HN-11500 – a Novel Thromboxane A2 Receptor Antagonist With Antithrombotic Activity in Humans at Arterial Blood Flow Conditions

He, Roald; Rm, Barstad; Engen, A van; Kierulf, Peter; Skjørten, F; Ks, Sakariassen

doi:10.1055/s-0038-1642391

Cited by 34 publications

(12 citation statements)

References 21 publications

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“…This physical effect was apparently enhancing the platelet-collagen adhesion at 2600 s" 1 and probably also at 650 s~\ even though aspirin had only marginal effect on the thrombus volume. Similar findings were previously observed in studies with the platelet inhibitors clopidogrel 16 and the reversible TxA 2 receptor antagonist HN-11500 17 in the same experimental model and at similar experimental conditions.…”

Section: Discussionsupporting

confidence: 78%

Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion.

Roald

Ørvim

Bakken

et al. 1994

Arterioscler Thromb

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Cigarette smoking is a known risk factor for cardiovascular disease in men and women, and it has been suggested that this risk is linked to enhanced formation of platelet thromboxane A 2 (TxA 2 ). This led us to investigate the effect of cigarette smoking and TxA 2 formation on collagen-induced thrombogenesis in flowing nonanticoagulated human blood. Thrombus formation in blood from smokers and nonsmokers was compared before and 2 hours after ingestion of a single oral dose of 990 mg aspirin, which is sufficient to block platelet TxA 2 formation. Nonanticoagulated blood was drawn directly from an antecubital vein over collagen fibrils in a parallel-plate perfusion chamber by a peristaltic roller pump placed distalry to the chamber. Wall shear rates at the collagen surface were characteristic for medium-sized (650 s" 1 ) and moderately stenosed (2600 s" 1 ) arteries. Blood-collagen interactions were morphologically quantified, and markers of platelet release, £-thromboglobulin (0-TG), and activation of coagulation, fibrinopeptide A (FPA), were measured immediately distal to the perfusion chamber. The thrombus volume in blood from cigarette-smoking individuals was S everal prospective studies have demonstrated that cigarette smoking is a major risk factor for cardiovascular disease. 16 Enhanced thromboxane A 2 (TxA 2 ) synthesis in platelets has been implicated as a possible source of risk, since biochemical studies have shown increased TxA 2 production in cigarette smokers. 7The TxA 2 molecule is a potent vasoconstrictor and platelet aggregation agonist. Both events are closely associated with cardiovascular disorders.A single oral dose of 1 g aspirin blocks the platelet production of TxA 2 8 by irreversible acetylation of platelet cyclooxygenase. 9 The effect of blocking TxA 2 is partial inhibition of the aggregation response to low concentrations of ADP and collagen. Ingestion of aspirin abolishes acute and chronic effects of enhanced platelet aggregation observed in healthy habitual smokers. -11The goal of the present study was to investigate the effect of cigarette smoking on collagen-induced thrombogenesis in flowing nonanticoagulated human blood and to evaluate the effect of a 990-mg single oral dose of aspirin in both smokers and nonsmokers at arterial blood flow conditions. A well-characterized human ex

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Section: Discussionsupporting

confidence: 78%

Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion.

Roald

Ørvim

Bakken

et al. 1994

Arterioscler Thromb

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“…The antithrombotic activity of linotroban (HN-11500) was tested by using the Sakariassen human thrombosis blood perfusion chamber in healthy volunteers. A single oral dose of 100 lg linotroban was shown to be a potent inhibitor of formation of platelet-rich thrombi at a high arterial wall shear rate of 2.600 s À1 within 2 h following the administration [4]. At a lower arterial wall shear rate of 650 s À1 , linotroban administration resulted in loosely packed platelet-rich thrombi.…”

Section: Abnormalities Of the Platelet Tp Receptor In Patients With Dmentioning

confidence: 98%

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

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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.

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“…However, despite many TP receptor antagonists having developed since the 1980s such as sulotroban (BM‐13177), daltroban (BM‐13505), ONO‐11120, ICI‐192605, GR‐32191, ONO NT‐126, KW‐3635, SQ‐29548, ifetroban (BMS‐180291), I‐SAP, LCB‐2853, linotroban (HN‐11500), Z‐335, they have polarized considerable poor interest, and their development has been stopped because of their toxicity or modest activity in clinical situations . Only ramatroban (Bay‐u3405) and seratrodast (AA‐2414) has been used clinically for the treatment of asthma in Japan since the late 1990s.…”

Section: Cyclooxygenase Products and Cardiovascular Pathophysiologymentioning

confidence: 99%

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Capra

Bäck

Barbieri

et al. 2012

Medicinal Research Reviews

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Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists.

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HN-11500 – a Novel Thromboxane A2 Receptor Antagonist With Antithrombotic Activity in Humans at Arterial Blood Flow Conditions

Cited by 34 publications

References 21 publications

Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion.

Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion.

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

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

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