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Benedict R. Lucchesi - One of the best experts on this subject based on the ideXlab platform.
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prevention of Carotid Artery Thrombosis after oral administration of the glycoprotein iib iiia antagonist crl42796
Journal of Cardiovascular Pharmacology, 2003Co-Authors: James K. Hennan, David E. Willens, Edward M. Driscoll, Ting-ting Hong, Thierry A. Giboulot, Benedict R. LucchesiAbstract:This study investigates the effect of the glycoprotein IIb/IIIa receptor antagonist CRL42796 in a canine model of Carotid Artery Thrombosis. Both Carotid arteries developed occlusive Thrombosis in each of the five control animals (time to occlusion: right Carotid Artery, 92.6 minutes; left Carotid Artery, 89.0 minutes). A single oral dose of CRL42796 (3 mg/kg) prevented occlusive Thrombosis in 4 of 6 vessels and increased time to Thrombosis, albeit not significantly (right Carotid Artery, 134.1 minutes; left Carotid Artery, 145.0 minutes). When the initial dose of CRL42796 was followed by a second oral dose (3 mg/kg) 2 hours later, 10 of 10 Carotid arteries remained patent throughout the period of electrolytic injury. CRL42796 reduced thrombus weight in both treatment protocols. Ex vivo platelet aggregation with arachidonic acid (AA) or adenosine diphosphate (ADP) was reduced at 120, 240, and 360 minutes after two doses of CRL42796. A single oral dose reduced ADP-induced responses at 240 and 360 minutes, but significant effects were not observed with AA. Bleeding time increased 360 minutes after two oral doses of CRL42796, but not at 120 minutes. Bleeding time was unchanged with the single dose of CRL42796. The results demonstrate that oral administration of CRL42796 prevents Carotid Artery Thrombosis in response to deep vessel wall injury and may have potential value to be characterized in extended preclinical and clinical study.
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Prevention of Carotid Artery Thrombosis after oral administration of the glycoprotein IIb/IIIa antagonist CRL42796.
Journal of Cardiovascular Pharmacology, 2003Co-Authors: James K. Hennan, David E. Willens, Edward M. Driscoll, Ting-ting Hong, Thierry A. Giboulot, Benedict R. LucchesiAbstract:This study investigates the effect of the glycoprotein IIb/IIIa receptor antagonist CRL42796 in a canine model of Carotid Artery Thrombosis. Both Carotid arteries developed occlusive Thrombosis in each of the five control animals (time to occlusion: right Carotid Artery, 92.6 minutes; left Carotid Artery, 89.0 minutes). A single oral dose of CRL42796 (3 mg/kg) prevented occlusive Thrombosis in 4 of 6 vessels and increased time to Thrombosis, albeit not significantly (right Carotid Artery, 134.1 minutes; left Carotid Artery, 145.0 minutes). When the initial dose of CRL42796 was followed by a second oral dose (3 mg/kg) 2 hours later, 10 of 10 Carotid arteries remained patent throughout the period of electrolytic injury. CRL42796 reduced thrombus weight in both treatment protocols. Ex vivo platelet aggregation with arachidonic acid (AA) or adenosine diphosphate (ADP) was reduced at 120, 240, and 360 minutes after two doses of CRL42796. A single oral dose reduced ADP-induced responses at 240 and 360 minutes, but significant effects were not observed with AA. Bleeding time increased 360 minutes after two oral doses of CRL42796, but not at 120 minutes. Bleeding time was unchanged with the single dose of CRL42796. The results demonstrate that oral administration of CRL42796 prevents Carotid Artery Thrombosis in response to deep vessel wall injury and may have potential value to be characterized in extended preclinical and clinical study.
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prevention of Carotid Artery Thrombosis by oral platelet gpiib iiia antagonist in dogs
Stroke, 1997Co-Authors: Shaker A. Mousa, Benedict R. LucchesiAbstract:Background and Purpose Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/IIIa antagonist, DMP728, in an electrically induced Carotid Artery Thrombosis model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke. Methods Anesthetized dogs were instrumented for monitorin...
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Prevention of Carotid Artery Thrombosis by Oral Platelet GPIIb/IIIa Antagonist in Dogs
Stroke, 1997Co-Authors: Shaker A. Mousa, Benedict R. LucchesiAbstract:Background and Purpose Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/IIIa antagonist, DMP728, in an electrically induced Carotid Artery Thrombosis model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke. Methods Anesthetized dogs were instrumented for monitorin...
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Chimeric 7E3 prevents Carotid Artery Thrombosis in cynomolgus monkeys.
Stroke, 1994Co-Authors: William E. Rote, Mark A. Nedelman, Peter J. Manley, Harlan F. Weisman, Mark R. Cunningham, Benedict R. LucchesiAbstract:We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E3 Fab) directed against the human glycoprotein IIb/IIIa receptor in an animal model of arterial Thrombosis.Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arterial blood pressure, heart rate, and Carotid Artery flow velocity. Animals were treated with saline (n = 6), aspirin (25 mg PO daily for 3 days; n = 6), heparin (100 U/kg i.v. plus infusion adjusted to maintain activated partial thromboplastin time at 2 to 3 times baseline; n = 6), aspirin plus heparin (as administered separately, n = 6), or c7E3 Fab (0.10 mg/kg i.v., n = 7; 0.15 mg/kg i.v., n = 6; 0.20 mg/kg i.v., n = 6; 0.25 mg/kg i.v., n = 6). Thrombus formation via anodal electrolytic stimulation (100 microA) to the intimal surface of the right Carotid Artery was initiated 15 minutes after drug administration and continu...
Elizabeth A. Lyle - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of sodium nitroprusside and hydralazine in a rat model of topical FeCl3-induced Carotid Artery Thrombosis.
Thrombosis Research, 2003Co-Authors: Mary A Robinson, Denise C. Welsh, Denise J. Bickel, Joseph J. Lynch, Elizabeth A. LyleAbstract:Introduction: In the rat model of topical ferric chloride-induced Carotid Artery Thrombosis, a transient blood flow velocity (VEL) increase is observed immediately following ferric chloride application. The immediacy of the response suggested vasoconstriction, as thrombotic narrowing of the vessel lumen was hypothesized to be too slow to account for the rapidity of the response. Methods: To explore this phenomenon, the effects of two mechanistically distinct vasodilators, sodium nitroprusside (SNP) and hydralazine (HYD), on velocity increase, ex vivo platelet aggregation and Thrombosis, were assessed in the rat ferric chloride-induced Thrombosis model. Results: Sodium nitroprusside (10, 30 and 50 μg/kg/min i.v.) and hydralazine (0.1, 0.3 and 1.0 mg/kg/min i.v.) reduced the mean arterial pressure with the higher dose regimens eliciting equivalent hypotensive effects. Both sodium nitroprusside and hydralazine blunted the initial velocity increase, but only sodium nitroprusside significantly reduced the incidence of thrombotic occlusion. No differences in ex vivo platelet aggregation responses to adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were observed between the sodium nitroprusside and hydralazine treatment groups. However, platelet aggregation response to thrombin was significantly reduced in the 50 μg/kg/min i.v. sodium nitroprusside compared to the 1.0 mg/kg/min i.v. hydralazine and vehicle groups. Conclusions: Inhibition of the initial velocity increase by two mechanistically distinct vasodilators, and the dissociation between this velocity change and antithrombotic efficacy, support the hypothesis that the early velocity increase results from a change in vascular tone rather than due to enhanced platelet activation and thrombus formation. Inhibition of thrombin-induced platelet activation may contribute to the antithrombotic actions of sodium nitroprusside in this preparation.
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Differential effects of sodium nitroprusside and hydralazine in a rat model of topical FeCl3-induced Carotid Artery Thrombosis.
Thrombosis Research, 2003Co-Authors: Mary A Robinson, Denise C. Welsh, Denise J. Bickel, Joseph J. Lynch, Elizabeth A. LyleAbstract:In the rat model of topical ferric chloride-induced Carotid Artery Thrombosis, a transient blood flow velocity (VEL) increase is observed immediately following ferric chloride application. The immediacy of the response suggested vasoconstriction, as thrombotic narrowing of the vessel lumen was hypothesized to be too slow to account for the rapidity of the response. To explore this phenomenon, the effects of two mechanistically distinct vasodilators, sodium nitroprusside (SNP) and hydralazine (HYD), on velocity increase, ex vivo platelet aggregation and Thrombosis, were assessed in the rat ferric chloride-induced Thrombosis model. Sodium nitroprusside (10, 30 and 50 microg/kg/min i.v.) and hydralazine (0.1, 0.3 and 1.0 mg/kg/min i.v.) reduced the mean arterial pressure with the higher dose regimens eliciting equivalent hypotensive effects. Both sodium nitroprusside and hydralazine blunted the initial velocity increase, but only sodium nitroprusside significantly reduced the incidence of thrombotic occlusion. No differences in ex vivo platelet aggregation responses to adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were observed between the sodium nitroprusside and hydralazine treatment groups. However, platelet aggregation response to thrombin was significantly reduced in the 50 microg/kg/min i.v. sodium nitroprusside compared to the 1.0 mg/kg/min i.v. hydralazine and vehicle groups. Inhibition of the initial velocity increase by two mechanistically distinct vasodilators, and the dissociation between this velocity change and antithrombotic efficacy, support the hypothesis that the early velocity increase results from a change in vascular tone rather than due to enhanced platelet activation and thrombus formation. Inhibition of thrombin-induced platelet activation may contribute to the antithrombotic actions of sodium nitroprusside in this preparation.
Hugo Cate - One of the best experts on this subject based on the ideXlab platform.
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Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of Carotid Artery Thrombosis
Basic Research in Cardiology, 2003Co-Authors: Janine Dörffler-melly, Martijn Kruif, Lothar A. Schwarte, Rendrik F. Franco, Sandrine Florquin, C. Arnold Spek, Can Ince, Pieter H. Reitsma, Hugo CateAbstract:Thrombomodulin (TM) bound thrombin initiates the protein C anticoagulant pathway and defects in TM result in enhanced coagulation. Recent studies suggest a role for TM in arterial vascular disease. In order to corroborate this association we studied arterial thrombus formation in mice with a functional TM defect. We used mice homozygous for a ^404Glu-to-Pro mutation in the TM gene (TM^pro/pro) and compared these with wildtype littermates in a model of FeCl_3 induced Carotid Artery Thrombosis. Time-to-occlusion (TTO) was assessed by arterial blood flow measurement, using a Doppler flow probe. Complete occlusion occurred in 8/10 (80%) TM^pro/pro mice and in 3/11 (27%) littermate controls. Mean time to occlusion (TTO) [± SE] was 767 ± 196 s in the F2-TM^pro/pro mice, versus 1507 ± 159 s in controls (p = 0.007, Mann Whitney U test). Histology and immunostaining for tissue factor did not reveal any differences in thrombus morphology or thrombogenicity between the two groups. These data confirm and extend the fiding that a functional deficiency in TM results in enhanced thrombus formation in a murine model of Carotid Artery Thrombosis and support a role for TM defects in arterial thrombotic disease.
Mary A Robinson - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of sodium nitroprusside and hydralazine in a rat model of topical FeCl3-induced Carotid Artery Thrombosis.
Thrombosis Research, 2003Co-Authors: Mary A Robinson, Denise C. Welsh, Denise J. Bickel, Joseph J. Lynch, Elizabeth A. LyleAbstract:Introduction: In the rat model of topical ferric chloride-induced Carotid Artery Thrombosis, a transient blood flow velocity (VEL) increase is observed immediately following ferric chloride application. The immediacy of the response suggested vasoconstriction, as thrombotic narrowing of the vessel lumen was hypothesized to be too slow to account for the rapidity of the response. Methods: To explore this phenomenon, the effects of two mechanistically distinct vasodilators, sodium nitroprusside (SNP) and hydralazine (HYD), on velocity increase, ex vivo platelet aggregation and Thrombosis, were assessed in the rat ferric chloride-induced Thrombosis model. Results: Sodium nitroprusside (10, 30 and 50 μg/kg/min i.v.) and hydralazine (0.1, 0.3 and 1.0 mg/kg/min i.v.) reduced the mean arterial pressure with the higher dose regimens eliciting equivalent hypotensive effects. Both sodium nitroprusside and hydralazine blunted the initial velocity increase, but only sodium nitroprusside significantly reduced the incidence of thrombotic occlusion. No differences in ex vivo platelet aggregation responses to adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were observed between the sodium nitroprusside and hydralazine treatment groups. However, platelet aggregation response to thrombin was significantly reduced in the 50 μg/kg/min i.v. sodium nitroprusside compared to the 1.0 mg/kg/min i.v. hydralazine and vehicle groups. Conclusions: Inhibition of the initial velocity increase by two mechanistically distinct vasodilators, and the dissociation between this velocity change and antithrombotic efficacy, support the hypothesis that the early velocity increase results from a change in vascular tone rather than due to enhanced platelet activation and thrombus formation. Inhibition of thrombin-induced platelet activation may contribute to the antithrombotic actions of sodium nitroprusside in this preparation.
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Differential effects of sodium nitroprusside and hydralazine in a rat model of topical FeCl3-induced Carotid Artery Thrombosis.
Thrombosis Research, 2003Co-Authors: Mary A Robinson, Denise C. Welsh, Denise J. Bickel, Joseph J. Lynch, Elizabeth A. LyleAbstract:In the rat model of topical ferric chloride-induced Carotid Artery Thrombosis, a transient blood flow velocity (VEL) increase is observed immediately following ferric chloride application. The immediacy of the response suggested vasoconstriction, as thrombotic narrowing of the vessel lumen was hypothesized to be too slow to account for the rapidity of the response. To explore this phenomenon, the effects of two mechanistically distinct vasodilators, sodium nitroprusside (SNP) and hydralazine (HYD), on velocity increase, ex vivo platelet aggregation and Thrombosis, were assessed in the rat ferric chloride-induced Thrombosis model. Sodium nitroprusside (10, 30 and 50 microg/kg/min i.v.) and hydralazine (0.1, 0.3 and 1.0 mg/kg/min i.v.) reduced the mean arterial pressure with the higher dose regimens eliciting equivalent hypotensive effects. Both sodium nitroprusside and hydralazine blunted the initial velocity increase, but only sodium nitroprusside significantly reduced the incidence of thrombotic occlusion. No differences in ex vivo platelet aggregation responses to adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were observed between the sodium nitroprusside and hydralazine treatment groups. However, platelet aggregation response to thrombin was significantly reduced in the 50 microg/kg/min i.v. sodium nitroprusside compared to the 1.0 mg/kg/min i.v. hydralazine and vehicle groups. Inhibition of the initial velocity increase by two mechanistically distinct vasodilators, and the dissociation between this velocity change and antithrombotic efficacy, support the hypothesis that the early velocity increase results from a change in vascular tone rather than due to enhanced platelet activation and thrombus formation. Inhibition of thrombin-induced platelet activation may contribute to the antithrombotic actions of sodium nitroprusside in this preparation.
James C. Grotta - One of the best experts on this subject based on the ideXlab platform.
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Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal
Current Neurology and Neuroscience Reports, 2017Co-Authors: Sujan Reddy, T. C. Cossey, Sean I Savitz, James C. GrottaAbstract:Purpose of Review An 80-year-old man presents with an acute right hemiparesis and National Institutes of Health Stroke Scale (NIHSS) of 25, 14 h after taking dabigatran. Activated partial thromboplastin time (aPTT) is 42.8 s. Arteriogram demonstrates left internal Carotid Artery Thrombosis. What is the appropriate management of this patient with acute ischemic stroke while on a NOAC?
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Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal
Current Neurology and Neuroscience Reports, 2017Co-Authors: Sujan T. Reddy, T. C. Cossey, Sean I Savitz, James C. GrottaAbstract:Purpose of Review An 80-year-old man presents with an acute right hemiparesis and National Institutes of Health Stroke Scale (NIHSS) of 25, 14 h after taking dabigatran. Activated partial thromboplastin time (aPTT) is 42.8 s. Arteriogram demonstrates left internal Carotid Artery Thrombosis. What is the appropriate management of this patient with acute ischemic stroke while on a NOAC? Recent Findings Idarucizumab is a reversal agent approved for dabigatran, and two more reversal agents, andexanet alfa and aripazine, are currently in development for NOACs. Summary In this article, we review currently available NOACs, their laboratory monitoring, and reversal agents.