Antithrombotic effects in a rat model of aspirin-insensitive arterial thrombosis of desethyl KBT-3022, the main active metabolite of a new antiplatelet agent, KBT-3022

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.

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Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽

10.3390/molecules26020278 ◽

2021 ◽

Vol 26 (2) ◽

pp. 278

Author(s):

Jennifer Lagoutte-Renosi ◽

Bernard Royer ◽

Vahideh Rabani ◽

Siamak Davani

Keyword(s):

Active Metabolite ◽

Plasma Concentrations ◽

Antiplatelet Agent ◽

High Plasma ◽

Therapeutic Drug ◽

Routine Practice ◽

Daily Routine ◽

Limit Of Quantification ◽

Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

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

Thrombosis and Haemostasis ◽

10.1160/th11-07-0451 ◽

2011 ◽

Vol 106 (12) ◽

pp. 1062-1068 ◽

Cited By ~ 10

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.

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Sex differences in the antithrombotic effects of aspirin

Blood ◽

10.1182/blood.v52.5.1073.1073 ◽

1978 ◽

Vol 52 (5) ◽

pp. 1073-1076 ◽

Cited By ~ 55

Author(s):

JG Kelton ◽

J Hirsh ◽

CJ Carter ◽

MR Buchanan

Keyword(s):

Clinical Trials ◽

Animal Model ◽

Arterial Thrombosis ◽

Sodium Salicylate ◽

Inhibitory Effect ◽

Prostaglandin Synthesis ◽

Antithrombotic Effect ◽

Antithrombotic Agent ◽

Male And Female ◽

Antithrombotic Effects

Abstract Aspirin inhibits platelet function by acetylating platelet cyclooxygenase. Recent clinical trials indicate that aspirin is a promising antithrombotic agent against both venous and arterial thrombosis, but somewhat surprisingly this protective effect appears to be limited to males. To examine the potential sex-related differences in response to aspirin, we developed an animal model for quantitating fibrin accretion into an injury-induced thrombus and used it to study the effects of aspirin on thrombus size in male and female rabbits. Platelet prostaglandin synthesis was estimated by assay of platelet malondialdehyde and was significantly decreased in both male and female rabbits following treatment with 10 mg/kg aspirin (p less than 0.001). This inhibitory effect was not different for platelets from male and female rabbits. Thrombus size was significantly decreased in aspirin- treated male rabbits when compared to controls (p less than 0.05), but this aspirin effect was not apparent in female rabbits or rabbits of either sex treated with 10 mg/kg sodium salicylate. These findings support the results of clinical trials that were obtained by retrospective subgroup analysis. The reason for the sex difference is not known, but the findings raise an important issue in relationship to this mechanism of the antithrombotic effect of aspirin.

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Comparison of Antithrombotic Activity of Heparin, ASA, Sulfinpyrazone and VK 744 in a Rat Model of Arterial Thrombosis

Pathophysiology of Haemostasis and Thrombosis ◽

10.1159/000214270 ◽

1978 ◽

Vol 7 (5) ◽

pp. 282-293 ◽

Cited By ~ 1

Author(s):

R.B. Philp ◽

I. Francey ◽

B.A. Warren

Keyword(s):

Rat Model ◽

Arterial Thrombosis ◽

Antithrombotic Activity

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Mumefural Improves Blood Flow in a Rat Model of FeCl3-Induced Arterial Thrombosis

Nutrients ◽

10.3390/nu12123795 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3795

Author(s):

Jihye Bang ◽

Won Kyung Jeon

Keyword(s):

Blood Flow ◽

Blood Vessels ◽

Rat Model ◽

Arterial Thrombosis ◽

Thrombus Formation ◽

Sprague Dawley ◽

Fiber Damage ◽

Sprague Dawley Rats ◽

Related Proteins

Mumefural (MF), a bioactive component of the processed fruit of Prunus mume Sieb. et Zucc, is known to inhibit platelet aggregation induced by agonists in vitro. In this study, we investigated the anti-thrombotic effects of MF using a rat model of FeCl3-induced arterial thrombosis. Sprague–Dawley rats were intraperitoneally injected with MF (0.1, 1, or 10 mg/kg) 30 min before 35% FeCl3 treatment to measure the time to occlusion using a laser Doppler flowmeter and to assess the weight of the blood vessels containing thrombus. MF treatment significantly improved blood flow by inhibiting occlusion and thrombus formation. MF also prevented collagen fiber damage in injured vessels and inhibited the expression of the platelet activation-related proteins P-selectin and E-selectin. Moreover, MF significantly reduced the increased inflammatory signal of nuclear factor (NF)-κB, toll-like receptor 4 (TLR4), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in blood vessels. After administration, MF was detected in the plasma samples of rats with a bioavailability of 36.95%. Therefore, we suggest that MF may improve blood flow as a candidate component in dietary supplements for improving blood flow and preventing blood circulation disorders.

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