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At least 595 records · Page 33Linked to original sources
PubMed2003

Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.

OBJECTIVES: Ximelagatran is a novel, oral direct thrombin inhibitor designed to overcome the low and variable oral absorption of melagatran, its active form. The pharmacokinetics and pharmacodynamics of ximelagatran following single and repeated oral administration were investigated. The primary objectives were to determine the dose linearity and reproducibility of melagatran exposure and the influence of food intake. METHODS: Two open-label studies were performed in healthy male subjects. Study I was a dose-escalation study, in which subjects received single oral doses of ximelagatran (1-98 mg). Study II was a randomised, two-way crossover study consisting of two 5-day treatment periods, in which subjects received a 20-mg oral dose of ximelagatran twice daily, either before breakfast and with dinner, or with breakfast and after dinner. RESULTS: Ximelagatran was rapidly absorbed and converted to melagatran, which was the predominant compound in plasma. The mean (+/- standard deviation) bioavailability of melagatran was 22.2+/-4.3% and 17.4+/-2.8% after single and repeated dosings, respectively. The maximum plasma concentration of melagatran and the area under the melagatran plasma concentration-time curve (AUC) increased linearly with dose. Inter- and intra-subject variability in melagatran AUC was 8% and 12%, respectively, with no relevant food- or time dependence. Anticoagulation, assessed as activated partial thromboplastin time, was correlated with melagatran plasma concentration. There was virtually no increase in capillary bleeding time over the dose range studied, and ximelagatran was well tolerated. CONCLUSION: After oral administration of ximelagatran to healthy male subjects, the pharmacokinetic and pharmacodynamic profile of melagatran is predictable and reproducible.

Administration, Oral↗
PubMed2003

Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid.

OBJECTIVE: The aim of this study was to evaluate the effect of acetylsalicylic acid (ASA or aspirin) on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran in healthy volunteers. Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran. METHODS: This was a double-blind, randomised, two-way, crossover study consisting of two treatment periods separated by a washout period of at least 2 weeks. Twelve subjects received, in a randomised order, either melagatran plus ASA in the first treatment period and melagatran plus placebo in the second treatment period or vice versa. Two single doses of ASA were given, first 450 mg on the day before (day 1) and then 150 mg just before administration of melagatran on day 2. Melagatran 4.12 mg was administered as an intravenous (i.v.) infusion over 4 h on day 2 of both treatment periods. Serial blood samples were collected over the course of the study for the determination of melagatran plasma concentration and coagulation analyses [activated partial thromboplastin time (APTT) and activated clotting time (ACT)]. Capillary bleeding time was measured before ASA/placebo on day 1 and before and after the start of the melagatran infusion on day 2. RESULTS: The plasma concentration of melagatran during the i.v. infusion was maintained at about 0.2 micro mol/l, and ASA did not influence the PK parameters of melagatran. APTT and ACT increased with increasing melagatran plasma concentration, and the observed increases were similar whether melagatran was administered on top of ASA or placebo. Administration of ASA significantly prolonged the capillary bleeding time (by 41% relative to placebo). Melagatran also prolonged the bleeding time significantly (by 25% relative to placebo alone), but this prolongation was not significantly different from the observed prolongation when melagatran was administered on top of ASA (by 17% relative to ASA alone). CONCLUSION: In young healthy volunteers, ASA had no effect on the PK or PD properties of melagatran at the studied dose. That the combination of ximelagatran with ASA may be used with acceptable safety must be verified in the relevant patient populations.

Administration, Oral↗
PubMed2003

Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.

OBJECTIVE: To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran. METHODS: In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing. RESULTS: The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls. CONCLUSION: The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.

Administration, Oral↗
PubMed2006

Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran.

OBJECTIVE: Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran. METHODS: Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2x36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2x24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed. RESULTS: In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups. CONCLUSION: The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.

Administration, Oral↗
PubMed2007

The effect of simvastatin, ezetimibe and their combination on the lipid profile, arterial stiffness and inflammatory markers.

OBJECTIVE: Arterial stiffness and highly sensitive C-reactive protein (hsCRP) serum level predict the risk for cardiovascular events. The most commonly used drugs for lowering cholesterol levels, the statins, also have anti-inflammatory effects and can decrease arterial stiffness. Ezetimibe is the first drug of a new class of cholesterol absorption inhibitors in common use and, to date, its effect on arterial stiffness has not yet been studied. The aim of this study was to compare the effect of simvastatin and ezetimibe, both singly and in combination, on arterial stiffness and hsCRP serum concentration in hypercholesterolemic patients. METHODS: Forty hypercholesterolemic patients were studied. Group1 comprised previously untreated patients, who received simvastatin at doses of 40 mg/day during the study; group 2 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 80 mg/day during the study; group 3 consisted of patients previously untreated, who received ezetimibe at doses of 10 mg/day during the study; group 4 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 40 mg/day and ezetimibe at 10 mg/day during the study. Arterial stiffness expressed as the Augmentation Index (AIx) (assessed by pulse wave analysis), the lipid profile and the hsCRP level were measured at baseline and after 3 months of treatment. RESULTS: The reduction in low-density lipoprotein (LDL) after treatment was significantly greater in groups 1 and 4 (39.9 and 35.7%) than in groups 2 and 3 (17.7 and 16.9%; p = 0.005). The AIx decreased significantly only in group 1 patients, from 30.2 +/- 8.3% before treatment to 21.6 +/- 6.5% after treatment (p < 0.001). Changes in hsCRP paralleled the changes in AIx, with a significant decrease in patients in group 1 only, from 2.8 +/- 2.5 mg/L before treatment to 1.6 +/- 1.5 mg/L after treatment (p = 0.016). CONCLUSION: Ezetimibe as a monotherapy had no effect on arterial stiffness or hsCRP, while the administration of simvastatin at 40 mg per day improved arterial stiffness and CRP. However, increasing the dose of simvastatin or administering ezetimibe in combination with simvastatin had no beneficial effects on arterial stiffness.

Aged↗
PubMed2002

Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [123i]5-i-A-85380 in healthy human subjects.

The biodistribution of radioactivity after the administration of a new tracer for alpha4beta2 nicotinic acetylcholine receptors (nAChRs), [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), was studied in ten healthy human subjects. Following administration of 98+/-6 MBq [123I]5-I-A-85380, serial whole-body images were acquired over 24 h and corrected for attenuation. One to four brain single-photon emission tomography (SPET) images were also acquired between 2.5 and 24 h. Estimates of radiation absorbed dose were calculated using MIRDOSE 3.1 with a dynamic bladder model and a dynamic gastrointestinal tract model. The estimates of the highest absorbed dose (microGy/MBq) were for the urinary bladder wall (71 and 140), lower large intestine wall (70 and 72), and upper large intestine wall (63 and 64), with 2.4-h and 4.8-h urine voiding intervals, respectively. The whole brain activity at the time of the initial whole-body imaging at 14 min was 5.0% of the injected dose. Consistent with the known distribution of alpha4beta2 nAChRs, SPET images showed the highest activity in the thalamus. These results suggest that [123I]5-I-A-85380 is a promising SPET agent to image alpha4beta2 nAChRs in humans, with acceptable dosimetry and high brain uptake.

Adult↗
PubMed2003

Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET.

The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33 +/- 15 years) participated in both a bolus (dose: 317 +/- 42 MBq) and a bolus plus constant infusion (dose of bolus: 98 +/- 32 MBq, B/I=6.7 +/- 2.6 h, total dose: 331 +/- 55 MBq) study. The study duration was 5-8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (VT') and specific (VS') distribution volumes. A two-tissue compartment model was applied to identify VS'. VT' was also calculated in B/I studies. In bolus studies, VT' was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave VT' values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm(-3) in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify VS' well. B/I studies provided poor accuracy of VT' measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [123I]5-I-A-85380 in humans and support the use of VT' measured by bolus studies.

Adult↗
PubMed2005

[Atrial fibrillation and thromboprophylaxis in elderly patients].

Chronic, nonvalvular atrial fibrillation occurs more frequently with increasing age, together with an increasing risk for ischemic stroke. Guidelines recommend oral anticoagulation with a vitamin K antagonist for patients >65 years without risk factors and patients <65 years with risk factors for cardiac diseases. Advancing age also increases the risk for bleeding complications under oral anticoagulants; thus, only a part of these patients receives anticoagulant therapy. The risk of falls in elderly patients is of advancing relevance for this therapeutic decision. Oral direct thrombin inhibitors like ximelagatran may be an alternative choice for therapy. Ischemic strokes and systemic embolism in the same frequency with 2x36 mg ximelagatran over 18 months (91/3664 patients: 1.6%/year, for study Sportif III and Sportif V) compared with warfarin (93/3665 patients: 1.6%/year for study Sportif III and Sportif V). All bleeding complications occurred less frequently under therapy with ximelagatran. This could be of importance for elderly patients with risk factors for bleeding or risk of falling.

Administration, Oral↗
PubMed2001

[The Ca(2+) sensitizers CGP 48506 and EMD 57033, but not the Na(+) channel modulator BDF 9148, prolong relaxation in isolated cardiomyocytes of the guinea pig].

The sodium channel modulator DPI 201-106 has been described to posses Ca(2+)-sensitizing properties. Therefore, the present study investigated the inotropic effect of the Na(+)-channel modulator BDF 9148 (1 microM), a congener of DPI 201-106, in comparison with the Ca(2+)-sensitizers CGP 48506 (1-50 mumol/l) and EMD 57033 (1-30 mumol/l) in electrically driven left ventricular cardiomyocytes isolated from guinea pigs. The changes of the contraction amplitude in comparison to the basal cell shortening (cell shortening in micron and %) were continuously recorded with a one-dimensional high speed camera. BDF 9148, CGP 48506, and EMD 57033 exerted a significant increase in the contraction amplitude (p < 0.05 vs. control). The maximal positive inotropic effects of CGP 48506 (50 mumol/l) and EMD 57033 (30 mumol/l) were +249 +/- 30% and +226 +/- 28%, respectively. The corresponding value for BDF 9148 (1 mumol/l) was +176 +/- 16%. However, only the Ca(2+)-sensitizers CGP 48506 and EMD 57033, but not BDF 9148, prolonged the contractile twitch. Especially in patients with an already enhanced intracellular myocardial Ca(2+)-concentration, Ca(2+)-sensitizers, which impair relaxation, may be disadvantageous for therapeutical use despite their positive inotropic effect.

Animals↗
PubMed1998

Effect of inotropic interventions on the force-frequency relation in the human heart.

In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.

Adrenergic beta-Agonists↗
PubMed2006

Anticoagulant action of melagatran: a comparison between neonates and adults using calibrated automated thrombography (CAT).

In the present study, we comparatively evaluated the anticoagulant efficacy of the new direct thrombin inhibitor melagatran in cord vs. adult plasma. In contrast to heparin, melagatran does not require antithrombin as a cofactor. Thus, anticoagulant treatment with melagatran is of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We evaluated the anticoagulant action of increasing amounts of melagatran (0.1-2.0 micromol/l) in both cord and adult plasma by means of calibrated automated thrombography (CAT) with respect to the lag time until the onset of thrombin formation, time to thrombin peak maximum (TTP), endogenous thrombin potential (ETP), and thrombin peak height. Melagatran exhibited approximately the same ability to prolong lag times or TTPs in both cord and adult plasma. Similar concentrations (IC(50)) of melagatran were required to double the lag times (0.44+/-0.04 micromol/l vs. 0.52+/-0.05 micromol/l) or to double the TTPs (0.91+/-0.08 micromol/l vs. 1.06+/-0.09 micromol/l) in cord vs. adult plasma. Melagatran exhibited a higher ability to suppress ETPs or thrombin peak heights in cord vs. adult plasma. Markedly lower concentrations (IC(50)) of melagatran were required to suppress ETPs (0.27+/-0.03 micromol/l vs. 0.70+/-0.06 micromol/l) or thrombin peak heights by 50% (0.29+/-0.03 micromol/l vs. 0.53+/-0.04 micromol/l) in cord vs. adult plasma. We conclude that our results suggest a higher ability of melagatran to suppress thrombin formation in cord vs. adult plasma. Thus, lower amounts of melagatran might be required in neonates undergoing antithrombotic therapy.

Adult↗
PubMed2003

Novel anticoagulants for the prevention and treatment of venous thromboembolism.

Unfractionated heparin, low molecular weight heparin and vitamin K antagonists are anticoagulants currently used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Considerable limitations of these agents, such as a narrow therapeutic window, a variable dose response or lack of oral bioavailability, created the need for new anticoagulants. Numerous new compounds with different mechanisms of action have been developed and some have been already approved for clinical use. Quite recently, fondaparinux, an indirect anti-factor Xa inhibitor, has been licensed in Europe and in the US for prevention of VTE in patients undergoing hip or knee replacement surgery. In addition, lepirudin, a recombinant hirudin derivative, and the heparinoid danaparoid, have been approved in Austria for treatment of heparin-induced thrombocytopenia. Recombinant nematode anticoagulant protein c2, the orally available thrombin inhibitor ximelagatran and ART-123, a recombinant soluble thrombomodulin, are in advanced stages of clinical development. This article reviews mechanisms and sites of action, and the current state of preclinical and clinical research of these and various other agents with respect to the prevention and treatment of venous thromboembolism).

Anticoagulants↗
PubMed2005

Ximelagatran compared with warfarin for the prevention of systemic embolism and stroke. An imputed placebo analysis.

The active control trials, SPORTIF III and SPORTIF V, compared the direct thrombin inhibitor ximelagatran to warfarin, where each was given as a treatment to prevent systemic embolism and stroke in patients with atrial fibrillation. Because warfarin has previously been compared to placebo in similar patients and ximelagatran has now been compared to warfarin, an indirect comparison between ximelagatran and placebo is possible (imputed placebo analysis). In this analysis, ximelagatran reduces the risk of stroke and systemic embolism by 66% (hazard ratio 0.338; 95% confidence interval [CI] 0.204-0.560). Ximelagatran preserves 102% (95% CI 72-132%) of the benefit of warfarin. Based on these data, ximelagatran may be an effective alternative to warfarin for the prevention of stroke and systemic embolism in high-risk patients with atrial fibrillation.

Aged↗
PubMed2006

Effect of ezetimibe on insulin sensitivity and lipid profile in obese and dyslipidaemic patients.

AIM: To evaluate the effect of ezetimibe on insulin sensitivity and lipid profile in obese and dyslipidaemic patients. METHODS: A randomized, double-blind, placebo-controlled clinical trial was carried out in 12 obese, dyslipidaemic patients, independently of their basal insulin sensitivity. At the beginning of the study, a metabolic profile was measured, and insulin sensitivity estimated using the euglycaemic-hyperinsulinaemic clamp technique. The volunteers were randomly assigned to receive ezetimibe (10 mg/day in the morning) or placebo for a period of 90 days. After intervention, a similar metabolic profile was measured and a second clamp study was performed. RESULTS: Ezetimibe administration for 90 days decreased total (6.0 +/- 0.5 vs. 4.2 +/- 0.9 mmol/L, p = 0.011) and low-density lipoprotein (4.0 +/- 0.7 vs. 2.2 +/- 0.8 mmol/L, p=0.003) cholesterol concentrations without modification of insulin sensitivity (3.0 +/- 0.6 vs. 2.9 +/- 0.7 mg/kg/min, p = 0.345). CONCLUSIONS: Ezetimibe significantly decreased total cholesterol and low-density lipoprotein cholesterol concentrations without affecting insulin sensitivity in obese and dyslipidaemic patients.

Administration, Oral↗
PubMed2006

Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777.

Atrophic gastritis, characterized as parietal cell loss or oxyntic atrophy, is the primary event in the evolution of the spectrum of metaplastic and hyperplastic lineage changes thought to predispose to gastric neoplasia. A number of animal models have provided insights into the lineage changes induced by oxyntic atrophy. Recently, we have reported a model for pharmacological induction of oxyntic atrophy with DMP-777. DMP-777 ablates parietal cells selectively and leads to the gastric cell lineage changes including foveolar hyperplasia and spasmolytic polypeptide expressing metaplasia (SPEM). Previous investigations showed that DMP-777 dissipated a gastric tubulovesicle proton gradient without impairing the H/K-ATPase activity, consistent with its pharmacological action as a parietal cell-specific protonophore which could induce parietal cell necrosis through backwash of luminal acid into actively secreting cells. We hypothesized that, if DMP-777 was acting as a parietal cell protonophore, then suppression of acid secretion should protect parietal cells from the toxic effects of the drug. In this study, we pretreated and coadministered the proton pump inhibitor omeprazole with DMP-777 to determine the effect of active acid secretion inhibition on the DMP-777-induced histologic changes in the stomachs of male rats. Omeprazole pretreatment ameliorated DMP-777-induced parietal cell loss as well as foveolar hyperplasia. These results indicate that active acid secretion is required for DMP-777 cytotoxicity, consistent with its suggested behavior as a parietal cell-specific protonophore.

Analysis of Variance↗
PubMed2004

Drotrecogin alfa (activated, Xigris) in combination with heparin or melagatran: an in vitro investigation.

BACKGROUND: The present in vitro study of human plasma investigated the anticoagulant effects of recombinant human activated protein C (rhAPC; drotrecogin alfa [activated, Xigris]), combined with either unfractionated heparin (UH) or the direct thrombin inhibitor melagatran. METHODS: Prolongation of clotting time and generation of prothrombin fragments 1 and 2 (F1 + 2) and of thrombin-antithrombin (TAT) complex were measured in vitro. Clot formation was induced by adding low levels (final concentration, 20 pmol/L) of lipidated tissue factor (TF) to citrated venous plasma samples from healthy human volunteers (n = 16). It has been suggested that experimental activation of plasma with low levels of TF more closely simulates conditions in vivo. RESULTS: rhAPC, melagatran, or UH alone concentration-dependently prolonged the clotting time and suppressed F1 + 2 and TAT generation. rhAPC-mediated prolongation of clotting time concentration-dependently increased with the addition of either UH or melagatran, the effect being more pronounced with the addition of melagatran. Similarly, rhAPC-mediated generation of F1 + 2 and TAT also increased concentration-dependently with the addition of either UH or melagatran; the effect being, in this case, more pronounced with the addition of UH. CONCLUSIONS: This study demonstrated the effects of rhAPC, alone and combined with either UH or melagatran, on clotting time and markers of thrombin generation in human plasma. These results may guide facilitate estimation of appropriate doses of rhAPC and melagatran in future clinical trials.

Anticoagulants↗