Management of major bleedings during anticoagulant treatment with the oral direct thrombin inhibitor ximelagatran or warfarin.

Several new oral anticoagulants are currently investigated in phase III programmes, mainly with inhibition of factor Xa or thrombin as their pharmacological target. Advantages are expected with these new drugs compared with vitamin K antagonists, but one potential drawback is the lack of specific antidotes. During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures.

No influence of food on the pharmacokinetics, pharmacodynamics or tolerability of the 24mg and 36mg oral tablet formulations of ximelagatran.

Objective: To assess the potential effects of food on the pharmacokinetics and tolerability/safety of ximelagatran, an oral direct thrombin inhibitor developed for the prevention and treatment of thromboembolic disease that is rapidly bioconverted to its active form, melagatran.

Design And Study Participants: In two open-label, randomised, crossover studies, healthy male and female volunteers received oral ximelagatran as a single 24mg tablet (study 1, n = 30) or a single 36mg tablet (study 2, n = 50). Potential effects of food on the pharmacodynamics (activated partial thromboplastin time; APTT) of the 36mg tablet were also investigated in study 2.

Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers.

Objective: To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system.

Methods: Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran.

Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long-term secondary prevention of venous thromboembolism.

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo.

Influence of erythromycin on the pharmacokinetics of ximelagatran may involve inhibition of P-glycoprotein-mediated excretion.

A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-over-expressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.

No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers.

The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double-blind, 2-way crossover study. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4- to 14-day washout period. All volunteers received a single oral dose of digoxin 0.

No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran.

In this randomized, 2-way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors.

The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol.

Ximelagatran-a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration-is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36-mg oral dose of ximelagatran +/- a single oral dose of alcohol (0.5 and 0.

Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation.

Objective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.

Research Design And Methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.

Fibrinolytic capacity increases with age in healthy humans, while endothelium-dependent vasodilation is unaffected.

The capacity for stimulated endothelial release of tissue-type plasminogen activator (tPA) and endothelium-dependent vasodilation is diminished in patients with cardiovascular risk factors. We examined the effect of age on desmopressin-stimulated tPA release and endothelium-dependent vasodilation, using the perfused-forearm model. Thirty-two healthy subjects were divided into quartiles by age (mean age 24, 36, 54, and 72 years, respectively).