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

Abstract

Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2Јdeoxy-2Јfluoro-1-␤-Darabinofuranosyl-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, FIAU 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 FIAUtreated 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. (HEPATOLOGY 1998;28:179-191.)

Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection

“…All entecavir groups and the placebo group were comparable with regard to sex and age. Fifty-two percent of patients were of Asian origin (n ϭ 22). Approximately 50% of patients were treatment-naive at start of entecavir therapy.…”

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

“…The abundance of defective mtDNA may increase to a point at which a threshold of energy depletion may be reached and symptoms become manifested. This threshold effect on energetics in NRTI toxicity is analogous to that seen with heritable mitochondrial illnesses, including those that include mtDNA depletion Wallace, 1992a, Cooley et al, 1990Lambert et al, 1990 Distorted cristae and decreased mtDNA in CEM cells Cui et al, 1997Martin et al, 1994Medina et al, 1994Youssef and Badr, 1992 D4T Peripheral nerve Painful peripheral neuropathy in 55% of patients Browne et al, 1993Cohen et al, 1994 Distorted cristae and decreased mtDNA in CEM cells Cui et al, 1997Martin et al, 1994Medina et al, 1994 Cui et al, 1995Klecker et al, 1994Lewis et al, 1994aLewis and Tankersley, 1995Richardson et al, 1994Tennant et al, 1998 NRTIs, nucleoside reverse transcriptase inhibitors; AZT, zidovudine; DDC, zalcitabine; 3TC, lamivudine; DDI, didanosine; D4T, stavudine.…”

“…The steady-state abundance of mtDNA in the liver, myocardium, skeletal muscle, and kidney is significantly decreased in tissue samples from fialuridine-treated woodchucks. The magnitude of the decreases varies among the tissues examined (Lewis et al, 1997;Tennant et al, 1998).…”

Drug-induced liver injury: Mechanisms and test systems

“…Immunoassays showed a marked accumulation of fialuridine in both mitochondrial and chromosomal DNA. 41 Of importance, fialuridine hepatotoxicity occurred equally in woodchuck hepatitis-infected as in noninfected animals. Thus, the underlying liver disease did not predispose to this injury.…”

“…41,42 Fialuridine inhibits DNA polymerase ␥ (the enzyme responsible for replication of mitochondrial DNA) but has little effect at physiologic concentrations on DNA polymerase ␣ or ␤. Similar findings for AZT suggest that differential inhibition of DNA polymerase activities may account for mitochondrial toxicity of nucleoside analogues.…”