Combined therapy with danazol, pegilated interferon, and ribavirin improves thrombocytopenia and liver injury in rats with fibrosis

Abstract

The aim of this study was to investigate the effects of combinations of pegilated–interferon (PEG–IFN), ribavirin, and danazol on thrombocytopenia and liver injury in rats with fibrosis. Male adult Wistar rats were treated with either mineral oil, danazol (0.83 mg/kg per day), PEG–interferon α-2a (PEG–IFN, 0.3 μg/ week) + ribavirin (12 mg/kg per day), PEG–IFN + ribavirin + danazol, CCl4 (4 g/kg for eight weeks), CCl4 + PEG–IFN + ribavirin, or CCl4 + PEG-IFN + ribavirin + danazol. The following assays were conducted: hematology, clinical chemistry, liver function, liver fibrosis, lymphocyte cytokine mRNA expression, and bone-marrow DNA content. Platelet counts were low in sham-treated animals and animals treated with PEG– IFN + ribavirin (30% and 25% respectively; P < 0.05). PEG–IFN + ribavirin + danazol reduced platelet counts of fibrotic animals by only 9% (P < 0.05). PEG– IFN + ribavirin reduced hepatic collagen content by 50%, whereas danazol + PEG–IFN + ribavirin reduced hepatic collagen content by 60% (P < 0.05). PEG–IFN + ribavirin reduced the total bilirubin concentration by 27%, alanine amino transferase (ALT) activity by 75% and γ-glutamyl transpeptidase (γ-GTP) activity by 74% (P < 0.05). In contrast, danazol + PEG-IFN + ribavirin reduced total bilirubin levels by 61%, alkaline phosphatase activity by 45%, ALT activity by 76%, and γ-GTP activity by 74% (P < 0.05). The only treatment that increased interleukin 10 (IL-10) mRNA in fibrotic rats was PEG–IFN + ribavirin. However, danazol + PEG–IFN + ribavirin reduced the expression of IL-6, IL-10, tumor necrosis factor α and transforming growth factor Β. Bone-marrow DNA content was not altered by any treatment. In conclusion, PEG–IFN + ribavirin + danazol could be a new therapeutic option for patients with liver injury, fibrosis, and thrombocytopenia.