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In Vitro And In Vivo Pharmacodynamic Characterization Of The Novel Plasma Kallikrein Inhibitor Pf-04886847, Dhaval Sanjeev Kolte

Electronic Theses and Dissertations

Plasma kallikrein plays an important role in the pathogenesis of inflammation and thrombosis. Kallikrein cleaves high molecular weight kininogen (HK) to liberate the potent pro-inflammatory peptide bradykinin (BK). BK upon activation of its constitutive B2 receptors on endothelial cells leads to an increase in intracellular Ca2+ level and subsequent production of nitric oxide (NO) and prostacyclin (PGI2), ultimately leading to vasodilation, hypotension, increased vascular permeability and vascular leakage. Further, kallikrein activates the complement system and stimulates neutrophil chemotaxis, aggregation and elastase release. Furthermore, kallikrein mediates the conversion of factor XII (FXII) to activated factor XII (FXIIa) thereby potentiating the intrinsic …