Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study

Fiessinger, J. N.; Bounameaux, H; Cairols, Marc; Clément, Denis; Coccheri, S.; Fletcher, J.; Hoffmann, Ulrich; Turpie, A. G. G.

doi:10.1111/j.1538-7836.2010.04020.x

Cited by 25 publications

(13 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Terutroban has been extensively used in clinical trials in vascular diseases and proven to be safe. 14,36,37 Our study demonstrates that in vivo chronic TP-receptor blockade with terutroban produced a similar reduction in portal pressure in two different models, CCl 4 and BDL. The decrease in portal pressure was not associated with changes in portal blood flow, suggesting a reduction in hepatic vascular resistance.…”

Section: Discussionsupporting

confidence: 56%

See 1 more Smart Citation

Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

et al. 2013

View full text Add to dashboard Cite

Increased production of vasoconstrictive prostanoids, such as thromboxane A 2 (TXA 2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA 2 induces vasoconstriction by way of activation of the thromboxane-A 2 /prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl 4 ) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl 4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl 4 -cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl 4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl 4 -cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (a-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. Conclusion: Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl 4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation. (HEPA-TOLOGY 2013;58:1424-1435

show abstract

Section: Discussionsupporting

confidence: 56%

“…We hereby report the effects of terutroban, a specific TP‐receptor blocker, in cirrhotic rats. Terutroban has been extensively used in clinical trials in vascular diseases and proven to be safe …”

Section: Discussionmentioning

confidence: 99%

Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Using the Badimon blood perfusion chamber in a porcine model, 100 μg kg −1 day −1 of terutroban showed antithrombotic effects similar to the purinergic P2Y 12 receptor antagonist clopidogrel . Antithrombotic effects of escalating doses of terutroban have also been shown in patients with peripheral artery disease (PAD) .…”

Section: Role Of Tp Receptor Activation In Thrombosis: Pharmacologicamentioning

confidence: 99%

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Capra

Bäck

Angiolillo

et al. 2014

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

To cite this article: Capra V, B€ ack M, Angiolillo DJ, Cattaneo M, Sakariassen KS. Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation. J Thromb Haemost 2014; 12: 126-37.Summary. The activation of thromboxane prostanoid (TP) receptor on platelets, monocytes/macrophages, endothelial cells, and vascular smooth muscle cells (SMC) plays important roles in regulating platelet activation and vascular tone and in the pathogenesis of thrombosis and vascular inflammation. Oxidative stress and vascular inflammation increase the formation of TP receptor agonists, which promote initiation and progression of atherogenesis and thrombosis. Furthermore, TP receptor activation promotes angiogenesis and vessel wall constriction. Besides thromboxane A 2 and its endoperoxide precursors, prostaglandin G 2 and H 2 , isoprostanes, and 20-hydroxyeicosatetraenoic acid also activate TP receptor as autocrine or paracrine ligands. These additional TP activators play a role in pathological conditions such as diabetes, obesity, and hypertension, and their biosynthesis is not inhibited by aspirin, at variance with that of thromboxane A 2 . The understanding of TP receptor function increased our current knowledge of the pathogenesis of atherosclerosis and thrombosis, highlighting the great impact that this receptor has in cardiovascular disorders.

show abstract

“…Terutroban was associated with similar level of inhibition of arachidonic acid– and collagen-induced platelet aggregation as aspirin in patients with peripheral arterial disease and was superior to aspirin in inhibiting platelet aggregation and thrombus formation in an ex vivo model of thrombosis. 78,79 However, the phase III clinical trial, PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack), failed to demonstrate superiority of terutroban than of aspirin in secondary prevention of cerebrovascular and cardiovascular events in ≈20 000 patients with stroke. 80 …”

Section: Other Novel P2y12 Receptor Antagonistsmentioning

confidence: 99%

G-Protein–Coupled Receptors Signaling Pathways in New Antiplatelet Drug Development

Gurbel

Kuliopulos

Tantry

2015

ATVB

View full text Add to dashboard Cite

Platelet G-protein–coupled receptors influence platelet function by mediating the response to various agonists, including ADP, thromboxane A2, and thrombin. Blockade of the ADP receptor, P2Y12, in combination with cyclooxygenase-1 inhibition by aspirin has been among the most widely used pharmacological strategies to reduce cardiovascular event occurrence in high-risk patients. The latter dual pathway blockade strategy is one of the greatest advances in the field of cardiovascular medicine. In addition to P2Y12, the platelet thrombin receptor, protease activated receptor-1, has also been recently targeted for inhibition. Blockade of protease activated receptor-1 has been associated with reduced thrombotic event occurrence when added to a strategy using P2Y12 and cyclooxygenase-1 inhibition. At this time, the relative contributions of these G-protein–coupled receptor signaling pathways to in vivo thrombosis remain incompletely defined. The observation of treatment failure in ≈10% of high-risk patients treated with aspirin and potent P2Y12 inhibitors provides the rationale for targeting novel pathways mediating platelet function. Targeting intracellular signaling downstream from G-protein–coupled receptor receptors with phosphotidylionisitol 3-kinase and Gq inhibitors are among the novel strategies under investigation to prevent arterial ischemic event occurrence. Greater understanding of the mechanisms of G-protein–coupled receptor–mediated signaling may allow the tailoring of antiplatelet therapy.

show abstract

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study

Cited by 25 publications

References 26 publications

Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

G-Protein–Coupled Receptors Signaling Pathways in New Antiplatelet Drug Development

Contact Info

Product

Resources

About