Development of eptifibatide☆,☆☆,★
Section snippets
Development of inhibitors of the platelet receptor GP IIb/IIIa
The first GP IIb/IIIa inhibitor to be tested in clinical trials was a Fab fragment of an anti-GP IIb/IIIa murine monoclonal antibody, m7E3.10 Several small clinical trials demonstrated that m7E3 Fab can effectively block GP IIb/IIIa in human beings. It was evident from these studies that several potential safety concerns might be associated with this pharmacologic approach.11, 12 Low titers of anti-m7E3 serum antibodies were detected in a number of healthy individuals and patients with stable
Synthesis of eptifibatide
During the past decade, a wide range of snake viper venoms have been shown to contain a family of compounds called disintegrins, small proteins that act as powerful antithrombotics and strongly inhibit platelet aggregation.22, 23 Almost all these small proteins contain the amino acid sequence RGD (Arg-Gly-Asp), which is believed to play a role in the binding of fibrinogen to GP IIb/IIIa. However, RGD-containing venom disintegrins also bind to a number of other integrins, such as α5β1
Pharmacology of eptifibatide
Eptifibatide, like other antagonists of platelet receptor GP IIb/IIIa, functions by blocking the binding of the adhesive proteins fibrinogen and von Willebrand factor to GP IIb/IIIa on the surface of activated platelets. It is a potent antithrombotic because the binding of these proteins to GP IIb/IIIa is the event that precipitates platelet aggregation and subsequent arterial thrombus formation. As a critical prelude to clinical trials, studies were undertaken to determine the relation between
Antiplatelet activity of eptifibatide
Determination of an ex vivo surrogate to predict in vivo activity of eptifibatide has relied primarily on its effects in an ex vivo platelet aggregation assay. In all early clinical studies, this assay was routinely performed in blood anticoagulated with citrate. Citrate prevents in vitro clotting of blood samples by reducing the ionized calcium concentration from the 1.1 mmol/L normally found in circulating blood to 40 to 50 μmol/L. Therefore ionized calcium concentration has been
Pharmacodynamics of eptifibatide in animal models
Several preclinical experiments to test the efficacy and safety of eptifibatide in nonhuman species produced promising results. An animal study with a canine model to investigate the effects of eptifibatide on fibrinogen-triggered platelet adhesion and postoperative bleeding related to cardiopulmonary bypass found a rapidly reversible antihemostatic effect of eptifibatide, which was associated with seemingly paradoxic minimization of postoperative bleeding. The reduction of postoperative
Studies in healthy volunteers
A potent and rapidly reversible inhibition of GP IIb/IIIa by eptifibatide was demonstrated in healthy volunteers in a variety of clinical settings. For infusions ranging from 0.2 to 1.5 μg/kg/min, plasma concentrations of eptifibatide were proportional to the dose and rate of eptifibatide administration. In these studies, the plasma elimination half-life of eptifibatide was 50 to 60 minutes. In a phase I investigation of 63 healthy volunteers, ADP-stimulated platelet aggregation was completely
The IMPACT-II trial
IMPACT II was a randomized, double-blind, placebo-controlled phase III clinical trial designed to investigate the efficacy of eptifibatide in reducing ischemic complications of percutaneous coronary revascularization in a broad range of patients.37 The study was performed in 84 centers in the United States between November 1993 and November 1994 and involved 4010 patients scheduled for either elective, urgent, or emergency coronary intervention (balloon angioplasty, directional coronary
Summary
There are several physiologic cascades that ultimately lead to the aggregation of platelets and thrombosis, but all converge on the platelet receptor GP IIb/IIIa. The interaction of activated GP IIb/IIIa with its ligands represents the final common pathway for platelet aggregation. For this reason, a GP IIb/IIIa blockade has promise as an almost ideal antithrombotic therapy, overcoming the limitations of traditional antithrombotic therapies. Because GP IIb/IIIa is found only on platelets and
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2020, Toxicon: XCitation Excerpt :This changed the paradigm from “toxin as a villain” to “toxin as a savior”. Similarly, discovery of disintegrins from Trimeresurus gramineus (Indian green pit viper) and Echis carinatus (saw scaled viper) venoms (Huang et al., 1987, 1989; Gan et al., 1988) culminated in the development of potent antiplatelet agents, eptifibatide (Scarborough et al., 1993; Phillips and Scarborough, 1997; Scarborough, 1999) and tirofiban (Barrett et al., 1994; Lynch et al., 1995). Vipegitide, a folded peptidomimetic is being developed as partial antagonist of α2β1 integrin and an antithrombotic agent based on a snaclec from Vipera palaestinae venom (Arlinghaus et al., 2013; Momic et al., 2015).
Detection and identification of antibacterial proteins in snake venoms using at-line nanofractionation coupled to LC-MS
2018, ToxiconCitation Excerpt :Many academic groups have put significant efforts into studying snake venoms and understanding their biological effects. Moreover, snake venoms have traditionally served as an important source of compounds in drug discovery (Cook et al., 1999; King, 2011; Ryan J. R. McCleary, 2015; Scarborough, 1999; Smith and Vane, 2003). On the antibacterial properties of both crude snake venoms and compounds purified from snake venoms, many studies have been conducted.
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Guest Editor for this manuscript was David P. Faxon, MD, University of Southern California School of Medicine, Los Angeles.
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Reprint requests: Robert M. Scarborough, PhD, COR Therapeutics, Inc, 256 E Grand Ave, South San Francisco, CA 94080.
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