Combined therapy with danazol, pegilated interferon, and ribavirin improves thrombocytopenia and liver injury in rats with fibrosis.
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.
Alvarez
Guillermo Cabrera
GC
Internal Medicine Division, Gastroenterology and Hepatology Department, Hospital General Regional con UMF 1, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, Mexico.
Madrid-Marina
Vicente
V
Jimenez-Mendez
Ricardo
R
Buitimea
Angel Leon
AL
Román
Margarita Bahena
MB
Cortez-Gomez
Rudyard
R
Esparza
Jorge Reyes
JR
Rodríguez-Fragoso
Lourdes
L
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*
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