Effects of SanOrg123781A, a Synthetic Hexadecasaccharide, in a Mouse Model of Electrically Induced Carotid Artery Injury: Synergism with the Antiplatelet Agent Clopidogrel

Lorrain, J; Lechaire, Irène; Gauffeny, Christiane; Masson, Régis; Roome, Nigel; Hérault, Jean-Pascal; O'Connor, Stephen E.; Schaeffer, Paul; Herbert, Jean‐Marc

doi:10.1124/jpet.103.059873

Cited by 16 publications

(13 citation statements)

References 28 publications

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“…Interestingly, the addition of this low-dose clopidogrel to the low-dose razaxaban enhanced their antithrombotic effects but did not elicit additional increases in bleeding time over that of clopidogrel. Similarly, greater antithrombotic effects were also noted when clopidogrel was added to melagatran, a direct thrombin inhibitor, and SanOrg123781A, an antithrombin-dependent inhibitor of FXa and thrombin, in animals [23,24]. Unlike razaxaban plus clopidogrel, a greater increase in bleeding times was observed with melagatran plus clopidogrel [23], whereas the bleeding time effect of SanOrg123781A plus clopidogrel was not reported [24].…”

Section: Discussionmentioning

confidence: 84%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

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Section: Discussionmentioning

confidence: 84%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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“…Several groups have done series with the carotid artery FeCl 3 model [26][27][28], showing a clopidogrel dose-response for prolonging or preventing occlusion, for doses ranging from 3 to 75 mg/kg, but not at 1 mg/kg. Other murine carotid artery injury models [29][30][31] showed comparable effects for various doses of clopidogrel. Similar results were found for reducing arteriolar thrombosis induced by FeCl 3 [32][33][34].…”

Section: Discussionmentioning

confidence: 85%

Cross-modulatory effects of clopidogrel and heparin on platelet and fibrin incorporation in thrombosis

Cooley

Herrera

2013

Blood Coagulation &Amp; Fibrinolysis

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Pharmacologic inhibition of platelet activation and aggregation is a mainstay for reducing the incidence of arterial thrombosis, whereas anticoagulation is the primary approach for preventing the development of venous thrombosis. The effect of standard pharmacologic agents on their reciprocal vessel - anticoagulants on arterial thrombosis and platelet inhibitor on venous thrombosis - is relatively understudied. This study was designed to evaluate murine large-vessel arterial or venous thrombosis under conditions of either fibrin or platelet inhibition. In this study, heparin and clopidogrel were used as standard anticoagulant and platelet inhibitor, respectively, evaluating both large artery and vein thrombosis in mice, using in-vivo fluorescence imaging to simultaneously measure fibrin and platelet levels at the thrombus induction site. Heparin reduced both fibrin and platelet development in both arteries and veins, with stronger influences on fibrin accrual. Clopidogrel had a stronger effect in arteries, reducing both platelet and fibrin accumulation. Clopidogrel also reduced platelet accumulation with venous thrombosis, but the reductions in fibrin formation did not reach statistical significance. These findings illustrate the interactive role of platelet activity and coagulation in the development of large-vessel thrombosis, with inhibition of one thrombotic component showing profound effects on the other component in both arterial and venous thrombosis.

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“…Elalamy and coworkers showed in a whole-blood in vitro assay that fondaparinux prolonged the lag time of prothrombin activation for all concentrations explored, and for physiologically relevant concentrations (0.11–0.28 anti-FXa IU/ml), reduced the maximal rate of thrombin formation to approximately 47%–55% of its nominal value [52]. Herbert and colleagues explored fondaparinux and the sulfated analog SANORG 32701 in in vivo mouse, rat, and rabbit coagulation models [53,54]; SANORG 32701 has a high affinity for ATIII ( K d = 3.7 ± 0.7 nM) and shows more potent anti-FXa activity (1,100 ± 31 versus 850 ± 21 U/mg for fondaparinux). DTIs have also been explored as anticoagulants [55].…”

Section: Discussionmentioning

confidence: 99%

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

2007

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The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein–protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa) activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of fragility of human relevant cascades could be used as a rational basis for target selection despite model uncertainty.

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Effects of SanOrg123781A, a Synthetic Hexadecasaccharide, in a Mouse Model of Electrically Induced Carotid Artery Injury: Synergism with the Antiplatelet Agent Clopidogrel

Cited by 16 publications

References 28 publications

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Cross-modulatory effects of clopidogrel and heparin on platelet and fibrin incorporation in thrombosis

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

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