Title:PF-04886847 (an Inhibitor of Plasma Kallikrein) Attenuates Inflammatory Mediators and Activation of Blood Coagulation in Rat Model of Lipopolysaccharide (LPS) - Induced Sepsis
Volume: 10
Issue: 2
Author(s): D. Kolte, J. W. Bryant, G. W. Gibson, J. Wang and Z. Shariat-Madar
Affiliation:
Keywords:
Acute respiratory distress syndrome, disseminated intravascular coagulation, kallikrein inhibitor, PF-04886847
Abstract: The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has
shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the
treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide
(LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg)
prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced
the elevated plasma 6-keto PGF1α levels in LPS treated rats, suggesting that PF-04886847 could be useful in preventing
hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-α level. Pretreatment
of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma
fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against
LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein
(the zymogen form of plasma kallikrein) deficient patients have prolonged activated partial thromboplastin time
(aPTT) without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847
was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events,
PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both aPTT and prothrombin
time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited
anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin
mediated diseases.
