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.

Inhibition by D-MePhe-Pro-Arg-H (GYKI-14766) of Thrombus Growth in Experimental Models of Thrombosis

1992 ◽  
Vol 68 (02) ◽  
pp. 125-129 ◽  
Author(s):  
Dániel Bagdy ◽  
Gabriella Szabó ◽  
Éva Barabás ◽  
Sándor Bajusz
Keyword(s):  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Mechanical Damage ◽  
Inhibitory Effect ◽  
Vascular Lesion ◽  
Experimental Models ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Thrombosis Model ◽  
Venous Shunt

SummaryThe antithrombotic action of the highly effective synthetic thrombin inhibitor D-MePhe-Pro-Arg-H (GYKI-14766) was studied in various models of experimental thrombosis. The compound administered to rats and rabbits by i. v. bolus injections, continuous i. v. infusions, subcutaneously and orally, respectively, induced significant decrease in thrombus weight (i) in a quantitative venous thrombosis model with stasis based on vascular lesion in rats, (ii) in an extracorporeal arterio-venous shunt model in rabbits, and (iii) prevented the occlusion of the vessel in arterial thrombosis induced by mechanical damage in rats. By using the arterio-venous shunt model in rabbits the inhibitory effect on thrombus growth could be demonstrated as a function of dose and time in self-controlled experiments. Blood level of the inhibitor determined by a bioassay varied between 0.09-0.67 µg/ml whole blood when doses of 15 and 20 mg/kg were administered orally. A correlation was found between thrombin time, platelet aggregation induced by thrombin ex vivo and the weight of thrombi formed.

Effects of Antithrombotic Drugs in a Rat Model of Aspirin-Insensitive Arterial Thrombosis

1993 ◽  
Vol 69 (05) ◽  
pp. 509-514 ◽  
Author(s):  
W A Schumacher ◽  
T E Steinbacher ◽  
C L Heran ◽  
J R Megill ◽  
S K Durham
Keyword(s):  
Arterial Thrombosis ◽  
Light And Electron Microscopy ◽  
Platelet Activating Factor ◽  
Thrombin Inhibitor ◽  
Experimental Conditions ◽  
Once Daily ◽  
Thromboxane Receptor ◽  
Vessel Patency ◽  
Electrolytic Injury ◽  
Thromboxane Receptor Antagonist

SummaryThese studies describe experimental conditions where aspirin is less effective than other antiplatelet and anticoagulant drugs in inhibiting acute arterial thrombosis. External electrolytic injury of the rat carotid artery was used to induce occlusive thrombi in 97% of vehicle-treated rats. Thrombi were revealed by light and electron microscopy to be comprised primarily of platelets enmeshed in a fibrin network. The thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethy ketone (PPACK; 6 mg/kg, i. v.) decreased thrombus weight by 90%. Aspirin alone (1, 10 and 30 mg/kg, i. v.), dipyridamole alone (5 mg/kg i. v.) and aspirin (1 and 10 mg/kg, i. v.) in combination with dipyridamole (5 mg/kg, i. v.) did not inhibit thrombosis. The platelet-activating factor (PAF) antagonist, WEB 2086, (1 mg/kg i. v.) was also ineffective. Other drugs had intermediate activity. Thrombi were decreased 56% by the thromboxane receptor antagonist, BMS 180,291, either alone (5.8 mg/kg i.v.) or in combination with aspirin (10 mg/kg, i.v.). Heparin (900 U/kg, i.v.), warfarin (0.25 mg/kg, p.o. once daily for 3 days) and ticlopidine (200 mg/ kg, p.o. once daily for 3 days) reduced thrombus weight by 63, 73 and 43% respectively. Reductions in thrombus weight were always associated with improvements in either average blood flow or vessel patency.

scholarly journals ROLE OF NITRIC OXIDE (NO) IN CAPSAICIN MEDIATED ANTI-PLATELET ACTIVITY IN IN VITRO, IN VIVO, EX-VIVO MODEL OF PLATELET AGGREGATION ASSAY AND ARTERIAL THROMBOSIS IN RAT: POTENTIAL THERAPEUTIC TARGET?

2018 ◽  
Vol 10 (4) ◽  
pp. 44
Author(s):  
Mihir K Patel ◽  
Kiranj K. Chaudagar ◽  
Anita A. Mehta
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Platelet Activity ◽  
Aggregation Assay ◽  
Thrombosis Model ◽  
Platelet Aggregation Assay

Objective: Although recent advances in the treatment of congestive heart disease, mortality among patients’ remains a questionable remark. Therefore, we evaluated the role of capsaicin on in vitro and ex vivo platelet aggregation induced by Adenosine Di-Phosphate (ADP) as well as in in vivo thrombosis models and role of NO, KATP was also identified in the capsaicin-induced anti-platelet animal model as well as in vivo model of arterial thrombosis.Methods: According to body weight wistar rats were divided into five groups. Group I and Group II was treated with saline and capsaicin (3 mg/kg, i. v), while animals from Group III were treated with N(ω)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg, i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group IV animals were treated with glibenclamide (10 mg/kg,i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group V was considered as a positive control and administered clopidogrel (30 mg/kg, p. o). Animals were subjected for in vitro, ex-vivo platelet aggregation assay. ADP (30µM) was utilized as an aggregating agent in these experiments. After these assays; animals of each group were subjected for subaqueous tail bleeding time in a rat model and FeCl3-induced arterial thrombosis model in rats.Results: In ADP-induced in vitro platelet aggregation, a significant reduction in % platelet aggregation was observed at 50µM (64.35±4.641) and 100µM (52.72±4.192) concentration of capsaicin as compared to vehicle control (85.82±3.716). Capsaicin (3 mg/kg, i. v) also showed a significant reduction (49.53±4.075) in ex-vivo ADP-induced platelet aggregation as compared to vehicle control (89.38±2.057). In FeCl3 induced arterial thrombosis model, Capsaicin (3 mg/kg, i. v) exhibited an increase in time to occlusion in this rodent model and presence of the L-NAME and glibenclamide had inhibited the activity of capsaicin.Conclusion: In our study, capsaicin (50 µM, 100µM) exhibited potent anti-platelet activity in ADP-induced platelet aggregation, similarly capsaicin exhibited significant anti-platelet action in the ex-vivo study. Moreover, the presence of L-NAME and glibenclamide inhibited the anti-thrombotic and anti-platelet action of capsaicin. Therefore, it was concluded that NO and KATP may be involved in the anti-thrombotic action of capsaicin.

EP217609, a neutralisable dual-action FIIa/FXa anticoagulant, with antithrombotic effects in arterial thrombosis

2015 ◽  
Vol 113 (02) ◽  
pp. 385-395 ◽  
Author(s):  
Ghina Alame ◽  
Pierre H. Mangin ◽  
Monique Freund ◽  
Nadia Riehl ◽  
Stéphanie Magnenat ◽  
...  
Keyword(s):  
Blood Loss ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Parent Compound ◽  
Thrombin Inhibitor ◽  
Potential Candidate ◽  
Low Doses ◽  
Response Curves ◽  
Dual Action

SummaryEP217609 is a new synthetic parenteral dual-action anticoagulant combining a direct thrombin inhibitor (α-NAPAP analog), an indirect factor Xa inhibitor (fondaparinux analog) and a biotin moiety allowing its neutralisation. EP217609 exhibited similar in vitro anticoagulant properties as its parent compounds. On the basis of dose-response curves, we identified low and moderate doses of EP217609 resulting in similar ex vivo prolongation of the APTT as α-NAPAP analog and comparable ex vivo anti-FXa activity as fondaparinux. The effects of EP217609 were compared to those of its parent compounds used alone or in combination in two models of experimental thrombosis induced by FeCl3 injury of the carotid artery or mechanical injury of atherosclerotic plaques in ApoE-deficient mice. When administered at low doses increasing the APTT by only 1.1 fold, EP217609 significantly reduced the thrombus area in both models as compared to α-NAPAP analog or fondaparinux alone, but not to the combination of these drugs. In contrast, at higher doses increasing the APTT 1.5 times, EP217609 was not superior to either parent compound. Low doses of EP217609 did not prolong the tail bleeding time or increase the volume of blood loss, although a tendency towards an increased blood loss was observed in five out of 12 mice. Finally, the effects of EP217609 could be neutralised in vivo by injection of avidin. The pharmacological profile of EP217609, its performance in arterial thrombosis models and its possible neutralisation make it an interesting molecule and a potential candidate as an antithrombotic drug.

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