Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist.

Mousa, Shaker A.; Bozarth, Jeffrey M.; Forsythe, Mark S.; Jackson, Sharon M.; Leamy, Andrew W.; Diemer, Margretta; Kapil, Ram P.; Knabb, Robert M.; Mayo, Michael C.; Pierce, S K

doi:10.1161/01.cir.89.1.3

Cited by 96 publications

(37 citation statements)

References 29 publications

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“…15,16 The distribution of 3 H-XV459 in human blood was compared with that of 3 H-DMP728. Total blood XV459 concentration (dissociated from platelets by EDTA plus free in plasma) was markedly greater (10-to 12-fold) than corresponding free plasma concentrations (Table 4).…”

Section: Distribution Of Xv459 Between Platelet and Plasma Compartmentsmentioning

confidence: 99%

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Mousa

Kapil

1999

ATVB

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Abstract-Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a recently discovered, potent antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC 50 ϭ0.030 to 0.05 mol/L) or anticoagulant used for blood collection. DMP754 rapidly converts to its active free-acid form, XV459, which has a comparable high affinity for both resting and activated platelets (K d ϭ1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of DMP754 and XV459 and to compare them with those of other antiplatelet and anticoagulant agents in canine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-A anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosis, which resulted in either total occlusive thrombus formation or cyclic flow reduction, respectively. DMP754 and XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the canine carotid artery electrolytic injury model were compared. DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED 90 -100 ϭϽ0.1 mg/kg IV or PO). Additionally, both DMP754 and XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO) demonstrated maximal antithrombotic efficacy in preventing electrically induced carotid and coronary artery thrombosis and significant antithrombotic efficacy (PϽ0.001) at relatively low doses in different settings of arterial thrombosis in the canine model. DMP754 resulted in a significant reduction in thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive thrombosis. In contrast, administration of aspirin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU/kg IV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial thrombosis. These studies demonstrated a distinct antithrombotic efficacy of DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders. (Arterioscler Thromb Vasc Biol. 1999;19:2535-2541.)

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Section: Distribution Of Xv459 Between Platelet and Plasma Compartmentsmentioning

confidence: 99%

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Mousa

Kapil

1999

ATVB

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“…For this key reason, the selection of specific and relevant CAM to target certain disease condition without interfering with other normal cellular functions is a very important prerequisite for the ultimate success in developing truly active and safe therapeutic strategies [1,2]. Exciting advances in our understanding of several CAMs, most notably the avb3, avb5, a4b1, a5b1 and aIIb/b3 integrin receptors and their direct relationships to different disease states represent a tremendous therapeutic and diagnostic opportunities [1][2][3][4][5][6][7][8]. A potential role of specific CAM in different disease states including: cardiovascular, cancer, inflammatory, ocular, pulmonary, bone, central nervous system, kidney, and gastrointestinal system have been implicated.…”

Section: Introductionmentioning

confidence: 99%

“…A potential role of specific CAM in different disease states including: cardiovascular, cancer, inflammatory, ocular, pulmonary, bone, central nervous system, kidney, and gastrointestinal system have been implicated. For example, the role of the integrin a IIb /b 3 in the prevention, treatment, and diagnosis of various thromboembolic disorders provide excellent proof of this concept [3][4][5][6][7][8]. Additionally, the potential prophylactic role of anti-selectins, the role of b 1 along with other leukointegrins in various inflammatory conditions, the potential utility of various soluble adhesion molecules as a surrogate markers for acute and chronic endothelial injury, and the potential role of a v b 3 in angiogenesis, and osteoporosis has been implicated [9,10].…”

Section: Introductionmentioning

confidence: 99%

Cell Adhesion Molecules: Potential Therapeutic & Diagnostic Implications

Mousa

2007

Mol Biotechnol

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The role of cell adhesion molecules (CAM) and extracellular matrix proteins (ECM) in various pathological processes including angiogenesis, thrombosis, apoptosis, cell migration & proliferation are well documented. These processes can lead to both acute and chronic disease states such as ocular diseases, metastasis, unstable angina, myocardial infarction, stroke, osteoporosis, a wide range of inflammatory diseases, vascular remodeling, and neurodegenerative disorders. A key success in this field is evident from the potential role of the platelet GPIIb/IIIa integrin in the prevention and diagnosis of various thromboembolic disorders. Additionally, the use of soluble adhesion molecules as potential diagnostic markers for acute and chronic leukocyte, platelet, and endothelial cellular insult are increasingly utilized. The development of various therapeutic and diagnostic candidates based on the key role of CAM, with special emphasis on integrins in various diseases as well as the structure-function aspects of cell adhesion and signaling of the different CAM and ECM are highlighted.

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“…It has been shown that RGD containing synthetic peptides and nonpeptides mimetics modeled after the RGDbinding sequence of fibrinogen possess pow erful antiplatelet and antithrombotic activity [3][4][5][6]. Thus, because of their ability to prevent pathological platelet activation and thrombo sis, these compounds are being considered for the treatment and/or prevention of ischemic heart disease, stroke, and sudden coronary death [7][8][9], In addition to thrombosis it is well known that any local platelet activation at sites of atherosclerotic injury to the endothelium re sults in a release of vasoconstrictors (throm boxane Ao.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic and Vasorelaxant Properties of a Novel Synthetic RGD Peptide Containing Nitric Oxide

Gurevich

Lominadze²,

Adeagbo

et al. 1997

Pharmacology

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We have developed a novel synthetic peptide containing both the antiadhesive Arg-Gly-Asp (RGD) amino acid sequence and a nitric oxide (NO) moiety well known for its vasorelaxant properties. The main objective of this study was to determine whether this hybrid molecule is concurrently effective with regard to antithrombotic and vasorelaxation actions. Studies of in vitro platelet adhesion and of in vivo platelet thrombus formation in the rat demonstrated that the RGD-NO peptide increased the antithrombotic characteristics of the RGD peptide alone. The RGD-NO peptide also caused relaxation of rat aortic rings, while the RGD peptide did not induce relaxation. These characteristics of Ac-RGDC-SNO suggest that this or similar compounds may have potential as effective antithrombotic agents in coronary and peripheral artery disorders.

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Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist.

Cited by 96 publications

References 29 publications

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Cell Adhesion Molecules: Potential Therapeutic & Diagnostic Implications

Antithrombotic and Vasorelaxant Properties of a Novel Synthetic RGD Peptide Containing Nitric Oxide

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