Written by Marcia J. Egles, MD. Patients who supplemented with N-acetyl cysteine maintained their level of lung function longer than 6 months compared to the placebo group that experienced a 4% loss of FEV1 over the same 6 month period.
A multi-centered American study led by Stanford University demonstrated that cystic fibrosis patients receiving oral N-acetylcysteine had better maintenance of lung function over a 6-month trial as compared to those patients who received placebo 1.
Cystic fibrosis is a severe genetic disease which especially targets the lungs with inflammation. The hallmarks of cystic fibrosis lung disease include the influx of massive numbers of neutrophilic white blood cells to the lungs, the production of highly viscous (thick) mucus, chronic infections of the respiratory tract, and progressive airway obstruction and tissue damage with loss of lung function 1. Therapies for cystic fibrosis include anti-inflammatory medications such as prednisone (a steroid) and ibuprofen (a non-steroid) which can be associated with significant adverse side-effects that limit long-term use 2,3. Promising, albeit expensive, new drug treatments for cystic fibrosis are also emerging 4,5.
Patients with cystic fibrosis have markedly decreased levels of the antioxidant glutathione. These glutathione levels in cystic fibrosis are abnormally low throughout the entire body — in the plasma, in the blood cells such as neutrophils, and in the fluids of the lung. Glutathione is synthesized in the liver from cysteine sources. The Sanford researchers theorized that by bolstering the nutritional supply of cysteine, the low-levels of glutathione may be alleviated and the inflammatory situation improved in patients with cystic fibrosis 1,6.
The study, a preliminary phase-II randomized trial, selected 70 cystic fibrosis patients ages 9 to 59 years with mild to moderate lung disease. The group’s average baseline lung function as measured by “FEV1” was “63% of predicted” compared to normal. Half of the patients, the treatment group, were to drink three daily doses of 900 mg N-acetylcysteine effervescent tablets dissolved in liquid. This is considered a high dose of N-acetylcysteine. The other half of the patients, the placebo group, received placebo tablets to be likewise consumed. Compliance, as assessed by tablet count for the 24-week study, was estimated at over 90%. Compliance with the study’s other requirements may have been less impressive. Eleven protocol violations such as prohibited use of steroids and antibiotics occurred in the treatment group and 8 similar protocol violations occurred in the placebo group.
When the two groups were compared during and after the 6 months of treatment, there were no significant differences found in inflammation measures, in blood glutathione levels, in measures of neutrophil activity, in sputum neutrophil counts, in incidence of pulmonary exacerbations, or in the usage of new antibiotics. These results were not what the researchers had expected. They had expected to observe an increase in glutathione levels and improvement in inflammatory measurements in the N-acetylcysteine group. No safety issues such as the development of pulmonary hypertension were reported with the high dose N-acetylcysteine.
However, when the lung function of the two groups was compared, the placebo group showed a 4% loss in FEV1 over the 6 months. The treatment group maintained lung function over the 6 months. Not only was this statistically significant (p=0.02), this is also clinically significant, if true.
The study was not able to demonstrate a change in a sputum inflammation between the two groups, or an anti-inflammatory mechanism for the N-acetylcysteine. However, this preliminary trial suggests a clinically important outcome, that is the preservation of lung function in the N-acetylcysteine treatment group while the placebo group experienced lung function deterioration. This unexpected beneficial finding will require verification by further studies, as well as investigation of optimum dosage of N-acetyl cysteine.
Source: Conrad, C., et al. “Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.” Journal of Cystic Fibrosis 14.2 (2015): 219-227.
© 2014 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.
Posted April 17, 2017.
References:
- Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. Journal of Cystic Fibrosis. 2015;14(2):219-227.
- Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. American journal of respiratory and critical care medicine. 2007;176(11):1084-1089.
- Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV, Group CFFPT. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. The Journal of pediatrics. 1995;126(4):515-523.
- Cohen D, Raftery J. Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding. BMJ: British Medical Journal. 2014;348.
- Davis PB. Another beginning for cystic fibrosis therapy. Mass Medical Soc; 2015.
- Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB, Herzenberg LA. High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(12):4628-4633.
