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A Perspective on the Toxicological Mechanisms Possibly Contributing to the Failure of Oral Glycoprotein IIb/IIIa Antagonists in the Clinic

Abstract

In clinical trials in patients with acute or unstable coronary syndromes and/or undergoing percutaneous coronary intervention, oral glycoprotein (GP) IIb/IIIa antagonists did not show therapeutic benefit over aspirin during long-term administration. Moreover, high-dose oral administration of these agents was associated with greater fatality risk compared with that of lower doses. This article postulates that continuous exposure of the GP IIb/IIIa receptor (integrin αIIbβ3) to these agents may result in some form of resistance or activation of other biological systems. These toxicological mechanisms may help explain some factors that could potentially contribute to the failure of these agents in clinical trials.

Several hypotheses are presented: (i) modulation of platelet response because of long-term exposure to GP IIb/IIIa antagonists; (ii) role of related integrins and associated proteins to compensate for the loss of platelet activity because of dysfunctional GP IIb/IIIa receptors occupied by inhibitors; (iii) effects of the GP IIb/IIIa antagonists on other cellular systems such as the caspase and procaspase enzymes in apoptosis and possibly the ryanodine receptor involved in sarcoplasmic reticulum calcium release.

These toxicological mechanisms could potentially limit the utility of these oral agents in long-term administration.

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References

  1. 1.

    Fitzgerald DJ, Roy L, Catella F, et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983–9

  2. 2.

    Folts JD, Schafer AI, Loscalzo J, et al. A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials. J Am Coll Cardiol 1999; 33: 295–303

  3. 3.

    Pytela R, Pierschbacher MD, Ginsberg MH, et al. Platelet membrane glycoprotein IIb/IIIa: member of a family of Asp-Gly-Asp-specific adhesion receptors. Science 1986; 231: 1559–62

  4. 4.

    Du XP, Plow EF, Frelinger AL, et al. Ligands “activate” integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa). Cell 1991; 65: 409–16

  5. 5.

    CAPTURE Investigators. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels: c7E3 Fab antiplatelet therapy in unstable refractory angina. N Engl J Med 1999; 340: 1623–9

  6. 6.

    EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and lowdose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689–96

  7. 7.

    PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436–43

  8. 8.

    RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96: 1445–53

  9. 9.

    EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk angioplasty. N Engl J Med 1994; 330: 956–61

  10. 10.

    PRISM-PLUS Study Investigators. Inhibition of platelet glycoprotein IIb/IIIa with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488–97

  11. 11.

    SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomized trial. Lancet 2000; 355: 337–45

  12. 12.

    Cannon CP. Glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST segment elevation myocardial infarction. Coron Artery Dis 1999; 10: 561–6

  13. 13.

    Chew DP, Bhatt DL, Sapp S, et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201–6

  14. 14.

    Cox D, Smith R, Quinn M, et al. Evidence of platelet activation during treatment with a glycoprotein IIb/IIIa antagonist in patients presenting with acute coronary syndromes. J Am Coll Cardiol 2000; 36: 1514–9

  15. 15.

    Nicholson NS, Abood NA, Panzer-Knodle SG, et al. Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist. Med Res Rev 2001; 21: 211–26

  16. 16.

    Kereiakes DJ, Kleiman NS, Ferguson JJ, et al. Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial. Circulation 1998; 98: 1268–78

  17. 17.

    Reimann D, Modi NB, Novotny W. Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered GP IIb/IIIa antagonist, following coadministration of aspirin and heparin. J Clin Pharmacol 2000; 40: 488–95

  18. 18.

    Modi NB, Novotny W, Reimann JD, et al. Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered IIb/IIIa antagonist, in patients with acute coronary syndrome. J Clin Pharmacol 1999; 39: 675–84

  19. 19.

    Mould D, Chapelsky M, Aluri J, et al. A population pharmacokinetic-pharmacodynamic and logistic regression analysis of lotrafiban in patients. Clin Pharmacol Ther 2001;69: 210–22

  20. 20.

    Harrington RA, Armstrong PW, Graffagnino C, et al. Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease. Circulation 2000; 102: 728–35

  21. 21.

    Barrett JS, Murphy G, Peerlinck K, et al. Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther 1994; 56: 377–88

  22. 22.

    Alton KB, Kosoglou T, Baken S, et al. Disposition of 14C-eptifibatide after intravenous administration to healthy men. Clin Ther 1998; 20: 307–23

  23. 23.

    Tcheng JE, Talley JD, O’shea JC, et al. Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study). Am J Cardiol 2001;88: 1097–102

  24. 24.

    Tcheng JE, Ellis SG, George BS, et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab7E3 in high-risk coronary angioplasty. Circulation 1994; 90: 1757–64

  25. 25.

    Holmes MB, Sobel BE, Cannon CP, et al. Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an POUS-TIMI 16 substudy. Am J Cardiol 2000; 85: 491–3

  26. 26.

    Dooley M, Goa KL. Sibrafiban. Drugs 1999; 57: 225–30

  27. 27.

    Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial: thrombolysis in myocardial infarction. J Am Coll Cardiol 1999; 33: 634–9

  28. 28.

    Kereiakes DJ. Oral platelet glycoprotein IIb/IIIa inhibitors. Coron Artery Dis 1999; 10: 581–94

  29. 29.

    Mousa SA, Khurana S, Forsythe MS. Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet-mediated clot strength induced by tissue factor with use of thromboelastography: differentiation among glycoprotein IIb/IIIa antagonists. Artherioscler Thromb Vasc Biol 2000; 20: 1162–7

  30. 30.

    Pieniaszek HJ, Sy SK, Ebling W, et al. Safety, tolerability, pharmacokinetics and time course of pharmacologic response of the active metabolite of roxifiban, XV459, a glycoprotein IIb/IIIa antagonist, following oral administration in healthy volunteers. J Clin Pharmacol 2002; 42: 738–53

  31. 31.

    Mousa SA, Forsythe M, Bozarth J, et al. XV454, a novel nonpeptide small molecule platelet GPIIb/IIIa antagonist with comparable platelet αIIbβ3-binding kinetics to c7E3. J Cardiovasc Pharmacol 1998; 32: 736–44

  32. 32.

    Sebastian M, Makkar R. Glycoprotein IIb/IIIa receptor antagonists: clinical pharmacology in cardiovascular disease of aging. Drugs Aging 1999; 15: 207–18

  33. 33.

    Frelinger AL, Furman MI, Krueger LA, et al. Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fibrinogen binding or platelet aggregation. Circulation 2001; 104: 1374–9

  34. 34.

    Rabbani SS, Aggarwai A, Terrien EF, et al. Suboptimal early inhibition of platelets by treatment with tirofiban and implications for coronary interventions. Am J Cardiol 2002; 89: 647–50

  35. 35.

    Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation 2001; 103: 2572–8

  36. 36.

    Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation 2002; 106: 379–85

  37. 37.

    Crenshaw BS, Harrington RA, Tcheng JE. Novel antiplatelet agents: the glycoprotein IIb/IIIa inhibitors. Expert Opin Investig Drugs 1995; 4: 1033–44

  38. 38.

    Coller BS. Platelets and thrombolytic therapy. N Engl J Med 1990; 322: 33–42

  39. 39.

    Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90: 2126–46

  40. 40.

    Folts JD. Drugs for the prevention of coronary thrombosis: from an animal model to clinical trials. Cardiovasc Drugs Ther 1995; 9: 31–43

  41. 41.

    Willerson JT, Golino P, Eidt J, et al. Specific platelet mediators and unstable coronary artery lesions: experimental evidence and potential clinical implications. Circulation 1989; 80: 198–205

  42. 42.

    Ashton JH, Ogletree ML, Michel IM, et al. Cooperative mediation by serotonin S2 and thromboxane A2/prostaglandin H2 receptor activation of cyclic flow variations in dogs with severe coronary artery stenoses. Circulation 1987; 76: 952–9

  43. 43.

    Yao SK, Ober JC, McNatt J, et al. ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothe-lium-injured canine coronary arteries. Circ Res 1992; 70: 39–48

  44. 44.

    Weiss HJ, Turitto VT, Baumgartner HR. Further evidence that glycoprotein IIb–IIIa mediates platelet spreading on subendothelium. Thromb Haemost 1991; 65: 202–5

  45. 45.

    Shattil SJ, Hoxie JA, Cunningham M, et al. Changes in the platelet membrane glycoprotein IIb–IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107–14

  46. 46.

    Stenberg PE, McEver RP, Shuman MA, et al. A platelet alpha granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. Cell Biol 1985; 101: 880–6

  47. 47.

    Fitzgerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68: 11B–5B

  48. 48.

    Topol EJ, Byzova TV, Plow EF. Platelet glycoprotein IIb–IIIa blockers. Lancet 1999; 353: 227–31

  49. 49.

    Shattil SJ, Ginsberg MH. Integrin signaling in vascular biology. J Clin Invest 1997; 100: S91–5

  50. 50.

    Humphries MJ. Integrin activation. Curr Opin Cell Biol 1996; 8: 632–40

  51. 51.

    Schwartz MA, Schaller MD, Ginsberg MH. Integrins. Annu Rev Cell Biol 1995; 11: 549–99

  52. 52.

    Payrastre B, Missy K, Trumel C, et al. The integrin αIIb/β3 in human platelet signal transduction. Biochem Pharmacol 2000; 60: 1069–74

  53. 53.

    Cierniewski CS, Byzova T, Papierak M, et al. Peptide ligands can bind to distinct sites in integrin αIIbβ3 and elicit different functional responses. J Biol Chem 1999; 274: 16923–32

  54. 54.

    Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood 1998; 91: 2645–57

  55. 55.

    Parise LV. Integrin αIIb/β3 signaling in platelet adhesion and aggregation. Curr Opin Cell Biol 1999; 11: 597–601

  56. 56.

    Berridge MJ. Inositol trisphosphate and calcium signaling. Nature 1993; 361: 315–25

  57. 57.

    Elalamy I, Emadi S, Vargaftig BB, et al. Signal transduction involved in the platelet adenylate cyclase sensitization associated with PGH2/TxA2 receptor desensitization. Br J Haematol 1997; 99: 190–6

  58. 58.

    Hackeng CM, Relou IA, Pladet MW, et al. Early platelet activation by low density lipoprotein via p38MAP kinase. Thromb Haemost 1999; 82: 1749–56

  59. 59.

    Van Willigen G, Gorter G, Akkerman JW. LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granules. Arterioscler Thromb 1994; 14: 41–6

  60. 60.

    Surya II, Akkerman JW. The influence of lipoproteins on blood platelets. Am Heart J 1993; 125: 272–5

  61. 61.

    Andrews HE, Aitken JW, Hassall DG, et al. Intracellular mechanisms in the activation of human platelets by low density lipoproteins. Biochem J 1987; 242: 559–64

  62. 62.

    Nofer JR, Tepel M, Kehrel B, et al. Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets: a novel mechanism enhancing platelet activity in hypercholesterolemia. Circulation 1997; 95: 1370–7

  63. 63.

    Block LH, Knorr M, Vogt E, et al. Low density lipoprotein causes general cellular activation with increased phosphatidylinositol turnover and lipoprotein catabolism. Proc Natl Acad Sci U S A 1988; 85: 885–9

  64. 64.

    Hackeng CM, Huigsloot M, Pladet MW, et al. LDL enhances platelet secretion via integrin αIIbβ3-mediated signaling. Arterioscler Thromb Vasc Biol 1999; 19: 239–47

  65. 65.

    Charo IF, Fitzgerald LA, Steiner B, et al. Platelet glycoproteins IIb and IIIa: evidence for a family of immunologically and structurally related glycoproteins in mammalian cells. Proc Natl Acad Sci U S A 1986; 83: 8351–6

  66. 66.

    Altieri DC, Eddicton TS. A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CD11b/ CD18 (Mac-1). J Immunol 1988; 141: 2656–60

  67. 67.

    Trikha M, Zhou Z, Timar J, et al. Multiple roles for platelet GPIIb/IIIa and αVβ3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 2002; 62: 2824–33

  68. 68.

    Coller BS. Binding of abciximab to αVβ3 and activated αMβ2 receptors: with a review of platelet-leukocyte interactions. Thromb Haemost 1999; 82: 326–36

  69. 69.

    Lele M, Sajid M, Wajih N, et al. Eptifibatide and 7E3, but not tirofiban, inhibit alpha(v)beta(3) integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin. Circulation 2001; 104: 582–7

  70. 70.

    Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 1996; 12: 697–715

  71. 71.

    Meredith JE, Schwartz MA. Integrins, adhesion and apoptosis. Trends Cell Biol 1997; 7: 146–50

  72. 72.

    Werb Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 1997; 91: 439–42

  73. 73.

    Schvartz I, Seger D, Shaltiel S. Vitronectin. Int J Biochem Cell Biol 1999; 31: 539–44

  74. 74.

    Preissner KT, Seifert D. Role of vitronectin and its receptors in haemostasis and vascular remodeling. Thromb Res 1998; 89: 1–21

  75. 75.

    Barrett JS, Chan C, Vilaire G, et al. Agonist-activated αVβ3 on platelets and lymphocytes binds to the matrix protein osteopontin. J Biol Chem 1997; 272: 8137–40

  76. 76.

    Brooks PC, Stromblad S, Klemke R, et al. Anti-integrin αVβ3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96: 1815–22

  77. 77.

    Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996; 8: 724–30

  78. 78.

    Byzova TV, Ramin R, D’souza SE, et al. Role of integrin αVβ3 in vascular biology. Thromb Hemost 1998; 80: 726–34

  79. 79.

    Srivatsa SS, Fizpatrick LA, Tsao PW, et al. Selective αVβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: evidence for the functional importance of integrin αIIbβ3 and osteopontin expression during neointima formation. Cardiovasc Res 1997; 36: 408–28

  80. 80.

    Stouffer GA, Hu Z, Sajid M, et al. Beta3 integrins are upregulated after vascular injury and modulated thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells. Circulation 1998; 97: 907–15

  81. 81.

    Lincoff AM, Califf RM, Moliterno DH, et al. for the Evaluation of Platelet IIb/IIIa Inhibition in Stenting (EPISTENT) Investigators. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341: 319–27

  82. 82.

    Porter JC, Hogg N. Integrins take partners: cross-talk between integrins and other membrane receptors. Trends Cell Biol 1998; 8: 390–6

  83. 83.

    Chung J, Gao AG, Frazier WA. Thrombospondin acts via integrin-associated protein to activate the platelet integrin alphaIIb beta3. J Biol Chem 1997; 272: 14740–6

  84. 84.

    Buckley CD, Pilling D, Henriquez NV, et al. RGD peptides induce apoptosis by direct caspase-3 activation. Nature 1999; 397: 534–9

  85. 85.

    Adderley SR, Fitzgerald DJ. Glycoprotein IIb/IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase-3 activation. J Biol Chem 2000; 275: 5760–6

  86. 86.

    Eisner DA, Trafford AW, Diaz ME, et al. The control of Ca release from the cardiac sarcoplasmic reticulum: regulation versus autoregulation. Cardiovasc Res 1998; 38: 589–604

  87. 87.

    Ogawa Y, Kurebayashi N, Murayama T. Ryanodine receptor isoforms in excitation-contraction coupling. Adv Biophys 1999; 36: 27–64

  88. 88.

    Wu X, Mogford JE, Platts SH, et al. Modulation of calcium current in arteriolar smooth muscle by αVβ3 and αVβ1 integrin ligands. J Cell Biol 1998; 143: 241–52

  89. 89.

    Chan WL, Holstein-Rathlou NH, Yip KP. Integrin mobilizes intracellular calcium in renal vascular smooth muscle cells. Am J Physiol Cell Physiol 2001; 280: C593–603

  90. 90.

    Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000; 101: 365–76

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Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. The author would like to thank Drs Laurence Mangin and Peter Swain for scientific and editorial reviews of the manuscript, respectively.

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Correspondence to dr Sherwin K. K. Sy.

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Sy, S.K.K., Levenstadt, A.L. A Perspective on the Toxicological Mechanisms Possibly Contributing to the Failure of Oral Glycoprotein IIb/IIIa Antagonists in the Clinic. Am J Cardiovasc Drugs 4, 1–10 (2004). https://doi.org/10.2165/00129784-200404010-00001

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Keywords

  • Percutaneous Coronary Intervention
  • Abciximab
  • Ryanodine Receptor
  • Eptifibatide
  • Tirofiban