Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P13726 (thromboplastin)
 8,888 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmaco-kinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUC(tau) and C(max) and digoxin AUC(t) and C(max). Digoxin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.
 ...
PMID:No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers. 1528 98

The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single-blind, randomized, placebo-controlled, parallel-group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600-mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC(0-120) and C(max) were 0.87 (0.69-1.08) and 0.86 (0.66-1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89-1.12) for AUC(0-120) and 0.92 (0.77-1.09) for C(max). The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1.21 (1.17-1.25) for melagatran AUC(0-12) and 1.23 (1.18-1.28) for melagatran C(max). These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8-1.25 for the effect of amiodarone on melagatran and 0.7-1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration-effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.
 ...
PMID:A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor. 1531 34

PD-198961, 3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-hydroxybenzenecarboximidamide, is a novel, synthetic factor Xa inhibitor with a Ki of 2.7 nM against human factor Xa. The aim of the present study was to evaluate the pharmacokinetic profile and antithrombotic efficacy of PD-198961 in rabbits. When tested in vitro, PD-198961 doubled prothrombin time (PT) and activated partial thromboplastin time (aPTT) at concentrations of 0.13 and 0.32 microM in human plasma, 0.2 and 0.09 microM in rabbit plasma, 0.3 and 0.4 microM in dog plasma, respectively. Intravenous administration of PD-198961 at 1 mg/kg over 30 minutes resulted in a maximal prolongation in PT and aPTT of 4.9 +/- 0.4 and 4.1 +/- 0.9-fold of baseline, respectively. The peak plasma concentration of PD-198961 was 977 +/- 96 ng/ml. The anticoagulant effect of PD-198961 was readily reversible; coagulation parameters and plasma concentration returned to near baseline 15 minutes after cessation of infusion. There was a good correlation between PT prolongation and plasma concentration of PD-198961 (r = 0.93). In an FeCl3-induced model of arterial thrombosis in rabbits, the antithrombotic effects of PD-198961 were compared with that of LB-30057, a direct thrombin inhibitor, and enoxaparin, a low molecular weight heparin (LMWH). PD-198961 dose dependently increased the time to occlusion (TTO), reduced thrombus weight (TW), and decreased the incidence of occlusion. When administered at 3.0 microg/kg/min IV, PD-198961 prolonged TTO from 28 +/- 5 minutes (control) to 120 +/- 0 minutes (P < 0.001) and reduced TW from 9.9 +/- 1.5 mg (control) to 2.8 +/- 0.9 mg (P < 0.01). PD-198961 also dose dependently inhibited ex vivo plasma FXa activity. At the highest dose tested, PD-198961 increased aPTT to 1.4 +/- 0.1-fold of baseline (compared with 1.5 +/- 0.1 and 2.8 +/- 0.3-fold of baseline for LB-30057 [CI-1028] and enoxaparin, respectively), and had modest effects on bleeding time (< or = 2-fold). These results indicate that PD-198961 is a potent FXa inhibitor and an effective antithrombotic agent at doses that produce only modest changes in normal hemostasis.
 ...
PMID:In vitro and in vivo antithrombotic activity of PD-198961, a novel synthetic factor Xa inhibitor. 1545 59

We investigated the anticoagulant effects of argatroban, a direct thrombin inhibitor, versus heparin in extracorporeal membrane oxygenation (ECMO) circuits. Three sham circuits were prepared according to our hospital's standard practice and run for six hours simultaneously. Two circuits were anticoagulated with argatroban (one with heparin in the wet prime and one without). One circuit had heparin in the initial prime and was then anticoagulated with heparin. We measured thrombin generation (prothrombin fragment 1+2, D-dimer and thrombin-antithrombin complexes), activated clotting times (ACTs) and partial thromboplastin times (aPTTs), and monitored thrombus formation using thromboelastography. ACTs were >1000 s in each circuit throughout assessment. No clot initiation was detected by thromboelastography. Thrombin generation was decreased in circuits anticoagulated with argatroban versus heparin, despite aPTTs being less prolonged. These results suggest that argatroban may be more efficacious than heparin for anticoagulation in ECMO. Additional studies are warranted to further evaluate argatroban in this setting.
 ...
PMID:Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits. 1550 32

Recombinant human activated protein C (rhAPC) has recently been demonstrated to be a promising candidate to improve the outcome for patients with severe sepsis. Plasma-derived activated protein C and unfractionated heparin (UH) exert anticoagulant synergy due to mechanisms that simultaneously decrease thrombin generation. Melagatran, a new direct thrombin inhibitor, does not bind to plasma proteins or requires antithrombin as a cofactor. The latter is often consumed in patients with severe sepsis. We investigated the anticoagulant efficiency in combined administration of rhAPC and UH or melagatran in terms of prolongation of the standard clotting assays activated partial thromboplastin time (aPTT) and prothrombin time (PT) in pooled plasma samples in vitro. RhAPC dose-dependently prolonged the aPTT but not the PT. The ability of UH and melagatran to prolong the aPTT was significantly enhanced in combination with rhAPC. The combined administration of rhAPC and melagatran, but not UH, resulted in additive prolongation of the PT. In control measurements the capability of rhAPC to suppress prothrombin fragment 1.2 generation dose-dependently increased in combination with heparin and melagatran. Our study demonstrates the respective effects of rhAPC, UH, melagatran and further different additive effects in combined administration of rhAPC and UH or melagatran on the prolongation of the aPTT and PT clotting assays usually used to monitor anticoagulant treatment.
 ...
PMID:Drotrecogin alfa activated (recombinant human activated protein C) in combination with heparin or melagatran: effects on prothrombin time and activated partial thromboplastin time. 1561 25

Protease specificity is crucial to the design of thrombin inhibitors as inhibition of other physiologically relevant serine-proteases can compromise their clinical use. Dipetarudin, a potent thrombin inhibitor, also inhibits trypsin and plasmin. Due to the specificity of an inhibitor being influenced by the amino acid residue at the P1 position, we replaced the Arg10 at P1 position of dipetarudin by a histidine, which is the P1 residue of rhodniin, a very specific thrombin inhibitor. The amino acid replacement was carried out by site directed mutagenesis. The mutant, dipetarudinR10H, showed a loss of plasmin and trypsin inhibitory activities present in its wild-type counterpart and a 3-fold higher dissociation constant for thrombin than dipetarudin. However, compared to dipetarudin and r-hirudin, dipetarudinR10H showed similar activity in coagulation screening assays such as activated partial thromboplastin time (aPTT), prothrombin time (PT), ecarin clotting time (ECT) and ecarin chromogenic assay (ECA).
 ...
PMID:Improvement of the specificity of dipetarudin by site directed mutagenesis. 1573 91

Heparin-induced thrombocytopenia (HIT) is a major obstacle in cardiovascular surgeries. In this case report, we used argatroban, a direct thrombin inhibitor, to achieve and maintain anticoagulation for carotid endarterectomy. Unlike heparin, the direct thrombin inhibitors bind directly to thrombin, bypassing antithrombin III and the potential to precipitate HIT. A bolus of argatroban 150 microg/kg followed by an infusion of 5 microg . kg(-1) . min(-1) was used, and adequate anticoagulation was demonstrated with multiple laboratory tests (at 28 min, prothrombin time = 29.8 s, partial thromboplastin time = 69.1 s, international normalized ratio = 3.52 s, and activated clotting time = 220 s). The surgery was successful, and the patient was discharged the next day with no postoperative neurologic sequelae or other complications. We conclude that argatroban can be used safely and successfully for carotid endarterectomy in a patient with a history of HIT.
 ...
PMID:The use of argatroban for carotid endarterectomy in heparin-induced thrombocytopenia. 1636 57

Argatroban is a direct thrombin inhibitor used for the treatment of heparin-induced thrombocytopenia. The drug is administered by continuous infusion, at a recommended initial dose of 2 microg/kg per min, to achieve activated partial thromboplastin times (aPTTs) 1.5-3.0 times baseline. We evaluated the effect of argatroban, at clinically relevant concentrations, on aPTTs using 21 commercially available reagents. The aPTTs of plasma containing argatroban at 0.125-8.0 microg/ml (final concentration) were assessed using each reagent and an ACL 3000+ coagulation analyzer. Argatroban increased aPTTs (and aPTT ratios relative to control) in a broadly comparable fashion among reagents. Concentration-aPTT ratio profiles linearized well using logarithmic-logarithmic transformation (r > 0.98), with the regression slope taken as the reagent's sensitivity to argatroban. Sensitivity ranged from 0.304 +/- 0.006 to 0.364 +/- 0.007. Only the least and two most sensitive reagents (all now unavailable in the United States) differed significantly in sensitivity from the other reagents (P < 0.05). aPTT ratios of 2.25 occurred for all reagents at 0.41-0.92 mug/ml argatroban, and for 14 (67%) reagents at 0.53-0.67 microg/ml. This corresponds to a approximately 0.5 microg/kg per min dose difference in healthy subjects. We conclude that most aPTT reagents are similarly sensitive to argatroban, and reagent choice is unlikely to significantly affect argatroban monitoring in patients with heparin-induced thrombocytopenia.
 ...
PMID:Effect of argatroban on the activated partial thromboplastin time: a comparison of 21 commercial reagents. 1587 May 44

Argatroban, a direct thrombin inhibitor used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT), is routinely monitored using the activated partial thromboplastin time (aPTT) yet also prolongs the international normalized ratio (INR). Peritransitional INRs, aPTTs, anticoagulant dosing patterns, and outcomes were evaluated in 165 HIT patients who were transitioned, without guidelines, from argatroban to warfarin therapy. Argatroban (median doses: 1.5-2.0 mcg/kg/min) and warfarin (median dose: 5 mg initially with 3.8 mg/day thereafter) overlapped a median 4 days. Median (5-95th percentile) aPTTs (in seconds) and INRs, respectively, were 59.8 (38.8-82.9) and 3.2 (1.7-7.0) during argatroban monotherapy, 68.6 (44.5-104) and 5.3 (2.4-16) maximally during cotherapy, 59.9 (38.7-92.2) and 4.0 (2.2-11.6) immediately before argatroban cessation during cotherapy, and 36.0 (25.6-60.2) and 2.3 (1.3-7.3) within a median 10-12 hours after argatroban cessation. Major bleeding occurred in 1 (0.6%) patient pretransitionally and no patient during or after cotherapy. Eighteen (10.9%) patients experienced 19 peritransitional adverse outcomes (one death, two amputations, 16 new thromboses); these patients had more severe HIT than event-free patients (median baseline platelet count, 39 vs. 83 x 10(9)/L). Of 108 patients with post-transitional INR data, 43 achieved a therapeutic INR (prospectively defined as 1.9-3.5), 34 were subtherapeutic, and 31 were supratherapeutic, with no across-group trend in new thrombosis. Hence in the absence of guidelines, physicians transfer patients from argatroban to warfarin therapy with acceptably low complication rates in HIT, without systematically over- or under-dosing warfarin. Furthermore, INRs greater than 5 commonly occur in HIT patients during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding.
 ...
PMID:Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. 1601 13

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.
 ...
PMID:Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma. 1611 86


<< Previous 1 2 3 4 5 6 7 8 9 10