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Chemical Compound Review

Integrelin     2-[20-aminocarbonyl-12-[4...

Synonyms: Integrilin, Intrifiban, Eptifibatide, SB-1, CHEMBL1174, ...
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Disease relevance of Integrilin

  • DESIGN AND SETTING: Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997 [1].
  • Moreover, platelet-derived LPA deprivation in mice, achieved by treatment with the platelet antagonist Integrilin, inhibited the progression of bone metastases caused by parental and LPA(1)-overexpressing MDA-BO2 cells and reduced the progression of osteolytic lesions in mice bearing CHO-beta3wt ovarian cancer cells [2].
  • BACKGROUND: We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis [3].
  • The Integrelin group also had less total postoperative blood loss (control, 447 +/- 97 mL; Integrelin, 248 +/- 30 mL; P < .05) [4].
  • No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies [5].

High impact information on Integrilin

  • CONTEXT: In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, treatment with eptifibatide, a platelet glycoprotein IIb/IIIa integrin blocker, was found to reduce the ischemic complications of nonurgent coronary stent implantation at 48 hours and 30 days [6].
  • Integrilin, a alphaIIbbeta3 antagonist, but not an antibody to CD40 that blocked the ligand-binding activity, inhibited these platelet-stimulatory events [7].
  • The glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors abciximab and eptifibatide (Integrilin) inhibited the binding to fibrinogen and fibronectin but had minimal effect on binding to collagen [8].
  • However, citrate can enhance the potency of at least eptifibatide (Integrilin), and turbidimetry is insensitive to microaggregate formation [9].
  • Potency measured in PRP was 2- to 3-fold greater compared with whole blood for MK-0852 and GR144053 but 3- to 4-fold greater for eptifibatide [9].

Chemical compound and disease context of Integrilin

  • Two patients, treated with enoxaparin and eptifibatide, developed significant guide catheter-associated thrombus while undergoing intravascular ultrasound (IVUS) [10].
  • The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. METHODS AND RESULTS: Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment [11].

Biological context of Integrilin

  • At 120 minutes after CPB, the control group had significantly lower platelet counts (expressed as percent of pre-CPB values) when compared with the Integrelin group (control, 35.2 +/- 4.6%; Integrelin, 68.2 +/- 4.9%; mean +/- SEM; P < .05) [4].
  • Van't Hoff analyses of dimerization constants for alpha(IIb)beta(3) complexed with cHArGD, cRGD, or eptifibatide yielded large, favorable entropy changes partly offset by unfavorable enthalpy changes [12].
  • METHOD: Thirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load [13].
  • The mean TRAP IC50 values for citrate and PPACK were 88.2 +/- 12.2 nM and 126.1 +/- 28.4 nM for abciximab (1.4 fold enhancement; p = 0.0007), 75.9 +/- 13.3 nM and 142.6 +/- 32.6 nM for tirofiban (1.9-fold enhancement; p = 0.001), and 260.2 +/- 62.5 nM and 810.3 +/- 182.5 nM for eptifibatide (3.1-fold enhancement; p = 0.001) [14].
  • The binding of eptifibatide to the receptor involves displacement of receptor-associated Ca2+ from the activated binding site [15].

Anatomical context of Integrilin


Associations of Integrilin with other chemical compounds

  • METHODS AND RESULTS: Lower concentrations of Integrilin were found to inhibit platelet aggregation in plasma anticoagulated with citrate (for ADP, mean+/-SD IC(50)=140+/-40 nmol/L, n=6; Ca2+ =40 to 50 micromol/L) than with PPACK (IC(50)=570+/-70 nmol/L, P<.0001, n=6; Ca2+ approximately 1 mmol/L) [21].
  • Simultaneous turbidimetry and platelet counting performed in PRP indicated that this is because GP IIb/IIIa antagonists are more potent inhibitors of in vitro macroaggregation than microaggregation, this effect being greater for eptifibatide in hirudinized PRP compared with GR144053 (P=0.032) [9].
  • Study group 1 (10 healthy volunteers) received a DDAVP infusion to establish dose-response curves for the in vitro inhibition of platelet function by eptifibatide, abciximab, and tirofiban together with l-aspirin before and after DDAVP [22].
  • In group 2, DDAVP accelerated the normalization of CADP-CT and CEPI-CT after the stop of eptifibatide infusion with a maximum effect at 1.5 hours to 2 hours [22].
  • These new antiplatelet agents (ticlopidine, clopidogrel, abciximab, eptifibatide, and tirofiban) reduce the rate of ischemic complications and have become standard adjunctive therapy for patients who undergo PTCA [23].

Gene context of Integrilin


Analytical, diagnostic and therapeutic context of Integrilin

  • CONCLUSION: Adjunctive eptifibatide therapy during coronary stent implantation provides benefit through 6-month follow-up [29].
  • OBJECTIVE: To determine whether the beneficial effects of eptifibatide persist at 6 months after treatment [29].
  • BACKGROUND: Integrilin (eptifibatide), a potent inhibitor of the fibrinogen binding function of GP IIb-llla, has been shown to reduce the thrombotic complications of angioplasty and of acute coronary syndromes [21].
  • The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P = .006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P = .05) [30].
  • The study group (n = 6) received a 90-micrograms/kg IV bolus of the glycoprotein IIb/IIIa inhibitor Integrelin, followed by continuous infusion (2 micrograms/kg per minute) during CPB; the control group (n = 6) received only drug vehicle [4].


  1. Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation. PURSUIT Steering Committee. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. Alexander, J.H., Sparapani, R.A., Mahaffey, K.W., Deckers, J.W., Newby, L.K., Ohman, E.M., Corbalán, R., Chierchia, S.L., Boland, J.B., Simoons, M.L., Califf, R.M., Topol, E.J., Harrington, R.A. JAMA (2000) [Pubmed]
  2. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. Boucharaba, A., Serre, C.M., Grès, S., Saulnier-Blache, J.S., Bordet, J.C., Guglielmi, J., Clézardin, P., Peyruchaud, O. J. Clin. Invest. (2004) [Pubmed]
  3. Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis. Nicolini, F.A., Lee, P., Rios, G., Kottke-Marchant, K., Topol, E.J. Circulation (1994) [Pubmed]
  4. Inhibition of platelet adhesion during cardiopulmonary bypass reduces postoperative bleeding. Uthoff, K., Zehr, K.J., Geerling, R., Herskowitz, A., Cameron, D.E., Reitz, B.A. Circulation (1994) [Pubmed]
  5. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Bougie, D.W., Wilker, P.R., Wuitschick, E.D., Curtis, B.R., Malik, M., Levine, S., Lind, R.N., Pereira, J., Aster, R.H. Blood (2002) [Pubmed]
  6. Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention. O'Shea, J.C., Buller, C.E., Cantor, W.J., Chandler, A.B., Cohen, E.A., Cohen, D.J., Gilchrist, I.C., Kleiman, N.S., Labinaz, M., Madan, M., Hafley, G.E., Califf, R.M., Kitt, M.M., Strony, J., Tcheng, J.E. JAMA (2002) [Pubmed]
  7. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Prasad, K.S., Andre, P., He, M., Bao, M., Manganello, J., Phillips, D.R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Platelet microparticles promote platelet interaction with subendothelial matrix in a glycoprotein IIb/IIIa-dependent mechanism. Merten, M., Pakala, R., Thiagarajan, P., Benedict, C.R. Circulation (1999) [Pubmed]
  9. Differential effects of glycoprotein IIb/IIIa antagonists on platelet microaggregate and macroaggregate formation and effect of anticoagulant on antagonist potency. Implications for assay methodology and comparison of different antagonists. Storey, R.F., Wilcox, R.G., Heptinstall, S. Circulation (1998) [Pubmed]
  10. Effect of multielement intravascular ultrasound on the anticoagulant potency of enoxaparin. Stouffer, G.A., Pathak, A., Whinna, H.C., Ohman, E.M. Am. J. Cardiol. (2004) [Pubmed]
  11. Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Lincoff, A.M., Harrington, R.A., Califf, R.M., Hochman, J.S., Guerci, A.D., Ohman, E.M., Pepine, C.J., Kopecky, S.L., Kleiman, N.S., Pacchiana, C.M., Berdan, L.G., Kitt, M.M., Simoons, M.L., Topol, E.J. Circulation (2000) [Pubmed]
  12. Ligand binding promotes the entropy-driven oligomerization of integrin alpha IIb beta 3. Hantgan, R.R., Lyles, D.S., Mallett, T.C., Rocco, M., Nagaswami, C., Weisel, J.W. J. Biol. Chem. (2003) [Pubmed]
  13. Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study. Dalby, M., Montalescot, G., Bal dit Sollier, C., Vicaut, E., Soulat, T., Collet, J.P., Choussat, R., Gallois, V., Drobinski, G., Drouet, L., Thomas, D. J. Am. Coll. Cardiol. (2004) [Pubmed]
  14. Effect of Ca2+ chelation on the platelet inhibitory ability of the GPIIb/IIIa antagonists abciximab, eptifibatide and tirofiban. Marciniak, S.J., Jordan, R.E., Mascelli, M.A. Thromb. Haemost. (2001) [Pubmed]
  15. Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide. Gilchrist, I.C. Clinical pharmacokinetics. (2003) [Pubmed]
  16. Short-term intravenous eptifibatide infusion combined with reduced dose recombinant tissue plasminogen activator inhibits platelet recruitment at sites of coronary artery injury. Rubenstein, M.H., Finn, A.V., Leinbach, R.C., Hollenbach, S., Aretz, H.T., Virmani, R., Gold, H.K. J. Am. Coll. Cardiol. (2004) [Pubmed]
  17. Mechanisms of thrombotic microangiopathy following xenogeneic hematopoietic progenitor cell transplantation. Alwayn, I.P., Buhler, L., Appel, J.Z., Goepfert, C., Csizmadia, E., Correa, L., Harper, D., Kitamura, H., Down, J., Awwad, M., Sackstein, R., Cooper, D.K., Robson, S.C. Transplantation (2001) [Pubmed]
  18. Glycoprotein IIb/IIIa inhibition reduces prothrombotic events under conditions of deep hypothermic circulatory arrest. Straub, A., Azevedo, R., Beierlein, W., Wendel, H.P., Dietz, K., Ziemer, G. Thromb. Haemost. (2005) [Pubmed]
  19. Open-label phase I clinical study to assess the safety of intravenous eptifibatide in patients undergoing internal carotid artery angioplasty and stent placement. Qureshi, A.I., Ali, Z., Suri, M.F., Kim, S.H., Fessler, R.D., Ringer, A.J., Guterman, L.R., Hopkins, L.N. Neurosurgery (2001) [Pubmed]
  20. Primary and secondary safety endpoints from IMPACT II. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis. Kleiman, N.S. Am. J. Cardiol. (1997) [Pubmed]
  21. Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Phillips, D.R., Teng, W., Arfsten, A., Nannizzi-Alaimo, L., White, M.M., Longhurst, C., Shattil, S.J., Randolph, A., Jakubowski, J.A., Jennings, L.K., Scarborough, R.M. Circulation (1997) [Pubmed]
  22. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Reiter, R.A., Mayr, F., Blazicek, H., Galehr, E., Jilma-Stohlawetz, P., Domanovits, H., Jilma, B. Blood (2003) [Pubmed]
  23. Ischemic complications after percutaneous transluminal coronary angioplasty. Bates, E.R. Am. J. Med. (2000) [Pubmed]
  24. Assembly of a fibronectin matrix by adherent platelets stimulated by lysophosphatidic acid and other agonists. Olorundare, O.E., Peyruchaud, O., Albrecht, R.M., Mosher, D.F. Blood (2001) [Pubmed]
  25. A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states. Longhurst, C.M., White, M.M., Wilkinson, D.A., Jennings, L.K. Eur. J. Biochem. (1999) [Pubmed]
  26. Effect of eptifibatide for acute coronary syndromes: rapid versus late administration--therapeutic yield on platelets (The EARLY Platelet Substudy). Gurbel, P.A., Galbut, B., Bliden, K.P., Bahr, R.D., Roe, M.T., Serebruany, V.L., Gibler, W.B., Christenson, R.H., Ohman, E.M. J. Thromb. Thrombolysis (2002) [Pubmed]
  27. (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human platelets. Bourdon, D.M., Mahanty, S.K., Jacobson, K.A., Boyer, J.L., Harden, T.K. J. Thromb. Haemost. (2006) [Pubmed]
  28. Eptifibatide and 7E3, but not tirofiban, inhibit alpha(v)beta(3) integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin. Lele, M., Sajid, M., Wajih, N., Stouffer, G.A. Circulation (2001) [Pubmed]
  29. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. O'Shea, J.C., Hafley, G.E., Greenberg, S., Hasselblad, V., Lorenz, T.J., Kitt, M.M., Strony, J., Tcheng, J.E. JAMA (2001) [Pubmed]
  30. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Ohman, E.M., Kleiman, N.S., Gacioch, G., Worley, S.J., Navetta, F.I., Talley, J.D., Anderson, H.V., Ellis, S.G., Cohen, M.D., Spriggs, D., Miller, M., Kereiakes, D., Yakubov, S., Kitt, M.M., Sigmon, K.N., Califf, R.M., Krucoff, M.W., Topol, E.J. Circulation (1997) [Pubmed]
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