Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis

Blood coagulation starts immediately after damage to the vascular endothelium. This system is essential for minimizing blood loss from an injured blood vessel but also contributes to vascular thrombosis. Although it has long been thought that the intrinsic coagulation pathway is not important for clotting in vivo, recent data obtained with genetically altered mice indicate that contact phase proteins seem to be essential for thrombus formation. We show that recombinant Ixodes ricinus contact phase inhibitor (Ir-CPI), a Kunitz-type protein expressed by the salivary glands of the tick Ixodes ricinus, specifically interacts with activated human contact phase factors (FXIIa, FXIa, and kallikrein) and prolongs the activated partial thromboplastin time (aPTT) in vitro. The effects of Ir-CPI were also examined in vivo using both venous and arterial thrombosis models. Intravenous administration of Ir-CPI in rats and mice caused a dose-dependent reduction in venous thrombus formation and revealed a defect in the formation of arterial occlusive thrombi. Moreover, mice injected with Ir-CPI are protected against collagen- and epinephrine-induced thromboembolism. Remarkably, the effective antithrombotic dose of Ir-CPI did not promote bleeding or impair blood coagulation parameters. To conclude, our results show that a contact phase inhibitor is an effective and safe antithrombotic agent in vivo

Cent scientifiques répliquent à SEA (Suppression des Expériences sur l’Animal vivant) et dénoncent sa désinformation

La lutte contre la maltraitance animale est sans conteste une cause moralement juste. Mais elle ne justifie en rien la désinformation à laquelle certaines associations qui s’en réclament ont recours pour remettre en question l’usage de l’expérimentation animale en recherche

Beta3-adrenergic receptors in cardiac and vascular tissues emerging concepts and therapeutic perspectives

Catecholamines released by the orthosympathetic system play a major role in the short- and long-term regulation of cardiovascular function. Beta1- and beta2-adrenoreceptors (ARs) have classically been considered as mediating most of their effects on cardiac contraction. After their initial cloning and pharmacologic characterization in the late 1980s, beta3-ARs have been mostly thought of as receptors mediating metabolic effects (e.g., lipolysis) in adipocytes. However, definitive evidence for their expression and functional coupling in cardiovascular tissues (including in humans) has recently initiated a re-examination of their implication in the pathophysiology of cardiovascular diseases. Distinctive pharmacodynamic properties of beta3-AR, e.g., their upregulation in disease and resistance to desensitization, suggest that they may be attractive targets for therapeutic intervention. They may substitute efficient vasodilating pathways when beta1/2-ARs are inoperative. In the heart, their contractile effects, which are functionally antipathetic to those of beta1/2-AR, may protect the myocardium against adverse effects of excessive catecholamine stimulation and perhaps mediate additional ancillary effects on key aspects of electrophysiology or remodeling. Longitudinal studies in animals and patients with different stages of heart failure are now needed to identify the optimal therapeutic scheme using specific combinations of agonists or antagonists at all three beta-ARs

Use of endothelin-1 antagonists for improving cancer therapy. WO2004100991

The present invention relates to a method and composition for treating or for diagnosing cancer. In particular, the present invention relates to methods and compositions for improving the efficacy of conventional cancer therapy and diagnosis. The invention comprises the use of an endothelin antagonist, and in particular of a specific ET-A endothelin antagonist and/or a non-specific ET-A/ET-B endothelin antagonist for treating or for diagnosing cancer or for improving the efficacy of conventional cancer therapy and diagnosis