Kolte D, Bryant J W, Gibson G W, Wang J, Shariat-Madar Z
School of Pharmacy, Department of Pharmacology, University of Mississippi, University, MS 38677-1848, USA.
Cardiovasc Hematol Agents Med Chem. 2012 Jun;10(2):154-66. doi: 10.2174/187152512800388939.
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.
血浆激肽释放酶介导的蛋白水解作用对血栓形成和炎症反应均有调节作用。先前的研究表明，PF-04886847是一种有效的激肽释放酶竞争性抑制剂，这表明它可能对治疗激肽释放酶-激肽介导的炎症和血栓性疾病有用。在本研究使用的脂多糖（LPS）诱导的大鼠脓毒症模型中，在给予LPS（10mg/kg）之前用PF-04886847（1mg/kg）预处理大鼠，可防止内毒素诱导的全身循环中粒细胞计数增加。PF-04886847显著降低了LPS处理大鼠血浆中升高的6-酮-前列腺素F1α水平，这表明PF-04886847可能有助于预防脓毒症期间的低血压休克。PF-04886847不抑制LPS诱导的血浆肿瘤坏死因子-α水平升高。在给予LPS之前用PF-04886847预处理大鼠，并未减弱内毒素诱导的血小板计数和血浆纤维蛋白原水平降低以及血浆D-二聚体水平升高。PF-04886847不能保护动物免受LPS介导的急性肝损伤、肾损伤和弥散性血管内凝血（DIC）。由于前激肽释放酶（血浆激肽释放酶的酶原形式）缺乏的患者活化部分凝血活酶时间（aPTT）延长，但无任何出血性疾病，因此对PF-04886847的抗血栓特性及作用机制进行了评估。在一个旨在模拟急性血栓形成事件临床情况的兔球囊损伤模型中，PF-04886847剂量依赖性地减少血栓量。PF-04886847（1mg/kg）剂量依赖性地延长aPTT和凝血酶原时间（PT）。尽管本研究结果表明PF-04886847具有有限的抗血栓和抗炎作用，但PF-04886847在其他激肽释放酶-激肽介导的疾病中可能具有治疗潜力。
