First, patients' serum Ang-2 levels are increased during severe sepsis and associated with disease severity. The strong relationship of serum Ang-2 with serum tumor necrosis factor-alpha suggests that the latter may participate in the regulation of Ang-2 production in sepsis. Second, inflammatory mediators reduce Ang-2 release from human lung microvascular endothelial cells, implying that this vascular bed may not be the source of increased Ang-2 in human sepsis.

Angiopoietins (Angs) are endothelium-selective ligands that exert most of their actions through the Tie-2 receptor.

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0001).Stepwise regression analysis revealed that company size and SA compliance were independent predictors of outcome. The proportion of the MAAs that had received SA increased from 22% in 2004 to 47% in 2007. Company size and product type were associated with the frequency of requesting SA (26, 33 and 46% for small, medium-sized and large companies, respectively; 16, 39 and 48% for known chemical substances, new chemical substances and biologics, respectively). Factors related to compliance with SA were company size and OD status (25, 60 and 84% for small, medium-sized, and large companies, respectively; 77 and 38% for non-OD and OD status, respectively). Conclusions The strong association between company size and outcome suggests that resources and experience in drug development and obtaining regulatory approval are critical factors for a successful MAA. In addition, obtaining and complying with SA appears to be a predictor of outcome. Based on this analysis, companies, particularly smaller ones and those developing orphan drugs, are recommended to engage in a dialogue with European regulators via the SA procedure. Obtaining SA early in development and at major transition points as well as compliance with the advice given by the CHMP are recommended.

The angiopoietin (Ang) family of growth factors includes four members, all of which bind to the endothelial receptor tyrosine kinase Tie2. Two of the Angs, Ang-1 and Ang-4, activate the Tie2 receptor, whereas Ang-2 and Ang-3 inhibit Ang-1-induced Tie2 phosphorylation. While genetic models have underscored the importance of Angs in the developing cardiovascular system, other studies have demonstrated that Ang-1 promotes endothelial cell survival, sprouting and tube formation. More recently, a new aspect of the biology of this class of growth factors has emerged, namely the ability of Ang-1 to reduce inflammation. This review presents an outline of Angs and their receptors, examining their structure, expression, signalling, regulation and biological significance and comments on the role and potential usefulness of Angs in medicine.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

Tumor necrosis factor alpha (TNF-alpha) is a cytokine, implicated in the pathogenesis of many inflammatory diseases, as well as in the immune-mediated response to infection, especially against intracellular pathogens. TNF-alpha antagonists have represented a revolution in the management of connective tissue diseases, such as rheumatoid arthritis. However, the use of these agents has been implicated with the emergence of a growing number of opportunistic infections. Here we report the case of a visceral Leishmaniasis in a 77-year-old woman who had been previously treated for rheumatoid arthritis with infliximab. The atypical presentation of this patient, previously treated with an anti-TNF-alpha biologic agent, where no splenomegaly or hepatomegaly was identified, is emphasized.

Background and purpose: Angiopoietins (Ang) are crucial for new blood vessel formation and exert their effects by acting on the Tie2 receptor. We have recently described a sulindac analogue 2-((1E,Z)-1-benzylidene-5-bromo-2-methyl-1H-inden-3-yl)acetic acid; termed C-18 from now onwards) that inhibits Tie2 receptor activity in kinase assays in vitro. Here, we have assessed the ability of C-18 to inhibit angiogenesis-related properties of endothelial cells and tested its selectivity for the Tie2 receptor. Experimental approach: For in vitro experiments human umbilical vein endothelial cells (HUVEC) were used. Proliferation was measured using the MTT assay; migration assays were performed in a modified Boyden chamber and tube-like structure formation was determined on matrigel. The effects of C-18 in vivo were evaluated in the chicken chorioallantoic membrane (CAM). Key results: Pre-treatment of HUVEC with C-18 blocked Ang-1-stimulated migration, but also abolished vascular endothelial cell growth factor (VEGF)-and fibroblast growth factor 2-induced responses. Incubation with C-18 inhibited serum-induced proliferation in a concentration-dependent manner; C-18 was, however, without effect on Ang-1-induced survival. In addition, we observed that C-18 did not inhibit ligand-induced receptor phosphorylation of Tie2 or VEGFR2. On the other hand, C-18 blocked activation of members of the mitogen-activated protein kinase family and of the Ser/Thr kinase Akt induced by both VEGF and Ang-1. Furthermore, incubation of CAMs with C-18 led to a dose-dependent inhibition of vascular length. Conclusions and implications: C-18 did not act as a Tie2 inhibitor, as originally thought, but rather inhibited growth factorstimulated signalling pathways that regulate endothelial cell migration and potently reduces neovascularization in vivo.