Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men

Barrett, Jeffrey S.; Murphy, Gail; Peerlinck, Kathelijne; Lepeleire, Inge De; Gould, Robert J.; Panebianco, Deborah; Hand, Elizabeth; Deckmyn, Hans; Vermylen, Jos; Arnout, Jef

doi:10.1038/clpt.1994.152

Cited by 138 publications

(63 citation statements)

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“…First, EP224283 has a stabilizing effect on the tirofiban moiety, which otherwise has a very short half-life and hence cannot be used for outpatients (Barrett et al, 1994). Second, this pharmacokinetic advantage could be augmented by the colocalization at the site of injury of convergent inhibitory properties.…”

Section: Discussionmentioning

confidence: 99%

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Hechler¹,

Freund²,

Alame³

et al. 2011

J Pharmacol Exp Ther

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EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-␣IIb␤3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(Ϫ/Ϫ) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to ␣IIb␤3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate ␣IIb␤3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events.

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Section: Discussionmentioning

confidence: 99%

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Hechler¹,

Freund²,

Alame³

et al. 2011

J Pharmacol Exp Ther

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“…The most widely used method is turbidometric aggregometry, which was used in the dose selection for the larger trials conducted to date. 27,36,59,60 Although the relative ease of measuring ex vivo platelet aggregation might suggest that this measurement would be appropriate for these purposes, platelet aggregation is highly variable within patient populations, is highly dependent on the skill and experience of the investigators performing the measurements, and may be affected by preparation and handling of blood samples. 58 Although most laboratories assess the extent of platelet aggregation by the maximal change in percentage of light transmission, it is also possible, and perhaps equally valid, to measure the initial slope of the aggregation response.…”

Section: Platelet Monitoring: Pharmacodynamic Surrogatesmentioning

confidence: 99%

Platelet Glycoprotein IIb-IIIa Antagonists as Prototypical Integrin Blockers: Novel Parenteral and Potential Oral Antithrombotic Agents

2000

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Abstract-During the last decade, intensive efforts have been made to evaluate the role of the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus formation. Significant efforts have also been made to design potent antagonists of this "final common pathway" of platelet aggregation to be used as novel therapeutic strategies to treat acute coronary syndromes. Although several different GP IIb/IIIa antagonists have convincingly demonstrated the usefulness of this platelet-directed therapeutic strategy, a number of lingering unsolved and sometimes misunderstood issues concerning the pharmacology and optimal clinical usefulness of these agents remain to be explored. This article reviews these issues, which include antagonist affinity, reversibility, and receptor specificity. Other issues are related to the effects of GP IIb/IIIa receptor availability, neoepitopes induced by antagonist binding with the potential to mediate thrombocytopenia, optimal methods of platelet monitoring and, perhaps ultimately, the potential therapeutic index of the oral class of GP IIb/IIIa antagonists. All of these specific issues are likely to be illuminated in the next several years, which will greatly determine the breadth of this therapeutic class. (Circulation. 1999;100:437-444.)Key Words: platelet aggregation inhibitors Ⅲ pharmacology Ⅲ angioplasty Ⅲ angina Ⅲ thrombosis E vidence that platelets play a central role in acute coronary syndromes has accumulated over the last several decades and verifies the need for more effective, yet safe, antiplatelet agents. 1 Aspirin continues to be used routinely in coronary angioplasty and to treat patients with myocardial infarction or unstable angina. Mechanistic considerations argue that a more vigorous approach to the inhibition of platelet aggregation should afford greater antithrombotic protection. Glycoprotein (GP) IIb/IIIa (␣ IIb ␤ 3 ) serves as the receptor on platelets that binds plasma-borne adhesive proteins, such as fibrinogen and von Willebrand factor (vWF), to permit platelet aggregation. 2 Aggregation is mediated by this pathway, irrespective of the agonist that stimulates platelets and irrespective of the stimulus-response-coupling pathway that is used to activate GP IIb/IIIa to aggregate platelets. Agents that block this final common pathway by blocking the binding of adhesive proteins to GP IIb-IIIa, termed GP IIb/IIIa antagonists, are currently considered the most powerful specific inhibitors of platelet participation in acute thrombosis. 3 However, the hemostatic function of platelets is also dependent on this pathway. Thus, this novel form of antiplatelet therapy comes with potential safety risks, yet the first fruits of the benefits of this therapeutic approach have begun to emerge.Various antagonists of GP IIb/IIIa are currently receiving considerable attention from the pharmaceutical industry and clinical cardiologists, and they are being studied in a variety of clinical settings. 4 -7 The first of these agents, the monoclonal antibody abciximab, has...

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“…208,209 Similar results in these and other animal models were obtained with low molecular weight ␣IIb␤3 antagonists, including eptifibatide, a cyclic heptapeptide patterned on a KGD motif that conferred selectivity for ␣IIb␤3, 210 and the nonpeptide RGDmimetic tirofiban. 211 …”

Section: ␣Iib␤3 As a Therapeutic Targetmentioning

confidence: 99%

The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend

Coller

Shattil

2008

Blood

312

342

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Starting 90 years ago with a clinical description by Glanzmann of a bleeding disorder associated with a defect in platelet function, technologic advances helped investigators identify the defect as a mutation(s) in the integrin family receptor, ␣IIb␤3, which has the capacity to bind fibrinogen (and other ligands) and support platelet-platelet interactions (aggregation). The receptor's activation state was found to be under exquisite control, with activators, inhibitors, and elaborate inside-out signaling mechanisms controlling its conformation. Structural biology has produced high-resolution images defining the ligand binding site at the atomic level. Research on ␣IIb␤3 has been bidirectional, with basic insights resulting in improved Glanzmann thrombasthenia carrier detection and prenatal diagnosis, assays to identify single nucleotide polymorphisms responsible for alloimmune neonatal thrombocytopenia, and the development of ␣IIb␤3 antagonists, the first rationally designed antiplatelet agents, to prevent and treat thrombotic cardiovascular disease. The future looks equally bright, with the potential for improved drugs and the application of gene therapy and stem cell biology to address the genetic abnormalities. The ␣IIb␤3 saga serves as a paradigm of rigorous science growing out of careful clinical observations of a rare disorder yielding both important new scientific information and improved diagnosis, therapy, and prevention of other disorders. (Blood. 2008;112: 3011-3025) Introduction"Thus blood, for all its raw physicality, its heat, color and smell, remains first and foremost a powerfully symbolic substancecapable of representing the most primeval forces of life, and of death." 1 "… for the blood is life …" Deuteronomy 12:23To celebrate the 50th anniversary of Blood, we offer an historical account of research on our favorite receptor on the platelet surface, GPIIb/IIIa, or integrin ␣IIb␤3. This receptor plays an important role in hemostasis and thrombosis, and in accord with the quotations above, both processes have profound effects on life and health. The origin of the English word blood is uncertain. It may derive from a postulated Indo-European root bhel, "bloom" or "sprout," and it has been speculated that "ancient people looked upon the effusion from incised skin as a sort of blooming," 2 an image well known to practitioners of the bleeding time.The dominant theme in this review is how improved understanding of the structure and function of ␣IIb␤3 has led to opportunities to translate that knowledge into biomedical advances, including the development of ␣IIb␤3 antagonists, the first class of rationally designed antiplatelet agents. The subtheme is how advances in scientific technology deriving from discoveries in other fields have been crucial to improving our understanding of ␣IIb␤3. Figure 1 is a timeline depicting, by category, approximately when different technologies were introduced into the investigation of blood platelets and/or ␣IIb␤3. Thus, as with a musical fugue, we will try to tell 2 sto...

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Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men

Cited by 138 publications

References 0 publications

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Platelet Glycoprotein IIb-IIIa Antagonists as Prototypical Integrin Blockers: Novel Parenteral and Potential Oral Antithrombotic Agents

The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend

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