title: 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 alpha-2a (PEG-IFN, 0.3 microg/ week) + ribavirin (12 mg/kg per day), PEG-IFN + ribavirin + danazol, CCl(4) (4 g/kg for eight weeks), CCl(4) + PEG-IFN + ribavirin, or CCl(4) + 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 gamma-glutamyl transpeptidase (gamma-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 gamma-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 alpha and transforming growth factor ss. 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.
authors.affiliation: Internal Medicine Division, Gastroenterology and Hepatology Department, Hospital General Regional con UMF 1, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, Mexico.
authors.forename: Guillermo Cabrera
authors.initials: GC
authors.lastname: Alvarez
authors.forename: Vicente
authors.initials: V
authors.lastname: Madrid-Marina
authors.forename: Ricardo
authors.initials: R
authors.lastname: Jimenez-Mendez
authors.forename: Angel Leon
authors.initials: AL
authors.lastname: Buitimea
authors.forename: Margarita Bahena
authors.initials: MB
authors.lastname: Román
authors.forename: Rudyard
authors.initials: R
authors.lastname: Cortez-Gomez
authors.forename: Jorge Reyes
authors.initials: JR
authors.lastname: Esparza
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rodríguez-Fragoso
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002251:Carbon Tetrachloride; D002453:Cell Cycle; D003094:Collagen / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D003613:Danazol / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008111:Liver Function Tests; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D003094:Collagen; D002251:Carbon Tetrachloride; D003613:Danazol; C100416:peginterferon alfa-2a