Profound and Sustained Inhibition of Platelet Aggregation by Fradafiban, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, and Its Orally Active Prodrug, Lefradafiban, in Men

Müller, Thomas; Weisenberger, H; Brickl, R.; Narjes, H.; Himmelsbach, Frank; Krause, J.

doi:10.1161/01.cir.96.4.1130

Cited by 79 publications

(43 citation statements)

References 29 publications

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“…24 Ultimately, it would be presumed that a rapid acting intravenous agent would be administered acutely during the hospitalization for the acute coronary syndrome or revascularization procedure, with outpatient conversion to an orally active preparation of the same compound; indeed, several such products are in development. 25 However, it has been shown that the pharmacodynamic response to an oral GP IIb/IIIa receptor antagonist is potentiated by antecedent treatment with abciximab. 26 Whether this finding will be observed with other combinations of oral and parenteral GP IIb/IIIa receptor antagonists is unknown.…”

Section: Safetymentioning

confidence: 99%

Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety

Vorchheimer

Fuster

1998

Circulation

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A n indisputable body of angiographic, 1,2 angioscopic, 3 pathological, 4 and biochemical 5 evidence supports the role of thrombus in the pathogenesis of acute myocardial infarction, unstable angina, and percutaneous coronary intervention. 6 Compelling data from large-scale trials and analyses have established the role of platelet inhibitors in reducing coronary events in patients with the acute coronary syndromes and in maintaining patency of vascular grafts in the long term. 7,8 Persistent reports of high clinical event rates in the modern era of acute coronary syndromes despite aggressive medical therapy have spurred the development of more effective antiplatelet agents. Despite its efficacy, aspirin is a relatively weak antiplatelet agent, inhibiting only thromboxane A 2 -mediated platelet aggregation. The final common pathway of platelet aggregation involves activation of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor to allow fibrinogen binding.9 Studies involving a number of intravenous inhibitors of GP IIb/IIIa receptors have demonstrated efficacy in reducing ischemic complications after percutaneous angioplasty 10 -12 and in the acute coronary syndromes. 13-16 See p 340In patients who have survived an episode of unstable angina or myocardial infarction, activation of the hemostatic system may persist for several months after the acute event.5 Studies with GP IIb/IIIa inhibitors 12,16 and with specific antithrombins 17 have demonstrated efficacy of these agents during the short-term period coinciding with intravenous administration, with subsequent decay in clinical benefit after cessation of parenteral treatment so that no demonstrable clinical benefit is evident at late (1 month) follow-up. Hence, there exists a compelling rationale for long-term antiplatelet treatment, including GP IIb/IIIa inhibition. More than one dozen oral GP IIb/IIIa inhibitors are in clinical trials, and early reports from several phase II studies are appearing. The Present StudyIn the present issue of Circulation, Cannon et al 18 conducted a dose-ranging study of sibrafiban, an orally active peptidomimetic GP IIb/IIIa antagonist. In the pharmacokinetic/pharmacodynamic study, seven dosing regimens of sibrafiban were assessed with serial evaluations of platelet aggregation; four doses that achieved at least minimum-grade platelet inhibition (defined as Ͼ50% inhibition of ADP-induced platelet aggregation for Ͼ75% of the day) were then chosen for evaluation in the safety study, and aspirin served as control. In the safety cohort, 223 patients with documented coronary artery disease after an acute coronary syndrome (unstable angina, non-Qwave myocardial infarction [MI], Q-wave MI) were studied for 28 days.High levels of platelet inhibition were achieved (mean peak values, 47% to 97% inhibition of 20 mol/L ADP-induced platelet aggregation on day 28). Good correlations between blood level and degree of platelet inhibition were noted. Major hemorrhage occurred in 1.5% of sibrafiban-treated and 1.9% of aspirin-treated patien...

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Section: Safetymentioning

confidence: 99%

Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety

Vorchheimer

Fuster

1998

Circulation

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“…In this case, even a long-term medication with the antiplatelet agents ASA and ticlopidine was not able to reduce the increased platelet activation sufficiently. A potential therapeutic alternative for this group of patients could be the new generation of orally available synthetic antiplatelet agents, which bind to the platelet glycoprotein receptor IIb/IIIa by mimicking the RGD-sequence of the ligand fibrinogen [44][45][46]. This alternative concept of a long term antithrombotic therapy awaits evaluation in large clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Analysis of vessel wall morphology, blood flow velocity, and the hemostatic system in a patient with a large intracoronary thrombus

Haude

Altmann

Eick

et al. 1998

Cathet. Cardiovasc. Diagn.

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A patient with AMI caused by a large thrombus in the proximal LAD was successfully treated with PTCA and an intracoronary lysis combined with the platelet‐receptor antagonist c7E3. Analysis of cellular hemostasis after 1 and 6 months revealed a sustained platelet activation despite combined anti‐platelet therapy with ASA and ticlopidine. A progredient slow‐flow phenomenon appeared during control angiographies, confirmed by intracoronary Doppler examination. Cathet. Cardiovasc. Diagn. 43:298–305, 1998. © 1998 Wiley‐Liss, Inc.

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“…Boehringer Ingelheim [19] tive [17±22] ). The underlying design principles for all these compounds are quite similar.…”

Section: Fradafibanmentioning

confidence: 99%

Synthesis and Biological Evaluation of Integrin Antagonists Containingtrans- andcis-2,5-Disubstituted THF Rings

et al. 2000

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The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).

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Profound and Sustained Inhibition of Platelet Aggregation by Fradafiban, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, and Its Orally Active Prodrug, Lefradafiban, in Men

Abstract: Oral administration of Lefradafiban maintains the potent platelet GP IIb/IIIa antagonism of Fradafiban during treatment of healthy subjects for 1 week without signs of loss of the antiplatelet activity.

Cited by 79 publications

References 29 publications

Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety

Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety

Analysis of vessel wall morphology, blood flow velocity, and the hemostatic system in a patient with a large intracoronary thrombus

Synthesis and Biological Evaluation of Integrin Antagonists Containingtrans- andcis-2,5-Disubstituted THF Rings

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