McGuire Research Institute, McGuire Veterans Administration Medical Center, Richmond, VA, USA.
Aliment Pharmacol Ther. 2010 May;31(9):969-78. doi: 10.1111/j.1365-2036.2010.04264.x. Epub 2010 Feb 16.
Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF-03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases.
To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV.
Double-blind, randomized, placebo-controlled, parallel-dose study in 204 patients treated with placebo or PF-03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly.
Significant reductions in serum AST and ALT were observed within 1 week of initiating PF-03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF-03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue.
PF-03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks.
天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）血清水平升高反映了慢性丙型肝炎病毒（HCV）患者的肝细胞损伤。这些患者中存在凋亡增加和激活的半胱天冬酶。PF-03491390 抑制多种半胱天冬酶，降低慢性肝病患者的血清 AST 和 ALT 水平。
确定口服多半胱氨酸酶抑制剂是否能降低 HCV 患者的血清 AST 和 ALT。
204 例患者进行了双盲、随机、安慰剂对照、平行剂量研究，患者接受安慰剂或 PF-03491390（5、25 或 50mg）口服，每日 2 次（b.d.），持续 12 周。每周监测血清 AST 和 ALT。
在所有治疗组中，PF-03491390 治疗开始后 1 周内即可观察到血清 AST 和 ALT 的显著降低（P<0.0001）。AST 和 ALT 的这些降低在 12 周的治疗期间得以维持，当 PF-03491390 停药时，AST 和 ALT 水平恢复到基线水平。增加剂量并不能进一步降低 AST 或 ALT。最常报告的不良事件是头痛和疲劳。
PF-03491390 可显著降低慢性 HCV 患者的血清 AST 和 ALT 水平，且在 12 周内耐受性良好。
