Antithrombotic Properties of SSR182289A, a New, Orally Active Thrombin Inhibitor

Lorrain, J; Millet, L; Lechaire, Irène; Lochot, Sylvette; Ferrari, P.; Visconte, Catherine; Sainte-Marie, M.; Lunven, Catherine; Berry, Catherine; Schaeffer, Paul; Herbert, Jean‐Marc; O'Connor, Stephen E.

doi:10.1124/jpet.102.044610

Cited by 19 publications

(14 citation statements)

References 16 publications

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“…16 In addition, a dissociation between antithrombotic efficacy and absence of bleeding time prolongation was reported in studies using different oral thrombin inhibitors. 34-36 …”

Section: Discussionmentioning

confidence: 99%

Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage

et al. 2011

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Background The direct thrombin inhibitor dabigatran etexilate (DE) may constitute a future replacement of vitamin K antagonists for long-term anticoagulation. Whereas warfarin pre-treatment is associated with greater hematoma expansion following intracerebral hemorrhage (ICH), it remains unclear what effect direct thrombin inhibitors would have. Using different experimental models of ICH, this study compared hematoma volume between DE treated mice, warfarin treated mice and controls. Methods and Results CD-1 mice were fed with DE or warfarin. Sham-treated mice served as controls. At the time point of ICH induction, DE mice revealed an increased activated partial thromboplastin time as compared to controls (46.1±5.0 vs. 18.0±1.5sec; p=0.022), whereas warfarin pre-treatment resulted in a prothrombin time prolongation (51.4±17.9 vs. 10.4±0.3sec; p<0.001). Twenty-four hours after collagenase-induced ICH formation, hematoma volume was 3.8±2.9μL in controls, 4.8±2.7μL in DE mice, and 14.5±11.8μL in warfarin mice (n=16; Welch's ANOVA between group differences p=0.007, post-hoc analysis with Dunnett's method: DE vs. controls, p=0.899; warfarin vs. controls, p<0.001; DE vs. warfarin, p=0.001). In addition, a model of laser-induced cerebral microhemorrhage was applied, and the distances which red blood cells and blood plasma were pushed into the brain were quantified. Warfarin mice showed enlarged red blood cell- and blood plasma diameters as compared to controls, but no difference was found between DE mice and controls. Conclusions In contrast to warfarin, pretreatment with DE did not increase hematoma volume in two different experimental models of ICH. In terms of safety, this observation may represent a potential advantage of anticoagulation with DE over warfarin.

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“…16 In addition, a dissociation between antithrombotic efficacy and absence of bleeding time prolongation was reported in studies using different oral thrombin inhibitors. 34-36 …”

Section: Discussionmentioning

confidence: 99%

Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage

et al. 2011

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“…63,2006 Review Article 2779 good selectivity toward trypsin (K i = 54 µM) and other human proteases [121]. Data from the rat model suggest a prolonged duration of action at least similar to that of melagatran 13 [122,123]. Furthermore, a recent study on a rabbit thrombolysis model shows that SSR182289A 18 may enhance thrombolysis induced by either recombinant tissue plasminogen activator or streptokinase [124].…”

Section: Direct Thrombin Inhibitors In Clinical Trialsmentioning

confidence: 93%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

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“…Rat arteriovenous shunt (silk thread model) was prepared according to a previous technique, with slight modification (Lorrain et al, 2003). In brief, fasted male rats were anesthetized with chloral hydrate (350 mg/kg body weight, i.p.).…”

Section: Arteriovenous Shunt (Silk Thread Model) In Ratsmentioning

confidence: 99%

Antithrombotic activities of aqueous extract fromGardenia jasminoidesand its main constituent

Zhang

Líu

Yang³

et al. 2012

Pharmaceutical Biology

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Antithrombotic Properties of SSR182289A, a New, Orally Active Thrombin Inhibitor

Abstract: ABSTRACT

Cited by 19 publications

References 16 publications

Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage

Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage

Direct thrombin inhibitors – a survey of recent developments

Antithrombotic activities of aqueous extract fromGardenia jasminoidesand its main constituent

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