NUEVAS NOCIONES ACERCA DE LOS ANTAGONISTAS DE LOS RECEPTORES GPIIB/GPIIIA





NUEVAS NOCIONES ACERCA DE LOS ANTAGONISTAS DE LOS RECEPTORES GPIIB/GPIIIA

(especial para SIIC © Derechos reservados)
Los inhibidores de la GPIIb/IIIa ejercen cierto agonismo parcial que limita su efecto terapéutico y favorece la aparición de efectos colaterales cuando son administrados por vía oral. Existen polimorfismos genéticos del receptor que reducen su afinidad por la droga.
cox.jpg Autor:
Dermot Cox
Columnista Experto de SIIC
Artículos publicados por Dermot Cox
Recepción del artículo
27 de Mayo, 2003
Primera edición
19 de Septiembre, 2003
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
La unión del fibrinógeno a su receptor en las plaquetas, la glucoproteína (GP) IIb/IIIa, es un requisito indispensable para la agregación plaquetaria. Este hecho fue confirmado por el éxito del tratamiento con antagonistas de estos mediadores en los síndromes agudos coronarios y la angioplastia. Sin embargo, a la inversa de lo que sucede con los compuestos de administración endovenosa, los de incorporación por vía oral no mostraron beneficio y aun incrementaron la mortalidad. Hay varias explicaciones posibles para el escaso rendimiento de los fármacos administrados por esta vía: fueron empleados para tratar un cuadro crónico y no agudo; tuvieron escasa biodisponibilidad, y como consecuencia niveles plasmáticos de la droga relativamente bajos; fueron agonistas parciales y generaron señales pro agregación plaquetaria; su afinidad por la GPIIb/IIIa se vio afectada por polimorfismos en el receptor. El fracaso obedeció, probablemente, a una combinación de todos estos factores. No obstante, al identificar tales problemas debería ser posible desarrollar antagonistas GPIIb/IIIa eficaces por vía oral.

Palabras clave
Plaquetas, antagonistas, glucoproteína IIb/IIIa, trombosis, agregación plaquetaria, síndromes agudos coronarios, fibrinógeno, vía oral, angor inestable


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Abstract
The binding of fibrinogen to its receptor on platelets, glycoprotein (GP) IIb/IIIa, is an absolute requirement for platelet aggregation. This was confirmed by the success of GPIIb/IIIa antagonists in the treatment of acute coronary syndromes and angioplasty. However, in sharp contrast to the iv compounds, the oral compounds showed no benefit and even increased mortality. There are a number of possible explanations for the poor performance of the oral compounds: they were used to treat a chronic condition rather than an acute condition; they had low bioavailability resulting in relatively low plasma levels of the drug; they were partial agonists and could generate pro-aggregatory signals; their affinity for GPIIb/IIIa was affected by polymorphisms in the receptor. Their failure was probably a combination of all these factors. However, by addressing these issues it should be possible to develop successful oral GPIIb/IIIa antagonists

Key words
Plaquetas, antagonistas, glucoproteína IIb/IIIa, trombosis, agregación plaquetaria, síndromes agudos coronarios, fibrinógeno, vía oral, angor inestable


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Especialidades
Principal: Farmacología
Relacionadas: Cardiología, Medicina Farmacéutica, Medicina Interna



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Bibliografía del artículo
  1. Nachman RL, Leung LL. Complex formation of platelet membrane glycoproteins IIb and IIIa with fibrinogen. J Clin Invest 1982;69:263-9.
  2. Lefkovits J, Ivanhoe RJ, Califf RM, Bergelson BA, Anderson KM, Stoner GL, Weisman HF, Topol EJ. Effects of Platelet Glycoprotein IIb/IIIa Receptor Blockade by a Chimeric Monoclonal Antibody (Abciximab) on Acute and Six-Month Outcomes After Percutaneous Transluminal Coronary Angioplasty for Acute Myocardial Infarction. The American Journal of Cardiology 1996;77:1045-1051.
  3. McLane MA, Marcinkiewicz C, Vijay-Kumar S, Wierzbicka-Patynowski I, Niewiarowski S. Viper venom disintegrins and related molecules. Proc Soc Exp Biol Med 1998;219:109-19.
  4. Scarborough RM. Development of eptifibatide. Am Heart J 1999;138:1093-104.
  5. The 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;96:1445-1453.
  6. Simpfendorfer C, Kottke-Marchant K, Lowrie M, Anders RJ, Burns DM, Miller DP, Cove CS, DeFranco AC, Ellis SG, Moliterno DJ, Raymond RE, Sutton JM, Topol EJ. First Chronic Platelet Glycoprotein IIb/IIIa Integrin Blockade : A Randomized, Placebo-Controlled Pilot Study of Xemilofiban in Unstable Angina With Percutaneous Coronary Interventions. Circulation 1997;96:76-81.
  7. Nicholson NS, Abood NA, Panzer-Knodle SG, Frederick LG, Page JD, Salyers AK, Suleymanov OD, Szalony JA, Taite BB, Anders RJ. Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist. Med Res Rev 2001;21:211-26.
  8. Liu F, Craft RM, Morris SA, Carroll RC. Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker. Expert Opin Investig Drugs 2000;9:2673-87.
  9. Cannon CP, McCabe CH, Borzak S, Henry TD, Tischler MD, Mueller HS, Feldman R, Palmeri ST, Ault K, Hamilton SA, Rothman JM, Novotny WF, Braunwald E. Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome : Results of the TIMI 12 Trial. Circulation 1998;97:340-349.
  10. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189-98.
  11. Kleiman NS, Lincoff AM, Flaker GC, Pieper KS, Wilcox RG, Berdan LG, Lorenz TJ, Cokkinos DV, Simoons ML, Boersma E, Topol EJ, Califf RM, Harrington RA. Early percutaneous coronary intervention, platelet inhibition with eptifibatide, and clinical outcomes in patients with acute coronary syndromes. PURSUIT Investigators. Circulation 2000;101:751-7.
  12. Kereiakes DJ, Kleiman NS, Ferguson JJ, Masud AR, Broderick TM, Abbottsmith CW, Runyon JP, Anderson LC, Anders RJ, Dreiling RJ, Hantsbarger GL, Bryzinski B, Topol EJ. 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.
  13. Cannon CP, McCabe CH, Wilcox RG, Langer A, Caspi A, Berink P, Lopez-Sendon J, Toman J, Charlesworth A, Anders RJ, Alexander JC, Skene A, Braunwald E. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000;102:149-56.
  14. Topol EJ, Easton JD, Amarenco P, Califf R, Harrington R, Graffagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, Shuaib A, Koudstaal PJ, Theroux P, Van de Werf F, Willerson JT, Chan R, Samuels R, Ilson B, Granett J. Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Am Heart J 2000;139:927-33.
  15. Newby LK. Long-term oral platelet glycoprotein IIb/IIIa receptor antagonism with sibrafiban after acute coronary syndromes: study design of the sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes (SYMPHONY) trial. Symphony Steering Committee. Am Heart J 1999;138:210-8.
  16. The SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The SYMPHONY Investigators. Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes. Lancet 2000;355:337-45.
  17. Newby LK, Califf RM, White HD, Harrington RA, Van de Werf F, Granger CB, Simes RJ, Hasselblad V, Armstrong PW. The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events. Am J Med 2002;112:647-58.
  18. Nicholson NS, Panzer-Knodle SG, Salyers AK, Taite BB, Szalony JA, Haas NF, King LW, Zablocki JA, Keller BT, Broschat K, et al. SC-54684A: an orally active inhibitor of platelet aggregation. Circulation 1995;91:403-10.
  19. Refino CJ, Modi NB, Bullens S, Pater C, Lipari MT, Robarge K, Blackburn B, Beresini M, Weller T, Steiner B, Bunting S. Pharmacokinetics, pharmacodynamics and tolerability of a potent, non-peptidic, GP IIb/IIIa receptor antagonist following multiple oral administrations of a prodrug form. Thromb Haemost 1998;79:169-76.
  20. Quinn MJ, Cox D, Foley JB, Fitzgerald DJ. Glycoprotein IIb/IIIa receptor number and occupancy during chronic administration of an oral antagonist. J Pharmacol Exp Ther 2000;295:670-6.
  21. Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald DJ. Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes. J Am Coll Cardiol 2000;36:1514-9.
  22. Holmes MB, Sobel BE, Cannon CP, Schneider DJ. Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an OPUS-TIMI 16 substudy. Orbofiban in Patients with Unstable coronary syndromes. Thrombolysis In Myocardial Infarction. Am J Cardiol 2000;85:491-3, A10.
  23. van Noesel C, Miedema F, Brouwer M, de Rie MA, Aarden LA, van Lier RA. Regulatory properties of LFA-1 alpha and beta chains in human T-lymphocyte activation. Nature 1988;333:850-2.
  24. Stephens G, O\'Luanaigh N, Reilly D, Harriott P, Walker B, Fitzgerald D, Moran N. A sequence within the cytoplasmic tail of GpIIb independently activates platelet aggregation and thromboxane synthesis. J Biol Chem 1998;273:20317-22.
  25. O\'Neill S, Robinson A, Deering A, Ryan M, Fitzgerald DJ, Moran N. The platelet integrin alpha IIbbeta 3 has an endogenous thiol isomerase activity. J Biol Chem 2000;275:36984-90.
  26. Du XP, Plow EF, Frelinger AL, 3rd, O\'Toole TE, Loftus JC, Ginsberg MH. Ligands "activate" integrin alpha IIb beta 3 (platelet GPIIb-IIIa). Cell 1991;65:409-16.
  27. Frelinger AL, Du XP, Plow EF, Ginsberg MH. Monoclonal antibodies to ligand-occupied conformers of integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) alter receptor affinity, specificity, and function. J Biol Chem 1991;266:17106-11.
  28. Quinn MJ, Fullard J, Kerrigan S, Harriott P, Cox D, Fitzgerald DJ. Characterization of a ligand-attenuated binding site on glycoprotein IIb/IIIa. Thromb Haemost 2002;88:811-6.
  29. Cox D, Aoki T, Seki J, Motoyama Y, Yoshida K. Pentamidine is a specific, non-peptide, GPIIb/IIIa antagonist. Thromb Haemost 1996;75:503-9.
  30. Kouns WC, Kirchhofer D, Hadvary P, Edenhofer A, Weller T, Pfenninger G, Baumgartner HR, Jennings LK, Steiner B. Reversible conformational changes induced in glycoprotein IIb-IIIa by a potent and selective peptidomimetic inhibitor. Blood 1992;80:2539-47.
  31. Quinn M, Deering A, Stewart M, Cox D, Foley B, Fitzgerald D. Quantifying GPIIb/IIIa receptor binding using 2 monoclonal antibodies: discriminating abciximab and small molecular weight antagonists. Circulation 1999;99:2231-8.
  32. Kong DF, Califf RM, Miller DP, Moliterno DJ, White HD, Harrington RA, Tcheng JE, Lincoff AM, Hasselblad V, Topol EJ. Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease. Circulation 1998;98:2829-2835.
  33. Di Castelnuovo A, de Gaetano G, Donati MB, Iacoviello L. Platelet glycoprotein receptor IIIa polymorphism PLA1/PLA2 and coronary risk: a meta-analysis. Thromb Haemost 2001;85:626-33.
  34. Wheeler GL, Braden GA, Bray PF, Marciniak SJ, Mascelli MA, Sane DC. Reduced inhibition by abciximab in platelets with the PlA2 polymorphism. American Heart Journal 2002;143:76-82.
  35. O\'Connor FF, Shields DC, Fitzgerald A, Cannon CP, Braunwald E, Fitzgerald DJ. Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes. Blood 2001;98:3256-60.
  36. Hellstrom HR. Platelet Glycoprotein IIb/IIIa Inhibitors. Circulation 2003;107:39e-.

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