Acetylcysteine

Acetylcysteine
Systematic (IUPAC) name
(R)-2-acetamido-3-sulfanylpropanoic acid
Clinical data
Trade names Acetadote
AHFS/Drugs.com monograph
Licence data US FDA:link
Pregnancy cat. B(US) B2 (Aus)
Legal status Schedule 4 (Aus)
OTC or Rx (U.S.)
Not available (UK)
Routes inhalation, IV, oral
Pharmacokinetic data
Bioavailability 6–10% (oral)
<3% (topical)
Metabolism hepatic
Half-life 5.6 hours (adults)
11 hours (neonates)
Excretion renal
Identifiers
CAS number 616-91-1 Y
ATC code R05CB01 S01XA08 V03AB23
PubChem CID 12035
DrugBank DB06151
ChemSpider 11540 Y
UNII WYQ7N0BPYC Y
KEGG D00221 Y
ChEBI CHEBI:28939 Y
ChEMBL CHEMBL600 Y
Synonyms (R)-2-acetamido-3-mercaptopropanoic acid
Chemical data
Formula C5H9NO3S 
Mol. mass 163.19
SMILES eMolecules & PubChem
 Y(what is this?)  (verify)

Acetylcysteine rINN ( /əˌsɛtəlˈsɪstn/), also known as N-acetylcysteine or N-acetyl-L-cysteine (abbreviated NAC), is a pharmaceutical drug and nutritional supplement used primarily as a mucolytic agent and in the management of paracetamol (acetaminophen) overdose. Other uses include sulfate repletion in conditions, such as autism, where cysteine and related sulfur amino acids may be depleted.[1]

Acetylcysteine is a derivative of cysteine; an acetyl group is attached to the nitrogen atom. This compound is sold as a dietary supplement commonly claiming antioxidant and liver protecting effects. It is used as a cough medicine because it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. It is also this action of breaking disulfide bonds that makes it useful in thinning the abnormally thick mucus in Cystic Fibrosis patients.

Contents

Medical uses

Paracetamol overdose

Intravenous acetylcysteine is indicated for the treatment of paracetamol (acetaminophen) overdose. When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to inactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, therefore damaging hepatocytes. This may lead to severe liver damage and even death by fulminant liver failure.

For this indication, acetylcysteine acts to augment the glutathione reserves in the body and, together with glutathione, directly bind to toxic metabolites. These actions serve to protect hepatocytes in the liver from NAPQI toxicity.

Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,[2] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting. Studies conducted by Baker and Dilger[3] suggest that the prior pharmacokinetic studies of N-acetylcysteine did not include acetylation as a reason for the low bioavailability of N-acetylcysteine. In the research conducted by Baker,[3] it was concluded that oral N-acetylcysteine was identical in bioavailability to Cysteine precursors. However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting.[4] Repeated overdoses of intravenous N-acetylcysteine will cause these allergic reactions to progressively worsen in these people.

Several studies have found this anaphylaxis-like reaction to occur more often in people given IV acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.[5][6][7][8]

In some countries, a specific intravenous formulation does not exist to treat paracetamol overdose. In these cases, the formulation used for inhalation may be used intravenously.

Mucolytic therapy

Inhaled acetylcysteine is indicated for mucolytic ("mucus-dissolving") therapy as an adjuvant in respiratory conditions with excessive and/or thick mucus production. Such conditions include emphysema, bronchitis, tuberculosis, bronchiectasis, amyloidosis, pneumonia, cystic fibrosis and Chronic Obstructive Pulmonary Disease. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis.[9] However, a recent paper in the Proceedings of the National Academy of Sciences reports that high-dose oral N-acetylcysteine modulates inflammation in cystic fibrosis and has the potential to counter the intertwined redox and inflammatory imbalances in CF.[10] Oral acetylcysteine may also be used as a mucolytic in less serious cases.

For this indication, acetylcysteine acts to reduce mucus viscosity by splitting disulfide bonds linking proteins present in the mucus (mucoproteins).

Nephroprotective agent

Oral acetylcysteine is used for the prevention of radiocontrast-induced nephropathy (a form of acute renal failure). Some studies show that prior administration of acetylcysteine markedly decreases (90%) radiocontrast nephropathy,[11] whereas others appear to cast doubt on its efficacy.[12][13] Worth considering is the newest data published in two papers in the New England Journal of Medicine and the Journal of the American Medical Association. The authors' conclusions in those papers were:

  1. "Intravenous and oral N-acetylcysteine may prevent contrast-medium–induced nephropathy with a dose-dependent effect in patients treated with primary angioplasty and may improve hospital outcome."[14]
  2. "Acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiographic procedures, with minimal adverse effects and at a low cost"[15]

The latest clinical trial, whose results were announced in November 2010, has found that acetylcysteine is ineffective for the prevention of contrast-induced nephropathy. This trial, involving 2,308 patients, found that acetylcysteine was no better than placebo; whether acetylcysteine or placebo was used, the incidence of nephropathy was the same—13%.[16]

Acetylcysteine continues to be commonly used in individuals with renal impairment to prevent the precipitation of acute renal failure.

Microbiological use

Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for diagnosis of tuberculosis.

Interstitial lung disease

Acetylcysteine is used in the treatment of interstitial lung disease to prevent disease progression.[17][18][19][20]

Psychiatry

Acetylcysteine has been shown to reduce the symptoms of both schizophrenia[21] and bipolar disorder[22] in two placebo controlled trials conducted at Melbourne University. It is thought to act via modulation of NMDA glutamate receptors or by increasing glutathione. Replicatory trials in bipolar disorder, schizophrenia and depression are underway.

Adverse effects

Researchers at the University of Virginia reported in 2007 study using very large doses in a mouse model that acetylcysteine, which is found in many bodybuilding supplements, could potentially cause damage to the heart and lungs.[23] They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (SNOAC), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia). The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in vivo.

The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans;[23] nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[24]

Complexing agent

N-Acetylcysteine has been used to complex palladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzed coupling reactions.[25]

Chemistry

Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals.

Trade names

In addition to being available as an over-the-counter nutritional supplement, acetylcysteine is also marketed under these trade names:

Dosage forms

Acetylcysteine is available in different dosage forms for different indications:

The IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries.

Research

The following uses have not been well-established or investigated:

References

  1. ^ a b Geier, David A.; Geier, Mark R. (2006). "A Clinical and Laboratory Evaluation of Methionine Cycle-Transsulfuration and Androgen Pathway Markers in Children with Autistic Disorders". Hormone Research 66 (4): 182–8. doi:10.1159/000094467. PMID 16825783. 
  2. ^ Borgström, L.; Kågedal, B.; Paulsen, O. (1986). "Pharmacokinetics of N-acetylcysteine in man". European Journal of Clinical Pharmacology 31 (2): 217–222. doi:10.1007/BF00606662. PMID 3803419. 
  3. ^ a b Dilger, R. N.; Baker, D. H. (2007). "Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine". Journal of Animal Science 85 (7): 1712. doi:10.2527/jas.2006-835. PMID 17371789. 
  4. ^ Kanter, M. Z. (2006). "Comparison of oral and i.v. Acetylcysteine in the treatment of acetaminophen poisoning". American Journal of Health-System Pharmacy 63 (19): 1821. doi:10.2146/ajhp060050. PMID 16990628. 
  5. ^ Dawson, AH; Henry, DA; McEwen, J (1989). "Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning". The Medical journal of Australia 150 (6): 329–31. PMID 2716644. 
  6. ^ Bailey, B; McGuigan, M (1998). "Management of Anaphylactoid Reactions to Intravenous -Acetylcysteine". Annals of Emergency Medicine 31 (6): 710–5. doi:10.1016/S0196-0644(98)70229-X. PMID 9624310. 
  7. ^ Schmidt, L. E.; Dalhoff, K (2008). "Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning". British Journal of Clinical Pharmacology 51 (1): 87–91. doi:10.1046/j.1365-2125.2001.01305.x. PMC 2014432. PMID 11167669. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2014432. 
  8. ^ Lynch, R; Robertson, R (2004). "Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study". Accident and Emergency Nursing 12 (1): 10–5. doi:10.1016/j.aaen.2003.07.001. PMID 14700565. 
  9. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  10. ^ Tirouvanziam, R.; Conrad, CK; Bottiglieri, T; Herzenberg, LA; Moss, RB; Herzenberg, LA (2006). "High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis". Proceedings of the National Academy of Sciences 103 (12): 4628–33. doi:10.1073/pnas.0511304103. PMC 1450222. PMID 16537378. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1450222. 
  11. ^ Tepel, Martin; Van Der Giet, Marcus; Schwarzfeld, Carola; Laufer, Ulf; Liermann, Dieter; Zidek, Walter (2000). "Prevention of Radiographic-Contrast-Agent–Induced Reductions in Renal Function by Acetylcysteine". New England Journal of Medicine 343 (3): 180–4. doi:10.1056/NEJM200007203430304. PMID 10900277. 
  12. ^ Hoffmann, U.; Fischereder, M; Krüger, B; Drobnik, W; Krämer, BK (2004). "The Value of N-Acetylcysteine in the Prevention of Radiocontrast Agent-Induced Nephropathy Seems Questionable". Journal of the American Society of Nephrology 15 (2): 407–10. doi:10.1097/01.ASN.0000106780.14856.55. PMID 14747387. 
  13. ^ Miner, S; Dzavik, V; Nguyen-Ho, P; Richardson, R; Mitchell, J; Atchison, D; Seidelin, P; Daly, P et al. (2004). "N-acetylcysteine reduces contrast-associated nephropathy but not clinical events during long-term follow-up". American Heart Journal 148 (4): 690–5. doi:10.1016/j.ahj.2004.05.015. PMID 15459602. 
  14. ^ Marenzi, Giancarlo; Assanelli, Emilio; Marana, Ivana; Lauri, Gianfranco; Campodonico, Jeness; Grazi, Marco; De Metrio, Monica; Galli, Stefano et al. (2006). "N-Acetylcysteine and Contrast-Induced Nephropathy in Primary Angioplasty". New England Journal of Medicine 354 (26): 2773–82. doi:10.1056/NEJMoa054209. PMID 16807414. 
  15. ^ Kay, J.; Chow, WH; Chan, TM; Lo, SK; Kwok, OH; Yip, A; Fan, K; Lee, CH et al. (2003). "Acetylcysteine for Prevention of Acute Deterioration of Renal Function Following Elective Coronary Angiography and Intervention: A Randomized Controlled Trial". JAMA 289 (5): 553. doi:10.1001/jama.289.5.553. PMID 12578487. 
  16. ^ Smith, W. Thomas Jr. "Drug Thought To Protect Kidneys From Imaging Dye Doesn't Work". Medical News Today, 17 November 2010.
  17. ^ Kasielski, M; Nowak, D (2001). "Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease". Respiratory Medicine 95 (6): 448–56. doi:10.1053/rmed.2001.1066. PMID 11421501. 
  18. ^ Grandjean, E; Berthet, P; Ruffmann, R; Leuenberger, P (2000). "Efficacy of oral long-term -acetylcysteine in chronic bronchopulmonary disease: A meta-analysis of published double-blind, placebo-controlled clinical trials". Clinical Therapeutics 22 (2): 209–21. doi:10.1016/S0149-2918(00)88479-9. PMID 10743980. 
  19. ^ Stey, C.; Steurer, J.; Bachmann, S.; Medici, T.C.; Tramèr, M.R (2000). "The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review". European Respiratory Journal 16 (2): 253–62. doi:10.1034/j.1399-3003.2000.16b12.x. PMID 10968500. 
  20. ^ Poole, P.; Black, PN (2001). "Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review". BMJ 322 (7297): 1271–4. doi:10.1136/bmj.322.7297.1271. PMC 31920. PMID 11375228. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=31920. 
  21. ^ Berk, Michael; Copolov, David; Dean, Olivia; Lu, Kristy; Jeavons, Sue; Schapkaitz, Ian; Anderson-Hunt, Murray; Judd, Fiona et al. (2008). "N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial". Biological Psychiatry 64 (5): 361–8. doi:10.1016/j.biopsych.2008.03.004. PMID 18436195. 
  22. ^ Berk, M; Copolov, D; Dean, O; Lu, K; Jeavons, S; Schapkaitz, I; Andersonhunt, M; Bush, A (2008). "N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial". Biological Psychiatry 64 (6): 468–75. doi:10.1016/j.biopsych.2008.04.022. PMID 18534556. 
  23. ^ a b Palmer, Lisa A.; Doctor, Allan; Chhabra, Preeti; Sheram, Mary Lynn; Laubach, Victor E.; Karlinsey, Molly Z.; Forbes, Michael S.; MacDonald, Timothy et al. (2007). "S-Nitrosothiols signal hypoxia-mimetic vascular pathology". Journal of Clinical Investigation 117 (9): 2592–601. doi:10.1172/JCI29444. PMC 1952618. PMID 17786245. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1952618. 
  24. ^ Hildebrandt, W.; Alexander, S; Bärtsch, P; Dröge, W (2002). "Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity". Blood 99 (5): 1552–5. doi:10.1182/blood.V99.5.1552. PMID 11861267. 
  25. ^ Garrett, Christine E.; Prasad, Kapa (2004). "The Art of Meeting Palladium Specifications in Active Pharmaceutical Ingredients Produced by Pd-Catalyzed Reactions". Advanced Synthesis & Catalysis 346: 889–900. doi:10.1002/adsc.200404071. 
  26. ^ Kaneto, H.; Kajimoto, Y.; Miyagawa, J.; Matsuoka, T.; Fujitani, Y.; Umayahara, Y.; Hanafusa, T.; Matsuzawa, Y. et al. (1999). "Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity". Diabetes 48 (12): 2398–406. doi:10.2337/diabetes.48.12.2398. PMID 10580429. 
  27. ^ ClinicalTrials.gov NCT00539513 N-Acetylcysteine Augmentation in Treatment-Refractory Obsessive-Compulsive Disorder
  28. ^ Berk, M; Jeavons, S; Dean, OM; Dodd, S; Moss, K; Gama, CS; Malhi, GS (2009). "Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting". CNS spectrums 14 (7): 357–60. PMID 19773711. 
  29. ^ Mardikian, P; Larowe, S; Hedden, S; Kalivas, P; Malcolm, R (2007). "An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study". Progress in Neuro-Psychopharmacology and Biological Psychiatry 31 (2): 389–94. doi:10.1016/j.pnpbp.2006.10.001. PMID 17113207. 
  30. ^ Larowe, S. D.; Myrick, H.; Hedden, S.; Mardikian, P.; Saladin, M.; McRae, A.; Brady, K.; Kalivas, P. W. et al. (2007). "Is Cocaine Desire Reduced by N-Acetylcysteine?". American Journal of Psychiatry 164 (7): 1115–7. doi:10.1176/appi.ajp.164.7.1115. PMID 17606664. 
  31. ^ Pela, R.; Calcagni, A.M.; Subiaco, S.; Isidori, P.; Tubaldi, A.; Sanguinetti, C.M. (1999). "N-Acetylcysteine Reduces the Exacerbation Rate in Patients with Moderate to Severe COPD". Respiration 66 (6): 495–500. doi:10.1159/000029447. PMID 10575333. 
  32. ^ Breitkreutz, Raoul; Pittack, Nicole; Nebe, Carl Thomas; Schuster, Dieter; Brust, Jürgen; Beichert, Matthias; Hack, Volker; Daniel, Volker et al. (2000). "Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials". Journal of Molecular Medicine 78 (1): 55–62. doi:10.1007/s001090050382. PMID 10759030. 
  33. ^ Ungheri, D; Pisani, C; Sanson, G; Bertani, A; Schioppacassi, G; Delgado, R; Sironi, M; Ghezzi, P (2000). "Protective effect of n-acetylcysteine in a model of influenza infection in mice". International journal of immunopathology and pharmacology 13 (3): 123–128. PMID 12657201. 
  34. ^ Kopke, Richard; Bielefeld, Eric; Liu, Jianzhong; Zheng, Jiefu; Jackson, Ronald; Henderson, Donald; Coleman, John (2005). "Prevention of impulse noise-induced hearing loss with antioxidants". Acta Oto-Laryngologica 125 (3): 235–43. doi:10.1080/00016480410023038. PMID 15966690. 
  35. ^ Acker-Mills, B., Robinette, M., LaPrath, A., and Kopke, R. (December, 2004). Effects of N-acetylcysteine on otoacoustic emissions following noise exposure. Proceedings of the 2004 Army Science Conference, Orlando, Florida. AD Number: ADA433105
  36. ^ Kopke, R; Jackson, R; Coleman, J; Liu, J; Bielefeld, E; Balough, B (2007). "NAC for noise: From the bench top to the clinic∗". Hearing Research 226 (1-2): 114. doi:10.1016/j.heares.2006.10.008. PMID 17184943. 
  37. ^ De Flora, S.; Grassi, C.; Carati, L. (1997). "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment". European Respiratory Journal 10 (7): 1535–41. doi:10.1183/09031936.97.10071535. PMID 9230243. 
  38. ^ Bachert, C.; Hormann, K.; Mosges, R.; Rasp, G.; Riechelmann, H.; Muller, R.; Luckhaupt, H.; Stuck, B. A. et al. (2003). "An update on the diagnosis and treatment of sinusitis and nasal polyposis". Allergy 58 (3): 176–91. doi:10.1034/j.1398-9995.2003.02172.x. PMID 12653791. 
  39. ^ Fawkes, SW CERI: Living with Alcohol Smart Drug News 1996 Dec 13
  40. ^ Resat Ozaras, Veysel Tahan, Seval Aydin, Hafize Uzun, Safiye Kaya, Hakan Senturk. N-acetylcysteine attenuates alcohol-induced oxidative stess in rats World Journal of Gastroenterology 2003 Apr 15
  41. ^ Fulghesu, A; Ciampelli, M; Muzj, G; Belosi, C; Selvaggi, L; Ayala, GF; Lanzone, A (2002). "N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome". Fertility and Sterility 77 (6): 1128–35. doi:10.1016/S0015-0282(02)03133-3. PMID 12057717. 
  42. ^ Aitio, Mirja-Liisa (2006). "N-acetylcysteine - passe-partout or much ado about nothing?". British Journal of Clinical Pharmacology 61 (1): 5. doi:10.1111/j.1365-2125.2005.02523.x. PMC 1884975. PMID 16390346. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1884975.  and has been shown to reduce ocular soreness caused by Sjogren's syndrome.Williamson, J; Doig, W M; Forrester, J V; Tham, M H; Wilson, T; Whaley, K; Dick, W C (1974). "Management of the dry eye in Sjogren's syndrome.". British Journal of Ophthalmology 58 (9): 798. doi:10.1136/bjo.58.9.798. PMC 1215027. PMID 4433493. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1215027. 
  43. ^ Reliene, R.; Fischer, E; Schiestl, RH (2004). "Effect of N-Acetyl Cysteine on Oxidative DNA Damage and the Frequency of DNA Deletions in Atm-Deficient Mice". Cancer Research 64 (15): 5148. doi:10.1158/0008-5472.CAN-04-0442. PMID 15289318. 
  44. ^ Grant, J. E.; Odlaug, B. L.; Won Kim, S. (2009). "N-Acetylcysteine, a Glutamate Modulator, in the Treatment of Trichotillomania: A Double-blind, Placebo-Controlled Study". Archives of General Psychiatry 66 (7): 756–63. doi:10.1001/archgenpsychiatry.2009.60. PMID 19581567. 
  45. ^ Adams, J. B.; Baral, M.; Geis, E.; Mitchell, J.; Ingram, J.; Hensley, A.; Zappia, I.; Newmark, S. et al. (2009). "The Severity of Autism Is Associated with Toxic Metal Body Burden and Red Blood Cell Glutathione Levels". Journal of Toxicology 2009: 1. doi:10.1155/2009/532640. 
  46. ^ Fido, A.; Al-Saad, S (2005). "Toxic trace elements in the hair of children with autism". Autism 9 (3): 290. doi:10.1177/1362361305053255. PMID 15937043. 
  47. ^ Ballatori, Nazzareno; Lieberman, Michael W.; Wang, Wei (1998). "N-Acetylcysteine as an Antidote in Methylmercury Poisoning". Environmental Health Perspectives 106 (5): 267–71. doi:10.2307/3434014. JSTOR 3434014. PMC 1533084. PMID 9520359. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1533084. 
  48. ^ http://emedicine.medscape.com/article/1153370-overview
  49. ^ http://www.biomedcentral.com/1471-2210/9/7
  50. ^ "Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis" (in English). The New England Journal of Medicine (Massachusetts Medical Society) 365 (19): 1781. 11-10-2011. ISSN 0028-4793. 

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