Thromboxane Receptors Antagonists and/or Synthase Inhibitors

  • Giovanni Davì
  • Francesca Santilli
  • Natale Vazzana
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 210)

Abstract

Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA2. TXSI prevent the conversion of PGH2 to TXA2, reducing TXA2 synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA2 receptors (TP) activation.

TXA2 is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA2, but also by prostaglandin (PG) D2, PGE2, PGF, PGH2, PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.

Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA2 as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA2. Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.

Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed.

Keywords

Antiplatelet therapy Atherothrombosis Ischemic stroke Platelet activation Thromboxane biosynthesis TP antagonists 

References

  1. Ali S, Davis MG, Becker MW, Dorn GW 2nd (1993) Thromboxane A2 stimulates vascular smooth muscle hypertrophy by up-regulating the synthesis and release of endogenous basic fibroblast growth factor. J Biol Chem 268:17397–17403PubMedGoogle Scholar
  2. Ashton AW, Ware GM, Kaul DK, Ware JA (2003) Inhibition of tumor necrosis factor alpha-mediated NFkappaB activation and leukocyte adhesion, with enhanced endothelial apoptosis, by G protein-linked receptor (TP) ligands. J Biol Chem 278:11858–11866PubMedCrossRefGoogle Scholar
  3. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:1849–1860PubMedCrossRefGoogle Scholar
  4. Bal Dit Sollier C, Crassard I, Simoneau G, Bergmann JF, Bousser MG, Drouet L (2009) Effect of the thromboxane prostaglandin receptor antagonist terutroban on arterial thrombogenesis after repeated administration in patients treated for the prevention of ischemic stroke. Cerebrovasc Dis 28:505–513PubMedCrossRefGoogle Scholar
  5. Basili S, Raparelli V, Vestri A, Di Tanna GL, Violi F (2010) Comparison of efficacy of antiplatelet treatments for patients with claudication. A meta-analysis. Thromb Haemost 103:766–773PubMedCrossRefGoogle Scholar
  6. Belhassen L, Pelle G, Dubois-Rande JL, Adnot S (2003) Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin. J Am Coll Cardiol 41:1198–1204PubMedCrossRefGoogle Scholar
  7. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox K, Hennerici MG, Mattle HP, Rothwell PM (2009) Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study. Cerebrovasc Dis 27:509–518PubMedCrossRefGoogle Scholar
  8. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, Hennerici MG, Mattle HP, Rothwell PM, de Cordoue A, Fratacci MD (2011) Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. Lancet 377:2013–2022PubMedCrossRefGoogle Scholar
  9. Cathcart MC, Reynolds JV, O’Byrne KJ, Pidgeon GP (2010) The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer. Biochim Biophys Acta 1805:153–166PubMedGoogle Scholar
  10. Cathcart MC, Gately K, Cummins R, Kay E, O’Byrne KJ, Pidgeon GP (2011) Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer. Mol Cancer 10:25PubMedCrossRefGoogle Scholar
  11. Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren TJ, Cohen RA (2000) 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 20:1724–1728PubMedCrossRefGoogle Scholar
  12. Chamorro A (2009) TP receptor antagonism: a new concept in atherothrombosis and stroke prevention. Cerebrovasc Dis 27(Suppl 3):20–27PubMedCrossRefGoogle Scholar
  13. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R (2000) Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 31:1240–1249PubMedCrossRefGoogle Scholar
  14. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GA (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296:539–541PubMedCrossRefGoogle Scholar
  15. Davì G, Falco A (2005) Oxidant stress, inflammation and atherogenesis. Lupus 14:760–764PubMedCrossRefGoogle Scholar
  16. Davì G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494PubMedCrossRefGoogle Scholar
  17. Davì G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, Patrono C (1990) Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 322:1769–1774PubMedCrossRefGoogle Scholar
  18. Davì G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C (1999) In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99:224–229PubMedCrossRefGoogle Scholar
  19. Dogne JM, de Leval X, Hanson J, Frederich M, Lambermont B, Ghuysen A, Casini A, Masereel B, Ruan KH, Pirotte B, Kolh P (2004) New developments on thromboxane and prostacyclin modulators part I: thromboxane modulators. Curr Med Chem 11:1223–1241PubMedCrossRefGoogle Scholar
  20. Dogne JM, Hanson J, Pratico D (2005) Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis. Trends Pharmacol Sci 26:639–644PubMedCrossRefGoogle Scholar
  21. Egan KM, Wang M, Fries S, Lucitt MB, Zukas AM, Pure E, Lawson JA, FitzGerald GA (2005) Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 111:334–342PubMedCrossRefGoogle Scholar
  22. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S (2002) Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 105:1650–1655PubMedCrossRefGoogle Scholar
  23. Feletou M, Verbeuren TJ, Vanhoutte PM (2009) Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors. Br J Pharmacol 156:563–574PubMedCrossRefGoogle Scholar
  24. Feletou M, Cohen RA, Vanhoutte PM, Verbeuren TJ (2010) TP receptors and oxidative stress hand in hand from endothelial dysfunction to atherosclerosis. Adv Pharmacol 60:85–106PubMedCrossRefGoogle Scholar
  25. Ferroni P, Basili S, Falco A, Davì G (2004) Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2:1282–1291PubMedCrossRefGoogle Scholar
  26. Fiessinger JN, Bounameaux H, Cairols MA, Clement DL, Coccheri S, Fletcher JP, Hoffmann U, Turpie AG (2010) Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study. J Thromb Haemost 8:2369–2376PubMedCrossRefGoogle Scholar
  27. FitzGerald GA, Reilly IA, Pedersen AK (1985) The biochemical pharmacology of thromboxane synthase inhibition in man. Circulation 72:1194–1201PubMedCrossRefGoogle Scholar
  28. Gaussem P, Reny JL, Thalamas C, Chatelain N, Kroumova M, Jude B, Boneu B, Fiessinger JN (2005) The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies. J Thromb Haemost 3:1437–1445PubMedCrossRefGoogle Scholar
  29. Gelosa P, Ballerio R, Banfi C, Nobili E, Gianella A, Pignieri A, Brioschi M, Guerrini U, Castiglioni L, Blanc-Guillemaud V, Lerond L, Tremoli E, Sironi L (2010) Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, increases survival in stroke-prone rats by preventing systemic inflammation and endothelial dysfunction: comparison with aspirin and rosuvastatin. J Pharmacol Exp Ther 334:199–205PubMedCrossRefGoogle Scholar
  30. Giannarelli C, Zafar MU, Badimon JJ (2010) Prostanoid and TP-receptors in atherothrombosis: is there a role for their antagonism? Thromb Haemost 104:949–954PubMedCrossRefGoogle Scholar
  31. Guthikonda S, Lev EI, Patel R, DeLao T, Bergeron AL, Dong JF, Kleiman NS (2007) Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 5:490–496PubMedCrossRefGoogle Scholar
  32. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A (2006) Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 367:1665–1673PubMedCrossRefGoogle Scholar
  33. Ishizuka T, Suzuki K, Kawakami M, Hidaka T, Matsuki Y, Nakamura H (1996) Thromboxane A2 receptor blockade suppresses intercellular adhesion molecule-1 expression by stimulated vascular endothelial cells. Eur J Pharmacol 312:367–377PubMedCrossRefGoogle Scholar
  34. Ishizuka T, Kawakami M, Hidaka T, Matsuki Y, Takamizawa M, Suzuki K, Kurita A, Nakamura H (1998) Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells. Clin Exp Immunol 112:464–470PubMedCrossRefGoogle Scholar
  35. Kiff PS, Bergman G, Atkinson L, Jewitt DE, Westwick J, Kakkar VV (1983) Haemodynamic and metabolic effects of dazoxiben at rest and during atrial pacing. Br J Clin Pharmacol 15:73S–77SPubMedCrossRefGoogle Scholar
  36. Lesault PF, Boyer L, Pelle G, Covali-Noroc A, Rideau D, Akakpo S, Teiger E, Dubois-Rande JL, Adnot S (2011) Daily administration of the TP receptor antagonist terutroban improved endothelial function in high-cardiovascular-risk patients with atherosclerosis. Br J Clin Pharmacol 71:844–851PubMedCrossRefGoogle Scholar
  37. Mayeux PR, Morton HE, Gillard J, Lord A, Morinelli TA, Boehm A, Mais DE, Halushka PV (1988) The affinities of prostaglandin H2 and thromboxane A2 for their receptor are similar in washed human platelets. Biochem Biophys Res Commun 157:733–739PubMedCrossRefGoogle Scholar
  38. Meade EA, Smith WL, DeWitt DL (1993) Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268:6610–6614PubMedGoogle Scholar
  39. Meadows TA, Bhatt DL (2007) Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 100:1261–1275PubMedCrossRefGoogle Scholar
  40. Mehta P, Mehta J, Lawson D, Krop I, Letts LG (1986) Leukotrienes potentiate the effects of epinephrine and thrombin on human platelet aggregation. Thromb Res 41:731–738PubMedCrossRefGoogle Scholar
  41. Meja KK, Barnes PJ, Giembycz MA (1997) Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-alpha generation. Br J Pharmacol 122:149–157PubMedCrossRefGoogle Scholar
  42. Miggin SM, Kinsella BT (1998) Expression and tissue distribution of the mRNAs encoding the human thromboxane A2 receptor (TP) alpha and beta isoforms. Biochim Biophys Acta 1425:543–559PubMedCrossRefGoogle Scholar
  43. Moussa O, Ashton AW, Fraig M, Garrett-Mayer E, Ghoneim MA, Halushka PV, Watson DK (2008) Novel role of thromboxane receptors beta isoform in bladder cancer pathogenesis. Cancer Res 68:4097–4104PubMedCrossRefGoogle Scholar
  44. Moussa O, Ciupek A, Watson DK, Halushka PV (2011) Urinary thromboxane B(2) and thromboxane receptors in bladder cancer: opportunity for detection and monitoring. Prostaglandins Other Lipid Mediat 96(1–4):41–44PubMedCrossRefGoogle Scholar
  45. Nakahata N (2008) Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 118:18–35PubMedCrossRefGoogle Scholar
  46. Neri Serneri GG, Coccheri S, Marubini E, Violi F (2004) Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur Heart J 25:1845–1852PubMedCrossRefGoogle Scholar
  47. Patrono C (1990) Biosynthesis and pharmacological modulation of thromboxane in humans. Circulation 81:I12–I15, discussion I22–I23PubMedGoogle Scholar
  48. Patrono C, Falco A, Davì G (2005a) Isoprostane formation and inhibition in atherothrombosis. Curr Opin Pharmacol 5:198–203PubMedCrossRefGoogle Scholar
  49. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005b) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383PubMedCrossRefGoogle Scholar
  50. Patrono C, Baigent C, Hirsh J, Roth G (2008) Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:199S–233SPubMedCrossRefGoogle Scholar
  51. Patscheke H (1990) Thromboxane A2/prostaglandin H2 receptor antagonists. A new therapeutic principle. Stroke 21:IV139–IV142PubMedGoogle Scholar
  52. Praticó D, Cheng Y, FitzGerald GA (2000) TP or not TP: primary mediators in a close runoff? Arterioscler Thromb Vasc Biol 20:1695–1698PubMedCrossRefGoogle Scholar
  53. Rovati GE, Sala A, Capra V, Dahlen SE, Folco G (2010) Dual COXIB/TP antagonists: a possible new twist in NSAID pharmacology and cardiovascular risk. Trends Pharmacol Sci 31:102–107PubMedCrossRefGoogle Scholar
  54. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW (2008) Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 359:1238–1251PubMedCrossRefGoogle Scholar
  55. Santilli F, Rocca B, De Cristofaro R, Lattanzio S, Pietrangelo L, Habib A, Pettinella C, Recchiuti A, Ferrante E, Ciabattoni G, Davì G, Patrono C (2009) Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin “resistance”. J Am Coll Cardiol 53:667–677PubMedCrossRefGoogle Scholar
  56. Santilli F, Davì G, Basili S, Lattanzio S, Cavoni A, Guizzardi G, De Feudis L, Traisci G, Pettinella C, Paloscia L, Minuz P, Meneguzzi A, Ciabattoni G, Patrono C (2010) Thromboxane and prostacyclin biosynthesis in heart failure of ischemic origin: effects of disease severity and aspirin treatment. J Thromb Haemost 8:914–922PubMedCrossRefGoogle Scholar
  57. Santilli F, Mucci L, Davì G (2011) TP receptor activation and inhibition in atherothrombosis: the paradigm of diabetes mellitus. Intern Emerg Med 6:203–212PubMedCrossRefGoogle Scholar
  58. Santos-Garcia D, Blanco M, Serena J, Arias S, Millan M, Rodriguez-Yanez M, Leira R, Davalos A, Castillo J (2009) Brachial arterial flow mediated dilation in acute ischemic stroke. Eur J Neurol 16:684–690PubMedCrossRefGoogle Scholar
  59. Savage MP, Goldberg S, Bove AA, Deutsch E, Vetrovec G, Macdonald RG, Bass T, Margolis JR, Whitworth HB, Taussig A (1995) Effect of thromboxane A2 blockade on clinical outcome and restenosis after successful coronary angioplasty. Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART II). Circulation 92:3194–3200PubMedCrossRefGoogle Scholar
  60. Schramm TK, Gislason GH, Kober L, Rasmussen S, Rasmussen JN, Abildstrom SZ, Hansen ML, Folke F, Buch P, Madsen M, Vaag A, Torp-Pedersen C (2008) Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 117:1945–1954PubMedCrossRefGoogle Scholar
  61. Selg E, Buccellati C, Andersson M, Rovati GE, Ezinga M, Sala A, Larsson AK, Ambrosio M, Lastbom L, Capra V, Dahlen B, Ryrfeldt A, Folco GC, Dahlen SE (2007) Antagonism of thromboxane receptors by diclofenac and lumiracoxib. Br J Pharmacol 152:1185–1195PubMedCrossRefGoogle Scholar
  62. Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast EG, Wijns W, Rensing BJ, Vos J, Stibbe J (1991) Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT). Circulation 84:1568–1580PubMedCrossRefGoogle Scholar
  63. Shikano M, Ito T, Ogawa K, Satake T (1987) Effects of a selective thromboxane synthetase inhibitor (OKY-046) in patients with coronary artery disease during exercise. Jpn Heart J 28:663–674PubMedCrossRefGoogle Scholar
  64. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, Kitagawa Y, Kusuoka H, Nishimaru K, Tsushima M, Koretsune Y, Sawada T, Hamada C (2010) Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 9:959–968PubMedCrossRefGoogle Scholar
  65. Swinnen M, Vanhoutte D, Van Almen GC, Hamdani N, Schellings MW, D'Hooge J, Van der Velden J, Weaver MS, Sage EH, Bornstein P, Verheyen FK, VandenDriessche T, Chuah MK, Westermann D, Paulus WJ, Van de Werf F, Schroen B, Carmeliet P, Pinto YM, Heymans S (2009) Absence of thrombospondin-2 causes age-related dilated cardiomyopathy. Circulation 120:1585–1597PubMedCrossRefGoogle Scholar
  66. Thaulow E, Dale J, Myhre E (1984) Effects of a selective thromboxane synthetase inhibitor, dazoxiben, and of acetylsalicylic acid on myocardial ischemia in patients with coronary artery disease. Am J Cardiol 53:1255–1258PubMedCrossRefGoogle Scholar
  67. The Ridogrel Versus Aspirin Patency Trial (1994) Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. Circulation 89:588–595CrossRefGoogle Scholar
  68. Toth P, Rozsa B, Springo Z, Doczi T, Koller A (2011) Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors. J Cereb Blood Flow Metab 31:2096–2105PubMedCrossRefGoogle Scholar
  69. Tytgat GN, Van Nueten L, Van De Velde I, Joslyn A, Hanauer SB (2002) Efficacy and safety of oral ridogrel in the treatment of ulcerative colitis: two multicentre, randomized, double-blind studies. Aliment Pharmacol Ther 16:87–99PubMedCrossRefGoogle Scholar
  70. Uehara Y, Ishimitsu T, Kimura K, Ishii M, Ikeda T, Sugimoto T (1988) Regulatory effects of eicosanoids on thymidine uptake by vascular smooth muscle cells of rats. Prostaglandins 36:847–857PubMedCrossRefGoogle Scholar
  71. Uyama O, Nagatsuka K, Nakabayashi S, Isaka Y, Yoneda S, Kimura K, Abe H (1985) The effect of a thromboxane synthetase inhibitor, OKY-046, on urinary excretion of immunoreactive thromboxane B2 and 6-keto-prostaglandin F1 alpha in patients with ischemic cerebrovascular disease. Stroke 16:241–244PubMedCrossRefGoogle Scholar
  72. Vandeplassche G, Hermans C, Somers Y, Van de Werf F, de Clerck F (1993) Combined thromboxane A2 synthase inhibition and prostaglandin endoperoxide receptor antagonism limits myocardial infarct size after mechanical coronary occlusion and reperfusion at doses enhancing coronary thrombolysis by streptokinase. J Am Coll Cardiol 21:1269–1279PubMedCrossRefGoogle Scholar
  73. Violi F, Hiatt W (2007) A critical review of antiplatelet treatment in peripheral arterial disease. Intern Emerg Med 2:84–87PubMedCrossRefGoogle Scholar
  74. Watala C, Boncler M, Gresner P (2005) Blood platelet abnormalities and pharmacological modulation of platelet reactivity in patients with diabetes mellitus. Pharmacol Rep 57(Suppl):42–58PubMedGoogle Scholar
  75. Yui Y, Hattori R, Takatsu Y, Nakajima H, Wakabayashi A, Kawai C, Kayama N, Hiraku S, Inagawa T, Tsubojima M et al (1984) Intravenous infusion of a selective inhibitor of thromboxane A2 synthetase in man: influence on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation. Circulation 70:599–605PubMedCrossRefGoogle Scholar
  76. Zuccollo A, Shi C, Mastroianni R, Maitland-Toolan KA, Weisbrod RM, Zang M, Xu S, Jiang B, Oliver-Krasinski JM, Cayatte AJ, Corda S, Lavielle G, Verbeuren TJ, Cohen RA (2005) The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus. Circulation 112:3001–3008PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Giovanni Davì
    • 1
  • Francesca Santilli
    • 1
  • Natale Vazzana
    • 1
  1. 1.Internal MedicineUniversity of ChietiChietiItaly

Personalised recommendations