A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
Eur J Med Res (2009) 14: 352-358
August 12, 2009 © I. Holzapfel Publishers 2009
A PHASE II STUDY ON SAFETY AND EFFICACY OF HIGH-DOSE N-ACETYLCYSTEINE IN PATIENTS WITH CYSTIC FIBROSIS
N. Dauletbaev 1, P. Fischer 1, B. Aulbach 1, J. Gross 2, W. Kusche 3, U. Thyroff-Friesinger 2, T. O. F. Wagner 1, J. Bargon 1, 4 1 University
Hospital, Frankfurt/Main, 2 Hexal AG, Holzkirchen, 3A.CRO Clinical Research Services GmbH, Wiesbaden, 4 Hospital St. Elisabeth, Frankfurt/Main, Germany
Abstract Objective: We conducted a single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of NAC. Methods: Twenty-one patients (∆F508 homo/heterozygous, FEV1 > 40% pred.) were included in the study. After a 3-weeks placebo run-in phase, 11 patients received low-dose NAC, and 10 patients received high-dose NAC. Outcomes included safety and clinical parameters, inflammatory (total leukocyte numbers, cell differentials, TNF-α, IL-8) measures in induced sputum, and concentrations of extracellular glutathione in induced sputum and blood. Results: High-dose NAC was a well-tolerated and safe medication. High-dose NAC did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC. Conclusions: High-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways. Key words: Cystic fibrosis, N-acetylcysteine, induced sputum, glutathione, inflammation
INTRODUCTION
Cystic fibrosis (CF) lung disease is the main cause of morbidity and mortality in patients with CF. Excessive neutrophil-dominated inflammation in airways is one of the hallmarks of CF lung disease. This uncontrolled inflammation is believed to lead to lung damage and dysfunction. There is a clear need for new anti-inflammatory medications in CF. The use of existing anti-inflammatory therapies, such as oral corticosteroids [1, 2] or high-dose ibuprofen [3, 4], is limited because of extensive adverse events [5] or concerns thereof [6]. Antioxidant drugs, such as N-acetylcysteine (NAC), have attracted attention recently as potential therapies for CF. The rationale to employ e.g. NAC is based on the premise that CF airways are overexposed to oxidants derived from bacteria [7, 8] or activated neutrophils [9]. Overexposure to oxidants, i.e. oxidative stress, is a known amplifier of inflammation. There-
fore, antioxidant drugs may be useful to control both oxidative stress and excessive inflammation in CF airways. While the safety and clinical efficacy of corticosteroids and high-dose ibuprofen have been thoroughly tested in clinical studies, NAC has not been studied as extensively. To date, only one short-term, open, uncontrolled, phase I study on NAC in CF has been published [10]. These authors have tested NAC administered for 4 weeks. We have design
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