Direct thrombin inhibitors: novel antithrombotics on the horizon in the thromboprophylactic management of atrial fibrillation

Katira, R; Chauhan, Anoop; More, Ranjit

doi:10.1136/pgmj.2004.024521

Cited by 4 publications

(5 citation statements)

References 72 publications

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“…Melagatran inhibits both free and clot-bound thrombin with reproducible pharmacokinetic properties, low plasma protein binding and mainly renal clearance [103,104]. Melagatran 13 shows a plasma half-life of 2-3 h. Animal models and clinical trials suggest that melagatran 13 has a wider therapeutic window than warfarin [105,106]. Unfortunately, melagatran 13 has only low bioavailability (5.8%) after oral administration due to poor adsorption [104].…”

Section: The Case Of Ximelagatranmentioning

confidence: 96%

“…with fixed dosing every 12 h, was demonstrated in a number of clinical trials [for reviews see refs. 106,108,109]. The safety profile with respect to bleeding risk appears favorable for ximelagatran 14 relative to warfarin as monotherapy [108].…”

Section: The Case Of Ximelagatranmentioning

confidence: 96%

“…Actually, the carboxylic group is esterified and the basic amidino group is converted into an amidoxime moiety to increase lipophilicity [104]. In humans, ximelegatran is well absorbed in the small intestine with a bioavailability in the range of 20% [107] and low inter-subject variation [106].…”

Section: The Case Of Ximelagatranmentioning

confidence: 99%

“…Because it is not metabolized by the hepatic cytochrome 2778 A. Schwienhorst Direct thrombin inhibitors P450 system, there is a low incidence of drug-drug interactions and no relevant food dependence [106]. Efficacy, e.g.…”

Section: The Case Of Ximelagatranmentioning

confidence: 99%

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Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

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Section: The Case Of Ximelagatranmentioning

confidence: 96%

Section: The Case Of Ximelagatranmentioning

confidence: 96%

Section: The Case Of Ximelagatranmentioning

confidence: 99%

Section: The Case Of Ximelagatranmentioning

confidence: 99%

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Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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“…Melagatran is a dipeptide mimetic of the region of fibrinopeptide A that interacts with thrombin's active site. The pharmacokinetic and pharmacodynamic profile makes Ximelagatran an ideal successor of VitKAs [83,84]. Plasma levels of Melagatran increase linearly depending on the Ximelagatran dose and independently from concurrent ASA treatment [80,81].…”

Section: Direct Thrombin Inhibitorsmentioning

confidence: 99%

New Pharmacologic Approaches to Prevent Thromboembolism in Patients with Atrial Fibrillation

Hammwöhner

D’Alessandro²,

Wolfram³

et al. 2007

CVP

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Atrial fibrillation (AF) is associated with a 6 fold increased risk for ischemic stroke. Observational studies suggest that one in four to five strokes is due to AF. Depending on the risk profile of an individual patient, the yearly risk for ischemic stroke is between 2% and 14%. AF is accompanied by an increased propensity for atrial clot formation due to a combination of decreased atrial blood flow, increased activity of the platelet/plasmatic coagulation system and prothrombotic changes at the atrial endocardium. This review summarizes the current guidelines for thromboembolic prevention in patients with AF. In many cases, continuous oral anticoagulation therapy (OAT) with vitamin K antagonists (VitKAs) is indicated if AF is accompanied by more than one additional risk factor for thromboembolic complications. However, therapeutic range of VitKAs (Phenprocoumon, Warfarin, and others), the most commonly used oral anticoagulants, is narrow and their use requires regular anticoagulation monitoring. Possibly due to these limitations, about one third of eligible patients are not treated with VitKAs. Furthermore, in many treated patients OAT is not well controlled. Thus, in clinical practice anticoagulation therapy in AF is suboptimal. Therefore, new and more convenient pharmacologic approaches to prevent thromboembolism with i.e. direct thrombin inhibitors (DTI), synthetic polysaccharides (factor Xa Inhibitors), and others are discussed, and their possible future role in the treatment of AF is evaluated.

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Antiprotease and Antimetastatic Activity of Ursolic Acid Isolated from Salvia officinalis

Jedinák

Múčková²,

Kostálová

et al. 2006

Zeitschrift Für Naturforschung C

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Proteases play a regulatory role in a variety of pathologies including cancer, pancreatitis, thromboembolic disorders, viral infections and many others. One of the possible strategies how to combat with these pathologies seems to be the use of low molecular inhibitors. Natural products were evaluated in the in vitro antiprotease assay on serine proteases (trypsin, thrombin and urokinase) and on the cysteine protease cathepsin B. We found interesting results for -ursolic acid isolated from Salvia officinalis, which significantly inhibited all tested proteases in vitro in the micromolar range. -Ursolic acid showed the strongest inhibition activity to urokinase (IC 50 = 12 μm) and cathepsin B (IC 50 = 10 μm) as proteases included in tumour invasion and metastasis indicated possible anticancer effectivity. Therefore, we tested the ability of -ursolic acid at doses of 50, 75 and 100 mg/kg given i.p. to inhibit lung colonization of B16 mouse melanoma cells in vivo. We found, that -ursolic acid significantly decreased the number of B16 colonies in the lungs of mice at the dose 50 mg/kg (p Ͻ 0.05).

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Direct thrombin inhibitors: novel antithrombotics on the horizon in the thromboprophylactic management of atrial fibrillation

Cited by 4 publications

References 72 publications

Direct thrombin inhibitors – a survey of recent developments

Direct thrombin inhibitors – a survey of recent developments

New Pharmacologic Approaches to Prevent Thromboembolism in Patients with Atrial Fibrillation

Antiprotease and Antimetastatic Activity of Ursolic Acid Isolated from Salvia officinalis

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