10 research outputs found
Reversible elevations of serum creatinine levels but no effect on glomerular filtration during treatment with the direct thrombin inhibitor AZD0837
Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects
Venous thromboembolism. Aspects on risk factors, diagnostic tools and treatment with thrombin inhibition
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a multifactorial disease. The aims of the present thesis were to investigate Factor V Leiden and prothrombin G20210A mutations as potential risk factors for VTE during and after major surgery, to compare different D-dimer assays and evaluate their usefulness in the diagnosis of DVT, to investigate clinical effects, safety and pharmacokinetic properties of an oral thrombin inhibitor (ximelagatran) when treating VTE and finally to investigate the usefulness of coagulation assays (APTT and PT) during treatment with thrombin inhibition.In a European population (n=1600) subjected to elective orthopaedic surgery the prothrombin gene G20210A mutation was found to be a risk factor (OR=9.2, p<0.0002) for symptomatic VTE after elective surgery. The Factor V Leiden mutation was found to be a risk factor only for symptomatic PE (OR=5.3, p<0.03). During the 8 to 11-day period with mandatory anticoagulation prophylaxis no significant risk for any of the mutations for objectively verified VTE, mainly consisting of venographic screened DVT, was seen (OR=1.25, p=0.35). Despite establishing these point mutations as genetic risk factors, approximately 90% of the carriers will not suffer a symptomatic postoperative VTE when given prophylaxis and therefore general preoperative screening may be of questionable value.In a population of 95 consecutive patients, undergoing venography because of a suspicion of DVT, 40% of the venographies in our study verified thrombosis. During thrombus formation the simultaneous endogenous fibrinolysis will release fibrin degradation products measurable as plasma D-dimers. The positive predictive values for DVT diagnosis using plasma D-dimer tests are low and insufficient for clinical use when utilising venography verified DVT as the reference. The negative predictive values for the DVT diagnosis was in this study 82-100 % at a cut-off of 0.5 mg/L for conventional ELISAs, rapid membrane and latex tests. Thus, these tests may be one of several useful tools for excluding DVT. In two clinical studies initial treatments of acute DVT (350 patients) and PE (12 patients) with four fixed doses (24 - 60 mg bid) of ximelagatran were evaluated. In the DVT study LMWH/warfarin was used as a comparator. For DVT patients there were no significant differences between the treatment groups in changes of thrombus sizes, bleeding frequencies, clinical effects, mortalities or treatment discontinuations. In the PE treatment (48 mg bid), 11 of 12 patients showed regressed or unchanged scintigrafic signs of PE. Ximelagatran showed a reproducible pharmacokinetic and pharmacodynamic profile over the 6-9 days of treatment. The maximal plasma melagatran concentrations were obtained 2 - 2.4 h after intake and the half-life in plasma was 3.5 - 3.7 h. The onset of action was rapid, measured as prolongations of APTT, and there was a good correlation (R2 = 0.69) between plasma concentrations of melagatran and APTT values. Oral fixed doses were used in the clinical studies without coagulation monitoring. In an in vitro study the effects of melagatran on 17 different prothrombin time assays showed significant differences both in dose-response curves and in effects on INR values. These tests, standardized for treatment with vitamin K antagonists, are not suitable for monitoring the effects of thrombin inhibitors
Recommended from our members
Alpha2-adrenoreceptor stimulation does not inhibit L-type calcium channels in mouse pancreatic β-cells
The effects of α2-adrenergic stimulation on the Ca2+-current in mouse pancreatic β-cells were investigated using the patch-clamp technique. When using the conventional whole-cell recording configuration (dialysis of cell interior with pipette solution), addition of adrenaline (1 μM) or the α2-adrenergic agonist clonidine (5 μM) failed to reduce the Ca2+-current, irrespective of whether intracellular GTP (or GTPγ S) was present or not and at both physiological (1.3 mM) and elevated (10.2 mM) Ca2+-concentrations. In fact, in the absence of added guanine nucleotides, the agonists tended to increase the Ca2+-current amplitude in the presence of the higher Ca2+-concentration. Ca2+-channel activation measured at 1.3 mM Ca2+ was not affected by clonidine. Half-maximal activation was observed at ≈−20 mV. In addition, when Ca2+-currents were recorded from intact β-cells, using the perforated patch whole-cell configuration, clonidine (1 μM) also failed to detectably affect the Ca2+-current. It is therefore suggested that the inhibition of β-cell electrical activity and insulin-secretion produced by α2-adrenoreceptor stimulation does not result from suppression of the L-type Ca2+-current
Recommended from our members
Glucose-stimulated Insulin Biosynthesis Depends on Insulin-stimulated Insulin Gene Transcription
Glucose stimulation of pancreatic β-cells leads to insulin secretion as well as up-regulation of insulin biosynthesis. The acute elevation in pro-insulin levels is thought to be exclusively because of the activation of translation of pre-existing prepro-insulin mRNA. Glucose-stimulated insulin gene transcription is believed to be a long term effect and should therefore not contribute to the acute elevation in pro-insulin levels. We have recently shown that glucose activates insulin gene transcription within minutes and that secreted insulin is one of the key factors triggering this process in an autocrine manner. We now provide evidence that 50% of the glucose-stimulated, acute pro-insulin biosynthesis within 30 min results from up-regulated insulin gene transcription. Our data led us to propose that glucose elevates pro-insulin levels by stimulating both transcriptional and post-transcriptional/post-translational events to an equal extent. Whereas the stimulatory effect on transcription is mediated by insulin secreted in response to glucose, glucose directly stimulates the post-transcriptional/post-translational processes
Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran
Exposure- response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation.
AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor
Development of Human Target Validation Classification that Predicts Future Clinical Efficacy
Effects of AZD0837, a Novel Direct Thrombin Inhibitor, on the Electrophysiological Properties of the Human Heart
2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension : The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT
The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990–2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term “pulmonary hypertension” and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH