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Wirkungsweise von rekombinantem humanem aktiviertem Protein C

Mechanisms of action of recombinant human activated protein C

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Zusammenfassung

Humanes aktiviertes Protein C (APC) ist eine Serinprotease und wichtiger physiologischer Inhibitor des Gerinnungssystems, dem neben seiner antikoagulativen Wirkung zusätzlich profibrinolytische und antiinflammatorische Eigenschaften zugeschrieben werden. Die Anwendung von APC in rekombinanter Form (Xigris®, Drotrecogin alfa (aktiviert); rekombinantes humanes aktiviertes Protein C, rhAPC) führte bei Patienten mit schwerer Sepsis und Multiorganversagen zu einer signifikanten Senkung der Gesamtletalität. Aus In-vitro-Untersuchungen und Tierversuchen wurden neben den bekannten Wirkmechanismen zusätzlich antiapoptotische Effekte sowie positive Wirkungen von rhAPC auf das Immunsystem, die Permeabilität von Endothelzellen und auf die Mikrozirkulation postuliert. Resultierend aus den vielfältigen Wirkprinzipien wird aktuell der Einsatz von rhAPC in weiteren Indikationsbereichen experimentell untersucht, wie z. B. beim akuten Lungen- und Nierenversagen, beim Schlaganfall, bei Ischämie-Reperfusions-Störungen und der Pankreatitis. Die bessere Kenntnis der Wirkungsmechanismen von rhAPC könnte zukünftig sowohl für die Dosierung und Applikationsweise als auch für eine Erweiterung des Indikationsbereiches von Bedeutung sein.

Abstract

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.

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Authors and Affiliations

  1. I. Medizinische Klinik, Fakultät für Klinische Medizin, Universität Heidelberg, Mannheim

    G. Huhle

  2. Klinik für Anästhesie und Intensivtherapie, Klinikum, Phillips-Universität, Marburg

    M. Max

  3. I. Medizinische Klinik, Fakultät für Klinische Medizin, Universität Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167, Mannheim

    M. Brueckmann

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  1. M. Brueckmann
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Correspondence to M. Brueckmann.

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Brueckmann, M., Huhle, G. & Max, M. Wirkungsweise von rekombinantem humanem aktiviertem Protein C. Anaesthesist 55 (Suppl 1), 5–15 (2006). https://doi.org/10.1007/s00101-006-1001-z

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