Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Stroke prevention in elderly patients with atrial fibrillation: challenges for anticoagulation.

Elderly patients with atrial fibrillation (AF), who constitute almost half of all AF patients, are at increased risk of stroke. Anticoagulant therapies, especially vitamin K antagonists (VKA), reduce the risk of stroke in all patients including the elderly but are frequently under-used in older patients. Failure to initiate VKA in elderly AF patients is related to a number of factors, including the limitations of current therapies and the increased risk for major haemorrhage associated with advanced age and anticoagulation therapy. Of particular concern is the risk of intracranial haemorrhages (ICH), which is associated with high rates of mortality and morbidity. Novel oral anticoagulant agents that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should increase the use of antithrombotic therapy in the management of elderly AF patients. Amongst these new agents, the recently approved direct thrombin inhibitor dabigatran provides effective stroke prevention with a significant reduction of ICH, and enables clinicians to tailor the dose according to age and haemorrhagic risk.

[Mechanisms of action of recombinant human activated Protein C]. / Wirkungsweise von rekombinantem humanem aktiviertem Protein C.

Human activated protein C (APC) is a serineprotease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC. The administration of recombinant human activated protein C (rhAPC), drotrecogin alfa (activated), Xigris, to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials. Anti-apoptotic and immunomodulatory effects of rhAPC have been examined in in vitro experiments and in experimental animal studies. Moreover, a reduction of endothelial cell permeability, enhanced endothelial cell survival as well as improvements of microcirculatory disorders have been proposed for rhAPC. The manifold mechanisms of action of APC may give reasons for its application in diseases other than sepsis, which are characterized by endothelial and microcirculatory dysfunction, e.g. acute pulmonary or renal failure, ischemic stroke, ischemia-reperfusion injury and acute pancreatitis. A better understanding of the anti-inflammatory, anti-apoptotic and immunomodulatory modes of action of APC could be relevant for dosing and mode of application and may lead to a broadening of the indication field for rhAPC.

Drotrecogin alfa (activated) inhibits NF-kappa B activation and MIP-1-alpha release from isolated mononuclear cells of patients with severe sepsis.

OBJECTIVE AND DESIGN: Non-anticoagulant biological activities, such as anti-inflammatory and anti-apoptotic mechanisms of action, have been suggested for recombinant human activated protein C (rhAPC; drotrecogin alfa (activated)). However, these mechanisms are much less characterized and understood than rhAPC's anticoagulant activity. Aim of the study was to determine the effect of rhAPC on the activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB) in mononuclear cells isolated from septic patients and to characterize an effect downstream from NF-kappaB activation, such as the release of the NF-kappaB-controlled chemokine Macrophage Inflammatory Protein-1-alpha (MIP-1-alpha). SUBJECTS: Peripheral blood was obtained from 13 septic patients and from 8 healthy controls. METHODS: Mononuclear cells were isolated by Ficoll-Paque density gradient centrifugation and were incubated with or without rhAPC (10 microg/ml) for 2 h for the measurement of NF-kappaB activity in cell lysates or alternatively for 6 h for the determination of MIP-1-alpha levels in supernatants. NF-kappaB activity was measured by an ELISA-based assay directed against the p50 and the p65 subunit of NF-kappaB. RESULTS: RhAPC, at supra-pharmacological concentration (10 microg/ml), significantly inhibited NF-kappaB activity and the release of MIP-1-alpha ex vivo in isolated mononuclear cells from patients with severe sepsis. In mononuclear cells of healthy subjects, however, rhAPC did not change NF-kappaB activity. Basal NF-kappaB activity early in severe sepsis was not predictive for survival. CONCLUSIONS: RhAPC at supra-pharmacological concentration (10 microg/ml) inhibits the activity of NF-kappaB in ex vivo isolated mononuclear cells of septic patients as well as the release of MIP-1-alpha, a proinflammatory chemokine regulated by NF-kappaB. These findings may represent immunomodulatory pathways by which rhAPC exerts specific anti-inflammatory activity in vitro in addition to its known anticoagulant and profibrinolytic activity and should be further investigated in an in vivo setting.

Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis.

Calcific aortic stenosis is the main heart valve disease in the elderly, leading to massive focal calcification and thickening of the valve cusps. Matrix metalloproteinases (MMPs) are thought to contribute to this process. Therefore, the study assessed the expression of the gelatinases MMP-2 and MMP-9 and the endogenous tissue inhibitor of metalloproteinase (TIMP)-2 as well as the gelatinolytic activity in normal and stenotic valves. Human tricuspid aortic valves with and without calcific aortic stenosis were studied by immunohistochemistry for MMP-2, MMP-9 and TIMP-2. The gelatinolytic activity in native valve sections was assessed by gelatin in situ zymography with or without addition of the MMP activator p-aminophenymercuric acetate (APMA). Staining intensities for MMP-2 and TIMP-2 were elevated in stenotic valves as compared to controls. Minor staining of MMP-9 was present exclusively in stenotic valves. The morphologic distribution of gelatinolytic activity was comparable to the staining pattern of MMP-2, and since MMP-9 immunostaining demonstrated only a low number of positive cells, the observed gelatinolytic activity is likely due to MMP-2. Gelatinolytic activity was low in normal valves but significantly increased by the MMP activator APMA. In contrast, stenotic valves showed a strong basal gelatinolytic activity that could not be significantly enhanced by APMA suggesting that MMP-2 is present as a latent pro-enzyme in normal valves and activated in stenotic valves. Thus, MMP-2 might be involved in the matrix remodeling during calcific aortic stenosis.