Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

被引:77
作者
Tennant, BC [1 ]
Baldwin, BH
Graham, LA
Ascenzi, MA
Hornbuckle, WE
Rowland, PH
Tochkov, IA
Yeager, AE
Erb, HN
Colacino, JM
Lopez, C
Engelhardt, JA
Bowsher, RR
Richardson, FC
Lewis, W
Cote, PJ
Korba, BE
Gerin, JL
机构
[1] Cornell Univ, Coll Vet Med, Dept Clin Sci, Gastrointestinal Unit, Ithaca, NY 14853 USA
[2] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[3] Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45267 USA
[4] Georgetown Univ, Sch Med, Div Mol Virol & Immunol, Rockville, MD USA
关键词
D O I
10.1002/hep.510280124
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2' deoxy-2' fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil), In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, I;IAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1,5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAU treated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical toxicological evaluation of other nucleoside analogs before use in patients.
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页码:179 / 191
页数:13
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