Argatroban during percutaneous transluminal coronary angioplasty: Results of a dose-verification study

Herrman, Jean‐Paul R.; Suryapranata, Harry; Heijer, Peter den; Gabriël, Laurence; Kutryk, Michael J.B.; Serruys, Patrick W.

doi:10.1007/bf00133080

Cited by 37 publications

(15 citation statements)

References 36 publications

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“…By way of comparison, we have calibrated our dog ex vivo coagulation model using a highly bioavailable, long-acting subcutaneous formulation of argatroban (Berry et al, 2000). In this model, a dose of argatroban (2 mg/kg s.c.) that gave plasma levels within the clinical anticoagulant range (0.04 -2.5 g/ml; Herrman et al, 1996;Bergougnan et al, 1997;Jeske et al, 1999) was associated with maximum increases in thrombin time, ECT, and aPTT of 367, 203, and 25%, respectively, i.e., a much more modest level of anticoagulation than achieved after oral dosing with SSR182289A. The demonstration that SSR182289A is orally active as an anticoagulant agent with a long duration of action in four animal species gives grounds for optimism with respect to the oral bioavailability of this compound in human.…”

Section: Downloaded Frommentioning

confidence: 99%

SSR182289A, a Novel, Orally Active Thrombin Inhibitor: In Vitro Profile and ex Vivo Anticoagulant Activity

Berry

Lassalle²,

Lunven³

et al. 2002

J Pharmacol Exp Ther

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SSR182289A competitively inhibits human thrombin (K i ϭ 0.031 Ϯ 0.002 M) and shows good selectivity with respect to other human proteases, e.g., trypsin (K i ϭ 54 Ϯ 2 M), factor Xa (K i ϭ 167 Ϯ 9 M), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K i values Ͼ250 M). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC 100 thrombin time 96 Ϯ 7 nM) and inhibited tissue factor-induced thrombin generation (IC 50 of 0.15 Ϯ 0.02 M). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC 50 value of 32 Ϯ 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 Ϯ 356%; ecarin clotting time (ECT), 1134 Ϯ 204%; and activated partial thromboplastin time (aPTT), 91 Ϯ 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 Ϯ 425%; ECT, 2017 Ϯ 341%; and aPTT, 113 Ϯ 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.

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Section: Downloaded Frommentioning

confidence: 99%

SSR182289A, a Novel, Orally Active Thrombin Inhibitor: In Vitro Profile and ex Vivo Anticoagulant Activity

Berry

Lassalle²,

Lunven³

et al. 2002

J Pharmacol Exp Ther

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“…53,54 Argatroban has also been evaluated in several small, randomized, controlled trials in patients with acute coronary syndromes, but results were inconclusive. [55][56][57] …”

Section: Clinical Trials With Argatrobanmentioning

confidence: 99%

Translational Success Stories

Coppens

Eikelboom

Gustafsson

et al. 2012

Circulation Research

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Translational Success Stories Development of Direct Thrombin InhibitorsMichiel Coppens, John W. Eikelboom, David Gustafsson, Jeffrey I. Weitz, Jack Hirsh Abstract: Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis.Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care. (Circ Res. 2012;111:920-929.) Key Words: thrombin Ⅲ anticoagulant Ⅲ drug development D irect thrombin inhibitors (DTIs) are anticoagulants that bind directly to thrombin and block its activity. Prior to their development, the injectable anticoagulants in clinical use were heparin and low-molecular-weight heparins (LMWHs). Both are classified as indirect inhibitors because they have no intrinsic activity; instead, they produce their anticoagulant effect by activating antithrombin. The only class of oral anticoagulants that was available at that time was the vitamin K antagonists (VKAs), such as warfarin.Several key events led to the development of DTIs. The first was the observation in 1884 that salivary secretions of the medicinal leech, Hirudo medicinalis, prevented blood from clotting. 1 This finding subsequently led to the development of hirudin, which was initially extracted from leeches and later obtained via rDNA technology. [2][3][4][5] The second observation, made in 1956 by Bettelheim, was th...

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“…Argatroban has not been evaluated in appropriately designed randomized controlled trials in this setting and, like hirudin, evidence supporting its use is confined to 2 prospective cohort studies of patients treated with argatroban compared with historical controls. 87,88 Although trials have evaluated argatroban for treatment of unstable angina, 89 as an adjunct to thrombolysis, 90 and as an alternative to heparin in patients undergoing coronary angioplasty, 91 the studies are small and none has shown definitive advantages of argatroban over heparin.…”

Section: Argatrobanmentioning

confidence: 99%