scholarly journals Antithrombotic effect of MS-180, an orally active GPIIb/IIIa antagonist, on arterial thrombosis model in guineapigs

1998 ◽  
Vol 76 ◽  
pp. 176
Author(s):  
Hiroshi Kawazura ◽  
Kazuo Umemura ◽  
Takashi Kitamori ◽  
Hitoshi Banno ◽  
Hiroyuki Yamashita ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Antithrombotic Effect ◽  
Thrombosis Model ◽  
Orally Active

Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis

1998 ◽  
Vol 79 (02) ◽  
pp. 410-416 ◽  
Author(s):  
Kazuo Sato ◽  
Yumiko Sakai ◽  
Fukushi Hirayama ◽  
Hiroyuki Koshio ◽  
Yuta Taniuchi ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Test Drug ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Treatment And Prevention ◽  
Orally Active

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

scholarly journals The Effect of a Combination of Sulfinpyrazone (SUL) & Aspirin (ASA) on Platelet Survival & Thrombus Size in an Experimental Thrombosis Model

1977 ◽  
Author(s):  
A.R. Giles ◽  
M.R. Buchanan ◽  
J. Hirsh
Keyword(s):  
Arterial Thrombosis ◽  
Drug Effect ◽  
Mural Thrombus ◽  
Antithrombotic Effect ◽  
Apparent Lack ◽  
Thrombosis Model ◽  
Platelet Survival ◽  
Group A ◽  
The Difference ◽  
Group B

Platelet survival (PS) may be decreased in some thromboembolic disorders. Treatment of patients with drugs that suppress platelet function may or may not be associated with normalisation of PS. It is uncertain, however, whether a lack of influence on PS necessarily indicates lack of an antithrombotic effect. We have examined this problem in an arterial thrombosis model in rabbits. A non-occlusive mural thrombus was produced in the aortic arch and PS studied using 51Cr-labelled homologous platelets. Thrombus size was assessed by measuring 51Cr accretion. Three groups of 15 animals were studied as follows:group A - thrombus induced 30 min prior to start of PS, group B- as for group A but animals treated with SUL (25 mg/Kg) and ASA (25 mg/Kg) prior to thrombus induction and 12 hrly thereafter and group C- sham operated controls. Animals in group B showed a 45% reduction in thrombus size when compared with group A (p<0.05). The platelet Tl/2 in groups A, B, and C were 25.7, 25.6, and 33.8 hrs respectively. The difference between groups A and C and between groups B and C was significant (p<0.01).Thus, treatment with SUL and ASA reduced thrombus size but did not modify the change in PS associated with thrombus induction. Re-examination of PS data by 7 different analytical methods established that all were equally sensitive in discriminating thrombosis but all failed to detect a drug effect. It is concluded that failure to modify platelet survival does not necessarily exclude an antithrombotic effect and that this apparent lack of sensitivity does not relate to the method of data analysis used.

scholarly journals Antithrombotic effect of a novel recombinant hirudin analogue, CX-397, in a rat arterial thrombosis model

1995 ◽  
Vol 116 (7) ◽  
pp. 3056-3060 ◽  
Author(s):  
Yoshiharu Takiguchi ◽  
Fumitoshi Asai ◽  
Kouichiro Wada ◽  
Hideya Hayashi ◽  
Mitsuyoshi Nakashima
Keyword(s):  
Arterial Thrombosis ◽  
Antithrombotic Effect ◽  
Recombinant Hirudin ◽  
Thrombosis Model

The Tick Protein Ir-Cpi Efficiently Delays Contact Pathway Induced Thrombin Generation and Displays In Vivo Antithrombotic Activity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3336-3336
Author(s):  
Severine Robert ◽  
Yves Decrem ◽  
Géraldine Rath ◽  
Chantal Dessy ◽  
Olivier Feron ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Lag Time ◽  
Antithrombotic Effect ◽  
Contact Phase ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Contact Pathway

Abstract Abstract 3336 Introduction: The search for new anticoagulants is a major challenge in medicine. Contact factors have never been considered as interesting targets for the development of new anticoagulant agents since they are not required for in vivo coagulation (i.e. deficiencies affecting these factors do not cause excessive bleeding). The discovery that FXI and FXII deficiency protects against thrombosis without causing spontaneous bleeding in mice makes FXII a unique and ideal target for drug design. We demonstrated in vitro that Ir-CPI, a 67 amino acids recombinant Kunitz-type protein from Ixodes ricinus, specifically interacted with activated human contact phase factors (FXIIa, FXIa, and kallikrein). Aims: The goal of this study was to investigate the potential anticoagulant and antithrombotic efficacy of Ir-CPI. Methods: The effects of Ir-CPI were investigated on the thrombin activity during the coagulation process in human plasma using the CAT method. Three different inducers were employed to specifically trigger the coagulation pathways and to generate thrombin. A standard concentration of 5 pM TF with 4 μM PL and 16.7 mM CaCl2 was used to activate the TF pathway whereas a lower TF concentration of 1 pM with 4 μM PL and 16.7 mM CaCl2 was selected for stimulating the TF pathway in combination with the contact phase pathway through a thrombin-mediated positive feedback. The contact phase pathway was also triggered alone by ellagic acid, PL and 16.7 mM CaCl2 (25-fold diluted APTT reagent Actin FS). The effect of Ir-CPI on venous thrombus formation was assessed using a rat thrombosis model induced by complete venous stasis in the posterior vena cava and FeCl3 topical application on the outer vessel wall. Results: When stimulating plasma coagulation trough the contact pathway, Ir-CPI caused a concentration-dependent prolongation of the lag time and the Tmax and a concentration-dependent decrease in the Cmax compared to the control curve (i.e. without inhibitor). When the coagulation cascade was triggered by the TF pathway (5 or 1 pM TF), only a slight concentration-dependent decrease of the Cmax and a concentration-dependent prolongation of the lag time and the Tmax were observed. For comparison purpose, the effects of the specific competitive FXIIa inhibitor corn trypsin inhibitor (CTI) were also investigated using the three same inducers than for Ir-CPI. For the contact pathway, a concentration-dependent decrease of the Cmax and a concentration-dependent prolongation of the lag time and the Tmax were found. When stimulating the TF pathway (5 or 1 pM TF), no modification of the thrombin generation curves was observed with the tested concentrations of CTI. When comparing the results of the two inhibitors acting trough the delay of the contact pathway, we found that Ir-CPI was about 30-fold more potent than CTI. We further evaluated the antithrombotic effect of Ir-CPI on a rat venous thrombosis model induced by endothelial damage and vessel ligation, close to the physiological venous thrombus formation in humans. We showed that Ir-CPI reduced thrombosis in a dose-dependent manner with an ED50 close to 65 μg/kg. A maximum effect starting from 0.5 mg/kg was observed with a mean reduction in the clot weight/body weight of 75 ± 7%. This antithrombotic effect of Ir-CPI was exclusively mediated through the inhibition of thrombin generation since it did not interference with collagen-induced platelet aggregation. This is the first time that an inhibitor of the coagulation contact phase was shown to protect against the formation of venous thrombi. The antithrombotic effect of Ir-CPI was also confirmed using other venous and arterial thrombosis models. We also showed that the effective antithrombotic dose of Ir-CPI in these tests did not promote bleeding or impair blood coagulation parameters. Conclusions: The present study demonstrated that Ir-CPI, a recombinant protein from the tick Ixodes ricinus targeting the contact factors (FXII, FXI and kallikrein), displayed an anticoagulant activity mainly through the delay of the contact pathway induced thrombin generation. This drug also exhibited an antithrombotic activity in our venous and arterial thrombosis model. This drug may thus provide an interesting and innovative therapeutic tool for the prevention and the treatment of thromboembolic diseases with a minimal risk of therapy-associated bleeding. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antithrombotic effect of a new recombinant hirudin analog, CX-397, in rat arterial thrombosis model.

1994 ◽  
Vol 64 ◽  
pp. 334
Author(s):  
Yoshiharu Takiguchi ◽  
Fumitoshi Asai ◽  
Kouichirou Wada ◽  
Hiroshi Nishiyama ◽  
Takehiko Hitomi ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Antithrombotic Effect ◽  
Recombinant Hirudin ◽  
Thrombosis Model

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.

The Modification of Experimental Occlusive Arterial Thrombosis in the Rat by Malayan Pit Viper Venom

1968 ◽  
Vol 19 (01/02) ◽  
pp. 242-247 ◽  
Author(s):  
K. E Chan
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Arterial Occlusion ◽  
Control Group ◽  
Antithrombotic Effect ◽  
Daily Dose

SummaryThe effect of Malayan pit viper (Ancistrodon rhodostoma) venom on the fate of experimental arterial thrombosis was studied in rats. A suitable daily dose of venom (500 μg) was used to induce hypofibrinogenaemia in the treated rats for the greater part of each of three consecutive post-operative days.The treated animals showed a statistically significant overall reduction in the incidence of both red thrombus formation and thrombotic arterial occlusion when compared to a control group. This antithrombotic effect of the venom could be observed in the 7-day period following the cessation of the treatment.

Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat

1997 ◽  
Vol 78 (05) ◽  
pp. 1404-1407 ◽  
Author(s):  
B I Eriksson ◽  
S Carlsson ◽  
M Halvarsson ◽  
B Risberg ◽  
C Mattsson
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Clinical Situation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Low Molecular Weight ◽  
Surgical Trauma ◽  
Antithrombotic Effect ◽  
Caval Vein ◽  
Thrombosis Model

SummaryA sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 µ/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 µLg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

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.

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