BACKGROUND: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. AIM: To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. METHODS: Double-blind, randomized, placebo-controlled, parallel-dose study in 204 patients treated withplacebo 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. RESULTS: 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. CONCLUSION:PF-03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks.
RCT Entities:
BACKGROUND: 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. AIM: To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. METHODS: 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. RESULTS: 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. CONCLUSION:PF-03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks.
Authors: Vlad Ratziu; Muhammad Y Sheikh; Arun J Sanyal; Joseph K Lim; Hari Conjeevaram; Naga Chalasani; Manal Abdelmalek; Anezi Bakken; Christophe Renou; Melissa Palmer; Robert A Levine; B Raj Bhandari; Melanie Cornpropst; Wei Liang; Benjamin King; Elsa Mondou; Franck S Rousseau; John McHutchison; Mario Chojkier Journal: Hepatology Date: 2011-12-14 Impact factor: 17.425
Authors: Anna K Kopec; Alfred P Spada; Patricia C Contreras; Nigel Mackman; James P Luyendyk Journal: Toxicol Sci Date: 2018-04-01 Impact factor: 4.849