Antithrombotic effects of KBT-3022, a novel antiplatelet agent, in an arterial thrombosis model in the guinea-pig

1997 ◽  
Vol 40 (3) ◽  
pp. 217-222 ◽  
Author(s):  
Masamitsu Shimazawa ◽  
Yoshiharu Takiguchi ◽  
Kazuo Umemura ◽  
Mitsuyoshi Nakashima
Keyword(s):  
Guinea Pig ◽  
Arterial Thrombosis ◽  
Antiplatelet Agent ◽  
Thrombosis Model ◽  
Antithrombotic Effects

Antithrombotic effects of ximelagatran plus acetylsalicylic acid (ASA) and clopidogrel plus ASA in a human ex vivo arterial thrombosis model

2006 ◽  
Vol 95 (03) ◽  
pp. 447-453 ◽  
Author(s):  
Maria Eriksson-Lepkowska ◽  
Per Nyström ◽  
Ulf Eriksson ◽  
Troy Sarich ◽  
Juan Badimon ◽  
...  
Keyword(s):  
Shear Rate ◽  
Acetylsalicylic Acid ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Thrombin Inhibitor ◽  
Once Daily ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Chamber Model

SummaryIt was the objective of this study to compare the antithrombotic effects and bleeding profiles of the oral direct thrombin inhibitor ximelagatran, an anticoagulant, and the antiplatelet agent clopidogrel on top of steady-state acetylsalicylic acid (ASA) in a human arterial thrombosis model. Healthy male volunteers (n=62) received ASA (160 mg once daily),plus either clopidogrel for 6 days (loading dose 300 mg, then 75 mg once daily), or a single dose of ximelagatran (36 or 72 mg) on Day 6. Changes in total thrombus area (TTA) under low shear rate (LSR; 212 s-1) and high shear rate (HSR; 1690 s-1) conditions were measured, using the ex vivo Badimon perfusion chamber model pre-dose and 2 and 5 hours after dosing on Day 6, and capillary bleeding times (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone. Ximelagatran plus ASA reduced TTA more than clopidogrel plus ASA under LSR after2 hours (36 mg, P=0.0011; 72 mg, P<0.0001) and 5 hours (72 mg, P=0.0057), and under HSR after 2 and 5 hours (72 mg, P<0.05). Compared with ASA alone, CBT was markedly prolonged by clopidogrel plus ASA (ratio 6.4; P<0.0001) but only slightly by ximelagatran plus ASA (72 mg ximelagatran,ratio 1.4;P=0.0010).Both drug combinations were well tolerated. Oral ximelagatran plus ASA has a greater antithrombotic effect in this human ex vivo thrombosis model and a less prounounced prolongation of bleeding time than clopidogrel plus ASA.

Comparison of antithrombotic efficacy between edoxaban, a direct factor Xa inhibitor, and fondaparinux, an indirect factor Xa inhibitor under low and high shear rates

2011 ◽  
Vol 106 (12) ◽  
pp. 1062-1068 ◽  
Author(s):  
Naoki Tsuji ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Yoshiyuki Morishima ◽  
Toshiro Shibano ◽  
...  
Keyword(s):  
Shear Rate ◽  
Arterial Thrombosis ◽  
Factor Xa ◽  
High Shear ◽  
Shear Rates ◽  
Thrombosis Model ◽  
Perfusion Chamber ◽  
High Shear Rates ◽  
Antithrombotic Effects ◽  
Antithrombotic Efficacy

SummaryEdoxaban is an oral, direct factor Xa (FXa) inhibitor under late-phase clinical development. This study compared the antithrombotic efficacy of edoxaban with that of an indirect FXa inhibitor, fondaparinux, in in vivo venous and arterial thrombosis models and in ex vivo perfusion chamber thrombosis model under low and high shear rates in rats. Venous and arterial thrombi were induced by platinum wire insertion into the inferior vena cava and by application of FeCl3 to the carotid artery, respectively. The perfusion chamber thrombus was formed by blood perfusion into a collagen-coated capillary at 150 s-1 (low shear rate) and 1,600 s-1 (high shear rate). Effective doses of edoxaban that reduced thrombus formation by 50% (ED50) in venous and arterial thrombosis models were 0.076 and 0.093 mg/kg/h, respectively. In contrast, ED50 of fondaparinux in the arterial thrombosis model (>10 mg/kg/h) was markedly higher compared to ED50 in the venous thrombosis model (0.021 mg/kg/h). In the perfusion chamber thrombosis model, the ratio of ED50 under high shear rate (1.13 mg/kg/h) to that under low shear rate (0.63 mg/kg/h) for edoxaban was 1.9, whereas that for fondaparinux was more than 66. While the efficacy of fondaparinux markedly decreased in arterial thrombosis and in a high-shear state, edoxaban exerted consistent antithrombotic effects regardless of flow conditions. These results suggest that shear rate is a key factor in different antithrombotic effects between edoxaban and fondaparinux.

Arterial thrombosis model with photochemical reaction in guinea-pig and its property

1992 ◽  
Vol 67 (4) ◽  
pp. 435-445 ◽  
Author(s):  
Y. Takiguchi ◽  
Y. Hirata ◽  
K. Wada ◽  
M. Nakashima
Keyword(s):  
Guinea Pig ◽  
Arterial Thrombosis ◽  
Photochemical Reaction ◽  
Thrombosis Model

Orally administered heparins prevent arterial thrombosis in a rat model

2004 ◽  
Vol 91 (05) ◽  
pp. 919-926 ◽  
Author(s):  
Cory Pinel ◽  
Sandra M.Wice ◽  
Linda Hiebert
Keyword(s):  
Arterial Thrombosis ◽  
Jugular Vein ◽  
Oral Route ◽  
Low Molecular Weight ◽  
Jugular Vein Thrombosis ◽  
Vein Thrombosis ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Model Filter ◽  
One Way Anova

SummaryOur previous studies demonstrated that orally administered heparins prevent thrombosis in a rat jugular vein thrombosis model, where bovine unfractionated heparin (UFH) and the low molecular weight heparin tinzaparin reduced thrombotic incidence by 50% at 7.5 and 0.1 mg/kg, respectively. Our objectives were to determine if similar antithrombotic effects of oral heparin could be observed in an arterial thrombosis model. In this model, filter paper soaked in 30% ferric chloride was applied to the exposed rat carotid artery. A flowmeter recorded blood flow over a 60 min period determining time when the thrombus began forming (TTB) and time till occlusion (TTO). Immediately following, the thrombus was removed, dried and weighed 24 h later. Bovine UFH (7.5 mg/kg), tinzaparin (0.1 mg/kg) or saline was administered by stomach tube at 2, 5 and 25 h prior to thrombus initiation. TTB was significantly increased when UFH was given at 5 and 25 h but not 2 h prior, and when tinzaparin was given at 5 but not 2 or 25 h prior compared to rats given oral saline. TTO was significantly increased for both UFH and tinzaparin when given 5 and 25 h but not 2 h prior (one-way ANOVA). There was no difference in TTO and TTB between UFH and tinzaparin treated groups. A trend in reduction in thrombus weight was observed for UFH at 5 and 25 h prior and tinzaparin at 5 h prior to thrombus initiation (one-way ANOVA). Although no significant changes were observed in activated partial thromboplastin times, Heptest or anti-Xa activity from plasma of heparin treated rats, endothelial heparin concentrations were significantly greater than controls for UFH at 5 h and for tinzaparin at 2, 5, and 24 h. Thus, heparins administered by the oral route are effective antithrombotic agents in arterial as well as venous models.

BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase

2011 ◽  
Vol 106 (12) ◽  
pp. 1203-1214 ◽  
Author(s):  
Liang Hu ◽  
Zhichao Fan ◽  
Hongguang Du ◽  
Ran Ni ◽  
Si Zhang ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Atp Release ◽  
Bleeding Risk ◽  
P2y12 Receptor ◽  
Antithrombotic Agent ◽  
Thrombosis Model ◽  
P2y12 Antagonists ◽  
Pde Inhibition

SummaryThe addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y12 antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y12 antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y12 using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl3-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y12 antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y12 receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.

Comparison of the Antithrombotic Effects of FK633, GPIIb/IIIa Antagonist, and Aspirin in a Guinea Pig Thrombosis Model

1998 ◽  
Vol 89 (3) ◽  
pp. 129-136 ◽  
Author(s):  
Toshiaki Aoki ◽  
Dermot Cox ◽  
Kayoko Senzaki ◽  
Jiro Seki ◽  
Akito Tanaka ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Thrombosis Model ◽  
Antithrombotic Effects

Ecarin Clotting Time: a Predictive Coagulation Assay for the Antithrombotic Activity of Argatroban in the Rat

1998 ◽  
Vol 79 (01) ◽  
pp. 228-233 ◽  
Author(s):  
Catherine Lunven ◽  
Christine Girardot ◽  
Irène Lechaire ◽  
Denise Girard ◽  
Marie-Christine Charles ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Predictive Marker ◽  
Clotting Time ◽  
Antithrombotic Effect ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Ecarin Clotting Time ◽  
Predictive Assay

SummaryWe studied the use of the Ecarin Clotting Time (ECT) as a predictive assay of the antithrombotic effects of argatroban in a new tissue factor-dependent model of venous thrombosis and a model of arterial thrombosis in the rat. Heparin was used as a reference anticoagulant.Infusions of argatroban dose-dependently increased the ECT across the range of doses required for antithrombotic activity in models of venous and arterial thrombosis (1.25-40 μg/kg/min). The TT was only useful as a marker in the case of venous thrombosis, since, in the arterial thrombosis model, the clotting times were >200 s in the majority of animals receiving antithrombotic doses. The aPTT is not sufficiently sensitive to be predictive of an antithrombotic effect in the venous model, and shows only modest increases in the arterial thrombosis model. Heparin did not significantly increase the ECT at antithrombotic doses in the venous thrombosis model, and only increased the ECT by 53% at 40 μg/kg/min in the arterial model, despite a marked antithrombotic effect. Both the TT and aPTT were dose-dependently increased by heparin at doses active in the venous model, whereas both parameters were >200 s at doses active in the arterial thrombosis model.Thus, the ECT provides a predictive marker for the antithrombotic activity of argatroban in both venous and arterial thrombosis, at least in the rat.

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