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Thrombin Inhibitor (thrombin + inhibitor)
Kinds of Thrombin Inhibitor Selected AbstractsCutting through the statistical fog: understanding and evaluating non-inferiority trialsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 10 2010W. S. Weintraub Summary Every year, results from many important randomised, controlled trials are published. Knowing the elements of trial design and having the skills to critically read and incorporate results are important to medical practitioners. The goal of this article is to help physicians determine the validity of trial conclusions to improve patient care through more informed medical decision making. This article includes a review of 162 randomised, controlled non-inferiority (n = 116) and equivalence (n = 46) hypothesis studies as well as the larger Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation V study and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial. Evaluation of data from small and large trials uncovers significant flaws in design and models employed and uncertainty about calculations of statistical measures. As one example of questionable study design, discussion includes a large (n = 3922), double-blind, randomised, multicentre trial comparing the efficacy of ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and additional stroke risk factors. Investigators concluded that ximelagatran was effective compared with well-controlled warfarin for prevention of thromboembolism. However, deficiencies in design, as well as concerns about liver toxicity, resulted in the rejection of the drug by the US Food and Drug Administration. Many trials fail to follow good design principles, resulting in conclusions of questionable validity. Well-designed non-inferiority trials can provide valuable data and demonstrate efficacy for beneficial new therapies. Objectives and primary end-points must be clearly stated and rigorous standards met for sample size, establishing the margin, patient characteristics and adherence to protocol. [source] 3-Amino-4-sulfonylpyridinone Acetamide and Related Pyridothiadiazine Thrombin Inhibitors.CHEMINFORM, Issue 29 2003Philip E. J. Sanderson Abstract For Abstract see ChemInform Abstract in Full Text. [source] Cyanopeptide Analogues: New Lead Structures for the Design and Synthesis of New Thrombin Inhibitors.CHEMINFORM, Issue 7 2003G. Radau Abstract For Abstract see ChemInform Abstract in Full Text. [source] Anticoagulation Options for Pediatric HemodialysisHEMODIALYSIS INTERNATIONAL, Issue 2 2003Andrew Davenport Blood coagulation in the extracorporeal hemodialysis circuit is one of the manifestations of bio-incompatibility that is related to the activation of monocytes, platelets, and the coagulation cascades. Compared to adults, in pediatric patients, the surface area of the extracorporeal circuit is increased relative to blood volume. This is due to the patient's smaller blood volume and the combination of the higher relative surface area of the dialyzer, smaller lumen lines, and small-bore vascular catheters, potentially increasing contact activation of coagulation proteins, platelets, and inflammatory cells. Although unfractionated heparin remains the most commonly used anticoagulant, low molecular weight heparin offers the advantages of a single bolus, less fibrin and platelet deposition in the dialyzer, and perhaps more importantly, less osteoporosis, hyperkalemia, and abnormal lipoprotein profile. Although regional anticoagulants are available, these are often prohibitively expensive or require increased complexity of the dialysis procedure (e.g., citrate), but have the advantage of reducing the risk of bleeding when compared to heparin. Thrombin inhibitors are now available, and with the advent of argatroban, which is metabolized in the liver, have become the anticoagulants of choice for the few patients who develop heparin-induced thrombocytopenia type II. [source] Etiology of thrombocytopenia in all patients treated with heparin productsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2005Damian A. Laber Abstract:,Purpose:,To characterize the cause of thrombocytopenia in all patients treated with heparin products, to determine the incidence of heparin-induced thrombocytopenia (HIT) in unselected hospitalized patients, and to have modern data of the magnitude of this problem. Methods:,Retrospective hospital-based cohort study. During a random 2-month period, we reviewed the medical records of all patients treated with heparin agents, screened them for thrombocytopenia, and determined the cause of it. Results:,Out of 674 patients who received heparin products, 110 (16%) had thrombocytopenia. The most common causes included cancer chemotherapy, surgery, sepsis, and medications. Three patients met the clinical criteria for HIT. One had antibodies for heparin-platelet factor-4, and received a direct thrombin inhibitor. The other two individuals had a clinical syndrome that resembled immune HIT, but were not tested for HIT antibodies. One suffered a thrombotic episode that led to the death of her fetus. The other died of a possible thromboembolism. Conclusions:,This study provides evidence-based data for the differential diagnosis of thrombocytopenia after treatment with heparin products. Our findings suggest that increased awareness of the HIT syndrome might reduce morbidity and mortality. Patients exposed to heparin products, who develop thrombocytopenia, should not be overlooked. [source] Deep Hypothermic Circulatory Arrest and Bivalirudin Use in a Patient With Heparin-Induced Thrombocytopenia and Antiphospholipid SyndromeJOURNAL OF CARDIAC SURGERY, Issue 1 2007Kay B. Leissner M.D. Methods: Bivalirudin was used during CPB and deep hypothermic circulatory arrest (DHCA) for resection of multiple right atrial masses in a patient with HIT II and antiphospholipid antibodies syndrome (APS). Anticoagulation was monitored with the activated clotting time (ACT) and a target ACT of 450 seconds or greater was maintained. Results: Surgical removal of multiple right atrial masses was successful and there was no evidence of thromboembolic events. Clot was noticed in the cardiotomy and venous reservoir after CPB was discontinued and the system flushed. The postoperative course was uneventful. Conclusions: Anticoagulation was successfully managed with bivalirudin, a new short-acting, and direct thrombin inhibitor. Further studies are necessary to evaluate the safety of bivalirudin during DHCA. [source] Radiosynthesis of [11C]ximelagatran via palladium catalyzed [11C]cyanationJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2008Anu J. Airaksinen Abstract N -hydroxyamidines (amidoximes) may be used in prodrug technology in improving oral bioavailability of drugs containing amidino functional groups. In the body, amidoximes are reduced quickly to amidines by enzymes that are present in several organs. Ximelagatran is a benzamidoxime and ethyl ester prodrug of melagatran, which is a thrombin inhibitor. Our aim was to develop a fast and efficient labeling route for the synthesis of [11C]ximelagatran ([11C]3) with a label in a metabolically stable position. [11C]3 was synthesized via a two-step synthesis sequence, starting from palladium catalyzed [11C]cyanation of its corresponding bromide precursor (2-[2-(4-bromo-benzylcarbamoyl)-azetidin-1-yl]-1-cyclohexyl-2-oxo-ethyl amino-acetic acid ethyl ester) (1), followed by a reaction with hydroxylamine. [11C]3 was synthesized with 27±17% total overall decay corrected yield (specific radioactivity of 2360±165,Ci/mmol at EOS), with a total synthesis time of 45,min. A fast and efficient labeling route for the synthesis of [11C]3 was developed. Copyright © 2008 John Wiley & Sons, Ltd. [source] Experimental metastasis and primary tumor growth in mice with hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2006F. LANGER Summary., During experimental lung metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study experimental metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg,1), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding. [source] The role of thrombin in gliomasJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2005Y. HUA Summary.,Background:,In a previous study we found that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurologic deficits in a C6 glioma model. Objectives:,To examine the role of thrombin in gliomas and whether systemic argatroban administration can reduce glioma mass and neurologic deficits and extend survival time in C6 and F98 gliomas. Methods:,The presence of thrombin in human glioblastoma samples and rat C6 glioma cells (in vitro and in vivo) was assessed using immunohistochemistry. The effect of thrombin on C6 cell proliferation in vitro was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The role of thrombin in vivo was assessed in rat C6 and F98 glioma cell models using argatroban, a thrombin inhibitor. The effects of argatroban on tumor mass, neurologic deficits and survival time were investigated. Results:,Thrombin immunoreactivity was found in cultured rat C6 glioma cells and human glioblastomas. Thrombin induced C6 cell proliferation in vitro. In C6 glioma, argatroban reduced glioma mass (P < 0.05) and neurologic deficits (P < 0.05) at day 9. In F98 glioma, argatroban prolonged survival time (P < 0.05). Conclusion:,These results suggest that thrombin plays an important role in glioma growth. Thrombin may be a new therapeutic target for gliomas. [source] Thrombin induces neoangiogenesis in the chick chorioallantoic membraneJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003M. Caunt Summary., Most tumors have constitutively active tissue factor on their surface, capable of generating thrombin in the surrounding environment, and thrombosis is associated with cancer. Thrombin is known to induce a malignant phenotype by enhancing tissue adhesion and cell growth in vitro and in vivo in mice. Because tumors require angiogenesis for growth, we examined whether thrombin induces neoangiogenesis in a physiologically intact in vivo model. Thrombin (0.1 U mL,1) induced neoangiogenesis in the chick chorioallantoic membrane over a 24,72-h period by approximately 2,3-fold. This was inhibited by the potent thrombin inhibitor, hirudin and shown to have its mode of action by ligation of the thrombin protease-activated receptor, PAR-1. The thrombin receptor activation peptide, SFLLRNPNDKYEPF (200 µm) also enhanced neoangiogenesis c. 2,3-fold. Thrombin-induced neoangiogenesis was accompanied by the induction of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) mRNA at 24,48 h (approximately 2-fold) as determined by semi-quantitative reverse transcriptase-polymerase chain reaction. Thrombin-induced neoangiogenesis was inhibited to baseline level by the specific angiogenesis receptor inhibitors KDR-Fc (vs. VEGF) and Tie-2-Fc (vs. Ang-1 and Ang-2), as well as the non-specific angiogenesis inhibitor thrombospondin-1. Thrombin-induced neoangiogenesis was also inhibited to baseline level by agents known to inhibit thrombin receptor signaling in other cells: G-coupled protein receptor inhibitor, pertussis toxin (40 pg per egg), protein kinase C inhibitor, bisindolylmaleimide (1 µm per egg), MAP kinase inhibitor, PD980598 (10 µm per egg) and PI3 kinase inhibitor, LY294002 (0.25 µm per egg). Thus angiogenesis is stimulated by thrombosis, which could help explain the enhancement of experimental tumorigenesis by thrombin. [source] Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activityJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2003G. M. T. Vogel Summary., Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man. [source] The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: Successful treatment with direct thrombin inhibitor and fresh plasma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2009Takashi Suzuki A 71-year-old woman and her elder sister developed ligneous conjunctivitis after ocular surgery. Laboratory tests demonstrated that the proband and her sister had 6.6% and 8.1% of plasminogen activity, and 1.2 and 1.4 mg/dl of antigen, respectively. Thus, they were diagnosed as having severe type I plasminogen deficiency, for the first time, in Japan. DNA sequencing and PCR-RFLP analyses revealed that these two cases are homozygotes of a novel A-to-G mutation at the obligatory splicing acceptor site in intron-C. Both cases were satisfactorily treated with a direct thrombin inhibitor, topical Argatroban, and topical plasma obtained from their healthy family members. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 9 2008Article first published online: 21 MAY 200 Dabigatran launched Dabigatran (Pradaxa), an orally active direct thrombin inhibitor, has been introduced for the prophylaxis of venous thromboembolism in patients undergoing elective total hip or knee replacement. Treatment is initiated within four hours of surgery and continued for 10 days after knee replacement and 28-35 days after hip replacement. Dabigatran has been shown to be as effective and well tolerated as enoxaparin (Clexane). The launch was widely publicised in the lay media; the charity Lifeblood claimed it could help prevent tens of thousands of deaths. NICE is preparing a technology appraisal of the new agent but it has not announced a publication date. Loop diuretics may increase bone loss Continuous use of a loop diuretic appears to double the rate of bone loss in men compared with nonusers, an observational study suggests (Ann Intern Med 2008;168: 735-40). Up to five years' follow-up of 3269 men aged over 65 revealed that the mean rate of bone loss in the hip among those who did not use a loop diuretic was 0.33 per cent compared with 0.78 per cent among users and 0.58 per cent in those who had intermittently used a loop diuretic. Use of these agents should be included as a risk factor for fractures, the authors suggest. Rosuvastatin not for heart failure patients? Prescribers should pause before using rosuvastatin (Crestor). in patients with heart failure and ischaemic heart disease, the National Prescribing Centre (NPC). says. Commenting on the CORONA trial (N Engl J Med 2008; published online 5 Nov 2007; 10.1056/NEJMoa 0706201)., which found no reduction in cardiovascular events or mortality in older patients with systolic heart failure despite a reduction in LDL-C, the NPC says GPs should still consider evidence-based statins such as simvastatin in this patient group. The reason for the outcome of CORONA is unclear but the NPC points out that not all statins affect mortality equally. Rimonabant CV benefits sustained Two-year follow-up of the RIO-Europe trial has shown that the benefits of rimonabant (Acomplia). on weight loss and cardiovascular risk factors are sustained with continuing treatment (Eur Heart J 2008; published online doi: 10.1093/ eurheartj/ehn076). In addition to a dietary deficit of 600kcal per day, rimonabant 20mg per day achieved greater mean weight loss (5.5 vs 1.2kg). and improvements in waist circumference, HDL-cholesterol, triglycerides, fasting glucose and insulin levels, insulin resistance, and metabolic syndrome prevalence compared with placebo. Many patients discontinued treatment (placebo 42 per cent, rimonabant 45 per cent). but, although psychiatric events were more common with rimonabant during the first year, there was little difference in patients remaining in the second year. Early glatiramer cuts MS progression risk Early treatment with glatiramer acetate (Copaxone). appears to reduce the risk of progression to multiple sclerosis (MS), according to a study presented at the 60th Annual Meeting of the American Academy of Neurology in Chicago. Interim analysis of the PreCISE trial showed that, in patients with a single episode and MRI suggestive of MS, glatiramer was associated with a lower incidence of progression to a second episode of MS compared with placebo (25 vs 43 per cent). The placebo arm of the trial has now been stopped. NRT before quitting Beginning nicotine replacement therapy (NRT) before stopping smoking may double the six-month success rate compared with beginning treatment on the scheduled quit day, a meta-analysis suggests (Addiction 2008;103: 557-63). The analysis of four trials involving 755 participants found that starting NRT two to four weeks before the agreed quit date was twice as likely as the conventional strategy to achieve abstinence after six weeks and six months. Copyright © 2008 Wiley Interface Ltd [source] Anti-thrombin Therapy During Warm Ischemia and Cold Preservation Prevents Chronic Kidney Graft Fibrosis in a DCD ModelAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010F. Favreau Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran® (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-, (TGF-,) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival. [source] Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblastsARTHRITIS & RHEUMATISM, Issue 11 2009Galina S. Bogatkevich Objective Myofibroblasts are the principal mesenchymal cells responsible for tissue remodeling, collagen deposition, and the restrictive nature of lung parenchyma associated with pulmonary fibrosis. We previously reported that thrombin activates protease-activated receptor 1 (PAR-1) and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. We undertook this study to investigate whether a selective direct thrombin inhibitor, dabigatran, interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1. Methods Lung fibroblast proliferation was analyzed using the Quick Cell Proliferation Assay. Expression and organization of ,-smooth muscle actin (,-SMA) was studied by immunofluorescence staining and immunoblotting. Contractile activity of lung fibroblasts was measured by a collagen gel contraction assay. Connective tissue growth factor (CTGF) and type I collagen expression was analyzed on Western blots. Results Dabigatran, at concentrations of 50,1,000 ng/ml, inhibited thrombin-induced cell proliferation, ,-SMA expression and organization, and the production of collagen and CTGF in normal lung fibroblasts. Moreover, when treated with dabigatran (1 ,g/ml), scleroderma lung myofibroblasts produced 6-fold less ,-SMA, 3-fold less CTGF, and 2-fold less type I collagen compared with untreated cells. Conclusion Dabigatran restrains important profibrotic events in lung fibroblasts and warrants study as a potential antifibrotic drug for the treatment of fibrosing lung diseases such as scleroderma lung disease and idiopathic pulmonary fibrosis. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim Stangier Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source] Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery diseaseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2001Marie Cullberg Aims, The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease. Methods, Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT. Results, The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s l µmol,1, Emax 36 and 34 s, and EC50 0.54 and 0.72 µmol l,1, respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 µmol l,1 in the healthy volunteer and patient, respectively. Conclusions, The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre-specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects. [source] Synthesis of Novel Peptide Inhibitors of Thrombin-induced Platelet ActivationCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2006Fernanda M. Burke Inhibitors of the activation of platelet aggregation have promise as important therapeutic agents for the management of acute coronary syndrome (ACS). Platelet activation by thrombin, a serine protease, occurs by binding to and cleavage of the extracellular N-terminal domains of protease-activated receptors 1 and 4 (PAR1 and PAR4). The proteolysis of the PARs exposes new tethered ligands that then signal through transmembrane domains to initiate platelet activation as a downstream effect. A pentapeptide cleavage product of bradykinin with the sequence Arg-Pro-Pro-Gly-Phe serves as a thrombin inhibitor by blocking , - and , -thrombin-induced platelet aggregation. Analogs of RPPGF have been prepared that result in improved inhibition of thrombin activation of platelets. Specific amino acid residues required for activity against platelet aggregation have been identified, and a lead compound, rOicPaPhe(p -Me)-NH2 (FM19), has been developed. FM19, which completely inhibits threshold , -thrombin-induced platelet aggregation at a concentration of 16 ± 4 ,m, represents an important lead compound in the development of inhibitors of thrombin-mediated platelet aggregation for treatment of ACS. [source] Current concepts for the prevention of venous thromboembolismEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005P. Bramlage Abstract Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide and the annual incidence of VTE is 1 per 1000. The individual risk for venous thromboembolism may be substantially higher and is determined by expositional and dispositional factors. Unfractionated heparin and warfarin have been the mainstays for the prevention of VTE until the early 1980s. Bleeding complications and side effects limited the use of these agents and subsequently low molecular weight heparins (LMWH) were introduced into clinical practice. These are most commonly used for the prophylaxis and treatment of VTE today. In the last decade, the pace of development of further anticoagulants has accelerated with the introduction of new treatment regimens and new substances. In this context, novel drugs directed against clotting factor Xa (such as fondaparinux) and direct thrombin inhibitors (such as melagatran/ximelagatran) have been developed. Fondaparinux shows a favourable efficacy/safety profile and has been documented to be cost-effective compared to enoxaparin in the US and the UK. [source] Atrial fibrillation: insights from clinical trials and novel treatment optionsJOURNAL OF INTERNAL MEDICINE, Issue 6 2007Y. Blaauw Abstract., Blaauw Y, Crijns HJGM (University Hospital Maastricht, Maastricht, The Netherlands). Atrial fibrillation: insights from clinical trials and novel treatment options (Review). J Intern Med 2007; 262: 593,614. Atrial fibrillation (AF) is the most common encountered sustained arrhythmia in clinical practice. The last decade the result of large ,rate' versus ,rhythm' control trials have been published that have changed the current day practise of AF treatment. It has become clear that rate control is at least equally effective as a rhythm control strategy in ameliorating morbidity as well as mortality. Moreover, in each individual patient the risk of thromboembolic events should be assessed and antithrombotic treatment be initiated. There have also been great advances in understanding the mechanisms of AF. Experimental studies showed that as a result of electrical and structural remodelling of the atria, ,AF begets AF'. Pharmacological prevention of atrial electrical remodelling has been troublesome, but it seems that blockers of the renin angiotensin system, and perhaps statins, may reduce atrial structural remodelling by preventing atrial fibrosis. Clinical studies demonstrated that the pulmonary veins exhibit foci that can act as initiator and perpetuator of the arrhythmia. Isolation of the pulmonary veins using radiofrequency catheter ablation usually abolishes AF. The most promising advances in the pharmacological treatment of AF include atrial specific antiarrhythmic drugs and direct thrombin inhibitors. In the present review we will describe the results of recent experimental studies, discuss the latest clinical trials, and we will focus on novel treatment modalities. [source] Scoring ligand similarity in structure-based virtual screeningJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2009Maria I. Zavodszky Abstract Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein,ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein,ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70,000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein,ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein,ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein,ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring function, and from the different scoring functions, proved to be conserved interactions in known inhibitors. This was particularly true in the S1 pocket, which was occupied by all the docked compounds. Copyright © 2009 John Wiley & Sons, Ltd. [source] Factor Xa or thrombin: is factor Xa a better target?JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2007J. ANSELL Summary., Existing vitamin K antagonists (VKAs) have drawbacks that limit their effectiveness, safety, and overall frequency of use. Oral anticoagulants in development with targeted action against individual coagulation factors, specifically direct factor (F) Xa and IIa inhibitors, appear to have pharmacokinetic and pharmacodynamic properties that overcome the limitations of the VKAs. Based on the theory of how coagulation factors interact, on the results of in vitro studies, and on clinical outcomes, there is accumulating evidence that FXa may represent a better target for inhibition than FIIa. This is based on an understanding of the amplified nature of coagulation factor interactions and fibrin formation, the need for smaller doses of an anticoagulant to block coagulation progression earlier in the sequence of reactions, the evidence for incomplete suppression of thrombin generation with direct thrombin inhibitors, evidence for rebound hypercoagulability with thrombin inhibitors, and clinical results with the indirect, parenteral, FXa inhibitor (fondaparinux), as well as early phase II results of new oral Xa and IIa inhibitors compared with enoxaparin. The latter studies, although not comparative, provide some evidence for the effectiveness and safety of Xa inhibitors at a range of doses not seen with the direct IIa inhibitors. [source] Progress in the design of low molecular weight thrombin inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 1 2005Stuti Srivastava Abstract Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed. © 2004 Wiley Periodicals, Inc. [source] Laboratory tests for protein C deficiency,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2010Bernard Khor Hereditary protein C deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis. The recommended initial test for protein C is an activity (functional) assay, which may be clotting time based or chromogenic. The advantages and disadvantages of the various testing options are presented. The causes of acquired protein C deficiency are much more common than hereditary deficiency. Therefore, this article describes the appropriate steps to take when protein C activity is low, to confirm or exclude a hereditary deficiency. The causes of falsely normal results are also described, including lupus anticoagulants and direct thrombin inhibitors. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Laboratory monitoring of new anticoagulants,AMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2010Donna D. Castellone Maintaining a balance between bleeding and clotting has always been a challenge in treating coagulation disorders. A perturbation in that balance can be associated with substantial morbidity and mortality. As a result, anticoagulant monitoring is extremely important, and inappropriate testing may lead to complications. There are now a variety of new anticoagulant drugs in clinical use including several direct thrombin inhibitors (DTIs), such as argatroban, bivalirudin, and hirudin, as well as a Factor Xa inhibitor, fondaparinux. There are pitfalls associated with some of the currently used laboratory monitoring tests, and newer alternative laboratory monitoring tests have been investigated (Walenga and Hoppensteadt, Semin Thromb Hemost 2004;30:683,695). In addition, laboratory testing can assist with transitioning patients from DTI to warfarin therapy. Am. J. Hematol. 2010. © 2009 Wiley-Liss, Inc. [source] Update on Atrial Fibrillation: Part ICLINICAL CARDIOLOGY, Issue 2 2008Irina Savelieva M.D. Abstract Atrial fibrillation (AF) is an epidemic, affecting 1% to 1.5% of the population in the developed world. Projected data from the population-based studies suggest that the prevalence of AF will grow at least 3-fold by 2050. The health and economic burden imposed by AF and AF-related morbidity is enormous. Atrial fibrillation has a multiplicity of causes ranging from genetic to degenerative, but hypertension and heart failure are the commonest and epidemiologically most prevalent conditions associated with AF as both have been shown to create an arrhythmogenic substrate. Several theories emerged regarding the mechanism of AF, which can be combined into two groups: the single focus hypothesis and the multiple sources hypothesis. Several lines of evidence point to the relevance of both hypotheses to the mechanism of AF, probably with a different degree of involvement depending on the variety of AF (paroxysmal or persistent). Sustained AF alters electrophysiological and structural properties of the atrial myocardium such that the atria become more susceptible to the initiation and maintenance of the arrhythmia, a process known as atrial remodeling. Angiotensin II has been recognized as a key element in atrial remodeling in association with AF opening the possibility of exploitation of "upstream" therapies to prevent or delay atrial remodeling. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. The limitations of warfarin prompted the development of new antithrombotic drugs, which include anticoagulants, such as direct oral thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). Novel mechanical approaches for the prevention of cardioembolic stroke have recently been evaluated: percutaneous left atrial appendage occluders, minimally invasive surgical isolation of the left atrial appendage, and implantation of carotid filtering devices. Copyright © 2008 Wiley Periodicals, Inc. [source] Evolution of Anticoagulant and Antiplatelet Therapy: Benefits and Risks of Contemporary Pharmacologic Agents and Their Implications for Myonecrosis and Bleeding in Percutaneous Coronary InterventionCLINICAL CARDIOLOGY, Issue S2 2007Hector M. Medina M.D., M.P.H. Abstract Periprocedural myonecrosis, as evidenced by elevated creatine kinase,myocardial bound (CK-MB) levels, occurs in up to 25% of patients undergoing percutaneous coronary intervention (PCI) and has been linked with an increased risk of adverse short- and long-term clinical outcomes. Such myonecrosis arises from three main pathophysiological mechanisms: procedure-related complications, lesion-specific characteristics (e.g., large thrombus burden, plaque volume), and patient-specific characteristics (e.g., genetic predisposition, arterial inflammation). Periprocedural myonecrosis has not been definitively identified as the cause of postprocedural ischemic events, although agents that reduce or prevent thrombosis,including aspirin, thienopyridines, heparin, low-molecular-weight heparins, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors,have been shown to reduce the incidence of ischemic outcomes in this population, as have agents that reduce inflammation (aspirin, statins). At the same time, antithrombotic agents are known to increase the risk of bleeding and the use of transfusions, which have likewise been associated with worse outcomes in these patients. Thus, optimal management of patients undergoing PCI represents a balance between minimizing the risk of ischemic outcomes and simultaneously minimizing the risk of major bleeding. It may be that patients who have only minor, untreated postprocedural elevations in CK-MB level (with no clinical or angiographic signs of ischemia) might have a better prognosis than patients who have normal CK-MB levels but who suffer major bleeding complications. Copyright © 2007 Wiley Periodicals, Inc. [source] | |||||||||||||||||||||||||