Biological basis for the cardiovascular consequences of COX-2 inhibition: Therapeutic challenges and opportunities

Journal of Clinical Investigation

Volumn 116, Issue 1, 2006, Pages 4-15

  Grosser, Tilo ^a   Fries, Susanne ^a   FitzGerald, Garret A ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; CELECOXIB; CLOPIDOGREL; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; DICLOFENAC; ETORICOXIB; FLURBIPROFEN; IBUPROFEN; INDOMETACIN; LUMIRACOXIB; MELOXICAM; NABUMETONE; NAPROXEN; NIMESULIDE; NONSTEROID ANTIINFLAMMATORY AGENT; PARECOXIB; PROSTACYCLIN; PROSTAGLANDIN E2; PROTON PUMP INHIBITOR; ROFECOXIB; THROMBOXANE; VALDECOXIB;

ALZHEIMER DISEASE; ARTHRITIS; ATHEROGENESIS; CARDIOVASCULAR RISK; CLINICAL TRIAL; COLON ADENOCARCINOMA; DIGESTIVE SYSTEM ULCER; DRUG DESIGN; DRUG SELECTIVITY; ENZYME INHIBITION; GASTROINTESTINAL SYMPTOM; HEART INFARCTION; HEART PROTECTION; HUMAN; HYPERTENSION; LOW DRUG DOSE; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; STROKE; THROMBOCYTE; THROMBOGENESIS; TREATMENT INDICATION;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTIHYPERTENSIVE AGENTS; BLOOD PRESSURE; CARDIOVASCULAR SYSTEM; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; HUMANS; KIDNEY; MEMBRANE PROTEINS;

EID: 31044441042     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI27291     Document Type: Review

References (123)

1. Smyth, E., Burke, A., and FitzGerald, G.A. 2005. Lipid-derived autacoids. In Goodman & Gilman's The pharmacological basis of therapeutics. McGraw-Hill. New York, New York, USA. 653-670.
2. Funk, C.D. 2005. Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat. Rev. Drug Discov. 4:664-672.
3. Smith, W.L., DeWitt, D.L., and Garavito, R.M. 2002. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69:145-182.
4. Narumiya, S., and FitzGerald, G.A. 2001. Genetic and pharmacological analysis of prostanoid receptor function. J. Clin. Invest. 108:25-30. doi:10.1172/JCI200113455.
5. Burke, A., Smyth, E., and FitzGerald, G.A. 2005. Analgesic-anti-pyretic and anti-inflammatory agents and drugs employed in the treatment of gout. In Goodman & Gilman's The pharmacological basis of therapeutics. McGraw-Hill. New York, New York, USA. 673-715.
6. 2 in acute cutaneous inflammation. J. Immunol. 173:1321-1326.
7. Murata, T., et al. 1997. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature. 388:678-682.
8. Fajardo, M., and Di Caesare, P.E. 2005. Disease-modifying therapies for osteoarthritis: current status. Drugs Aging. 22:141-161.
9. Rosen, G.D., Birkenmeier, T.M., Raz, A., and Holzman, M.J. 1989. Identification of a cyclooxygenase-related gene and its potential role in prostaglandin formation. Biochem. Biophys. Res. Commun. 164:1358-1365.
10. Hla, T., and Bailey, J.M. 1989. Differential recovery of prostacyclin synthesis in cultured vascular endothelial vs. smooth muscle cells after inactivation of cyclooxygenase with aspirin. Prostaglandins Leukot. Essent. Fatty Acids. 36:175-184.
11. Sebalt, R.J., Sheller, J.R., Oates, J.A., Roberts, L.J., II, and FitzGerald, G.A. 1990. Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. Proc. Natl. Acad. Sci. U. S. A. 87:6974-6978.
12. Masferrer, J.L., Zweifel, B.S., Seibert, K., and Needleman, P. 1990. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J. Clin. Invest. 86:1375-1379.
13. Kujubu, D., and Herschman, H. 1992. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J. Biol. Chem. 267:7991-7994.
14. O'Banion, M.K., Winn, V.D., and Young, D. 1992. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc. Natl. Acad. Sci. U. S. A. 89:4888-4892.
15. Sirois, J., Simmons, D.L., and Richards, J.S. 1992. Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles. Induction in vivo and in vitro. J. Biol. Chem. 267:11586-11592.
16. Patrignani, P., et al. 1997. Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J. Physiol. Pharmacol. 48:623-631.
17. Warner, T.D., et al. 1999. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc. Natl. Acad. Sci. U. S. A. 96:7563-7568.
18. 2 synthase-1. Nature. 367:243-249.
19. Luong, C., et al. 1996. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol. 3:927-933.
20. Kurumbail, R.G., et al. 1996. Structural basis for selective inhibition of cyclooxygenase-2 by antiinflammatory agents. Nature. 384:644-648.
21. Seibert, K., et al. 1995. Mediation of inflammation by cyclooxygenase-2. Agents Actions. 46:41-50.
22. Devchand, P.L., and Wallace, J. 2005. Emerging roles for cyclooxygenase-2 in gastrointestinal mucosal defense. Br. J. Pharmacol. 145:275-282.
23. Fries, J.F., et al. 2004. The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis. Arthritis Rheum. 50:2433-2440.
24. Simon, L.S., et al. 1999. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 282:1921-1928.
25. Lanza, F.L., et al. 1999. Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen. Aliment. Pharmacol. Ther. 13:761-767.
26. Langman, M.J., et al. 1999. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA. 282:1929-1933.
27. Sikes, D.H., et al. 2002. Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur. J. Gastroenterol. Hepatol. 14:1101-1111.
28. FitzGerald, G.A., and Patrono, C. 2001. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med. 345:433-442.
29. McAdam, B.F., et al. 1999. 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. 96:272-277.
30. Catella-Lawson, F., et al. 1999. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J. Pharmacol. Exp. Ther. 289:735-741.
31. Patrignani, P., et al. 1999. COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J. Physiol. Pharmacol. 50:661-667.
32. Creminon, C., et al. 1995. Differential measurement of constitutive (COX-1) and inducible (COX-2) cyclooxygenase expression in human umbilical vein endothelial cells using specific immunometric enzyme immunoassays. Biochim. Biophys. Acta. 1254:341-348.
33. Moncada, S., Higgs, J., and Vane, J.R. 1977. Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation. Lancet. 1:18-20.
34. Topper, J.N., Cai, J., Falb, D., and Gimbrone, M.A., Jr. 1996. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc. Natl. Acad. Sci. U. S. A. 93:10417-10422.
35. 2. Science. 296:539-541.
36. Catella, F., and FitzGerald, G.A. 1990. Measurement of thromboxane metabolites by gas chromatography-mass spectrometry. Methods Enzymol. 187:42-50.
37. FitzGerald, G.A., Pedersen, A.K., and Patrono, C. 1983. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation. 67:1174-1177.
38. FitzGerald, G.A., Brash, A.R., Falardeau, P., and Oates, J.A. 1981. Estimated rate of prostacyclin secretion into the circulation of normal man. J. Clin. Invest. 68:1272-1276.
39. Roy, L., Knapp, H., Robertson, R., and FitzGerald, G.A. 1985. Endogenous biosynthesis of prostacyclin during cardiac catheterization and angiography in man. Circulation. 71:434-440.
40. Hla, T., and Nielsen, K. 1992. Human cyclooxygenase-2 cDNA. Proc. Natl. Acad. Sci. U. S. A. 89:7384-7388.
41. Jones, D.A., Carlton, D.P., McIntyre, T.M., Zimmerman, G.A., and Prescott, S. 1993. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 268:9049-9054.
42. Schonebeck, U., Sukhova, G.K., Graber, P., Coulter, S., and Libby, P. 1999. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am. J. Pathol. 155:1281-1291.
43. Belton, O., Byrne, D., Kearney, D., Leahey, A., and Fitzgerald, D.J. 2000. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation. 102:840-845.
44. FitzGerald, G.A., Smith, B., Pedersen, A.K., and Brash, A.R. 1984. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N. Engl. J. Med. 310:1065-1068.
45. Hennan, J.K., et al. 2001. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation. 104:820-825.
46. Pigeon, G.P., et al. 2004. Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2. Circulation. 110:2701-2707.
47. Buerkle, M.A., et al. 2004. Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo. Circulation. 110:2053-2059.
48. Rabausch, K., et al. 2005. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ. Res. 96:e1-e6.
49. 2 in cardiac ischemia-reperfusion injury: a study using mice lacking their respective receptors. Circulation. 104:2210-2215.
50. Dowd, N.P., Scully, M., Adderley, S.R., Cunningham, A.J., and Fitzgerald, D.J. 2001. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. J. Clin. Invest. 108:585-590. doi:10.1172/JCI200111334.
51. 2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J. Clin. Invest. 114:784-794. doi:10.1172/JCI200421446.
52. Egan, K., et al. 2004. COX-2-derived prostacyclin confers atheroprotection on female mice. Science. 306:1954-1957.
53. Watanabe, H., et al. 2005. Effects of salt loading on blood pressure in mice lacking the prostanoid receptor gene. Circ. J. 69:124-126.
54. Francois, H., et al. 2005. Hypertension in prostacylin receptor deficient mice. Cell. Metab. 2:201-207.
55. Rudic, R.D., et al. 2005. COX-2-derived prostacyclin modulates vascular remodeling. Circ. Res. 96:1240-1247.
56. Cheng, M.K., McGiff, J.C., and Carroll, M.A. 2003. Renal arterial 20-hydroxyeicosatetraenoic acid levels: regulation by cyclooxygenase. Am. J. Physiol. Renal Physiol. 284:F474-F479.
57. Kennedy, C.R., et al. 1999. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat. Med. 5:217-220.
58. FitzGerald, G.A. 2004. Coxibs and cardiovascular disease. N. Engl. J. Med. 351:1709-1711.
59. Fries, S., Grosser, T., Lawson, J., DeMarco, S., and FitzGerald, G.A. 2005. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology. Online publication ahead of print.
60. Brune, K., and Hinz, B. 2004. Selective cyclooxygenase-2 inhibitors: similarities and differences. Scand. J. Rheumatol. 33:1-6.
61. McAdam, B., et al. 2000. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J. Clin. Invest. 105:1473-1482.
62. Bombardier, C., et al. 2000. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343:1520-1528.
63. Watson, D.J., Rhoades, T., and Guess, H.A. 2003. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J. Rheumatol. 30:1196-1202.
64. VanHecken, A., et al. 2000. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen and naproxen on COX-2 versus COX-1 in healthy volunteers. J. Clin. Pharmacol. 40:1109-1120.
65. Silverstein, F.E., et al. 2000. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS Study: a randomized controlled trial. JAMA. 284:1247-1255.
66. Juni, P., Rutjes, M.A., and Dieppe, P.A. 2002. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ. 324:1287-1288.
67. FitzGerald, G.A. 2003. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nat. Rev. Drug Discov. 2:879-890.
68. Mukherjee, D., Nissen, S.E., and Topol, E.J. 2001. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 286:954-959.
69. Ray, W.A., et al. 2002. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet. 360:1071-1073.
70. Solomon, D.H., et al. 2004. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 109:2068-2073.
71. Solomon, D.H., Schneeweiss, S., Levin, R., and Avorn, J. 2004. Relationship between COX-2 specific inhibitors and hypertension. Hypertension. 44:140-145.
72. Bresalier, R.S., et al. 2005. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352:1092-1102.
73. Kimmel, S., et al. 2005. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann. Intern. Med. 142:157-164.
74. White, W.B., Strand, V., Roberts, R., and Whelton, A. 2004. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am. J. Ther. 11:244-250.
75. Anonymous. 2005. Petition to remove the COX-2 inhibitors celecoxib (CELEBREX) and valdecoxib (BEXTRA) from the market. Public Citizen. http://www.citizen.org/publications/release.cfm?ID=7358.
76. Cannata, A., Biglioli, P., Tremoli, E., and Parolari, A. 2004. Biological effects of coronary surgery: role of surgical trauma and CPB [letter]. Eur. J. Cardiothorac. Surg. 26:664.
77. Ott, E., et al. 2003. Efficacy and safety of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J. Thorac. Cardiovasc. Surg. 125:1481-1492.
78. Nussmeier, N.A., et al. 2005. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N. Engl. J. Med. 352:1081-1091.
79. Furberg, C., Psaty, B., and FitzGerald, G.A. 2005. Parecoxib, valdecoxib, and cardiovascular risk [editorial]. Circulation. 111:249.
80. Zimmermann, N., et al. 2003. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation. 108:542-547.
81. Solomon, S.D., et al. 2005. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352:1071-1080.
82. Schnitzer, T., et al. 2004. 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. 364:665-674.
83. Topol, E.J., and Falk, G.W. 2004. A coxib a day won't keep the doctor away. Lancet. 364:639-640.
84. Jones, B., Jarvis, P., Lewis, J.A., and Ebbutt, A.F. 1996. Trials to assess equivalence: the importance of rigorous methods. BMJ. 313:36-39.
85. Scott, G., et al. 2004. Pharmacokinetics of lumiracoxib in plasma and synovial fluid. Clin. Pharmacokinet. 43:467-478.
86. Tacconelli, S., Capone, M.L., and Patrignani, P. 2004. Clinical pharmacology of novel selective COX-2 inhibitors. Curr. Pharm. Des. 10:589-601.
87. Aldington, S., Shirtcliffe, P., Weatherall, M., and Beasley, R. 2005. Systematic review and meta-analysis of the risk of major cardiovascular events with etoricoxib therapy. N. Z. Med. J. 118:U1684.
88. Yu, Y., et al. 2005. Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition. J. Clin. Invest. 115:986-995. doi:10.1172/JCI200523683.
89. Catella-Lawson, F., et al. 2001. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N. Engl. J. Med. 345:1809-1817.
90. Wilner, K.D., et al. 2002. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J. Clin. Pharmacol. 42:1027-1030.
91. Capone, M.L., et al. 2005. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J. Am. Coll. Cardiol. 45:1295-1301.
92. MacDonald, T.M., and Wei, L. 2003. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 361:573-574.
93. Cannon, C., Curtis, S., Bolognese, J.A., and Laine, L. 2005. Cardiovascular outcomes with a COX-2 selective inhibitor vs. a traditional NSAID in patients with osteoarthritis and rheumatoid arthritis: clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program. Am. J. Cardiol. In press.
94. US Food and Drug Administration. 2005. Briefing package for NDA 21-389 Etoricoxib. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_31_AA- FDA-Tab-T.pdf.
95. Singh, G., Lanes, S., and Triadafilopoulos, G. 2004. Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam. Am. J. Med. 117:100-106.
96. Mickelwright, R., et al. 2003. Review article: NSAIDs, gastroprotection and cyclo-oxygenase-II-selective inhibitors. Aliment. Pharmacol. Ther. 17:321-332.
97. Panara, M.R., et al. 1998. Effects of nimesulide on constitutive and inducible prostanoid biosynthesis in human beings. Clin. Pharmacol. Ther. 63:672-681.
98. Hedner, T., et al. 2004. Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis. Drugs. 64:2315-2343.
99. Kurth, T., et al. 2003. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation. 108:1191-1195.
100. Hudson, M., Baron, M., Rahme, E., and Pilote, L. 2005. Ibuprofen may abrogate the benefits of aspirin when used for secondary prevention of myocardial infarction. J. Rheumatol. 32:1589-1593.
101. Curtis, J.P., and Krumholz, H. 2004. The case for an adverse interaction between aspirin and non-steroidal anti-inflammatory drugs: is it time to believe the hype? J. Am. Coll. Cardiol. 43:991-993.
102. Garcia Rodriguez, L., et al. 2004. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 109:3000-3006.
103. Graham, D.J., et al. 2005. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and nonselective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 365:475-481.
104. Hippisley-Cox, J., and Coupland, C. 2005. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 330:1366-1372.
105. Reilly, I.A., and FitzGerald, G.A. 1987. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood. 69:180-186.
106. Garcia Rodriguez, L.A., and Gonzalez-Perez, A. 2005. Long-term use of traditional non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. BMC Med. 3:17.
107. Capone, M.L., et al. 2004. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation. 109:1468-1471.
108. Fries, S., Grosser, T., and FitzGerald, G.A. 2005. Cyclooxygenase inhibition and blood pressure regulation. In Hypertension. E. Mohler, editor. BC Decker. Hamilton, Ontario, Canada. In press.
109. Yang, T., et al. 2004. Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice. Am. J. Physiol. Renal Physiol. 288:F1125-F1132.
110. Qi, Z., et al. 2002. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J. Clin. Invest. 110:61-69. doi:10.1172/JCI200214752.
111. Aw, T.J., Haas, S.J., Liew, D., and Krum, H. 2005. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch. Intern. Med. 165:490-496.
112. Elund, A. et al. 1985. Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation. Circulation. 71:1113-1120.
113. Forman, J.P., Stampfer, M.J., and Curhan, G.C. 2005. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension. 46:500-507.
114. García Rodríguez, L.A., and Hernández-Díaz, S. 2001. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 12:570-576.
115. Dai, C., Stafford, R.S., and Alexander, G.C. 2005. National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation. Arch. Intern. Med. 165:171-177.
116. Westgate, E., and FitzGerald, G.A. 2005. Pulmonary embolism in a woman taking oral contraceptives and valdecoxib. PLoS Med. 2:e197.
117. Herman, M., Krum, H., and Ruschitzka, F. 2005. To the heart of the matter: coxibs, smoking, and cardiovascular risk. Circulation. 112:941-945.
118. Hawkey, C.J., et al. 2004. Therapeutic arthritis research and gastrointestinal event trial of lumiracoxib - study design and patient demographics. Aliment. Pharmacol. Ther. 20:51-63.
119. Anonymous. 2004. Public health advisory: non-steriodal anti-inflammatory drug products (NSAIDS). US Food and Drug Administration. http://www.fda.gov/ cder/drug/advisory/nsaids.htm.
120. Anonymous. 2005. EMEA press release. European Medicines Agency. http://www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf.
121. Patrono, C., García Rodríguez, L.A., Landolfi, R., and Baigent, C. 2005. Low dose aspirin for the prevention of atherothrombosis. N. Engl. J. Med. 353:49-59.
122. Tegeder, I., Pfeilschifter, J., and Geisslinger, G. 2001. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 15:2057-2072.
123. Beckett, D. 1994. Biography. http://wotug.kent.ac.uk/parallel/www/occam/ occam-bio.html.