Argatroban and Inhibition of the Vasomotor Actions of Thrombin

Winn, Mark J.; Jain, Kalpana; Ku, David D.

doi:10.1097/00005344-199311000-00013

Cited by 18 publications

(3 citation statements)

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“…Argatroban inhibited thrombin-induced vasomotor actions in canine coronary arteries in vitro; half-maximal inhibition of relaxation was observed with argatroban »0.3 mmol L, and significant (p < 0.05 vs control) inhibition of constriction was observed with argatroban 10 mmol L. [34] In rat vascular smooth muscle cells in vitro, 24 hours' treatment with an argatroban dose of 1 or 10 mmol L inhibited (p < 0.05 vs control) thrombininduced proliferation, doses of 0.1, 1, or 10 mmol L suppressed thrombin-induced matrix metalloproteinase-2 activation, and a dose of 1 mmol L completely suppressed thrombin-induced increases in intracellular ionized calcium. [35] …”

Section: Other Effectsmentioning

confidence: 82%

Argatroban

Dhillon

2009

American Journal Cardiovascular Drugs

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Argatroban, a highly selective direct thrombin inhibitor, is indicated for use as an anticoagulant for the treatment and prophylaxis of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and in patients undergoing percutaneous coronary intervention (PCI) who have, or are at risk for, HIT. Intravenous argatroban improved clinical outcomes and was generally well tolerated in adults with HIT or HIT with thrombosis syndrome (HITTS). In two pivotal, open-label, historically controlled studies in adults with HIT, the incidence of the primary composite endpoint (all-cause death, all-cause amputation, or new thrombosis) was significantly lower in argatroban recipients than in historical controls, and more argatroban recipients than historical controls stayed event-free during the study according to a Kaplan-Meier analysis. In adults with HITTS in these trials, although the incidence of the primary composite endpoint did not differ significantly between argatroban recipients and historical controls, a Kaplan-Meier analysis showed that more patients receiving argatroban than historical controls remained event-free during the study. Major and minor bleeding rates in argatroban recipients were generally similar to those in historical controls in these studies. Argatroban was also an effective anticoagulant in patients with HIT undergoing PCI in three small, uncontrolled trials, pooled data from which showed that most (>or=95%) patients achieved a satisfactory outcome of the PCI procedure and adequate anticoagulation (coprimary endpoints). It was generally well tolerated in these patients, with the incidence of major bleeding being

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Section: Other Effectsmentioning

confidence: 82%

Argatroban

Dhillon

2009

American Journal Cardiovascular Drugs

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“…It is possible that thrombininduced hemostatic disorders contribute to alterations in vascular tone and permeability and thereby cause organ system dysfunction after CPB, but this is, as yet, an unproved hypothesis. It is interesting that argatroban, one of the synthetic direct thrombin antagonists, inhibits the vasomotor effects of thrombin [213]. This suggests a strategy to test the impact of thrombin on vascular tone during and after CPB.…”

Section: Vascular Tonementioning

confidence: 99%

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Ferraris

2011

Int J Angiol

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Extracorporeal circulation for the purpose of cardiopulmonary bypass (CPB) is used extensively for repair of cardiac defects. Complex mechanisms, many of which involve the generation of thrombin, are initiated by the institution of CPB. Thrombin is generated during CPB in spite of high doses of heparin. The tissue factor/ factor VII pathway is also activated and is probably responsible for generation of most of the thrombin seen during CPB. Plasma proteins (humoral phase) along with platelets, endothelium and white cells (cellular phase) are also activated by contact of blood with synthetic surfaces. Small amounts of thrombin activate endothelial cells which then generate tissue plasminogen activator (t-PA). Plasmin is generated by the action of t-PA and fibrinolysis ensues. The blood becomes a mix of vasoactive substances that alter vascular smooth muscle tone and endothelial cell contraction. The sum of these reactions is called the Ôwhole body inflammatory responseÕ and is responsible for postoperative morbidity including bleeding and organ system dysfunction.Attempts to control the morbidity of CPB have focused on reversible inhibitors of some of the reactions described above. Potentially helpful new strategies may include: 1) enhanced production of thrombin-activatable fibrinolysis inhibitor (TAFI) to limit fibrinolysis, 2) synthesis of thrombin receptor blockers to limit platelet and endothelial activation, 3) protection of endothelial cell receptors during CPB, 4) control of CPB-induced platelet-PMN and endothelial-PMN adhesion in order to limit postoperative organ system dysfunction, and 5) limitation of tissue factor pathway activation in order to minimize thrombin production during CPB. This review highlights recent developments in the understanding of the molecular mechanisms of the action of thrombin induced by CPB.

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“…Differences between the effective concentrations of argatroban in the damaged versus undamaged endothelia are consistent with mechanistic differences in thrombin-mediated vascular responses. 23…”

Section: Anticoagulant/antithrombotic Effects In Animal Modelsmentioning

confidence: 99%

Novastan^®(Brand of Argatroban): A Small-Molecule, Direct Thrombin Inhibitor

Hursting¹,

Alford²,

Becker³

et al. 1997

Semin Thromb Hemost

152

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Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.

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Argatroban and Inhibition of the Vasomotor Actions of Thrombin

Cited by 18 publications

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Argatroban

Argatroban

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Novastan^®(Brand of Argatroban): A Small-Molecule, Direct Thrombin Inhibitor

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Argatroban and Inhibition of the Vasomotor Actions of Thrombin

Cited by 18 publications

References 0 publications

Argatroban

Argatroban

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Novastan®(Brand of Argatroban): A Small-Molecule, Direct Thrombin Inhibitor

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Novastan^®(Brand of Argatroban): A Small-Molecule, Direct Thrombin Inhibitor