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Why cardiovascular actions of Vioxx are more serious than Celebrex and other conventional anti-inflammatory drug effects

Vittorio Tomasi, Vittorio Tomasi, Cristiana Griffoni and Enzo Spisni   (17 May 2005)

Why cardiovascular actions of Vioxx are more serious than Celebrex and other conventional anti-inflammatory drug effects 17 May 2005
Vittorio Tomasi, Professor of physiology Department of Biology, University of Bologna, 40126 Bologna, Italy, Vittorio Tomasi, Cristiana Griffoni and Enzo Spisni Send response to journal: Re: Why cardiovascular actions of Vioxx are more serious than Celebrex and other conventional anti-inflammatory drug effects	Prostacyclin discovery represented the culmination of the late Sir John Vane scientific accomplishments. It generated a tremendous amount of work in disciplines such as physiology, pharmacology, pathology, biochemistry, greatly advancing the field of vascular biology. It is now clear that prostacyclin generation by the endothelium is what protects against cardiovascular diseases and what modulates physiological angiogenesis [1,2]. Contrary to initial assumptions about cox-1 involvement, it is now clear that the coupling cox-2 /PGI2 synthase occurring in endothelial cell caveolae is the major event leading to a sustained production of prostacyclin released both in the circulation and into the sub-endothelium[3,4]. PGI2 synthase, a constitutively expressed enzyme in human endothelial cells, belongs to the cytochrome P450 family and it has two binding sites for caveolin 1 clearly separated from the PGH2 catalytic site. Thus, the enzyme produces PGI2 as soon as cox-2 is induced and inserted into caveolae, provided that arachidonate is made available by cytosolic phospholipase A2. PGI2 synthase gene is characterized by a promoter having a variable number of sp1 binding sites and its expression varies among individuals. According to Suita study, Japanese having several binding sites are less prone to hypertension with respect to individuals having few binding sites [2]. Clinical trials carried out in order to ascertain the absence of side effects of anti-inflammatory drugs during long term treapments, initially revealed that cox-2 specifics inhibitors at therapeutical doses were well tolerated. More recently Graham and colleagues pointed out the risk of acute myocardial infarction and sudden cardiac death in patients treated with cox-2 selective and non-selective non-steroidal anti-inflammatory compounds. Similar considerations have been aroused by FitzGerald in a recent editorial [1,5]. Clinical studies carried out by Merck on patients suffering from intestinal polyps and using rofecoxib (Vioxx) revealed the cardiotoxicity of this drug, forcing Merck to withdraw Vioxx from the market. Celebrex has been considered much less prone to affect the cardiovascular system [1,6,7]. Prompted by these observations we speculated that cardiotoxicity of Vioxx could be explained by assuming that not only an inhibition of cox-2 but also an inhibition of PGI2 synthase was involved [8]. As a matter of fact a compensatory increase of cox-1 level following cox-2 inhibition has been recently reported [9] If it is the case that under conditions in which PGI2 synthase is fully active, enough PGI2 to protect the cardiovascular system could be produced. We have verified that human endothelial cells exposed to Vioxx at therapeutic doses, dramatically reduce PGI2 synthase activity while little effect is observed when Celebrex as well as classical anti-inflammatory drugs are tested. We strongly recommend that in future novel specific cox-2 inhibitors should be tested in vitro and in vivo as PG2 synthase possible inhibitors. ____________________________________________________________________ References 1. GA FitzGerald, Coxibs and cardiovascular disease, N. Engl. J. Med. 351 (2004), pp. 1709-1711. 2. V Tomasi, E Spisni, C Griffoni, T Guarnieri, Caveolae, Caveolar enzymes and angiogenesis, Current Topics in Biochemical Research 3 (2000), pp. 81-90. 3. JY Liou, WG Deng, DW Gilroy, SK Shyue, KK Wu, Co-localization and interaction cyclooxygenase-2 with caveolin-1 in human fibroblasts, J. Biol. Chem. 276 (2001), pp. 34975-34982. 4. E Spisni, C Griffoni, S Santi, M Riccio, R Marulli, G Bartolini, M Toni, V Ullrich, V Tomasi, Colocalization prostacyclin (PGI2) synthase- caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis, Exp. Cell Res. 266 (2001), pp. 31-43. 5. DJ Graham, D Campen and R Hui et al., Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo- oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study, Lancet 365 (2005), pp. 475-481. 6. The Lancet Editorial, Vioxx: an unequal partnership between safety and efficacy, The Lancet 364 (2004), pp. 1287-1288. 7. M Wadman, Vioxx may go back on sale after scraping past FDA panel, Nature 433 (2005). 8. E Spisni, G Bartolini, M Orlandi, B Belletti, S Santi, V Tomasi, Prostacyclin (PGI2) synthase is a constitutively expressed enzyme in human endothelial cells, Exp. Cell Res. 219 (1995), pp. 507-513. 9. H Wang, W Ma, L Tejada, H Zhang, JD Morrow, SK Das, SK Dey, Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up -regulation of cyclooxygenase-1 is a function of genetic makeup, J. Biol. Chem. 279 (2004), pp. 10649-10658. Competing interests: None declared