Skip to main content
SpringerLink
Log in

Selective COX-2 Inhibitors, Eicosanoid Synthesis and Clinical Outcomes: A Case Study of System Failure

  • Review
  • Published:
Lipids

Abstract

Elucidation of differences between the active sites of COX-1 and COX-2 allowed the targeted design of the selective COX-2 inhibitors known as coxibs. They were marketed as non-steroidal anti-inflammatory drugs (NSAIDs) that had improved upper gastrointestinal (GI) safety compared with older non-selective NSAIDs such as diclofenac and naproxen. Two GI safety studies conducted with arthritis patients demonstrated that in terms of upper GI safety, celecoxib was not superior to diclofenac (CLASS study) but rofecoxib was superior to naproxen (VIGOR study). However, the VIGOR study revealed also that rofecoxib had increased cardiovascular (CV) risk compared with naproxen. This clinical outcome was supported by the existence of plausible eicosanoid-based biological mechanisms whereby selective COX-2 inhibition could increase CV risk. Nevertheless, the existence of CV risk with rofecoxib was successfully discounted by its pharmaceutical company owner, Merck & Co, with the assistance of specialist opinion leaders and rofecoxib achieved widespread clinical use for 4–5 years. Rofecoxib was withdrawn from the market when several clinical trials in colorectal cancer and post-operative pain revealed increased CV risk with not only rofecoxib, but also coxibs. The commercial success of rofecoxib provides a case-study of failure of the medical journal literature to guide drug usage. Attention to ethical issues may have provided a more useful guide for prescribers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moncada S, Ferreira SH, Vane JR (1975) Inhibition of prostaglandin biosynthesis as the mechanism of analgesia of aspirin-like drugs in the dog knee joint. Eur J Pharmacol 31:250–260

    Article  PubMed  CAS  Google Scholar 

  2. Vane JR, Bakhle YS, Botting RM (1998) Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38:97–120

    Article  PubMed  CAS  Google Scholar 

  3. Fries JF, Murtagh KN, Bennett M, Zatarain E, Lingala B, Bruce B (2004) The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis. Arthritis Rheum 50:2433–2440

    Article  PubMed  Google Scholar 

  4. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648

    Article  PubMed  CAS  Google Scholar 

  5. Hawkey CJ (1999) COX-2 inhibitors. Lancet 353:307–314

    Article  PubMed  CAS  Google Scholar 

  6. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR (1999) Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 96:7563–7568

    Article  PubMed  CAS  Google Scholar 

  7. Demasi M, Cleland LG, Cook-Johnson RJ, Caughey GE, James MJ (2003) Effects of hypoxia on monocyte inflammatory mediator production: dissociation between changes in cyclooxygenase-2 expression and eicosanoid synthesis. J Biol Chem 278:38607–38616

    Article  PubMed  CAS  Google Scholar 

  8. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ (2001) Roles of cyclooxygenase (COX) -1 and -2 in prostanoid production by human endothelial cells: selective upregulation of prostacyclin synthesis by COX-2. J Immunol 167:2831–2838

    PubMed  CAS  Google Scholar 

  9. Cook-Johnson RJ, Demasi M, Cleland LG, Gamble JR, Saint DA, James MJ (2006) Endothelial cell COX-2 expression and activity in hypoxia: transcriptional control mechanisms. BBA-Cell Mol Biol Lipids 1761:1443–1449

    CAS  Google Scholar 

  10. Caughey GE, Cleland LG, Gamble JR, James MJ (2001) Up-regulation of endothelial cyclooxygenase-2 and prostanoid synthesis by platelets: role of thromboxane A2. J Biol Chem 276:37839–37845

    PubMed  CAS  Google Scholar 

  11. Penglis PS, Cleland LG, Demasi M, Caughey GE, James MJ (2000) Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors. J Immunol 165:1605–1611

    PubMed  CAS  Google Scholar 

  12. Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, Antes L, Lasseter KC, Quan H, Gertz BJ, Fitzgerald GA (1999) Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 289:735–741

    PubMed  CAS  Google Scholar 

  13. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, Fitzgerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 96:272–277

    Article  PubMed  CAS  Google Scholar 

  14. Stemme V, Swedenborg J, Claesson H-E, Hansson GK (2000) Expression of cyclo-oxygenase-2 in human atherosclerotic carotid arteries. Eur J Vasc Endovasc Surg 20:146–152

    Article  PubMed  CAS  Google Scholar 

  15. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ (2000) Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 102:840–845

    PubMed  CAS  Google Scholar 

  16. Baker CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, Yacoub MH, Polak JM (1999) Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol 19:646–655

    PubMed  CAS  Google Scholar 

  17. Topper JN, Cai J, Falb D, Gimbrone MA (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 93:10417–10422

    Article  PubMed  CAS  Google Scholar 

  18. Dowd NP, Scully M, Adderley SR, Cunningham AJ, Fitzgerald DJ (2001) Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. J Clin Invest 108:585–590

    Article  PubMed  CAS  Google Scholar 

  19. Adderley SR, Fitzgerald DJ (1999) Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem 274:5038–5046

    Article  PubMed  CAS  Google Scholar 

  20. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, Dawn B (2002) Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 55:506–519

    Article  PubMed  CAS  Google Scholar 

  21. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383

    Article  PubMed  CAS  Google Scholar 

  22. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS (2000) 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 284:1247–1255

    Article  PubMed  CAS  Google Scholar 

  23. US Food and Drug Authority (accessed April 2007) FDA Advisory Committee briefing document. NDA 20–998/S-009. Celebrex capsules (Celecoxib). Medical Officer Review. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.doc

  24. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873–884

    Article  PubMed  CAS  Google Scholar 

  25. US Food and Drug Authority (accessed April 2007) FDA Advisory Committee briefing document. NDA 21–042, s007. VIOXX gastrointestinal safety. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_03_med.pdf

  26. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, Weaver A (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 343:1520–1528

    Article  PubMed  CAS  Google Scholar 

  27. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102

    Article  PubMed  CAS  Google Scholar 

  28. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM (2005) Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352:1081–1091

    Article  PubMed  CAS  Google Scholar 

  29. McGettigan P, Henry D (2006) Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 296:1633–1644

    Article  PubMed  CAS  Google Scholar 

  30. Couzin J (2004) Drug safety: withdrawal of vioxx casts a shadow over COX-2 inhibitors. Science 306:384–385

    Article  PubMed  CAS  Google Scholar 

  31. Juni P, Rutjes AWS, Dieppe PA (2002) Are selective COX-2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs? Br Med J 324:1287–1288

    Article  Google Scholar 

  32. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR (2002) Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 359:118–123

    Article  PubMed  CAS  Google Scholar 

  33. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR (2002) COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 360:1071–1073

    Article  PubMed  CAS  Google Scholar 

  34. Merck & Co (accessed April 2007) Annual Report. 2001–04. http://phx.corporate-ir.net/phoenix.zhtml?c=73184&p=irol-reportsannual

  35. Lexchin J (2002) Should doctors be prescribing new drugs? Int J Risk Safety Med 15:213–222

    Google Scholar 

  36. National Institute for Health Care Management (accessed April 2007) Prescription Drugs and Mass Media Advertising, 2000. http://www.nihcm.org/finalweb/DTCbrief2001.pdf

  37. Waxman HA (accessed April 2007) Statement of Rep. Henry A. Waxman for the hearing “The role of FDA and pharmaceutical companies in ensuring the safety of approved drugs, like Vioxx.” http://democrats.reform.house.gov/Documents/20050505113149–41995.pdf

  38. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, Gertz BJ (2001) Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 104:2280–2288

    Article  PubMed  CAS  Google Scholar 

  39. Topol EJ (2004) Failing the public health-rofecoxib, Merck, and the FDA. N Engl J Med 351:1707–1709

    Article  PubMed  CAS  Google Scholar 

  40. Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–959

    Article  PubMed  CAS  Google Scholar 

  41. Cleland LG, James MJ, Stamp LK, Penglis PS (2001) COX-2 inhibition and thrombotic tendency: a need for surveillance. Med J Aust 175:214–217

    PubMed  CAS  Google Scholar 

  42. Graham DJ (accessed April 2007) Testimony of Dr David Graham, US Senate Committee on Finance. http://www.senate.gov/∼finance/hearings/testimony/2004test/111804dgtest.pdf

Download references

Author information

Authors and Affiliations

  1. Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia

    M. J. James, R. J. Cook-Johnson & L. G. Cleland

Authors
  1. M. J. James
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. J. Cook-Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. G. Cleland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. J. James.

About this article

Cite this article

James, M.J., Cook-Johnson, R.J. & Cleland, L.G. Selective COX-2 Inhibitors, Eicosanoid Synthesis and Clinical Outcomes: A Case Study of System Failure. Lipids 42, 779–785 (2007). https://doi.org/10.1007/s11745-007-3069-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-007-3069-x

Keywords

Search

Navigation