Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development

Verstraete, Marc

doi:10.1161/01.cir.101.6.e76

Cited by 36 publications

(18 citation statements)

References 34 publications

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“…Therefore, inhibition of aggregation may increase the risk of bleeding, in agreement with studies using other antiplatelet agents. 26,27 The roles of GP Ib and of GP IIb/IIIa in the formation of a platelet-dependent thrombus are complementary. Indeed, we found that combined inhibition has a more pronounced effect on in vitro platelet accumulation onto collagen in a flow chamber and on the prevention of CFRs in the baboon.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Platelet Glycoprotein Ib, Glycoprotein IIb/IIIa, or Both by Monoclonal Antibodies Prevents Arterial Thrombosis in Baboons

Meiring

Kotzé

et al. 2002

ATVB

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Abstract-The antithrombotic efficacy of the monoclonal antibodies 6B4-Fab and MA-16N7C2 against platelet glycoprotein (GP) Ib and GP IIb/IIIa, respectively, on acute platelet-mediated thrombosis was evaluated in a baboon model of femoral artery stenosis, which is a modification of the original Folts model: platelet thrombi form on the injured stenosed artery, producing cyclic flow reductions (CFRs). A dose of 0.6 mg/kg 6B4-Fab significantly reduced the CFRs by 59Ϯ15%, whereas 2 mg/kg 6B4-Fab completely abolished the CFRs without prolongation of the bleeding time. MA-16N7C2 inhibited CFRs by 43Ϯ8% at a dose of 0.1 mg/kg and abolished the CFRs at a dose of 0.3 mg/kg but with a significant prolongation of the bleeding time. Finally, the combination of 0.6 mg/kg 6B4-Fab and 0.1 mg/kg MA-16N7C2 fully prevented the CFRs without prolongation of the bleeding time. The present study demonstrates that the inhibition of platelet GP Ib function by 6B4-Fab is a powerful intervention to prevent platelet thrombus formation in injured arteries without prolongation of the bleeding time; the latter is in contrast to the result after the inhibition of GP IIb/IIIa. Moreover, we demonstrate that combining a GP Ib blocker with a GP IIb/IIIa blocker can achieve a strong antithrombotic effect without increasing the bleeding time. This provides new information that will be beneficial in designing clinical therapeutic approaches. Key Words: platelet glycoprotein Ib Ⅲ platelet glycoprotein IIb/IIIa Ⅲ cyclic flow reductions Ⅲ antithrombotic agents Ⅲ bleeding time P latelets adhere to the subendothelium of damaged blood vessels through the collagen-von Willebrand factor (vWF)-platelet glycoprotein (GP) Ib axis. vWF forms the bridge between platelets and collagen in the vessel wall (especially under high-shear conditions) and in stenosed arteries and microvessels, where it initiates the formation of platelet aggregates. When vWF binds to GP Ib, platelets are slowed down, allowing direct platelet-collagen receptor interactions via, for example, integrin ␣ 2 ␤ 1 and glycoprotein VI, which activate platelets, finally resulting in a conformational change in the GP IIb/IIIa receptor to enable binding to fibrinogen and vWF, leading to the formation of platelet aggregates. 1,2 After extensive vessel injury or rupture of atherosclerotic plaques with subsequent exposure of thrombogenic surfaces, platelet aggregation can progress to result in complete thrombotic occlusion of the injured vessel. 3,4 Various clinical studies and studies in experimental animals have clearly shown that inhibition of platelet aggregation, through prevention of the binding of the adhesive proteins to GP IIb/IIIa, is an effective approach to prevent thrombosis. [5][6][7][8] Unfortunately, this approach increases the risk of bleeding, especially at the doses that are effective in preventing thrombotic episodes. 8 Blocking GP Ib 9 -11 or vWF 12 results in an inability of the platelets to attach to the exposed subendothelium. Therefore, the GP Ib-vWF axis is an attractive targe...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Platelet Glycoprotein Ib, Glycoprotein IIb/IIIa, or Both by Monoclonal Antibodies Prevents Arterial Thrombosis in Baboons

Meiring

Kotzé

et al. 2002

ATVB

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“…The contribution of platelets to the pathogenesis of potentially fatal ischemic and/or thromboembolic events, including stroke, myocardial infarct, and pulmonary embolism, is well documented [137]. Therefore, the discovery of effective modulators of platelet function that can prevent thrombus formation is the focus of intensified efforts in translational hematology and cardiovascular biology research [137][138][139][140][141][142][143][144][145][146][147][148]. Such agents may Int Rev Immunol Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15…”

Section: Thromboembolism and Lfm-a13mentioning

confidence: 99%

Clinical Potential of Targeting Bruton's Tyrosine Kinase

Uckun

2008

International Reviews of Immunology

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Targeting Bruton's tyrosine kinase (BTK) with a small-molecule inhibitor may be useful in treatment of BTK-expressing malignancies because of the antiapoptotic function of BTK in cancer cells. Furthermore, BTK inhibitors also exhibit antithrombotic properties, which may be desirable in the context of the increased risk of thromboembolic complications in cancer patients. This review will focus on the role of BTK in drug resistance in cancer, thromboembolism, and various pathologic immune responses, such as graft-versus-host disease. The therapeutic potential of targeting BTK is illustrated by discussion of the biologic activity profile of the rationally designed BTK inhibitor LFM-A13.

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“…Additional trials including a larger numbers of patients in a prospective double-bind randomized study will be required to confirm these results and to assess the effects of combining meloxicam with other newer antithrombotic therapies. 32,33 …”

Section: Circulation July 9 2002mentioning

confidence: 99%

Efficacy Assessment of Meloxicam, a Preferential Cyclooxygenase-2 Inhibitor, in Acute Coronary Syndromes Without ST-Segment Elevation

Altman¹,

Luciardi²,

Muntaner³

et al. 2002

Circulation

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Background-Despite the use of heparin, aspirin, and other antiplatelet agents, acute coronary syndrome patients without ST-segment elevation remain at risk of cardiovascular thrombotic events. Given the role of inflammation in the pathogenesis of arterial thrombosis, we tested the hypothesis that the combination of meloxicam, a preferential COX-2 inhibitor, and heparin and aspirin would be superior to heparin and aspirin alone. Methods and Results-In an open-label, randomized, prospective, single-blind pilot study, patients with acute coronary syndromes without ST-segment elevation were randomized to aspirin and heparin treatment (nϭ60) or aspirin, heparin, and meloxicam (nϭ60)

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Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development

Cited by 36 publications

References 34 publications

Inhibition of Platelet Glycoprotein Ib, Glycoprotein IIb/IIIa, or Both by Monoclonal Antibodies Prevents Arterial Thrombosis in Baboons

Inhibition of Platelet Glycoprotein Ib, Glycoprotein IIb/IIIa, or Both by Monoclonal Antibodies Prevents Arterial Thrombosis in Baboons

Clinical Potential of Targeting Bruton's Tyrosine Kinase

Efficacy Assessment of Meloxicam, a Preferential Cyclooxygenase-2 Inhibitor, in Acute Coronary Syndromes Without ST-Segment Elevation

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