The pharmacology of selective inhibition of COX-2

Tilo Grosser

doi:10.1160/TH06-08-0444

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(04): 393-400
DOI: 10.1160/TH06-08-0444

Theme Issue Article

Schattauer GmbH

The pharmacology of selective inhibition of COX-2

Tilo Grosser

¹Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

› Author Affiliations

Abstract

Summary

Selective inhibitors of cyclooxygenase (COX)-2 were developed to improve the safety of anti-inflammatory therapy in patients at elevated risk for gastrointestinal complications which are thought to be caused primarily by depression of COX-1 derived mucosal prostanoids. They were not expected to be more efficacious analgesics than compounds acting on both cyclooxygenases, the traditional (t) non-steroidal antiinflammatory drugs (NSAIDs). While these predictions were generally supported by clinical evidence, an elevated rate of severe cardiovascular complications was observed in randomized controlled trials of three chemically distinct COX-2 selective compounds. The cardiovascular hazard is plausibly explained by the depression of COX-2 dependent prostanoids formed in vasculature and kidney; vascular prostacyclin (PGI₂) constrains the effect of prothrombotic and atherogenic stimuli, and renal medullary prostacyclin and prostaglandin (PG) E₂ formed by COX-2 contribute to arterial pressure homeostasis. A drug development strategy more closely linking research into the biology of the drug target with clinical drug development may have allowed earlier recognition of these mechanisms and the cardiovascular risk of COX-2 inhibition. Open questions are i) whether the gastrointestinal benefit of COX-2 selective compounds drugs can be conserved by identifying individuals at risk and excluding them from treatment; ii) whether the risk extends to tNSAIDs; iii) and whether alternative strategies to anti-inflammatory therapy with a more advantageous risk-benefit profile can be developed.

Keywords

Clinical studies - atherothrombosis - atherosclerosis - inflammation - inflammatory mediators

Full Text

References

References
1 Smyth EM, Burke A, FitzGerald GA. Lipid-derived autacoids. In: Goodman & Gilman’s The Pharmacological basis of therapeutics. New-York, USA: McGraw-Hill; 2005: 653-70.
2 Grosser T, Yusuff S, Cheskis E. et al. Developmental expression of functional cyclooxygenases in zebrafish. Proc Natl Acad Sci USA 2002; 99: 8418-23.
3 Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000; 69: 145-82.
4 Yuan C, Rieke CJ, Rimon G. et al. Partnering between monomers of cyclooxygenase-2 homodimers. Proc Natl Acad Sci USA 2006; 103: 6142-7.
5 Patrono C, Coller B, Dalen JE. et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2001; 119: 39S-63S.
6 Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999; 79: 1193-226.
7 Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001; 108: 25-30.
8 Boie Y, Sawyer N, Slipetz DM. et al. Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 1995; 270: 18910-6.
9 Hirai H, Tanaka K, Yoshie O. et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 2001; 193: 255-61.
10 Sawyer N, Cauchon E, Chateauneuf A. et al. Molecular pharmacology of the human prostaglandin D(2) receptor, CRTH2. Br J Pharmacol 2002; 137: 1163-72.
11 Morita I, Schindler M, Regier MK. et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and –2. J Biol Chem 1995; 270: 10902-8.
12 Spencer AG, Woods JW, Arakawa T. et al. Subcellular localization of prostaglandin endoperoxide H synthases-1 and –2 by immunoelectron microscopy. J Biol Chem 1998; 273: 9886-93.
13 Chen W, Pawelek TR, Kulmacz RJ. Hydroperoxide dependence and cooperative cyclooxygenase kinetics in prostaglandin H synthase-1 and –2. J Biol Chem 1999; 274: 20301-6.
14 So OY, Scarafia LE, Mak AY. et al. The dynamics of prostaglandin H synthases. Studies with prostaglandin h synthase 2 Y355F unmask mechanisms of time-dependent inhibition and allosteric activation. J Biol Chem 1998; 273: 5801-7.
15 Yu Y, Fan J, Chen XS. et al. Genetic model of selective COX-2 inhibition reveals novel heterodimer signaling. Nat Med 2006; 12: 699-704.
16 Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem 1992; 267: 7991-4.
17 O’Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA 1992; 89: 4888-92.
18 Sirois J, Simmons DL, Richards JS. 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 1992; 267: 11586-92.
19 Garavito RM, DeWitt DL. The cyclooxygenase isoforms: structural insights into the conversion of arachidonic acid to prostaglandins. Biochim Biophys Acta 1999; 1441: 278-87.
20 Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994; 367: 243-9.
21 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: 1520-8 2 p following 8.
22 Bresalier RS, Sandler RS, Quan H. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092-102.
23 Ott E, Nussmeier NA, Duke PC. et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003; 125: 1481-92.
24 Nussmeier NA, Whelton AA, Brown MT. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081-91.
25 Seibert K, Masferrer J, Zhang Y. et al. Mediation of inflammation by cyclooxygenase-2. Agents Actions 1995; 46 (Suppl): 41-50.
26 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: 1095-101.
27 Schonbeck U, Sukhova GK, Graber P. et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155: 1281-91.
28 Willingale HL, Gardiner NJ, McLymont N. et al. Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 1997; 122: 1593-604.
29 Yamagata K, Andreasson KI, Kaufmann WE. et al. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11: 371-86.
30 Breder CD, Dewitt D, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 1995; 355: 296-315.
31 Kaufmann WE, Worley PF, Pegg J. et al. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996; 93: 2317-21.
32 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: 2504-10.
33 Murata T, Ushikubi F, Matsuoka T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678-82.
34 Vanegas H, Schaible HG. Prostaglandins and cyclooxygenases in the spinal cord. Prog Neurobiol 2001; 64: 327-63.
35 Samad TA, Moore KA, Sapirstein A. et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410: 471-5.
36 Pitcher GM, Henry JL. Mediation and modulation by eicosanoids of responses of spinal dorsal horn neurons to glutamate and substance P receptor agonists: results with indomethacin in the rat in vivo . Neuroscience 1999; 93: 1109-21.
37 Zimmermann KC, Sarbia M, Schror K. et al. Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa. Mol Pharmacol 1998; 54: 536-40.
38 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: 387-97.
39 Shigeta J, Takahashi S, Okabe S. Role of cyclooxygenase-2 in the healing of gastric ulcers in rats. J Pharmacol Exp Ther 1998; 286: 1383-90.
40 Lipsky PE, Brooks P, Crofford LJ. et al. Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med 2000; 160: 913-20.
41 Laine L, Harper S, Simon T. et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999; 117: 776-83.
42 Simon LS, Weaver AL, Graham DY. et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. J Am Med Assoc 1999; 282: 1921-8.
43 Kivitz A, Eisen G, Zhao WW. et al. Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis. J Fam Pract 2002; 51: 530-7.
44 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. J Am Med Assoc 2000; 284: 1247-55.
45 Schnitzer TJ, Burmester GR, Mysler E. 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: 665-74.
46 Singh G, Fort JG, Goldstein JL. et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 2006; 119: 255-66.
47 Witter J. Celebrex capsules (celecoxib). NDA 20–998/S-009. Mediclal Officer Review. In: US Department of Health and Human Services Food and Drug Administration; 2000
48 Dai C, Stafford RS, Alexander GC. National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation. Arch Intern Med 2005; 165: 171-7.
49 Almasi EA, Stafford RS, Kravitz RL, Mansfield PR. What are the public health effects of direct-to-consumer drug advertising?. PLoS Med 2006; 03: e145.
50 Fries JF, Murtagh KN, Bennett M. et al. The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2433-40.
51 FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433-42.
52 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: 1705-12.
53 Fries S, Grosser T, Lawson JA. et al. Inter- and intraindividual variability in the pharmacological response to inhibitors of cyclooxygenase-2. Arterioscler Thromb Vasc Biol 2004; 24: e53.
54 Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116: 4-15.
55 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology ofa selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7.
56 Catella-Lawson F, McAdam B, Morrison BW. et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999; 289: 735-41.
57 FitzGerald GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-8.
58 Cheng Y, Austin SC, Rocca B. et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539-41.
59 FitzGerald GA. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003; 02: 879-90.
60 Reicin A. AP News Wire April 28th, 2002
61 Fries S, Grosser T, Price TS. et al. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 2006; 130: 55-64.
62 Stichtenoth DO, Marhauer V, Tsikas D. et al. Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. Kidney Int 2005; 68: 2197-207.
63 Belton O, Byrne D, Kearney D. et al. Cyclooxygenase-1 and –2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000; 102: 840-5.
64 Cheng Y, Wang M, Yu Y. et al. Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 2006; 116: 1391-9.
65 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: 820-5.
66 Pidgeon GP, Tamosiuniene R, Chen G. et al. Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2. Circulation 2004; 110: 2701-7.
67 Buerkle MA, Lehrer S, Sohn HY. et al. Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo . Circulation 2004; 110: 2053-9.
68 Cryan LM, Pidgeon GP, Fitzgerald DJ. et al. COX-2 protects against thrombosis of the retinal vasculature in a mouse model of proliferative retinopathy. Mol Vis 2006; 12: 405-14.
69 FitzGerald GA, Brash AR, Falardeau P. et al. Estimated rate of prostacyclin secretion into the circulation of normal man. J Clin Invest 1981; 68: 1272-5.
70 Moncada S, Higgs EA, Vane JR. Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation. Lancet 1977; 01: 18-20.
71 Fitzgerald DJ, Roy L, Catella F. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
72 Roy L, Knapp HR, Robertson RM. et al. Endogenous biosynthesis of prostacyclin during cardiac catheterization and angiography in man. Circulation 1985; 71: 434-40.
73 Metais C, Li J, Simons M. et al. Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusion: role of COX-2 expression. Circulation 1999; 100: II328-34.
74 Therland KL, Stubbe J, Thiesson HC. et al. Cycloxygenase-2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors. J Am Soc Nephrol 2004; 15: 1189-98.
75 Zhou Y, Mitra S, Varadharaj S. et al. Increased expression of cyclooxygenase-2 mediates enhanced contraction to endothelin ETA receptor stimulation in endothelial nitric oxide synthase knockout mice. Circ Res 2006; 98: 1439-45.
76 Chen YL, Hu CS, Lin FY. et al. Salvianolic acidB attenuates cyclooxygenase-2 expression in vitro in LPS-treated human aortic smooth muscle cells and in vivo in the apolipoprotein-E-deficient mouse aorta. J Cell Biochem 2006; 98: 618-31.
77 Rudic RD, Brinster D, Cheng Y. et al. COX-2-derived prostacyclin modulates vascular remodeling. Circ Res 2005; 96: 1240-7.
78 Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1992; 89: 7384-8.
79 Jones DA, Carlton DP, McIntyre TM. et al. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 1993; 268: 9049-54.
80 Mitchell JA, Warner TD. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 2006; 05: 75-86.
81 Topper JN, Cai J, Falb D. et al. 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 USA 1996; 93: 10417-22.
82 Brueckmann M, Horn S, Lang S. et al. Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell proteinC receptor and activation of protease-activated receptor-1. Thromb Haemost 2005; 93: 743-50.
83 Syeda F, Grosjean J, Houliston RA. et al. Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-kappaB pathways. J Biol Chem 2006; 281: 11792-804.
84 Patrono C, Ciabattoni G, Pinca E. et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-27.
85 Patrono C, Ciabattoni G, Pugliese F. et al. Estimated rate of thromboxane secretion into the circulation of normal humans. J Clin Invest 1986; 77: 590-4.
86 Morham SG, Langenbach R, Loftin CD. et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83: 473-82.
87 Burleigh ME, Babaev VR, Oates JA. et al. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 2002; 105: 1816-23.
88 Rott D, Zhu J, Burnett MS. et al. Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice. J Am Coll Cardiol 2003; 41: 1812-9.
89 Pratico D, Tillmann C, Zhang ZB. et al. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci USA 2001; 98: 3358-63.
90 Olesen M, Kwong E, Meztli A. et al. No effect of cyclooxygenase inhibition on plaque size in atherosclerosis-prone mice. Scand Cardiovasc J 2002; 36: 362-7.
91 Egan KM, Wang M, Lucitt MB. et al. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 2005; 111: 334-42.
92 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231: 232-5.
93 Harats D, Shaish A, George J. et al. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 2100-5.
94 Shen J, Herderick E, Cornhill JF. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J Clin Invest 1996; 98: 2201-8.
95 Kobayashi T, Tahara Y, Matsumoto M. et al. Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest 2004; 114: 784-94.
96 Egan KM, Lawson JA, Fries S. et al. COX-2 derived prostacyclin confers atheroprotection on female mice. Science 2004; 360: 1954-7.
97 Cayatte AJ, Du Y, Oliver-Krasinski J. et al. The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20: 1724-8.
98 Rabausch K, Bretschneider E, Sarbia M. et al. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ Res 2005; 96: e1-6.
99 Qi Z, Hao CM, Langenbach RI. et al. Opposite effects of cyclooxygenase-1 and –2 activity on the pressor response to angiotensin II. J Clin Invest 2002; 110: 61-9.
100 Athirakul K, Kim HS, Audoly LP. et al. Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition. Kidney Int 2001; 60: 2324-9.
101 Francois H, Coffman TM. Prostanoids and blood pressure: which way is up?. J Clin Invest 2004; 114: 757-9.
102 Aw TJ, Haas SJ, Liew D. et al. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med 2005; 165: 490-6.
103 Merck Co I. Etoricoxib – FDA ACM Background Document. 2005; 53-4.
104 Trebino CE, Stock JL, Gibbons CP. et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci USA 2003; 100: 9044-9.
105 Roth-Cline MD. Clinical trials in the wake of Vioxx: requiring statistically extreme evidence of benefit to ensure the safety of new drugs. Circulation 2006; 113: 2253-9.
106 Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N Engl J Med 2006; 354: 1193.
107 Solomon SD, McMurray JJ, Pfeffer MA. et al. Cardiovascular risk associated with celecoxib ina clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-80.
108 Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib, and cardiovascular risk. Circulation 2005; 111: 249.
109 Lagakos SW. Time-to-event analyses for longterm treatments--the APPROVe trial. N Engl J Med 2006; 355: 113-7.
110 Garcia LARodriguez, Gonzalez-Perez A. Longterm use of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. BMC Med 2005; 03: 17.
111 Roden DM. An underrecognized challenge in evaluating postmarketing drug safety. Circulation 2005; 11: 246-8.
112 Strom BL. How the US drug safety system should be changed. J Am Med Assoc 2006; 295: 2072-5.
113 Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1986; 89: 2S-3S.
114 Cook DJ, Guyatt GH, Laupacis A. et al. Clinical recommendations using levels of evidence for antithrombotic agents. Chest 1995; 108: 227S-30S.
115 Cannon CP, Curtis SP, Bolognese JA. et al. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Longterm (MEDAL) Study Program: Cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J 2006; 152: 237-45.