Which is better for the liver ibuprofen or acetaminophen

Most things in life are about balance and moderation, and pain killers are no different. While Advil, Motrin and Tylenol offer relief when you’ve tweaked your neck or have a fever, taking too much of these medications can have serious health consequences, one of which is liver damage. But how much exactly is too much?

Acetaminophen, the active ingredient in Tylenol, is the one most closely linked to liver problems. The U.S. Food and Drug Administration warns against using higher than the recommended dose, even in the short-term; using more than one product containing the drug; or combining the drug with alcohol. “FDA believes that consumers need to know that these products can cause serious side effects, such as severe liver injury and stomach bleeding, when used improperly.” The maximum safe dose of extra strength Tylenol for adults, as per the company’s website, is 3,000 milligrams per day, or six pills. That’s lower than it used to be — Tylenol explains that the old dosage limit was 4,000 milligrams a day, and that it now recommends taking only two pills every six hours, when previously it said four to six hours.

Although the liver is the only organ that can regenerate damaged tissue, interfering with its function is dangerous, as it cleans the blood, helps to digest food and fights off infection. You’ll know your liver is damaged if your skin and the whites of your eyes turn yellow, a condition called jaundice that comes when the liver is not filtering out a yellowish substance called bilirubin and it builds up in the blood. Jaundice also makes urine dark and stool pale. Other symptoms of liver damage include itchy skin, swelling in the abdomen and legs, and bruising easily because the liver has stopped producing blood clotting proteins.

But sometimes the body shows no symptoms of liver damage at all, or only vague symptoms like fatigue. That can be dangerous because liver troubles that go untreated could become dangerous. The American Liver Foundation says that blood vessels leading to the liver can burst; and toxins can build up in the brain and interfere with mental function. “There is a risk of coma and death.”

Piroxicam induced hepato-canalicular cholestasis associated with ductopenia (notice absence of bile duct in the portal tract).

Other oxicam derivatives were also occasionally implicated in cases of acute cholestatic hepatitis included isoxicam and droxicam[73].

The mechanism of oxicams-induced hepatotoxicity appears to be idiosyncratic and dose independent. Due to the absence of immunoallergic features in most of the reported cases, it is very difficult to support an immune-mediated mechanism of liver injury[74].

NIMESULIDE

Nimesulide has analgesic, anti-inflammatory and anti-pyretic activity due to potent inhibitory effects on the COX-2 enzymes. Nimesulide bears a good gastro-intestinal tolerance. The mechanism of action has been attributed to a unique chemical structure of the sulphonanilides class of NSAIDs[75].

Our group in Argentina reported the first observation linking nimesulide with liver toxicity in 1997[76]. Since then, a steady flow of reports confirmed severe forms of hepatotoxicity, to the point that national health authorities of several countries withdrew nimesulide from the market[77-88]. Despite this, nimesulide commercialization is still maintained in several European countries, although the EMEA reports recommend a length of therapy restricted to 15 d and maximal dosage of 100 mg/d[13]. Controversy regarding nimesulide persists due to the fact that clinical series reports and epidemiological trials continue to involve nimesulide in severe liver damage[19,89,90]. On the other hand, health institutions conclude that nimesulide-induced-liver injury is statistically comparable to that of the remainder of the NSAIDs[91,92].

In our institution, 5 out of 30 cases (17%) had severe liver injury[93]. In 2009 our series included 43 well documented cases of nimesulide-induced liver damage associated to a wide clinical and histological spectrum of hepatotoxicity[94]. To our knowledge this constitutes the largest series of nimesulide hepatotoxicity ever reported. The main clinical symptoms at presentation are jaundice (70%), malaise (65%) and pruritus (50%). Interestingly, two thirds of patients start liver toxicity 15 to 90 d after drug intake. Relevant to drug safety, in only 11% latency was shorter than 15 d (Figure ​2). On the other hand, normalization exceeded 90 d in 27% of cases[94]. In cholestatic liver injury, normalization of alkaline phosphatase serum level usually takes more time than transaminases (i.e. more than 1 year)[95].

Latency (time from nimesulide intake to clinical onset) in 43 patients.

Nine patients in our series developed severe liver disease and FHF was observed in 6 cases. In agreement with the recent publication by Walker et al[96], this subpopulation was composed predominantly of females older than 50 years. Two patients died before liver transplant due to multiorgan failure, while a 9-year-old girl successfully underwent orthotopic liver transplantation.

We observed a wide range of variations of ALT/aspartate transaminase level in concordance with Bjarnason who analyzed 33 case reports documenting an elevation of ALT of at least 2-fold in 100%, and a 5-fold elevation in 89% of patients[97].

Nimesulide hepatotoxicity shows a wide spectrum of liver damage including acute hepatitis, cholestasis, mixed forms, massive and submassive hepatic necrosis. We found hepatocellular necrosis (Figure ​3) in 64%, cholestatic hepatitis in 27% and pure cholestasis in 9 %[94].

Acute hepatitis induced by nimesulide (hepatocellular collapsed areas are shown with arrows).

The mechanism of nimesulide induced hepatotoxicity remains unknown. It has been suggested that it could be due to the formation of a reactive metabolite. On the other hand, individual genetic variations in drug metabolism have also been proposed.

Acknowledging the true impact of nimesulide on the liver is not an easy task. Despite the proliferation of reports describing nimesulide-induced severe liver injury (mainly Argentina, Ireland and Finland), the epidemiological studies have almost unanimously concluded that severe hepatotoxicity is of low incidence determining a positive risk-benefit-ratio. Inquiring about nimesulide intake should be incorporated into standard anamnesis of liver disease, especially when acute liver damage is being investigated.

Addendum

Other than the previously analyzed drugs, indomethacin, naproxen, meloxican, tenoxican and etodoloc have also been associated with various hepatic reactions[73].

CONCLUSION

Aspirin was the first discovered NSAID. Dose dependent liver injury is accepted as the prevalent mechanism. Liver toxicity rate is very low currently since aspirin has been replaced by paracetamol and ibuprofen in pediatric patients and in various rheumatic diseases.

Diclofenac is probably the most used NSAID in rheumatology. Severe liver reactions and diclofenac hospitalization rate are uncommon. An increase in ALT levels of 3-10 × ULN is observed in 3% of cases.

Sulindac induced hepatotoxicity was documented more than fifty years ago. Liver damage occurrence was reported to be 5-10 times higher than that of other NSAIDs. A hypersensivity mechanism of liver injury was the most prevalent liver reaction.

Ibuprofen has the highest liver safety profile among NSAIDs and showed no severe liver injury in larger studies. Along with paracetamol and aspirin, it is considered one of the most common over the counter NSAIDs sold in the world.

Coxibs have currently replaced several NSAIDs due to safer GI profile. However, the high rate of cardiovascular events associated to rofecoxib is the main drawback related to drug marketing. Despite liver damage being a rare clinical situation, lumiracoxib has been discontinued in several countries due to severe hepatotoxicity.

Oxicams are associated with a well-documented hepatic safety profile. Uncommonly, piroxicam may cause severe hepatocellular damage. The clinical and histological pattern may be mixed or associated to clinical and biochemical prolonged cholestasis with or without ductopenia. Isoxicam and droxicam were only linked to liver toxicity in sporadic reports. The mechanism of liver damage appears to be an idiosyncratic one.

Nimesulide was removed from the market in several countries due to severe liver damage described in clinical series, but various epidemiological surveys do not document these findings. EMEA recommends that nimesulide should only be used for short periods at daily doses not higher than 200 mg/d in adults.

In summary, neither documenting the possibility of the causative role of a drug when confronting liver damage in an individual patient nor determining the true incidence of NSAIDs induced hepatotoxicity in the general population, are easy tasks. Rigorous data collecting, caution and clinical commitment are required when judging potential hepatotoxicity. The clinician always needs to critically evaluate the possibility whether other factors may play a role in the actual findings.

Despite the shortage of well-designed epidemiological studies, there is evidence showing that most of the NSAIDs are safe drugs with low risk of liver injury (mostly ranging from 0.29-3.1/100 000 exposed individuals when recent based-population studies were analyzed).

Both sulindac and nimesulide have been linked to a higher frequency of liver damage. NSAIDs induced liver injury which might potentially lead to a fatal outcome or need liver transplantation. As in other forms of DILI, jaundice entails poor prognosis with 25% of jaundiced patients developing severe liver disease. Drugs with an increased risk of liver damage should undergo close LFTs monitoring in order to prompt drug withdrawal to avoid severe hepatotoxicity.

Acknowledgments

I would like to thank Professor Luis Colombato for his support and for reviewing this manuscript and to Professor Miguel Bruguera for his counsel and advice.

Footnotes

Peer reviewer: Dr. Christoph Reichel, Priv.-Doz., Head, the Gastroenterological Rehabilitation Center Bad Brückenau, Clinic Hartwald, German Pension Insurance Federal Office, Schlüchterner Str. 4, 97769 Bad Brückenau, Germany

S- Editor Wang JL L- Editor O'Neill M E- Editor Lin YP

References

1. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, González-Grande R, Pizarro A, Durán JA, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–521. [PubMed] [Google Scholar]

2. Bjornsson E. Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther. 2010;32:3–13. [PubMed] [Google Scholar]

3. Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf. 2007;6:673–684. [PubMed] [Google Scholar]

4. Fosbøl EL, Gislason GH, Jacobsen S, Folke F, Hansen ML, Schramm TK, Sørensen R, Rasmussen JN, Andersen SS, Abildstrom SZ, et al. Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther. 2009;85:190–197. [PubMed] [Google Scholar]

5. Drug Safety Update. Volume 2, Issue 7, February 2009. [Google Scholar]

6. Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf. 2006;15:213–220. [PubMed] [Google Scholar]

7. Aithal GP, Day CP. Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis. 2007;11:563–575, vi-vii. [PubMed] [Google Scholar]

8. Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology. 2008;48:1680–1689. [PubMed] [Google Scholar]

9. Reuben A, Koch DG, Lee WM. Acute liver failure secondary to drug induced liver injury: causes and consequences (Abstract) Hepatology. 2009;50 Suppl:347A. [Google Scholar]

10. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:474–485. [PubMed] [Google Scholar]

11. Rabkin JM, Smith MJ, Orloff SL, Corless CL, Stenzel P, Olyaei AJ. Fatal fulminant hepatitis associated with bromfenac use. Ann Pharmacother. 1999;33:945–947. [PubMed] [Google Scholar]

12. Hunter EB, Johnston PE, Tanner G, Pinson CW, Awad JA. Bromfenac (Duract)-associated hepatic failure requiring liver transplantation. Am J Gastroenterol. 1999;94:2299–2301. [PubMed] [Google Scholar]

14. ANMAT Administración Nacional de Medicamentos Alimentos y Tecnología Medica Disposición 4087/03 (on-line) Argentina Acceso: 15/08/2009. Available from: http://www.anmat.gov.ar.

17. García Rodríguez LA, Williams R, Derby LE, Dean AD, Jick H. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med. 1994;154:311–316. [PubMed] [Google Scholar]

18. Pérez Gutthann S, García Rodríguez LA. The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs. Epidemiology. 1993;4:496–501. [PubMed] [Google Scholar]

19. Licata A, Calvaruso V, Cappello M, Craxì A, Almasio PL. Clinical course and outcomes of drug-induced liver injury: nimesulide as the first implicated medication. Dig Liver Dis. 2010;42:143–148. [PubMed] [Google Scholar]

20. Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut. 2009;58:1555–1564. [PubMed] [Google Scholar]

21. Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol. 2005;3:489–498. [PubMed] [Google Scholar]

22. García Rodríguez LA, Pérez Gutthann S, Walker AM, Lueck L. The role of non-steroidal anti-inflammatory drugs in acute liver injury. BMJ. 1992;305:865–868. [PMC free article] [PubMed] [Google Scholar]

23. Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ. 2003;327:18–22. [PMC free article] [PubMed] [Google Scholar]

24. de Abajo FJ, Montero D, Madurga M, GarcÃa RodrÃguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58:71–80. [PMC free article] [PubMed] [Google Scholar]

25. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, Cannon CP. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol. 2009;104:356–362. [PubMed] [Google Scholar]

26. Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2004;20:373–380. [PubMed] [Google Scholar]

27. FDA Working Group. PhRMA/FDA/AASLD. Drug-induced hepatotoxicity: white paper, postmarketing considerations. PhRMA/FDA/AASLD: 2000; 1-29. Accessed October 29, 2008. Available from: http://www.fda.gov/cder/livertox/postmarket.pdf. [Google Scholar]

28. FDA Working Group. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), July 2009. [Google Scholar]

29. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3–27. [PubMed] [Google Scholar]

30. Zimmerman HJ. Editorial: Aspirin-induced hepatic injury. Ann Intern Med. 1974;80:103–105. [PubMed] [Google Scholar]

31. Russell AS, Sturge RA, Smith MA. Serum transaminases during salicylate therapy. Br Med J. 1971;2:428–429. [PMC free article] [PubMed] [Google Scholar]

32. Rainsford KD. Side-effects and toxicology of the salicylates. In: Rainsford KD, ed , editors. Aspirin and Related Drugs. Boca Raton, Florida: CRC Press; 2004. pp. 367–554. [Google Scholar]

33. Teoh NC, Farrell GC. Hepatotoxicity associated with non-steroidal anti-inflammatory drugs. Clin Liver Dis. 2003;7:401–413. [PubMed] [Google Scholar]

34. Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Intern Med. 1981;141:333–342. [PubMed] [Google Scholar]

35. Doi H, Horie T. Salicylic acid-induced hepatotoxicity triggered by oxidative stress. Chem Biol Interact. 2010;183:363–368. [PubMed] [Google Scholar]

36. Cannon CP, Curtis SP, Bolognese JA, Laine L. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program: cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J. 2006;152:237–245. [PubMed] [Google Scholar]

37. Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, van der Heijde D, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368:1771–1781. [PubMed] [Google Scholar]

38. Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology. 1995;22:820–827. [PubMed] [Google Scholar]

39. Jick H, Derby LE, García Rodríguez LA, Jick SS, Dean AD. Liver disease associated with diclofenac, naproxen, and piroxicam. Pharmacotherapy. 1992;12:207–212. [PubMed] [Google Scholar]

40. Guldenschuh I, Hurlimann R, Muller A, Ammann R, Mullhaupt B, Dobbie Z, Zala GF, Flury R, Seelentag W, Roth J, et al. Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis. Dis Colon Rectum. 2001;44:1090–1097; discussion 1097-1099. [PubMed] [Google Scholar]

41. Tarazi EM, Harter JG, Zimmerman HJ, Ishak KG, Eaton RA. Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration. Gastroenterology. 1993;104:569–574. [PubMed] [Google Scholar]

42. Zou W, Devi SS, Sparkenbaugh E, Younis HS, Roth RA, Ganey PE. Hepatotoxic interaction of sulindac with lipopolysaccharide: role of the hemostatic system. Toxicol Sci. 2009;108:184–193. [PMC free article] [PubMed] [Google Scholar]

43. Zou W, Beggs KM, Sparkenbaugh EM, Jones AD, Younis HS, Roth RA, Ganey PE. Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury. J Pharmacol Exp Ther. 2009;331:114–121. [PMC free article] [PubMed] [Google Scholar]

44. Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology. 2009;17:275–342. [PubMed] [Google Scholar]

45. Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol. 1996;91:1626–1630. [PubMed] [Google Scholar]

46. Laurent S, Rahier J, Geubel AP, Lerut J, Horsmans Y. Subfulminant hepatitis requiring liver transplantation following ibuprofen overdose. Liver. 2000;20:93–94. [PubMed] [Google Scholar]

47. Riley TR 3rd, Smith JP. Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series. Am J Gastroenterol. 1998;93:1563–1565. [PubMed] [Google Scholar]

48. Boureau F, Schneid H, Zeghari N, Wall R, Bourgeois P. The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann Rheum Dis. 2004;63:1028–1034. [PMC free article] [PubMed] [Google Scholar]

49. Doyle G, Furey S, Berlin R, Cooper S, Jayawardena S, Ashraf E, Baird L. Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther. 1999;13:897–906. [PubMed] [Google Scholar]

50. Kellstein DE, Waksman JA, Furey SA, Binstok G, Cooper SA. The safety profile of nonprescription ibuprofen in multiple-dose use: a meta-analysis. J Clin Pharmacol. 1999;39:520–532. [PubMed] [Google Scholar]

51. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520–1528, 2 p following 1528. [PubMed] [Google Scholar]

52. Bessone F. Non-steroidal anti-inflammatory drugs do not protect against coronary heart disease among people at high risk. Evid base Cardiovasc Med. 2002;6:62. [Google Scholar]

53. Rainsford KD. Introduction - The coxib controversies. Inflammopharmacology. 2005;13:331–341. [PubMed] [Google Scholar]

55. Laine L, White WB, Rostom A, Hochberg M. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum. 2008;38:165–187. [PubMed] [Google Scholar]

56. Boelsterli UA. Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide. Drug Saf. 2002;25:633–648. [PubMed] [Google Scholar]

57. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247–1255. [PubMed] [Google Scholar]

58. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet. 2004;364:665–674. [PubMed] [Google Scholar]

61. Yan B, Leung Y, Urbanski SJ, Myers RP. Rofecoxib-induced hepatotoxicity: a forgotten complication of the coxibs. Can J Gastroenterol. 2006;20:351–355. [PMC free article] [PubMed] [Google Scholar]

62. Huster D, Schubert C, Berr F, Mössner J, Caca K. Rofecoxib-induced cholestatic hepatitis: treatment with molecular adsorbent recycling system (MARS) J Hepatol. 2002;37:413–414. [PubMed] [Google Scholar]

63. Papachristou GI, Demetris AJ, Rabinovitz M. Acute cholestatic hepatitis associated with long-term use of rofecoxib. Dig Dis Sci. 2004;49:459–461. [PubMed] [Google Scholar]

64. Baraf HS, Fuentealba C, Greenwald M, Brzezicki J, O'Brien K, Soffer B, Polis A, Bird S, Kaur A, Curtis SP. Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial. J Rheumatol. 2007;34:408–420. [PubMed] [Google Scholar]

65. Kang P, Dalvie D, Smith E, Renner M. Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts. Chem Res Toxicol. 2009;22:106–117. [PubMed] [Google Scholar]

66. Souto EO, Miyoshi H, Dubois RN, Gores GJ. Kupffer cell-derived cyclooxygenase-2 regulates hepatocyte Bcl-2 expression in choledocho-venous fistula rats. Am J Physiol Gastrointest Liver Physiol. 2001;280:G805–G811. [PubMed] [Google Scholar]

67. Farrell GC. Drug-induced liver disease. Edinburgh: Churchill Livingstone; 1994. [Google Scholar]

68. Lee SM, O'Brien CJ, Williams R, Whitaker S, Gould SR. Subacute hepatic necrosis induced by piroxicam. Br Med J (Clin Res Ed) 1986;293:540–541. [PMC free article] [PubMed] [Google Scholar]

69. Planas R, De León R, Quer JC, Barranco C, Bruguera M, Gassull MA. Fatal submassive necrosis of the liver associated with piroxicam. Am J Gastroenterol. 1990;85:468–470. [PubMed] [Google Scholar]

70. Paterson D, Kerlin P, Walker N, Lynch S, Strong R. Piroxicam induced submassive necrosis of the liver. Gut. 1992;33:1436–1438. [PMC free article] [PubMed] [Google Scholar]

71. Poniachik J, Guerrero J, Calderón P, Smok G, Morales A, Muñoz G, Venegas M. [Cholestatic hepatitis associated with piroxicam use. Case report] Rev Med Chil. 1998;126:548–552. [PubMed] [Google Scholar]

72. Hepps KS, Maliha GM, Estrada R, Goodgame RW. Severe cholestatic jaundice associated with piroxicam. Gastroenterology. 1991;101:1737–1740. [PubMed] [Google Scholar]

73. Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Semin Liver Dis. 2002;22:169–183. [PubMed] [Google Scholar]

74. Caballeria E, Masso RM, Arago JV, Sanchis A. Piroxicam hepatotoxicity. Am J Gastroenterol. 1990;85:898–899. [PubMed] [Google Scholar]

75. Bennett A. Nimesulide: a well-established cyclo-oxygenase-2inhibitor with many other pharmacological properties relevantto inflammatory disease. In: Vane JR, Botting RM, eds , editors. Therapeutic roles of selective COX-2 inhibitors. London: William Harvey Press; 2001. pp. 524–540. [Google Scholar]

76. Bessone F, Fay F, Vorobioff J, Passamonti ME, Godoy A, Tanno H. Nimesulide hepatotoxicity: Evidence from six cases. Hepatology. 1997;26:483A. [Google Scholar]

77. Grignola JC, Arias L, Rondan M, Sola L, Bagnulo H. Hepatoxicity associated to nimesulide [Revision of five cases] Arch Med Int. 1998;20:13–18. [Google Scholar]

78. Selig J, Liberek C, Kondo Oestreicher M, Desmeules J, Stoller R. Nimesulide hepatotoxicity. Poster presented at the 6th Annual Meeting of the European Society of Pharmacovigilance - Budapest, September 28-29, 1998. [Google Scholar]

79. Romero Gómez M, Nevado Santos M, Fobelo MJ, Castro Fernández M. [Nimesulide acute hepatitis: description of 3 cases] Med Clin (Barc) 1999;113:357–358. [PubMed] [Google Scholar]

80. Ozgür O, Hacihasanoğlu A, Karti SS, Ovali E. Nimesulide-induced fulminant hepatitis. Turk J Gastroenterol. 2003;14:208–210. [PubMed] [Google Scholar]

81. Lewin S. Post-marketing surveillance of nimesulide suspension. Indian Pediatr. 2002;39:890–891; author reply 891-892. [PubMed] [Google Scholar]

82. Andrade RJ, Lucena MI, Fernández MC, González M. Fatal hepatitis associated with nimesulide. J Hepatol. 2000;32:174. [PubMed] [Google Scholar]

83. Pérez-Moreno J, Llerena Guerrero RM, Puertas Montenegro M, Jiménez Arjona MJ. [Nimesulide toxic hepatitis in pregnancy] Gastroenterol Hepatol. 2000;23:498–499. [PubMed] [Google Scholar]

84. Papaioannides D, Korantzopoulos P, Athanassiou E, Sinapidis D. Nimesulide-induced acute hepatotoxicity. Indian J Gastroenterol. 2003;22:239. [PubMed] [Google Scholar]

85. Tejos S, Torrejón N, Reyes H, Meneses M. [Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide in a case] Rev Med Chil. 2000;128:1349–1353. [PubMed] [Google Scholar]

86. Dourakis SP, Sevastianos VA, Petraki K, Hadziyannis SJ. Nimesulide induced acute icteric hepatitis. Iatriki. 2001;79:275–278. [Google Scholar]

87. Rodrigo L, de Francisco R, Pérez-Pariente JM, Cadahia V, Tojo R, Rodriguez M, Lucena MI, Andrade RJ. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation. Scand J Gastroenterol. 2002;37:1341–1343. [PubMed] [Google Scholar]

88. Stadlmann S, Zoller H, Vogel W, Offner FA. COX-2 inhibitor (nimesulide) induced acute liver failure. Virchows Arch. 2002;440:553–555. [PubMed] [Google Scholar]

89. Polimeni G, Salvo F, Cutroneo P, Morreale I, Patrizio Caputi A. Adverse reactions induced by NSAIDs and antibacterials: analysis of spontaneous reports from the Sicilian regional database. Drug Saf. 2006;29:449–459. [PubMed] [Google Scholar]

90. Maciá MA, Carvajal A, del Pozo JG, Vera E, del Pino A. Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther. 2002;72:596–597. [PubMed] [Google Scholar]

91. Press Release: European Medicines Evaluation Agency (EMEA) states that nimesulide is safe and effective. 2003. Accessed September 16, 2004. Available from: http://www.mahalo.com/nimesulide. [Google Scholar]

92. Conforti A, Leone R, Moretti U, Mozzo F, Velo G. Adverse drug reactions related to the use of NSAIDs with a focus on nimesulide: results of spontaneous reporting from a Northern Italian area. Drug Saf. 2001;24:1081–1090. [PubMed] [Google Scholar]

93. Bessone F, Colombato L, Pasamonti ME, Godoy A, Vorobioff J, Tanno H. Nimesulide: clinical and histological evidences of severe hepatotoxicity. J Hepatol. 2001;34(Suppl 1):46. [Google Scholar]

94. Bessone F, Colombato L, Fassio E, Reggiardo MV, Vorobioff J, Tanno H. The spectrum of nimesulide-induced-hepatotoxicity. An overview. Anti-Inflamm & Anti-Allergy Agents Med Chem. 2010;9:355–365. [Google Scholar]

95. Bessone F, Tanno H. [Hepatotoxicity induced by non-steroidal anti-inflammatory drugs] Gastroenterol Hepatol. 2000;23:200–205. [PubMed] [Google Scholar]

96. Walker SL, Kennedy F, Niamh N, McCormick PA. Nimesulide associated fulminant hepatic failure. Pharmacoepidemiol Drug Saf. 2008;17:1108–1112. [PubMed] [Google Scholar]

97. Bjarnason I, Bissoli F, Conforti A, Maiden L, Moore N, Moretti U, Rainsford KD, Takeuchi K, Velo GP. Adverse reactions and their mechanisms from nimesulide. In: Rainsford KD, ed , editors. Nimesulide - Actions and Uses. Basel Switzerland: Birkhäuser Verlag; 2005. pp. 315–341. [Google Scholar]

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