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

• Short-term intravenous eptifibatide infusion combined with reduced dose recombinant tissue plasminogen activator inhibits platelet recruitment at sites of coronary artery injury [16].
• Purification of the progenitor cells from porcine PBPC and/or treatment of baboons with eptifibatide may be beneficial [17].
• Eptifibatide increased granulocyte content of aggregates at hypothermia in ADP-stimulated samples [18].
• Open-label phase I clinical study to assess the safety of intravenous eptifibatide in patients undergoing internal carotid artery angioplasty and stent placement [19].
• Patients undergoing elective, urgent, or emergency percutaneous coronary intervention who were treated with eptifibatide were not at increased risk for major hemorrhage, thrombocytopenia, or the need for transfusions of red blood cells or platelets, compared with a placebo-treated group [20].

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

• Conversely, integrilin did not attenuate deposition of FITC-FN but abolished binding of Alexa-FGN [24].
• The CD9 complex was immunoprecipitated in the presence of eptifibatide, demonstrating that alphaIIbbeta3 receptor occupancy was not sufficient to cause complex dissociation [25].
• PAC-1 (GP IIb/IIIa activity), CD 51/61 (vitronectin receptor) and CD 42b (GP Ib) were inhibited by eptifibatide (p <.05) [26].
• Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365 [27].
• In cell proliferation assays, eptifibatide inhibited alpha(v)beta(3)-mediated responses to soluble TSP by HASMCs and beta(3) integrin-expressing HEK cells [28].

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].

References