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David Gustafsson - One of the best experts on this subject based on the ideXlab platform.
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the pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor xiMelagatran and its active metabolite Melagatran a mini review
Thrombosis Research, 2003Co-Authors: David GustafssonAbstract:Abstract XiMelagatran (Exanta™, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to Melagatran, its active form, following absorption. Melagatran has been shown to be a potent, rapidly binding, competitive inhibitor of human α-thrombin that inhibits both thrombin activity and generation. Melagatran also effectively inhibits both free and clot-bound thrombin. Melagatran has a wide therapeutic interval that enables it to be administered safely across a wide range of doses with no increased risk of bleeding, in contrast with warfarin whose narrow therapeutic window necessitates monitoring of its pharmacodynamic effect. Although Melagatran has all the pharmacodynamic properties required of a new antithrombotic agent, low oral bioavailability that is even further reduced by the concomitant intake of food precludes its development as an oral agent. It was this that propelled the development of its prodrug, xiMelagatran, which is 170 times more lipophilic than Melagatran and uncharged at intestinal pH. XiMelagatran is therefore much better than Melagatran at penetrating the gastrointestinal barrier and, as a consequence, has sufficient bioavailability (20%) for oral administration. Moreover, its pharmacokinetic properties following oral administration are stable and reproducible, with no food interactions and a low potential for drug–drug interactions. These properties allow xiMelagatran to be administered twice daily according to a fixed dose regimen without coagulation monitoring. As a consequence of its favourable pharmacokinetic and pharmacodynamic properties, xiMelagatran is currently undergoing full-scale clinical development for the prophylaxis and treatment of thromboembolic disorders.
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pharmacokinetics of Melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous Melagatran and oral xiMelagatran a population model analysis
Clinical Pharmacokinectics, 2003Co-Authors: Ulf G. Eriksson, Lars Frison, Per Olsson Gisleskog, Ulrika Wahlby, Bengt Hamren, David Gustafsson, Jaap W Mandema, Mats O Karlsson, Bengt I ErikssonAbstract:Objective: XiMelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to Melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of Melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous Melagatran and oral xiMelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated Creatinine clearance was examined.
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absorption distribution metabolism and excretion of xiMelagatran an oral direct thrombin inhibitor in rats dogs and humans
Drug Metabolism and Disposition, 2003Co-Authors: Ulf G. Eriksson, Ulf Bredberg, Kurtjurgen Hoffmann, Gunnar Fager, Anneli Thuresson, Margareth Gabrielsson, Hans Ericsson, Martin Ahnoff, Kristina Gislen, David GustafssonAbstract:The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, xiMelagatran, and its active form, Melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. XiMelagatran was rapidly absorbed and metabolized following oral administration, with Melagatran as the predominant compound in plasma. Two intermediates (ethyl-Melagatran and OH-Melagatran) that were subsequently metabolized to Melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of Melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. XiMelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of xiMelagatran. Appreciable quantities of ethyl-Melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of xiMelagatran in the gastrointestinal tract, as demonstrated when xiMelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of Melagatran following oral administration of xiMelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of xiMelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of xiMelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of Melagatran.
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pharmacokinetics of Melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous Melagatran and oral xiMelagatran a population model analysis
Clinical Pharmacokinectics, 2003Co-Authors: Ulf Eriksson, Lars Frison, Per Olsson Gisleskog, Ulrika Wahlby, Bengt Hamren, David Gustafsson, Jaap W Mandema, Mats O Karlsson, Bengt I ErikssonAbstract:Objective: XiMelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to Melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of Melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous Melagatran and oral xiMelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated Creatinine clearance was examined. Design and methods: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous Melagatran alone or a sequential regimen of subcutaneous Melagatran followed by oral xiMelagatran, for 8–11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of Melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. Results: The pharmacokinetics of Melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous Melagatran and oral xiMelagatran. Melagatran clearance was correlated with renal function, assessed as calculated Creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of Melagatran after oral xiMelagatran relative to subcutaneous Melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and Melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on Creatinine clearance or bodyweight had no clinically relevant impact on the variability in Melagatran pharmacokinetics or on the effect on APTT. Conclusions: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of Melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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no influence of ethnic origin on the pharmacokinetics and pharmacodynamics of Melagatran following oral administration of xiMelagatran a novel oral direct thrombin inhibitor to healthy male volunteers
Clinical Pharmacokinectics, 2003Co-Authors: Linda C Johansson, David Gustafsson, Gunnar Fager, Magnus Andersson, Ulf ErikssonAbstract:To determine the influence of ethnic origin on the pharmacokinetic and pharmacodynamic properties of Melagatran after oral administration of xiMelagatran, a novel oral direct thrombin inhibitor. This was an open-label, non-randomised study with a single study session. Thirty-six young healthy male subjects living in France were divided equally according to their ethnic origin (African, Asian and Caucasian). All subjects received a single 50mg oral dose of xiMelagatran in solution. Blood and urine samples for pharmacokinetic evaluation were collected up to 12 and 24 hours after administration, respectively. Blood samples were also collected to determine the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin, up to 24 hours after administration. The absorption of xiMelagatran, and its bioconversion to Melagatran, was rapid in all three ethnic groups. The metabolite pattern in plasma and urine was similar in all groups, with Melagatran being the dominant compound. For xiMelagatran, the mean area under the plasma concentration-time curve (AUC) was similar in the three groups, suggesting that there was no difference in the extent to which xiMelagatran was absorbed. Melagatran AUC was higher in the Asian subjects, with a mean Asian/Caucasian ratio (95% CI) of 1.23 (1.04, 1.45). This was presumably because of their lower bodyweight, which is correlated to lower renal function. Following normalisation for bodyweight, there were no statistically significant differences between the three ethnic groups. This finding suggests that renal elimination was lower for Asian subjects, whereas there were no differences in the conversion of xiMelagatran to Melagatran. The interindividual variability of Melagatran AUC was low (coefficient of variation 19–26%), and the mean bioavailability of Melagatran, estimated using a mean value for Melagatran clearance obtained from Caucasian subjects in a previous study, was approximately 20% in all groups (range of mean values 19–23%). APTT increased nonlinearly with increasing Melagatran plasma concentration, and no difference in the concentration—response relationship was observed between the groups. After oral administration of xiMelagatran, the pharmacokinetic and pharmacodynamic properties of Melagatran are independent of ethnic origin. The elimination of Melagatran is correlated with renal function.
Bengt I Eriksson - One of the best experts on this subject based on the ideXlab platform.
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postoperative Melagatran xiMelagatran for the prevention of venous thromboembolism following major elective orthopaedic surgery effects of timing of first dose and risk factors for thromboembolism and bleeding complications on efficacy and safety
Clinical Drug Investigation, 2005Co-Authors: Ola E Dahl, Bengt I Eriksson, Anders Bylock, Giancarlo Agnelli, Patrick Mouret, Nadia Rosencher, Seva Panfilov, Alexander T Cohen, Magnus AnderssonAbstract:Objectives: To examine the influence of timing of postoperative initiation of subcutaneous Melagatran followed by oral xiMelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. Results: In the combined THR and TKR population, Melagatran initiated 4–<8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] ∼-4.4, 4.4) and major VTE (ARR −0.63; 95% CI −2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with Melagatran/ximela-gatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). Conclusions: Melagatran/xiMelagatran initiated 4–<8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous Melagatran followed by fixed-dose oral xiMelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients.
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significantly lower need for blood transfusions associated with postoperatively initiated subcutaneous Melagatran oral xiMelagatran compared with enoxaparin
Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Giancarlo Agnelli, Ola E Dahl, Patrick Mouret, Nadia Rosencher, Alexander T Cohen, Seva PanfilovAbstract:Significantly lower need for blood transfusions associated with postoperatively initiated subcutaneous Melagatran/oral xiMelagatran compared with enoxaparin -
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o1065 xiMelagatran and its subcutaneous form Melagatran vs enoxaparin as thromboprophylaxis in total hip or total knee replacement
Orthopaedic Proceedings, 2004Co-Authors: Bengt I Eriksson, Giancarlo Agnelli, Ola E Dahl, M R Lassen, Patrick Mouret, Alexander T Cohen, Nadia RosencherAbstract:Aims: To investigate the efficacy and safety of a new dosage regimen of the oral direct thrombin inhibitor xiMelagatran, and its subcutaneous (sc) form Melagatran, started in close proximity to surgery. Methods: In a randomised, double-blind, parallel-group study, duration 8–11 days, patients undergoing total hip or knee replacement (THR, n= 1856; TKR, n= 908) received either sc Melagatran 2 mg immediately before surgery followed by sc 3 mg in the evening after surgery, and then by oral xiMelagatran 24 mg bid as a fixed dose (the xiMelagatran group), or sc enoxaparin 40 mg od, started the evening before surgery. Bilateral venography was performed on the final day of treatment. Results: The rate of proximal deep vein thrombosis plus pulmonary embolism was 2.3% in the xiMelagatran group vs. 6.3% in the enoxaparin group (p Conclusion: Pre-operatively initiated sc Melagatran followed by oral xiMelagatran was superior in efficacy to enoxaparin in preventing VTE in patients undergoing THR or TKR.
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the direct thrombin inhibitor Melagatran followed by oral xiMelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement the express study
Journal of Thrombosis and Haemostasis, 2003Co-Authors: Bengt I Eriksson, Peter Kalebo, Giancarlo Agnelli, A T Cohen, Ola E Dahl, M R Lassen, Patrick Mouret, Nadia Rosencher, Seva Panfilov, C EskilsonAbstract:Summary. Background: XiMelagatran and its subcutaneous (s.c.) form Melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease. Methods: In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either Melagatran/xiMelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral xiMelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8–11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding. Results: The rates of major and total VTE were significantly lower in the Melagatran/xiMelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. ‘Excessive bleeding as judged by the investigator’ was more frequent with Melagatran/xiMelagatran than with enoxaparin. Conclusions: In patients undergoing total hip or knee replacement, preoperatively initiated s.c. Melagatran followed by oral xiMelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.
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clinical experience of Melagatran xiMelagatran in major orthopaedic surgery
Thrombosis Research, 2003Co-Authors: Bengt I ErikssonAbstract:Abstract The oral direct thrombin inhibitor (oral DTI) xiMelagatran (Exanta™, AstraZeneca) is rapidly absorbed and bioconverted to its active form Melagatran, which also can be administered subcutaneously (sc). Two large-scale clinical trials (Melagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of sc Melagatran followed by oral xiMelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU sc dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of sc Melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral xiMelagatran bid started 1–3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg sc enoxaparin od or 3 mg sc Melagatran bid started 4–12 h after surgery followed by 24 mg oral xiMelagatran. In METHRO II, there was a highly significant dose–response relationship for sc Melagatran plus oral xiMelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which sc Melagatran was started postoperatively and followed by oral xiMelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that sc Melagatran combined with oral xiMelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.
Christer Mattsson - One of the best experts on this subject based on the ideXlab platform.
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synergistic action between inhibition of p2y12 p2y1 and p2y12 thrombin in adp and thrombin induced human platelet activation
British Journal of Pharmacology, 2004Co-Authors: Sven Nylander, Christer Mattsson, Sofia Ramstrom, Tomas L LindahlAbstract:The objective of this study was to investigate if there is a synergistic effect of a combination of P2Y12 and P2Y1 inhibition and P2Y12 and thrombin inhibition, on ADP- and thrombin-induced platelet activation, respectively. The rationale being that these combinations will cause a concurrent inhibition of both Gαq and Gαi signalling. Blood from healthy volunteers was preincubated with AR-C69931MX, a reversible P2Y12 antagonist; MRS2179, a reversible P2Y1 antagonist; or Melagatran, a direct reversible thrombin inhibitor; alone or in various combinations prior to activation with ADP or thrombin. Platelet function in whole blood was assessed by flow cytometry using the antibody PAC-1 to estimate the expression of active αIIbβ3 (the fibrinogen receptor GPIIb/IIIa). A synergistic effect was evaluated by comparing the concentrations in the different combinations with those of corresponding equipotent concentrations of each single inhibitor alone. The equipotent single concentrations were experimentally obtained from concentration response curves performed in parallel. A synergistic effect regarding inhibition of ADP-induced platelet activation (10 μM) was obtained with different combinations of AR-C69931MX and MRS2179. Inhibition of thrombin-induced platelet activation (2 nM) with combinations of AR-C69931MX and the thrombin inhibitor Melagatran did also result in a strong synergistic effect. To our knowledge, this is the first time that data supporting a synergistic effect has been published for the inhibitor combinations described. Whether this synergistic effect in vitro also results in an improved antithrombotic effect in vivo with or without an increased risk of bleeding remains to be studied in well-conducted clinical studies. British Journal of Pharmacology (2004) 142, 1325–1331. doi:10.1038/sj.bjp.0705885
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Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 2003Co-Authors: Fredrik Scherstén, Christer Mattsson, Göran Wahlund, Tom Björnheden, Stefan Carlsson, Lars GripAbstract:Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model Melagatran is the active form of the oral direct thrombin inhibitor, xiMelagatran. The purpose of this study was to compare the effects of different doses of Melagatran with heparin or placebo on platelet deposition and relative fibrin content after coronary angioplasty in pigs. After 125I-labelled fibrinogen and autologous 111Indium-labelled platelets had been infused a balloon injury was performed in the left anterior descending and the right coronary arteries. Pigs were randomized to receive either heparin 200 IU/kg bolus plus 20 IU/kg per h infusion (n = 7); Melagatran 1 mg/kg bolus plus 0.33 mg/kg per h infusion (n = 7); Melagatran bolus 0.5 mg/kg plus 0.17 mg/kg per h infusion (n = 7); Melagatran 0.15 mg/kg bolus plus 0.05 mg/kg per h infusion (n = 6) or saline (n = 4). Seventy-five minutes after the angioplasty, the pigs were euthanized and the injured vessel segments were measured in a gamma counter. Compared with placebo, platelet deposition and relative fibrin content were reduced after both heparin and Melagatran, in the latter case with a dose-response relationship. Melagatran reduced platelet deposition and relative thrombus size in a dose-dependent manner when compared with placebo after coronary angioplasty in pigs. No statistically significant difference between Melagatran and heparin was found. Blood Coagul Fibrinolysis 14:235-241 © 2003 Lippincott Williams & Wilkins.
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effects of xiMelagatran the oral form of Melagatran in the treatment of caval vein thrombosis in conscious rats
Thrombosis Research, 2002Co-Authors: Stefan Carlsson, Margareta Elg, Christer MattssonAbstract:The antithrombotic effects of direct (xiMelagatran and hirudin) and indirect (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT) treatment model in conscious rats. Thrombus formation was induced in the inferior caval vein by total stasis plus topically applied ferric chloride. After 1-h thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a reference to which all other results were compared. In all other groups, the total occlusion was removed after 1 h but a partial stasis was retained, permitting some blood flow around the thrombus. Groups of animals received subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one of four oral doses of xiMelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline (control). After the 3-h treatment, mean thrombus weight in the saline group (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group (27.3 +/- 2.7 mg, see above). XiMelagatran decreased thrombus weight in a dose-dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus weight with the highest xiMelagatran dose (11.1 +/- 1.3 mg) was similar to that with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression was much less pronounced (20.2 +/- 1.2 mg), compared with xiMelagatran and hirudin, even though it was administered at a dose that yielded a similar activated partial thromboplastin time (APTT) prolongation. In conclusion, the results from this DVT treatment model showed that direct thrombin inhibitors xiMelagatran and hirudin exhibited superior antithrombotic properties to low molecular weight heparin (LMWH).
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inhibition of thrombin generation by the oral direct thrombin inhibitor xiMelagatran in shed blood from healthy male subjects
Thrombosis and Haemostasis, 2002Co-Authors: Troy C Sarich, Lars Frison, Ulf G. Eriksson, Michael Wolzt, Christer Mattsson, Gunnar Fager, David GustafssonAbstract:XiMelagatran, an oral direct thrombin inhibitor, whose active form is Melagatran, was studied using a model of thrombin generation in humans. Healthy male volunteers (18 per group) received xiMelagatran (60 mg p.o.), dalteparin (120 IU/kg s.c.) or a control (water p.o.). Shed blood, collected after incision of the forearm with standardised bleeding time devices at pre-dose, and at 2, 4 and 10 h post-dosing, was analysed for markers of thrombin generation. Statistically significant reductions (p < 0.05) in levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) in shed blood were detected at 2 and 4 h post-dosing in both the xiMelagatran and dalteparin groups. Shed blood F1+2 and TAT levels had returned to pre-dose levels at 10 h post-dosing. Using a shed blood model, we demonstrate that the reversible thrombin inhibitor Melagatran and, therefore, oral administration of xiMelagatran, inhibits thrombin generation in humans after acute activation of coagulation.
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Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (Melagatran).
Thrombosis and haemostasis, 2002Co-Authors: Christer Mattsson, Viveca Nerme, J. A. Björkman, T. Abrahamsson, Katinka Schatteman, Judith Leurs, S. Scharpe, Dirk HendriksAbstract:To test the hypothesis that the direct thrombin inhibitor, Melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with Melagatran, was given to dogs with a coronary artery thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA±Melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1,+ Melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following Melagatran treatment. These results demonstrate that Melagatran attenuates generation of CPU in the coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.
Ulf G. Eriksson - One of the best experts on this subject based on the ideXlab platform.
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utility of ecarin clotting time an ex vivo coagulation test for pharmacokinetic analysis of the direct thrombin inhibitor Melagatran
2006Co-Authors: Marie Cullberg, Ulrika Wahlby, Mats O Karlsson, Ulf G. ErikssonAbstract:Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor Melagatran
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effect of recombinant factor viia on Melagatran induced inhibition of thrombin generation and platelet activation in healthy volunteers
Thrombosis and Haemostasis, 2004Co-Authors: Michael Wolzt, Ulf G. Eriksson, Stig L. Boström, Marcel Levi, Troy C Sarich, Maria Erikssonlepkowska, Mia Svensson, Jeffrey I Weitz, Karin WahlanderAbstract:The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by Melagatran, the active form of the oral direct thrombin inhibitor xiMelagatran. In a single-blind, ran-domized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (iv) infusion to achieve steady-state Melagatran plasma concentrations of approximately 0.5 µmol/L, with a single iv bolus of rFVIIa (90 µg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, β -thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin poten-tial, thrombus precursor protein (TpP), and plasmin-α2 -antiplas-min complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of Melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower Melagatran concentrations has not been excluded.
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pharmacokinetics of Melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous Melagatran and oral xiMelagatran a population model analysis
Clinical Pharmacokinectics, 2003Co-Authors: Ulf G. Eriksson, Lars Frison, Per Olsson Gisleskog, Ulrika Wahlby, Bengt Hamren, David Gustafsson, Jaap W Mandema, Mats O Karlsson, Bengt I ErikssonAbstract:Objective: XiMelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to Melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of Melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous Melagatran and oral xiMelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated Creatinine clearance was examined.
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absorption distribution metabolism and excretion of xiMelagatran an oral direct thrombin inhibitor in rats dogs and humans
Drug Metabolism and Disposition, 2003Co-Authors: Ulf G. Eriksson, Ulf Bredberg, Kurtjurgen Hoffmann, Gunnar Fager, Anneli Thuresson, Margareth Gabrielsson, Hans Ericsson, Martin Ahnoff, Kristina Gislen, David GustafssonAbstract:The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, xiMelagatran, and its active form, Melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. XiMelagatran was rapidly absorbed and metabolized following oral administration, with Melagatran as the predominant compound in plasma. Two intermediates (ethyl-Melagatran and OH-Melagatran) that were subsequently metabolized to Melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of Melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. XiMelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of xiMelagatran. Appreciable quantities of ethyl-Melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of xiMelagatran in the gastrointestinal tract, as demonstrated when xiMelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of Melagatran following oral administration of xiMelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of xiMelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of xiMelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of Melagatran.
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xiMelagatran an oral direct thrombin inhibitor has a low potential for cytochrome p450 mediated drug drug interactions
Clinical Pharmacokinectics, 2003Co-Authors: Eva Bredberg, Lars Frison, Maria Erikssonlepkowska, Susanne Johansson, Marita Larsson, Tommy B Andersson, Annelie Thuresson, Ulf G. ErikssonAbstract:Background: XiMelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, xiMelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-Melagatran and hydroxy-Melagatran), to its active form, Melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of Melagatran.
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anticoagulant action of Melagatran a comparison between neonates and adults using calibrated automated thrombography cat
European Journal of Pediatrics, 2007Co-Authors: Gerhard Cvirn, Christina Cimenti, Joerg Kutschera, Siegfried Gallistl, Ulrika Ferstl, Thomas Wagner, W Muntean, Gunther Jurgens, Martin KoestenbergerAbstract: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 μmol/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 (IC50) of Melagatran were required to double the lag times (0.44±0.04 μmol/l vs. 0.52±0.05 μmol/l) or to double the TTPs (0.91±0.08 μmol/l vs. 1.06±0.09 μmol/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 (IC50) of Melagatran were required to suppress ETPs (0.27±0.03 μmol/l vs. 0.70±0.06 μmol/l) or thrombin peak heights by 50% (0.29±0.03 μmol/l vs. 0.53±0.04 μmol/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.
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the respective and combined anticoagulant effects of recombinant human activated protein c Melagatran and heparins using cat
Thrombosis Research, 2007Co-Authors: Christina Cimenti, Martin Koestenberger, Bettina Leschnik, W Muntean, Harald HaidlAbstract:Abstract Introduction Combinations of anticoagulants might be beneficial in some patients with sepsis, but most anticoagulants require specific clotting assays for monitoring. Thrombin generation assay, however, is a global function test of hemostasis. Materials and methods We performed an in vitro investigation of the respective effects of recombinant human activated protein C (rhAPC) alone and in combination with either Melagatran (a new direct thrombin inhibitor), unfractionated heparin (UH) or low molecular weight heparin (LMWH) in varying concentrations on the thrombin generation (TG) using the calibrated automated thrombography. Results RhAPC, UH, LMWH and Melagatran dose-dependently prolonged the lag time and the time to peak, and significantly suppressed the endogenous thrombin potential (ETP). Combined application of rhAPC with either Melagatran, UH or LMWH induced an additive prolongation of the lag time; this effect was more pronounced in a combination of rhAPC with UH or LMWH. Conclusion In our in vitro study adding either Melagatran, UH or LMWH augmented the capacity of rhAPC to suppress thrombin generation in human plasma. These findings suggest that patients with severe sepsis might benefit from a treatment with combinations of anticoagulant agents.
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recombinant human activated protein c heparin and Melagatran in umbilical cord versus adult plasma
Acta Paediatrica, 2005Co-Authors: Martin Koestenberger, Joerg Kutschera, Siegfried Gallistl, Gerhard Cvirn, W MunteanAbstract:Aim: We investigated the anticoagulant effects of recombinant human activated protein C (rhAPC), unfractionated heparin (UH) and Melagatran (a new direct thrombin inhibitor [DTI]), when administered individually and in combinations of rhAPC with either UH or Melagatran, in umbilical cord and adult plasma. rhAPC is a promising candidate treatment to improve the outcome of severe sepsis in neonates and adults; the DTI Melagatran represents a potential advance in antithrombotic therapy. Methods: The anticoagulant efficacy of these drugs was measured using the standard coagulation assays activated partial thromboplastin time (aPTT) and prothrombin time (PT). Results: Administered individually, rhAPC, UH and Melagatran dose-dependently prolonged aPTT to a significantly greater extent in umbilical cord than in adult plasma. Melagatran alone, but not rhAPC or UH alone, dose-dependently prolonged the PT in both umbilical cord and adult plasma. Combining rhAPC with either UH or Melagatran significantly augmented aPTT prolongation in both umbilical cord and adult plasma. Conclusion: Our results, which facilitate estimation of rhAPC and Melagatran dose requirements in umbilical cord plasma, may be of benefit in critically sick newborns with severe sepsis.
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additive effects of anticoagulants recombinant human activated protein c and heparin or Melagatran in tissue factor activated umbilical cord plasma
Thrombosis and Haemostasis, 2005Co-Authors: Martin Koestenberger, Siegfried Gallistl, Bettina Leschnik, W Muntean, Peter Fritsch, Gerhard CvirnAbstract:Severe sepsis in children or adults may cause a life-threatening coagulopathy, with widespread consumption of activated protein C (APC); recombinant human APC (rhAPC) is a promising candidate anticoagulant treatment.We investigated the effects of rhAPC and other anticoagulants on coagulation triggered by adding small quantities of lipidated tissue factor to human umbilical- cord plasma in vitro .rhAPC,unfractionated heparin (UH),and Melagatran (a direct thrombin inhibitor) were studied individually, and in combinations of rhAPC with either UH or Melagatran. rhAPC alone dose-dependently prolonged the activated partial-thromboplastin time (aPTT) but not the prothrombin time (PT), and dose-dependently suppressed two indices of thrombin generation,namely prothrombin fragment F 1.2 (F 1.2) generation and thrombin–antithrombin (TAT) complex formation. UH alone dose-dependently prolonged the aPTT but not the PT, while Melagatran alone dose-dependently prolonged both the aPTT and the PT. Adding either UH or Melagatran dose-dependently augmented the capacity of rhAPC to suppress F 1.2 generation (with addition of UH showing a greater effect) and TAT formation (with addition of Melagatran showing a greater effect). Both the capacity of UH to prolong the aPTT and the capacity of Melagatran to prolong the aPTT and the PT were augmented by adding rhAPC. In our in-vitro study, adding either UH or Melagatran augmented the capacity of rhAPC to suppress thrombin generation in human umbilical-cord plasma, with the anticoagulant effect of Melagatran being more predictable than that of UH. Hence, combining rhAPC with Melagatran might be a valuable therapeutic option in patients with severe sepsis.
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effect of the new direct thrombin inhibitor Melagatran in cord and adult plasma an in vitro examination
2005Co-Authors: M Kostenberger, Siegfried Gallistl, Gerhard Cvirn, Bettina Leschnik, W MunteanAbstract:The aim of our study was to compare the effects of the new thrombin inhibitor Melagatran on markers of thrombin generation in cord and adult plasma activated with either high or low amounts of tissue factor (TF). The new direct thrombin inhibitor Melagatran acts, in contrast to the most frequently administered anticoagulant heparin, independent of the antithrombin content in plasma. In the absence of Melagatran adult plasma clotted significantly prior to cord plasma when activated with high amounts of TF, while in contrast clotting of adult plasma is significantly delayed when compared to clotting times of cord plasma under low activation. Under both high and low activation of plasma clotting times dose-dependently increased when Melagatran concentrations were successively elevated. Increasing amounts of Melagatran resulted in dose-dependently decreased F 1.2 and TAT generation in both cord and adult plasma under both high and low amounts of TF.
