The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis

Elg, Margareta; Gustafsson, David; Deinum, Johanna

doi:10.1055/s-0038-1657729

Cited by 117 publications

(78 citation statements)

References 30 publications

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“…antithrombotic potency to SSR182289A in rat venous, AV shunt, and arterial thrombosis models (Berry et al, 1994). Another factor that appears to influence the relative antithrombotic properties of thrombin inhibitors is the association rate constant for the enzyme (Elg et al, 1997). The principal finding of this article is the demonstration that SSR182289A produces dose-dependent antithrombotic activity following oral administration in five different thrombosis models.…”

Section: Discussionmentioning

confidence: 84%

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

Lorrain¹,

Millet²,

Lechaire³

et al. 2003

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 84%

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

Lorrain¹,

Millet²,

Lechaire³

et al. 2003

J Pharmacol Exp Ther

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“…Why desulphato-hirudin may offer an advantage in the treatment of this category of patients has not been shown in similar trials with other direct thrombin inhibitors. On a molar basis, desulphatohirudin increases activated partial thromboplastin time more than other direct thrombin inhibitors in animal and in-vitro models [20,21] . Antithrombin decreased consistently during infusion in the heparin group only.…”

Section: Discussionmentioning

confidence: 95%

The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease

Linder

Oldgren²,

Egberg³

et al. 1999

European Heart Journal

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Aim This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease. Methods and ResultsIn the Thrombin Inhibition In Myocardial ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72 h. In a subpopulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion.Prothrombin fragment 1+2, indicating thrombin generation, decreased in the low, medium and high dose inogatran groups and in the heparin group during the first 6 h of treatment by 12%, 15%, 21% and 26%, respectively. From 6 h to 72 h after the start of infusion the levels changed by 7%, 6%, 4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin-antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6 h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively.After 72 h, at the end of infusion, patients treated with inogatran, to a larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked. ConclusionThe more pronounced decrease in thrombin generation and fibrin turnover during the first 6 h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion. (Eur Heart J 1999; 20: 506-518)

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“…For example, heparin is also less potent in the rat model, because smaller decreases in thrombus mass were observed at even larger prolongations in the APTT than those attained in the rabbit model. 15,17,21 Furthermore, preliminary studies show that neither anti-TF antibodies nor active siteblocked F.VIIa is inhibitory in the rat FeCl 3 model (C.J. Refino, unpublished observations, 1999), suggesting that coagulation in this model is not TF-mediated.…”

Section: Discussionmentioning

confidence: 99%

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

Refino¹,

Jeet²,

Deguzman³

et al. 2002

ATVB

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Abstract-10C12, a human antibody F(abЈ) 2 , which specifically binds to the ␥-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED 90 ) was a 30-g/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U · kg Ϫ1 · min Ϫ1 infusion of heparin. Heparin, at and below the ED 90 , significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED 90 . To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED 90 of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED 90 . The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.

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The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis

Cited by 117 publications

References 30 publications

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

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

The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

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