factor
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ABSTRACT: Cystic fibrosis (CF) is an autosomal recessive disease affecting many organ systems. In the lung, the underlying ion transport defect in CF establishes a perpetuating cycle of impaired airway clearance, chronic endobronchial infection, and exuberant inflammation. The interrelated nature of these components of CF lung disease makes it likely that the most effective therapeutic strategies will include treatments of each of these. This chapter reviews the preclinical and clinical data focused on ways to better understand and particularly to limit inflammation in the CF airway. Anti-inflammatories are an attractive therapeutic target in CF with a proven ability to decrease the rate of decline in lung function. However, the inherent complexity of the inflammatory response combined with the obvious dependency on this response to contain infection and the side effect profiles of common anti-inflammatories have made identifying the most suitable agents challenging. Research continues to discover impairments in signaling events in CF that may contribute to the excessive inflammation seen clinically. Concurrent with these findings, promising new therapies are being evaluated to determine which agents will be most effective and well tolerated. Available data from studies commenced over the last two decades, which have generated both encouraging and disappointing results, are reviewed below.Clinical Reviews in Allergy & Immunology 07/2008; 35(3):135-53. DOI:10.1007/s12016-008-8081-2 · 4.73 Impact Factor