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Application of N-Acetylcysteine in Pulmonary Disorders

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The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine

Abstract

In clinical medicine, N-acetylcysteine (NAC), is frequently used for the treatment of acetaminophen overdose and as a renal protection medication for patients undergoing radiologic evaluation with contrast dyes, which can be nephrotoxic. For several decades now, NAC has also been routinely applied to the treatment of inflammatory pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) to loosen thick mucus. The earliest published studies of the chemistry of NAC and its ability to reduce the viscosity of airway secretions were performed in 1963. However, only a few clinical studies have evaluated the efficacy of inhaled NAC in improving lung function over the long term, and none have determined that inhaled NAC is of obvious clinical benefit for CF patients when applied in this mode (Reas, J Pediatr 62:31, 1963; Duijvestijn and Brand, Acta Paediatr 88:38–41, 1999; Howatt and DeMuth, Univ Mich Med Cent J 32:82–85, 1966). In vitro, NAC has been demonstrated to reduce the viscosity and elasticity of mucus when directly in contact with airway secretions. This may make sputum easier to clear; however, thinner secretions could potentially be harder to expectorate due to this reduced viscosity. In addition, NAC is a very acidic compound (pH 2.2) and when inhaled results in airway irritation, induction of cough, and bronchospasm. Manufacturers therefore suggest that individuals receive pretreatment with a bronchodilator prior to inhalation. It has been suggested that induction of cough by inhaled NAC, rather than mucolysis, may explain any beneficial effect of NAC on expectoration. Thus, there is little published data to support using NAC in this mode.

NAC can also be given intravenously or taken by mouth. Some people use it as a dietary antioxidant.

Clinical trials have been performed to assess the efficacy of oral NAC in COPD, CF, and idiopathic pulmonary fibrosis (IPF). The results of the studies imply that NAC may benefit patients with both COPD and CF, but not apparently due to direct oxidant scavenging effects. In this chapter, we discuss the applications of NAC in treatment for CF, COPD, and IPF. This systematic review found that NAC treatment appears safe and tolerable with favorable evidence for the use of NAC only for COPD and CF, but contraindicated for use in IPF.

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References

  • Aruoma O, Halliwell B, Hoey B et al (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6:593–597

    Article  CAS  Google Scholar 

  • Atkuri K, Mantovani J, Herzenberg L et al (2007) N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 7:355–359

    Article  CAS  Google Scholar 

  • Barnes PJ (2013) New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov 12:543–559

    Article  Google Scholar 

  • Barnes PJ (2016) Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 138:16–27

    Article  CAS  Google Scholar 

  • Behr J, Richeldi L (2013) Recommendations on treatment for IPF. Respir Res 14(Suppl 1):S6

    PubMed  PubMed Central  Google Scholar 

  • Behr J, Bendstrup E, Crestani B et al (2016) Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 4:445–453

    Article  CAS  Google Scholar 

  • Bonanomi L, Gazzaniga A (1980) Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. Eur J Respir Dis Suppl 111:45–51

    CAS  PubMed  Google Scholar 

  • Brusselle G, Joos G, Bracke K (2011) New insights into the immunology of chronic obstructive pulmonary disease. Lancet 378:1015–1026

    Article  CAS  Google Scholar 

  • Canestaro W, Forrester S, Raghu G et al (2016) Drug treatment of idiopathic pulmonary fibrosis systematic review and network meta-analysis. Chest 149:756–766

    Article  Google Scholar 

  • Cantin A, North S, Hubbard R et al (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol 63:152–157

    Article  CAS  Google Scholar 

  • Cantin AM, Hubbard RC, Crystal RG (1989) Glutathione defficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139:370–372

    Article  CAS  Google Scholar 

  • Cantin AM, Bilodeau G, Ouellet C et al (2006) Oxidant stress suppresses CFTR expression. Am J Physiol Cell Physiol 290:C262–C270

    Article  CAS  Google Scholar 

  • Cazzola M, Calzetta L, Page C et al (2015) Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev 24:451–461

    Article  Google Scholar 

  • Celli BR, MacNee W (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932–946

    Article  CAS  Google Scholar 

  • Cogan JD, Kropski JA, Zhao M et al (2015) Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med 191:646–655

    Article  CAS  Google Scholar 

  • Conrad C, Lymp J, Thompson V et al (2015) 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. J Cyst Fibros 14:219–227

    Article  CAS  Google Scholar 

  • Dauletbaev N, Fischer P, Aulbach B et al (2009) A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis. Eur J Med Res 14:352–358

    CAS  PubMed  PubMed Central  Google Scholar 

  • De Benedetto F, Aceto A, Dragani B et al (2005) Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther 18:41–47

    Article  Google Scholar 

  • Decramer M, Rutten Van Molken M, Dekhuijzen P et al (2005) Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebocontrolled trial. Lancet 365:1552–1560

    Article  CAS  Google Scholar 

  • Demedts M, Behr J, Buhl R et al (2005) High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353:2229–2242

    Article  CAS  Google Scholar 

  • Drost EM, Skwarski KM, Sauleda J et al (2005) Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax 60:293–300

    Article  CAS  Google Scholar 

  • Duijvestijn YC, Brand PL (1999) Systematic review of Nacetylcysteine in cystic fibrosis. Acta Paediatr 88:38–41

    Article  CAS  Google Scholar 

  • Evans CM, Fingerlin TE, Schwarz MI et al (2016) Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol Rev 96:1567–1591

    Article  CAS  Google Scholar 

  • Fingerlin TE, Murphy E, Zhang W et al (2013) Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 45:613–620

    Article  CAS  Google Scholar 

  • Fioret D, Perez RL, Roman J (2011) Management of idiopathic pulmonary fibrosis. Am J Med Sci 341:450–453

    Article  Google Scholar 

  • Fowdar K, Chen H, He Z et al (2017) The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: a meta-analysis and systematic review. Heart Lung 46:120–128

    Article  Google Scholar 

  • Galli F, Battistoni A, Gambari R et al (2012) Oxidative stress and antioxidant therapy in cystic fibrosis. Biochim Biophys Acta 1822:690–713

    Article  CAS  Google Scholar 

  • Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report. www.goldcopd.org

  • GOLD (2014) Updated 2014. Global initiative for chronic obstructive lung disease Inc. Odense, Denmark

    Google Scholar 

  • Howatt WF, DeMuth GR (1966) A double-blind study of the use of acetylcysteine in patients with cystic fibrosis. Univ Mich Med Cent J 32:82–85

    CAS  PubMed  Google Scholar 

  • Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, Moschetti I, Phillips B, Thornton H, Goddard O, Hodgkinson M (2011) The Oxford 2011 levels of evidence. http://www.cebm.net/index.aspx?o=5653. Accessed 03 Sept 2011

  • Hurst GA, Shaw PB, LeMaistre CA (1967) Laboratory and clinical evaluation of the mucolytic properties of acetylcysteine. Am Rev Respir Dis 96:962–970

    CAS  PubMed  Google Scholar 

  • Jadad A, Moore R, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    Article  CAS  Google Scholar 

  • Kasielski M, Nowak D (2001) Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med 95:448–456

    Article  CAS  Google Scholar 

  • Lands L, Grey F, Smountas A et al (1999) Lymphocyte glutathione levels in children with cystic fibrosis. Chest 116:201–205

    Article  CAS  Google Scholar 

  • MacNee W (2000) Oxidants/antioxidants and COPD. Chest 117:303S–317S

    Article  CAS  Google Scholar 

  • MacNee W (2005) Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:50–60

    Article  CAS  Google Scholar 

  • Malhotra D, Th immulappa R, Navas-Acien A et al (2008) Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 178:592–604

    Article  CAS  Google Scholar 

  • Martinez FJ et al (2014) Randomized trial of Acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 370:2093–2101

    Article  Google Scholar 

  • Mayer-Hamblett N, Aitken M, Accurso F et al (2007) Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 175:822–828

    Article  Google Scholar 

  • Meyer A, Buhl R, Kampf S, Magnussen H (1995) Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respir Crit Care Med 152(3):1055–1060

    Article  CAS  Google Scholar 

  • Mitchell EA, Elliott RB (1982) Controlled trial of oral N-acetylcysteine in cystic fibrosis. Aust Paediatr J 18:40–42

    CAS  PubMed  Google Scholar 

  • Moss M, Guidot DM, Wong-Lambertina M et al (2000) The effects of chronic alcohol abuse on pulmonary glutathione homeostasis. Am J Respir Crit Care Med 161:414–419

    Article  CAS  Google Scholar 

  • Nogee LM, Dunbar AE, Wert SE et al (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344:573–579

    Article  CAS  Google Scholar 

  • Noth I, Zhang Y, Ma SF et al (2013) Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 1:309–317

    Article  CAS  Google Scholar 

  • Palmer LA, Doctor A, Chhabra P et al (2007) S-nitrosothiols signal hypoxia-mimetic vascular pathology. J Clin Invest 117:2592–2601

    Article  CAS  Google Scholar 

  • Pinheiro GA, Antao VC, Wood JM et al (2008) Occupational risks for idiopathic pulmonary fibrosis mortality in the United States. Int J Occup Environ Health 14:117–123

    Article  CAS  Google Scholar 

  • Poole P, Chong J, Cates CJ (2015) Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 29:CD001287

    Google Scholar 

  • Qaseem A, Wilt TJ, Weinberger SE et al (2011) Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 155:179–191

    Article  Google Scholar 

  • Raghu G, Depaso WJ, Cain K et al (1991) Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 144:291–296

    Article  CAS  Google Scholar 

  • Raghu G, Collard HR, Egan JJ et al (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824

    Article  Google Scholar 

  • Raghu G, Anstrom K, King T et al (2012) Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366:1968–1977

    Article  CAS  Google Scholar 

  • Rahman I, Yang SR, Biswas SK (2006) Current concepts of redox signaling in the lungs. Antioxid Redox Signal 8:681–689

    Article  CAS  Google Scholar 

  • Ratjen F, Wonne R, Posselt HG et al (1985) A double-blind placebo controlled trial with oral ambroxol and N-acetylcysteine for mucolytic treatment in cystic fibrosis. Eur J Pediatr 144:374–378

    Article  CAS  Google Scholar 

  • Reas H (1964) The use of N-acetylcysteine in the treatment of cystic fibrosis. J Pediatr 65:542–557

    Article  CAS  Google Scholar 

  • Reas HW (1963) The effect of N-acetylcysteine on the viscosity of tracheobronehial secretions in cystic fibrosis of the pancreas. J Pediatr 62:31

    Article  CAS  Google Scholar 

  • Richeldi L, Collard H, Jones M (2017) Idiopathic pulmonary fibrosis. Lancet 389:1941–1952

    Article  Google Scholar 

  • Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG (1993) Systemic deficiency of glutathione in cystic fibrosis. J Appl Physiol 75:2419–2424

    Article  CAS  Google Scholar 

  • Rushworth GF, Megson IL (2014) Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 141(2):150–159. https://doi.org/10.1016/j.pharmthera.2013.09.006

    Article  CAS  PubMed  Google Scholar 

  • Schermer T, Chavannes N, Dekhuijzen R et al (2009) Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir Med 103:542–551

    Article  Google Scholar 

  • Sheffner AL (1963) The reduction in vitro in viscosity of mucoprotein solutions by a new mucolytic agent, N-acetyl-l-cysteine. Ann N Y Acad Sci 106:298

    Article  CAS  Google Scholar 

  • Skov M, Pressler T, Lykkesfeldt J et al (2015) The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection — a pilot study. J Cyst Fibros 14:211–218

    Article  CAS  Google Scholar 

  • Stafanger G, Koch C (1989) N-acetylcysteine in cystic fibrosis and Pseudomonas aeruginosa infection: clinical score, spirometry and ciliary motility. Eur Respir J 2:234–237

    CAS  PubMed  Google Scholar 

  • Stafanger G, Garne S, Howitz P et al (1988) The clinical effect and the effect on the ciliary motility of oral N-acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia. Eur Respir J 1:161–167

    CAS  PubMed  Google Scholar 

  • Stey C, Steurer J, Bachmann S et al (2000) The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J 16:253–262

    Article  CAS  Google Scholar 

  • Stuart B, Choi J, Zaidi S et al (2015) Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet 47:512–517

    Article  CAS  Google Scholar 

  • Sun T, Liu J, Zhao DW (2016) Efficacy of N-acetylcysteine in idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Medicine 95:e3629

    Article  CAS  Google Scholar 

  • Taniguchi H, Kondoh Y, Ebina M, Azuma A, Ogura T, Taguchi Y, Suga M, Takahashi H, Nakata K, Sato A, Sugiyama Y, Kudoh S, Nukiwa T, Pirfenidone Clinical Study Group in Japan (2011) The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial. Respir Res 12:93. https://doi.org/10.1186/1465-9921-12-93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taskar VS, Coultas DB (2006) Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc 3:293–298

    Article  Google Scholar 

  • Thannickal VJ, Toews GB, White ES et al (2004) Mechanisms of pulmonary fibrosis. Annu Rev Med 55:395–417

    Article  CAS  Google Scholar 

  • Tirouvanziam R, Khazaal I, Péault B (2002) Primary inflammation in human cystic fibrosis small airways. Am J Physiol Lung Cell Mol Physiol 283:L445–L451

    Article  CAS  Google Scholar 

  • Tirouvanziam R, Conrad CK, Bottiglieri T et al (2006) High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A 103:4628–4633

    Article  CAS  Google Scholar 

  • Tsakiri KD, Cronkhite JT, Kuan PJ et al (2007) Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A 104:7552–7557

    Article  CAS  Google Scholar 

  • Tse HN, Raiteri L, Wong KY et al (2013) High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest 144:106–118

    Article  CAS  Google Scholar 

  • Van der Toorn M, Slebos D, de Bruin H et al (2013) Critical role of aldehydes in cigarette smoke-induced acute airway inflammation. Respir Res 14:45

    Article  Google Scholar 

  • Wada H, Takizawa H (2013) Future treatment for COPD: targeting oxidative stress and its related signal. Recent Patents Inflamm Allergy Drug Discov 7:1–11

    Article  CAS  Google Scholar 

  • Wang Y, Kuan PJ, Xing C et al (2009) Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 84:52–59

    Article  CAS  Google Scholar 

  • Zheng JP, Wen FQ, Bai CX et al (2014) Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2:187–194

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Stanford University, Palo Alto, CA, USA

    Carol Conrad

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  1. Carol Conrad
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Correspondence to Carol Conrad .

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Editors and Affiliations

  1. Barrow Neurological Institute, Phoenix Children’s Hospital, University of Arizona, College of Medicine – Phoenix, Phoenix, AZ, USA

    Richard Eugene Frye

  2. IMPACT SRC, Deakin University & Barwon Health, Geelong, VIC, Australia

    Michael Berk

1 Electronic Supplementary Material

Online Table 15.1

Summary of NAC efficacy trials in cystic fibrosis (DOCX 17 kb)

Online Table 15.2

Summary of NAC efficacy trials in chronic obstructive pulmonary disease (DOCX 15 kb)

Online Table 15.3

Summary of NAC trials idiopathic pulmonary fibrosis (DOCX 15 kb)

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Conrad, C. (2019). Application of N-Acetylcysteine in Pulmonary Disorders. In: Frye, R., Berk, M. (eds) The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Adis, Singapore. https://doi.org/10.1007/978-981-10-5311-5_15

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