, Volume 64, Issue 20, pp 2315–2343


Therapeutic Use and Safety Profile in the Management of Osteoarthritis and Rheumatoid Arthritis
  • Thomas Hedner
  • Ola Samulesson
  • Peter Währborg
  • Hans Wadenvik
  • Kjell-Arne Ung
  • Anders Ekbom
Review Article


Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabo-lite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and <1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces.

Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA.

The optimum oral dosage of nabumetone for OA patients is 1g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1g at bedtime is optimal, but an additional 0.5–1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen.

Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea.

In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function.

Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.


  1. 1.
    Data on file, Meda AB (Solna, Sweden), 2004Google Scholar
  2. 2.
    Smith CJ, Morrow JD, Roberts LJ, et al. Induction of prostaglandin endoperoxide synthase-1 (COX-1) in a human promonocytic cell line by treatment with the differentiating agent TPA. Adv Exp Med Biol 1997; 400A: 99–106PubMedCrossRefGoogle Scholar
  3. 3.
    Rocca B, Spain LM, Pure E, et al. Distinct roles of prostaglandin H synthases 1 and 2 in T-cell development. J Clin Invest 1999; 103(10): 1469–77PubMedCrossRefGoogle Scholar
  4. 4.
    Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2: mechanisms of catalysis and inhibition. J Biol Chem 1999; 274(33): 22903–6PubMedCrossRefGoogle Scholar
  5. 5.
    Pash JM, Bailey JM. Inhibition by corticosteroids of epidermal growth factor-induced recovery of cyclooxygenase after aspirin inactivation. FASEB J 1988; 2(10): 2613–8PubMedGoogle Scholar
  6. 6.
    Sebaldt RJ, Sheller JR, Oates JA, et al. Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. Proc Natl Acad Sci U S A 1990; 87(18): 6974–8PubMedCrossRefGoogle Scholar
  7. 7.
    Masferrer JL, Zweifel BS, Seibert K, et al. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest 1990; 86(4): 1375–9PubMedCrossRefGoogle Scholar
  8. 8.
    Xie WL, Chipman JG, Robertson DL, et al. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A 1991; 88(7): 2692–6PubMedCrossRefGoogle Scholar
  9. 9.
    Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem 1992; 267(12): 7991–4PubMedGoogle Scholar
  10. 10.
    O’Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A 1992; 89(11): 4888–92PubMedCrossRefGoogle Scholar
  11. 11.
    Lee SH, Soyoola E, Chanmugam P, et al. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem 1992; 267(36): 25934–8PubMedGoogle Scholar
  12. 12.
    Sheng H, Shao J, Dixon DA, et al. Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem 2000; 275(9): 6628–35PubMedCrossRefGoogle Scholar
  13. 13.
    Crofford LJ, Wilder RL, Ristimaki AP, et al. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1 beta, phorbol ester, and corticosteroids. J Clin Invest 1994; 93(3): 1095–101PubMedCrossRefGoogle Scholar
  14. 14.
    Schonbeck U, Sukhova GK, Graber P, et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155(4): 1281–91PubMedCrossRefGoogle Scholar
  15. 15.
    Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 1995; 2(8): 637–43PubMedCrossRefGoogle Scholar
  16. 16.
    Kurumbail RG, Stevens AM, Gierse JK, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 1996; 384(6610): 644–8PubMedCrossRefGoogle Scholar
  17. 17.
    Malkowski MG, Ginell SL, Smith WL, et al. The productive conformation of arachidonic acid bound to prostaglandin synthase. Science 2000; 289(5486): 1933–7PubMedCrossRefGoogle Scholar
  18. 18.
    Freeman AMUN, Thawley AR, Golding DN. Plasma and synovial fluid concentrations of nabumetone and BRL 10720 in patients given nabumetone. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 37–42Google Scholar
  19. 19.
    Boyle EA, Freeman PC, Mangan FR, et al. Nabumetone (BRL 14777, 4-[6-methoxy-2-naphthyl]-butan-2-one): a new antiinflammatory agent. J Pharm Pharmacol 1982; 34(9): 562–9PubMedCrossRefGoogle Scholar
  20. 20.
    Hyneck ML. An overview of the clinical pharmacokinetics of nabumetone. J Rheumatol 1992; 19 Suppl. 36: 20–4Google Scholar
  21. 21.
    Davies NM. Clinical pharmacokinetics of nabumetone: the dawn of selective cyclo-oxygenase-2 inhibition? Clin Pharmacokinet 1997; 33(6): 404–16PubMedCrossRefGoogle Scholar
  22. 22.
    Barnett J, Chow J, Ives D, et al. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochim Biophys Acta 1994; 1209(1): 130–9PubMedCrossRefGoogle Scholar
  23. 23.
    Laneuville O, Breuer DK, Dewitt DL, et al. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 1994; 271(2): 927–34PubMedGoogle Scholar
  24. 24.
    Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271(3): 1705–12PubMedGoogle Scholar
  25. 25.
    Schoen RT, Vender RJ. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med 1989; 86(4): 449–58PubMedCrossRefGoogle Scholar
  26. 26.
    Lichtenstein DR, Syngal S, Wolfe MM. Nonsteroidal antiin-flammatory drugs and the gastrointestinal tract: the doubleedged sword. Arthritis Rheum 1995; 38(1): 5–18PubMedCrossRefGoogle Scholar
  27. 27.
    Richardson CE, Emery P. Innovative treatment approaches for rheumatoid arthritis: new cyclo-oxygenase and cytokine inhibitors. Baillieres Clin Rheumatol 1995; 9(4): 731–58PubMedCrossRefGoogle Scholar
  28. 28.
    Blower PR. The unique pharmacologic profile of nabumetone. J Rheumatol 1992; 19 Suppl. 36: 13–9Google Scholar
  29. 29.
    Brett MA, Buscher G, Ellrich E, et al. Lack of enterohepatic circulation of the active metabolite of nabumetone in humans. J Rheumatol 1992; 19 Suppl. 36: 81–2Google Scholar
  30. 30.
    Mangan FR, Flack JD, Jackson D. Preclinical overview of nabumetone: pharmacology, bioavailability, metabolism, and toxicology. Am J Med 1987 Oct 30; 83(4B): 6–10PubMedCrossRefGoogle Scholar
  31. 31.
    Jackson RE, Mitchell FN, Brindley DA. Safety evaluation of nabumetone in United States clinical trials. Am J Med 1987; 83(4B): 115–20PubMedCrossRefGoogle Scholar
  32. 32.
    Dollery C. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  33. 33.
    Haddock RE, Jeffery DJ, Lloyd JA, et al. Metabolism of nabumetone (BRL 14777) by various species including man. Xenobiotica 1984; 14(4): 327–37PubMedCrossRefGoogle Scholar
  34. 34.
    von Schrader HW, Buscher G, Dierdorf D, et al. Nabumetone: a novel anti-inflammatory drug: bioavailability after different dosage regimens. Int J Clin Pharmacol Ther Toxicol 1984; 22(12): 672–6Google Scholar
  35. 35.
    Bourke BU, Thawley AR. An investigation into the penetration of nabumetone and its metabolites into synovial fluid in patients with rheumatoid arthritis. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 31–5Google Scholar
  36. 36.
    Sweetman SC. Martindale: the complete drug reference. 33rd ed. London: Pharmaceutical Press, 2002Google Scholar
  37. 37.
    Haig A, Flavin S, Macdonald B, et al. An open label study to establish dosing recommendations for nabumetone in juvenile rheumatoid arthirtis. J Rheumatol 2003 Apr; 30(4): 829–31PubMedGoogle Scholar
  38. 38.
    Ladely D, Lewitt B, Boike S. A study of the safety and pharmacokinetics of nabumetone and 6-MNA, and the protein binding of 6-MNA in patients with juvenile rheumatoid arthritis and in healthy adult volunteers following repeated oral doses of nabumetone (1000 mg) chewable tablets. SmithKline Beecham (now GlaxoSmithKline), 1997. Solna, Sweden: Meda AB, 1997 (Data on file)Google Scholar
  39. 39.
    Ostrov BE. Use of nabumetone (nab) to treat juvenile rheumatoid arthritis in children intolerant to other non-steroidal anti-inflammatory drugs [abstract no. 191]. Arthritis Rheum 1996; 39 (9 Suppl.): S58Google Scholar
  40. 40.
    Hamdy RC, Price JD, Undre NA, et al. The pharmacokinetics of nabumetone in elderly patients. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 173–83Google Scholar
  41. 41.
    Maleev A, Vlahov V, Gruev I, et al. Liver insufficiency as a factor modifying the pharmacokinetic characteristic of the preparation nabumetone. Int J Clin Pharmacol Ther Toxicol 1986; 24(8): 425–9PubMedGoogle Scholar
  42. 42.
    Clarke A, Hawkins S, Henderson RC, et al. Pharmacokinetics of nabumetone (BRL 14777) and its safety at steady state in patients with moderately imparied renal function [abstract]. Proceedings of the 2nd European Congress of Biopharmaceutics and Pharmacokinetics; 1984 Apr 24–27; SalamancaGoogle Scholar
  43. 43.
    Brier ME, Sloan RS, Aronoff GR. Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction. Clin Pharmacol Ther 1995; 57(6): 622–7PubMedCrossRefGoogle Scholar
  44. 44.
    Hilleman DE, Mohiuddin SM, Lucas Jr BD. Nonsteroidal anti-inflammatory drug use in patients receiving warfarin: emphasis on nabumetone. Am J Med 1993; 95(2A): 30S–4SPubMedCrossRefGoogle Scholar
  45. 45.
    Chan TY. Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance. Ann Pharmacother 1995 Dec; 29(12): 1274–83PubMedGoogle Scholar
  46. 46.
    Jennings MB, Alfieri DM, Jules KT, et al. A double-blind study of the effect on hemostasis of nabumetone (Relafen) compared to placebo. J Foot Ankle Surg 2000; 39(3): 168–73PubMedCrossRefGoogle Scholar
  47. 47.
    Friedel HA, Langtry HD, Buckley MM. Nabumetone: a reappraisal of its pharmacology and therapeutic use in rheumatic diseases. Drugs 1993; 45(1): 131–56PubMedCrossRefGoogle Scholar
  48. 48.
    Whelton A, White WB, Bello AE, et al. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002 Nov 1; 90(9): 959–63PubMedCrossRefGoogle Scholar
  49. 49.
    Dollery C. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  50. 50.
    Bellamy N, Bensen WG, Beaulieu A, et al. A multicenter study of nabumetone and diclofenac SR in patients with osteoarthritis. J Rheumatol 1995; 22(5): 915–20PubMedGoogle Scholar
  51. 51.
    Lister BJ, Poland M, DeLapp RE. Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993; 95(2A): 2S–9SPubMedCrossRefGoogle Scholar
  52. 52.
    Blechman WJ. Nabumetone therapy of osteoarthritis: a six-week, placebo-controlled study. Am J Med 1987; 83(4B): 70–3PubMedCrossRefGoogle Scholar
  53. 53.
    Gillgrass J, Grahame R. Nabumetone: a double-blind study in osteoarthrosis. Pharmatherapeutica 1984; 3(9): 592–4PubMedGoogle Scholar
  54. 54.
    Pisko EJ, Strader K, Rice D, et al. A 6-month, double-blind study comparing nabumetone to naproxen in the treatment of osteoarthritis. Pharmatherapeutica 1987; 5(2): 90–8PubMedGoogle Scholar
  55. 55.
    Appelrouth DJ, Baim S, Chang RW, et al. Comparison of the safety and efficacy of nabumetone and aspirin in the treatment of osteoarthritis in adults. Am J Med 1987; 83(4B): 78–81PubMedCrossRefGoogle Scholar
  56. 56.
    Cha HS, Koh JH, Jeon CH, et al. Comparison of the efficacy and safety of naproxen CR and nabumetone in the treatment of patients with osteoarthritis of the knee. Int J Clin Pharmacol Ther 2001; 39(12): 539–45PubMedGoogle Scholar
  57. 57.
    Fleischmann RM. Clinical efficacy and safety of nabumetone in rheumatoid arthritis and osteoarthritis. J Rheumatol 1992; 19 Suppl. 36: 32–40Google Scholar
  58. 58.
    Turner Jr RA, Brindley DA, Mitchell FN. Nabumetone: a single-center three-week comparison with placebo in the treatment of rheumatoid arthritis. Am J Med 1987; 83(4B): 36–9PubMedCrossRefGoogle Scholar
  59. 59.
    Lanier BG, Turner Jr RA, Collins RL, et al. Evaluation of nabumetone in the treatment of active adult rheumatoid arthritis. Am J Med 1987; 83(4B): 40–3PubMedCrossRefGoogle Scholar
  60. 60.
    Brobyn RD. Nabumetone in the treatment of active adult rheumatoid arthritis. Am J Med 1987; 83(4B): 50–4PubMedCrossRefGoogle Scholar
  61. 61.
    Pownall R, Knapp MS, Kowanko IC, et al. The therapeutic effectiveness of nabumetone given at different times of day including domiciliary self-measurement of circadian variations in the signs and symptoms of rheumatoid arthritis. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 113–23Google Scholar
  62. 62.
    Krug H, Broadwell LK, Berry M, et al. Tolerability and efficacy of nabumetone and naproxen in the treatment of rheumatoid arthritis. Clin Ther 2000; 22(1): 40–52PubMedCrossRefGoogle Scholar
  63. 63.
    Bernhard GC, Appelrouth DJ, Bankhurst AD, et al. Long-term treatment of rheumatoid arthritis comparing nabumetone with aspirin. Am J Med 1987; 83(4B): 44–9PubMedCrossRefGoogle Scholar
  64. 64.
    Department Rheumatology, PLA General Hospital Beijing 100853 China. Comparison of the efficacy and safety of nabumetone and diclofenc sodium in the treatment of patients with rheumatoid arthritis. Zhonghua Yi Xue Za Zhi 2001; 81(9): 557–60Google Scholar
  65. 65.
    Wojtulewski JA. A double-blind study of nabumetone in rheumatoid arthritis. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 79–88Google Scholar
  66. 66.
    Zoma A, Capell H. Double-blind study to compare the effectiveness and tolerance of nabumetone with indomethacin in patients with rheumatoid arthritis attending a hospital outpatient clinic. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 73–8Google Scholar
  67. 67.
    Goodman S, Howard P, Haig A, et al. An open label study to establish dosing recommendations for nabumetone in juvenile rheumatoid arthritis. J Rheumatol 2003; 30(4): 829–31PubMedGoogle Scholar
  68. 68.
    Short DJ, Brierley J, Hajiroussou V, et al. Comparison of nabumetone with indomethacin in the treatment of ankylosing spondylitis. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 125–30Google Scholar
  69. 69.
    Palferman TG, Webley M. A comparative study of nabumetone and indomethacin in ankylosing spondylitis. Eur J Rheumatol Inflamm 1991; 11(2): 23–9PubMedGoogle Scholar
  70. 70.
    Crean DM, Rotman H. An interim report of a study on the effect of nabumetone versus ibuprofen in acute soft-tissue injuries in sport. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 209–13Google Scholar
  71. 71.
    McLatchie GR, Allister C, McEwan C, et al. The management of acute soft-tissue injuries in the accident and emergency department (an open comparative study of nabumetone and soluble aspirin). In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 197–203Google Scholar
  72. 72.
    Muckle DS, Rotman H. A report on a study on the assessment of the effectiveness of nabumetone in the treatment of sports injuries by comparison with naproxen. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 187–92Google Scholar
  73. 73.
    Bouchier-Hayes TAI. A report on a study of the assessment of the effectiveness of nabumetone in the treatment of sports injuries by comparison with naproxen. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 203–8Google Scholar
  74. 74.
    Walkden L, Rotman H. A report of a study on the assessment of the effectiveness of nabumetone in the treatment of sports injuries by comparison with ibuprofen. In: Panayi GS, Price JD, Rotman H, editors. Nabumetone: a novel anti-inflammatory. International Congress and Symposium Series (ICSS) 69. London: Royal Society of Medicine Press, 1985: 193–6Google Scholar
  75. 75.
    Huang JQ, Sridhar S, Hunt RH. Gastrointestinal safety profile of nabumetone: a meta-analysis. Am J Med 1999; 107(6A): 55S–61SPubMedCrossRefGoogle Scholar
  76. 76.
    Bernhard GC. Worldwide safety experience with nabumetone. J Rheumatol 1992; 19 Suppl. 36: 48–57Google Scholar
  77. 77.
    Lipani JA, Poland M. Clinical update of the relative safety of nabumetone in long-term clinical trials. Inflammopharmacology 1995; 3: 351–61CrossRefGoogle Scholar
  78. 78.
    Nunn B, Chamberlain PD. Effect of nabumetone (BRL 14777), a new anti-inflammatory drug, on human platelet reactivity ex vivo: comparison with naproxen. J Pharm Pharmacol 1982; 34(9): 576–9PubMedCrossRefGoogle Scholar
  79. 79.
    FDA memorandum: Rofecoxib (MK-0966) [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf [Accessed 2004 Aug 23]
  80. 80.
    Willkens RF. An overview of the long-term safety experience of nabumetone. Drugs 1990; 40 Suppl. 5: 34–7PubMedCrossRefGoogle Scholar
  81. 81.
    Confino-Cohen R, Goldberg A. Safe full-dose one-step nabumetone challenge in patients with nonsteroidal anti-inflammatory drug hypersensitivity. Allergy Asthma Proc 2003; 24(4): 281–4PubMedGoogle Scholar
  82. 82.
    Fries JF, Williams CA, Bloch DA, et al. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 1991; 91(3): 213–22PubMedCrossRefGoogle Scholar
  83. 83.
    Soll AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl J Med 1990; 322(13): 909–16PubMedCrossRefGoogle Scholar
  84. 84.
    Hochberg MC. Association of nonsteroidal antiinflammatory drugs with upper gastrointestinal disease: epidemiologic and economic considerations. J Rheumatol 1992; 19 Suppl. 36: 63–7Google Scholar
  85. 85.
    Wallace JL, McKnight W, Vergnolle N. Inhibition of both cyclo-oxygenase (COX)-1 and COX-2 is required for NSAID-induced erosion formation [abstract]. Gastroenterology 2000; 118: A194CrossRefGoogle Scholar
  86. 86.
    Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995; 83(3): 483–92PubMedCrossRefGoogle Scholar
  87. 87.
    Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83(3): 473–82PubMedCrossRefGoogle Scholar
  88. 88.
    Wallace JL, Reuter BK, McKnight W, et al. Selective inhibitors of cyclooxygenase-2: are they really effective, selective, and GI-safe? J Clin Gastroenterol 1998; 27 Suppl. 1: S28–34PubMedCrossRefGoogle Scholar
  89. 89.
    Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112(2): 387–97PubMedCrossRefGoogle Scholar
  90. 90.
    Reuter BK, Asfaha S, Buret A, et al. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996; 98(9): 2076–85PubMedCrossRefGoogle Scholar
  91. 91.
    Gretzer B, Ehrlich K, Maricic N, et al. Selective cyclo-ox-ygenase-2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach. Br J Pharmacol 1998; 123(5): 927–35PubMedCrossRefGoogle Scholar
  92. 92.
    Lichtenberger LM. Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited. Biochem Pharmacol 2001; 61(6): 631–7PubMedCrossRefGoogle Scholar
  93. 93.
    Cooke AR, Goulston K. Failure of intravenous aspirin to increase gastrointestinal blood loss. BMJ 1969; 1(666): 330–2CrossRefGoogle Scholar
  94. 94.
    Ivey KJ, Paone DB, Krause WJ. Acute effect of systemic aspirin on gastric mucosa in man. Dig Dis Sci 1980; 25(2): 97–9PubMedCrossRefGoogle Scholar
  95. 95.
    Shorrock CJ, Rees WD. Mucosal adaptation to indomethacin induced gastric damage in man: studies on morphology, blood flow, and prostaglandin E2 metabolism. Gut 1992; 33(2): 164–9PubMedCrossRefGoogle Scholar
  96. 96.
    Konturek JW, Dembinski A, Konturek SJ, et al. Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans. Gastroenterology 1998; 114(2): 245–55PubMedCrossRefGoogle Scholar
  97. 97.
    Ligumsky M, Golanska EM, Hansen DG, et al. Aspirin can inhibit gastric mucosal cyclo-oxygenase without causing lesions in rat. Gastroenterology 1983; 84(4): 756–61PubMedGoogle Scholar
  98. 98.
    Ligumsky M, Sestieri M, Karmeli F, et al. Rectal administration of nonsteroidal antiinflammatory drugs: effect on rat gastric ulcerogenicity and prostaglandin E2 synthesis. Gastroenterology 1990; 98 (5 Pt 1): 1245–9PubMedGoogle Scholar
  99. 99.
    Brune K, Nurnberg B, Szelenyi I, et al. The enterohepatic circulation of some anti-inflammatory drugs may cause intestinal ulcerations. In: Rainsford KD, Velo GP, editors. Side effects of anti-inflammatory drugs. Pt 2. Boston (MA): MTP Press Limited, 1985: 29–39Google Scholar
  100. 100.
    Hucker HB, Zacchei AG, Cox SV, et al. Studies on the absorption, distribution and excretion of indomethasin in various species. J Pharmacol Exp Ther 1966; 153: 237–49Google Scholar
  101. 101.
    Yamada T, Deitch E, Specian RD, et al. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 1993; 17(6): 641–62PubMedCrossRefGoogle Scholar
  102. 102.
    Hansen D, Aures D, Grossman MI. Comparison of intravenous and intragastric aspirin in production of antral gastric ulcers in cats. Proc Soc Exp Biol Med 1980; 164(4): 589–92PubMedGoogle Scholar
  103. 103.
    Whittle BJ, Hansen D, Salmon JA. Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate. Eur J Pharmacol 1985; 116(1–2): 153–7PubMedCrossRefGoogle Scholar
  104. 104.
    Bugat R, Thompson MR, Aures D, et al. Gastric mucosal lesions produced by intravenous infusion of aspirin in cats. Gastroenterology 1976; 71(5): 754–9PubMedGoogle Scholar
  105. 105.
    Elliott SN, Wallace JL. Nitric oxide: a regulator of mucosal defense and injury. J Gastroenterol 1998; 33(6): 792–803PubMedCrossRefGoogle Scholar
  106. 106.
    Mahmud T, Rafi SS, Scott DL, et al. Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation. Arthritis Rheum 1996; 39(12): 1998–2003PubMedCrossRefGoogle Scholar
  107. 107.
    McCormack K, Brune K. Classical absorption theory and the development of gastric mucosal damage associated with the non-steroidal anti-inflammatory drugs. Arch Toxicol 1987; 60(4): 261–9PubMedCrossRefGoogle Scholar
  108. 108.
    Robert A. Prostaglandins and the gastrointestinal tract. New York: Raven Press, 1981Google Scholar
  109. 109.
    Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985; 89(5): 1162–88PubMedGoogle Scholar
  110. 110.
    Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other non-steroidal anti-inflammatory drugs. Scand J Gastroenterol Suppl 1989; 163: 24–31PubMedCrossRefGoogle Scholar
  111. 111.
    Rainsford KD, Willis C. Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production. Dig Dis Sci 1982; 27(7): 624–35PubMedCrossRefGoogle Scholar
  112. 112.
    Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988; II(8623): 1277–80CrossRefGoogle Scholar
  113. 113.
    Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123(4): 241–9PubMedGoogle Scholar
  114. 114.
    Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338(11): 727–34Google Scholar
  115. 115.
    Sawaoka H, Tsuji S, Tsujii M, et al. Expression of the cyclooxygenase-2 gene in gastric epithelium. J Clin Gastroenterol 1997; 25 Suppl. 1: S105–10115.PubMedCrossRefGoogle Scholar
  116. 116.
    Stenson WF. Cyclooxygenase 2 and wound healing in the stomach. Gastroenterology 1997; 112(2): 645–8PubMedCrossRefGoogle Scholar
  117. 117.
    Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and performation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994 Mar 26; 343(8900): 769–72PubMedCrossRefGoogle Scholar
  118. 118.
    Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115(10): 787–96PubMedGoogle Scholar
  119. 119.
    Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 1993; 105(4): 1078–88PubMedGoogle Scholar
  120. 120.
    McCarthy D. Nonsteroidal anti-inflammatory drug-related gastrointestinal toxicity: definitions and epidemiology. Am J Med 1998; 105(5A): 3S–9SPubMedCrossRefGoogle Scholar
  121. 121.
    Singh G, Rosen Ramey D. NSAID induced gastrointestinal complicatons: the ARMAIS perspective: 1997. J Rheumatol 1998; 25 Suppl. 51: 8–16Google Scholar
  122. 122.
    Florence AT, Jani PU. Novel oral drug formulations: their potential in modulating adverse effects. Drug Saf 1994; 10(3): 233–66PubMedCrossRefGoogle Scholar
  123. 123.
    Tramer MR, Williams JE, Carroll D, et al. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review. Acta Anaesthesiol Scand 1998; 42(1): 71–9PubMedCrossRefGoogle Scholar
  124. 124.
    Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993; 268(9): 6610–4PubMedGoogle Scholar
  125. 125.
    Rothstein R. Safety profiles of leading nonsteroidal anti-inflammatory drugs. Am J Med 1998; 105(5A): 39S–43SPubMedCrossRefGoogle Scholar
  126. 126.
    Somasundaram S, Hayllar H, Rafi S, et al. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995; 30(4): 289–99PubMedCrossRefGoogle Scholar
  127. 127.
    Lussier A, LeBel E. Radiochromium (chromium-51) evaluation of gastrointestinal blood loss associated with placebo, aspirin, and nabumetone. Am J Med 1987; 83(4B): 15–8PubMedCrossRefGoogle Scholar
  128. 128.
    Sigthorsson G, Tibbie J, Hayllar J, et al. Intestinal permeability and inflammation in patients on NSAIDs. Gut 1998; 43(4): 506–11PubMedCrossRefGoogle Scholar
  129. 129.
    Appleyard M, Fireman Z, Glukhovsky A, et al. A randomized trial comparing wireless capsule endoscopy with push enteroscopy-for the detection of small-bowel lesions. Gastroenterology 2000; 119(6): 1431–8PubMedCrossRefGoogle Scholar
  130. 130.
    Smale S, Tibbie J, Sigthorsson G, et al. Epidemiology and differential diagnosis of NSAID-induced injury to the mucosa of the small intestine. Best Pract Res Clin Gastroenterol 2001; 15(5): 723–38PubMedCrossRefGoogle Scholar
  131. 131.
    Bjarnason I, Fehilly B, Smethurst P, et al. Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut 1991; 32(3): 275–7PubMedCrossRefGoogle Scholar
  132. 132.
    Dandona P, Jeremy JY. Nonsteroidal anti-inflammatory drug therapy and gastric side effects: does nabumetone provide a solution? Drugs 1990; 40 Suppl. 5: 16–24PubMedCrossRefGoogle Scholar
  133. 133.
    Freston JW. Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events. Am J Med 1999; 107 Suppl. 6A: 78S–88SPubMedCrossRefGoogle Scholar
  134. 134.
    MacDonald TM, Morant SV, Robinson GC, et al. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997; 315(7119): 1333–7PubMedCrossRefGoogle Scholar
  135. 135.
    Singh G, Terry R, Ramey RT. Comparative toxicity of NSAIDs [abstract]. Arthritis Rheum 1997; 40(S115): 507Google Scholar
  136. 136.
    Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective–1997. Arthritis, Rheumatism, and Aging Medical Information. J Rheumatol Suppl 1998 May; 51: 8–16PubMedGoogle Scholar
  137. 137.
    Singh B, Terry R, Ramey DR. Epidemiology of serious NSAID-related complications: a prospective multivariate lifetable analysis [abstract]. Arthritis Rheum 1997; 40: S213Google Scholar
  138. 138.
    Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330(18): 1287–94PubMedCrossRefGoogle Scholar
  139. 139.
    Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326(5): 310–8PubMedCrossRefGoogle Scholar
  140. 140.
    Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 2003 Jun; 30(6): 1196–202PubMedGoogle Scholar
  141. 141.
    Funk CD, Funk LB, Kennedy ME, et al. Human platelet/ erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991; 5(9): 2304–12PubMedGoogle Scholar
  142. 142.
    Patrignani P, Sciulli MG, Manarini S, et al. COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J Physiol Pharmacol 1999; 50(4): 661–7PubMedGoogle Scholar
  143. 143.
    Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994; 367(6460): 243–9PubMedCrossRefGoogle Scholar
  144. 144.
    Loll PJ, Picot D, Ekabo O, et al. Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site. Biochemistry 1996; 35(23): 7330–40PubMedCrossRefGoogle Scholar
  145. 145.
    Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345(25): 1809–17PubMedCrossRefGoogle Scholar
  146. 146.
    FitzGerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68(7): 11B-5BCrossRefGoogle Scholar
  147. 147.
    Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61(6): 1081–5PubMedGoogle Scholar
  148. 148.
    Patrono C, Ciabattoni G, Patrignani P, et al. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 1985; 72(6): 1177–84PubMedCrossRefGoogle Scholar
  149. 149.
    Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69(6): 1366–72PubMedCrossRefGoogle Scholar
  150. 150.
    Weksler BB, Pett SB, Alonso D, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983; 308(14): 800–5PubMedCrossRefGoogle Scholar
  151. 151.
    Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978; 61(2): 314–9PubMedCrossRefGoogle Scholar
  152. 152.
    De Caterina R, Giannessi D, Boem A, et al. Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction. Thromb Haemost 1985; 54(2): 528–32PubMedGoogle Scholar
  153. 153.
    FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71(3): 676–88PubMedCrossRefGoogle Scholar
  154. 154.
    Fitzgerald DJ, Roy L, Catella F, et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315(16): 983–9PubMedCrossRefGoogle Scholar
  155. 155.
    Vejar M, Fragasso G, Hackett D, et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990; 63(2): 163–8PubMedGoogle Scholar
  156. 156.
    SALT TSCG. Swedish Acetylsalicylic acid Low-Dose Trial (SALT) of 75mg acetylsalicylic acid as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345–9CrossRefGoogle Scholar
  157. 157.
    Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286(8): 954–9PubMedCrossRefGoogle Scholar
  158. 158.
    Hawkey CJ. COX-1 and COX-2 inhibitors. Best Pract Res Clin Gastroenterol 2001; 15(5): 801–20PubMedCrossRefGoogle Scholar
  159. 159.
    Hochberg MC. What have we learned from the large outcomes trials of COX-2 selective inhibitors? The rheumatologist’s perspective. Clin Exp Rheumatol 2001; 19 (6 Suppl. 25): S15–22PubMedGoogle Scholar
  160. 160.
    Bombardier C, Laine L, Reicin A, 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(21): 1520–8PubMedCrossRefGoogle Scholar
  161. 161.
    Silverstein FE, Faich G, Goldstein JL, 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(10): 1247–55Google Scholar
  162. 162.
    US FDA. Statistical reviewer briefing document for the advisory committee. NDA# 21-042 s-007 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_04_stats.pdf [Accessed 2004 Jul 28]
  163. 163.
    US FDA. Statistical reviewer briefing document for the advisory committee. NDA20-998 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677bl_04_stats.pdf [Accessed 2003 Jul 28]
  164. 164.
    Scheiman JM. Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors. Cleve Clin J Med 2002; 69 Suppl. 1: SI40–6PubMedCrossRefGoogle Scholar
  165. 165.
    Singh G, Goldstein J, Bensen WG, et al. SUCCESS-1 in osteoarthritis (OA) trial: celecoxib significantly reduces risk of upper GI complications compared to NSAIDs while providing similar efficacy in 13,274 randomized patients [abstract]. Ann Rheum Dis 2001; 60 Suppl. 1: 58Google Scholar
  166. 166.
    Goldstein JL, Correa P, Zhao WW, et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001; 96(4): 1019–27PubMedCrossRefGoogle Scholar
  167. 167.
    Cipollone F, Ganci A, Panara MR, et al. Effects of nabumetone on prostanoid biosynthesis in humans. Clin Pharmacol Ther 1995; 58(3): 335–41PubMedCrossRefGoogle Scholar
  168. 168.
    Jeremy JY, Mikhailidis DP, Barradas MA, et al. The effect of nabumetone and its principal active metabolite on in vitro human gastric mucosal prostanoid synthesis and platelet function. Br J Rheumatol 1990; 29(2): 116–9PubMedCrossRefGoogle Scholar
  169. 169.
    Schnitzer TJ, Donahue JR, Toomey EP, et al. Effect of nabumetone on hemostasis during arthroscopic knee surgery. Clin Ther 1998; 20(1): 110–24PubMedCrossRefGoogle Scholar
  170. 170.
    Giuliano F, Ferraz JG, Pereira R, et al. Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation. Eur J Pharmacol 2001; 426(1-2): 95–103PubMedCrossRefGoogle Scholar
  171. 171.
    Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000; 40(2): 124–32PubMedCrossRefGoogle Scholar
  172. 172.
    Hennan JK, Huang J, Barrett TD, et al. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 2001; 104(7): 820–5PubMedCrossRefGoogle Scholar
  173. 173.
    Konstam MA, Weir MR, Reicin A, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001; 104(19): 2280–8PubMedCrossRefGoogle Scholar
  174. 174.
    Crofford LJ. Rational use of analgesic and antiinflammatory drugs. N Engl J Med 2001; 345(25): 1844–6PubMedCrossRefGoogle Scholar
  175. 175.
    Van Solingen RM, Rosenstein ED, Mihailescu G, et al. Comparison of the effects of ketoprofen on platelet function in the presence and absence of aspirin. Am J Med 2001; 111(4): 285–9PubMedCrossRefGoogle Scholar
  176. 176.
    Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324(7329): 71–86CrossRefGoogle Scholar
  177. 177.
    Fornaro G, Rossi P, Mantica PG, et al. Indobufen in the prevention of thromboembolic complications in patients with heart disease: a randomized, placebo-controlled, double-blind study. Circulation 1993; 87(1): 162–4PubMedCrossRefGoogle Scholar
  178. 178.
    Brochier ML. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial. Eur Heart J 1993; 14(7): 951–7Google Scholar
  179. 179.
    Garcia Rodriguez LA, Varas C, Patroni C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11: 382–7PubMedCrossRefGoogle Scholar
  180. 180.
    Pedersen AK, FitzGerald GA. Cyclooxygenase inhibition, platelet function, and metabolite formation during chronic sulfinpyrazone dosing. Clin Pharmacol Ther 1985; 37(1): 36–42PubMedCrossRefGoogle Scholar
  181. 181.
    FitzGerald GA, Smith B, Pedersen AK, et al. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310(17): 1065–8PubMedCrossRefGoogle Scholar
  182. 182.
    Catella-Lawson F, McAdam BF, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999; 289(2): 735–41PubMedGoogle Scholar
  183. 183.
    McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999; 96(1): 272–7PubMedCrossRefGoogle Scholar
  184. 184.
    Braden GA, Knapp HR, FitzGerald GA. Suppression of eicosa-noid biosynthesis during coronary angioplasty by fish oil and aspirin. Circulation 1991; 84(2): 679–85PubMedCrossRefGoogle Scholar
  185. 185.
    Gimbrone Jr MA, Topper JN, Nagel T, et al. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 2000; 902: 230–9PubMedCrossRefGoogle Scholar
  186. 186.
    James MJ, Walsh JA, Foreman RK. Effect of 50mg entericcoated aspirin (Astrix) on thromboxane and prostacyclin synthesis. Aust N Z J Surg 1987; 57(10): 763–6PubMedCrossRefGoogle Scholar
  187. 187.
    Olsen NV, Jensen NG, Hansen JM, et al. Non-steroidal anti-inflammatory drugs and renal response to exercise: a comparison of indomethacin and nabumetone. Clin Sci (Lond) 1999; 97(4): 457–65CrossRefGoogle Scholar
  188. 188.
    Whelton A. Renal and related cardiovascular effects of conventional and COX-2-specific NSAIDs and non-NSAID analgesics. Am J Ther 2000; 7(2): 63–74PubMedCrossRefGoogle Scholar
  189. 189.
    Thakur V, Cook ME, Wallin JD. Antihypertensive effect of the combination of fosinopril and HCTZ is resistant to interference by nonsteroidal antiinflammatory drugs. Am J Hypertens 1999; 12 (9 Pt 1): 925–8PubMedCrossRefGoogle Scholar
  190. 190.
    Palmer R, Weiss R, Zusman RM, et al. Effects of nabumetone, celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors. Am J Hypertens 2003; 16(2): 135–9PubMedCrossRefGoogle Scholar
  191. 191.
    Day RO, Henry DA, Muirden KD, et al. Non-steroidal anti-inflammatory drug induced upper gastrointestinal haemorrhage and bleeding. Med J Aust 1992; 157(11–12): 810–2PubMedGoogle Scholar
  192. 192.
    Adverse Drug Reactions Advisory Committee (ADRAC). Celecoxib: early Australian reporting experience. Aust Adv Drug React Bull 2000; 19: 6–7Google Scholar
  193. 193.
    Committee on Safety of Medicines. In focus: rofecoxib [abstract]. Curr Probl Pharmacovigil 2000; 26: 13Google Scholar
  194. 194.
    Crofford LJ, Oates JC, McCune WJ, et al. Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors: a report of four cases. Arthritis Rheum 2000; 43(8): 1891–6PubMedCrossRefGoogle Scholar
  195. 195.
    Dunn M. The role of arachidonic acid metabolites in renal homeostasis: non-steroidal anti-inflammatory drugs renal function and biochemical, histological and clinical effects and drug interactions. Drugs 1987; 33 Suppl. 1: 56–66PubMedCrossRefGoogle Scholar
  196. 196.
    Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 1997; 24 Suppl. 49: 15–9Google Scholar
  197. 197.
    Palmer BF, Henrich WL. Clinical acute renal failure with nonsteroidal anti-inflammatory drugs. Semin Nephrol 1995; 15(3): 214–27PubMedGoogle Scholar
  198. 198.
    Lipsky PE. Specific COX-2 inhibitors in arthritis, oncology, and beyond: where is the science headed? J Rheumatol 1999; 26 Suppl. 56: 25–30Google Scholar
  199. 199.
    Breyer MD. COX2 selective NSAIDs and renal function: gain without pain? Kidney Int 1999; 55(2): 738–9PubMedCrossRefGoogle Scholar
  200. 200.
    KomhoffM, Grone HJ, Klein T, et al. Localization of cyclooxy-genase-1 and -2 in adult and fetal human kidney: implication for renal function. Am J Physiol 1997; 272 (4 Pt 2): F460–8Google Scholar
  201. 201.
    Komers R, Anderson S, Epstein M. Renal and cardiovascular effects of selective cyclooxygenase-2 inhibitors. Am J Kidney Dis 2001; 38(6): 1145–57PubMedCrossRefGoogle Scholar
  202. 202.
    Khan KN, Paulson SK, Verburg KM, et al. Pharmacology of cyclooxygenase-2 inhibition in the kidney. Kidney Int 2002; 61(4): 1210–9PubMedCrossRefGoogle Scholar
  203. 203.
    Stichtenoth DO, Frolich JC. COX-2 and the kidneys. Curr Pharm Des 2000; 6(17): 1737–53PubMedCrossRefGoogle Scholar
  204. 204.
    Brater DC, Harris C, Redfern JS, et al. Renal effects of COX-2-selective inhibitors. Am J Nephrol 2001; 21(1): 1–15PubMedCrossRefGoogle Scholar
  205. 205.
    Guan Y, Chang M, Cho W, et al. Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol 1997; 273 (1 Pt 2): F18–26PubMedGoogle Scholar
  206. 206.
    Harris RC, McKanna JA, Akai Y, et al. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 1994; 94(6): 2504–10PubMedCrossRefGoogle Scholar
  207. 207.
    Pugliese F, Cinotti GA. Nonsteroidal anti-inflammatory drugs (NSAIDs) and the kidney. Nephrol Dial Transplant 1997; 12(3): 386–8PubMedCrossRefGoogle Scholar
  208. 208.
    Murray MD, Brater DC. Effects of NSAIDs on the kidney. Prog Drug Res 1997; 49: 155–71PubMedGoogle Scholar
  209. 209.
    Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 1993; 44(3): 643–53PubMedCrossRefGoogle Scholar
  210. 210.
    Bennett WM, Henrich WL, Stoff JS. The renal effects of nonsteroidal anti-inflammatory drugs: summary and recommendations. Am J Kidney Dis 1996; 28 (1 Suppl. 1): S56–62PubMedCrossRefGoogle Scholar
  211. 211.
    Freed MI, Audet PR, Zariffa N, et al. Comparative effects of nabumetone, sulindac, and indomethacin on urinary prostaglandin excretion and platelet function in volunteers. J Clin Pharmacol 1994; 34(11): 1098–108PubMedGoogle Scholar
  212. 212.
    Cook ME, Wallin JD, Thakur VD, et al. Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. J Rheumatol 1997; 24(6): 1137–44PubMedGoogle Scholar
  213. 213.
    Cangiano JL, Figueroa J, Palmer R. Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis. Clin Ther 1999; 21(3): 503–12PubMedCrossRefGoogle Scholar
  214. 214.
    Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med 2001; 111(1): 64–7PubMedCrossRefGoogle Scholar
  215. 215.
    Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001; 357(9272): 1946–7PubMedCrossRefGoogle Scholar
  216. 216.
    Henao J, Hisamuddin I, Nzerue CM, et al. Celecoxib-induced acute interstitial nephritis. Am J Kidney Dis 2002; 39(6): 1313–7PubMedCrossRefGoogle Scholar
  217. 217.
    Eversmeyer W, Poland M, DeLapp RE, et al. Safety experience with nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993; 95(2A): 10S–8SPubMedCrossRefGoogle Scholar
  218. 218.
    Morgan GJ, Poland M, De Lapp RE. Efficacy and safety of nabumetone versus diclofenac, naproxen, ibuprofen and piroxicam in the elderly. Am J Med 1993 Aug 9; 95 Suppl. 2A: 19S–27SPubMedCrossRefGoogle Scholar
  219. 219.
    DeWitt DL, Meade EA, Smith WL. PGH synthethase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs. Am J Med 1993; 95(2A): 40S–4SCrossRefGoogle Scholar
  220. 220.
    Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995; 378(6555): 406–9PubMedCrossRefGoogle Scholar
  221. 221.
    Eckmann L, Stenson WF, Savidge TC, et al. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria: bacterial entry induces epithelial prostaglandin synthase-2 expression and prostaglandin E2 and F2alpha production. J Clin Invest 1997; 100(2): 296–309PubMedCrossRefGoogle Scholar
  222. 222.
    Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage: influence of nitric oxide. J Clin Invest 1997; 99(6): 1231–7PubMedCrossRefGoogle Scholar
  223. 223.
    Stichtenoth DO, Wagner B, Frolich JC. Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers. J Investig Med 1998; 46(6): 290–6PubMedGoogle Scholar
  224. 224.
    Brooks DP, Adams J, DePalma PD, et al. The selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, but not 6-MNA affects renal hemodynamic and renal function in the dog [abstract]. J Invest Med 1998 Mar; 46 (3 Suppl. S): 227AGoogle Scholar
  225. 225.
    Sirois J, Dore M. The late induction of prostaglandin G/H synthase-2 in equine preovulatory follicles supports its role as a determinant of the ovulatory process. Endocrinology 1997; 138(10): 4427–34PubMedCrossRefGoogle Scholar
  226. 226.
    Rossat J, Maillard M, Nussberger J. Acute renal effects of selective inhibition of cyclooxygenase-2 in healthy salt-depleted subjects [abstract no.]. J Am Soc Nephrol 1998; 9: 346AGoogle Scholar
  227. 227.
    Pairet M, Churchill L, Engelhardt G. Differential inhibition of cyclooxygenases 1 and 2 by NSAIDs. Dordrecht: Kluwer Academic Publishers, 1996Google Scholar
  228. 228.
    Jouzeau JY, Terlain B, Abid A, et al. Cyclo-oxygenase isoenzymes: how recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs 1997; 53(4): 563–82PubMedCrossRefGoogle Scholar
  229. 229.
    Truitt KE, Sperling RS, Ettinger Jr WH, et al. A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis. Aging (Milano) 2001; 13(2): 112–21Google Scholar
  230. 230.
    Stricker S. Aus der Traubschen Klinik. Ueber die Resultate der Behandlung der Polyarthritis Rheumatica mit Salicylsäure. Berliner Klinische Wochestchr 1876; 13: 1–2, 8, 13, 15Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Thomas Hedner
    • 1
  • Ola Samulesson
    • 2
  • Peter Währborg
    • 3
  • Hans Wadenvik
    • 4
  • Kjell-Arne Ung
    • 5
  • Anders Ekbom
    • 6
  1. 1.Department of Clinical PharmacologySahlgrenska University HospitalGöteborgSweden
  2. 2.Department of NephrologySahlgrenska University HospitalGöteborgSweden
  3. 3.Department of CardiologySahlgrenska University HospitalGöteborgSweden
  4. 4.Department of HematologySahlgrenska University HospitalGöteborgSweden
  5. 5.Department of GastroenterologyKärnsjukhusetSkövdeSweden
  6. 6.Department of Medical EpidemiologyKarolinska InstituteStockholmSweden

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