Review of the Fialuridine (FIAU) Clinical Trials (1995) / Chapter Skim
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Recent Studies of FIAU Toxicity
Recent Studies of FIAU Toxicity
Pages 98-103
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From page 98... ...
enzymology by Douglas Kerr of Case Western Reserve University, which suggested that the liver toxicity from FIAU was related to injury to enzymes of the electron transport chain encoded in part by mt DNA. These liver samples showed relatively normal levels of mt enzymes of pyruvate metabolism, which are encoded largely from nuclear DNA.
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From page 99... ...
Slight to moderate decreases In erythrocytes, lymphocytes, and leukocytes were observed in both male and female rats treated with the higher dose; lymphocytes and erythrocytes were also decreased in male rats treated with the lower dose. Regarding clinical chemistry parameters, blood urea nitrogen values were increased slightly in both dosage groups, but not in a dose-dependent manner; there was a slight increase in total plasma bilirubin concentration in males at both dose levels, but only at the higher dose in females.
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From page 100... ...
Histologic evaluation of liver tissue indicated slightly increased apoptosis and increased numbers of multinucleated hepatocytes; mitotic figures were also increased, with some mitoses having atypical morphologies; dose-related nuclear atypia and cytoplasmic hyaline droplet accumulation were also observed. Hepatic lobular architecture was generally normal even in animals most affected by cytologic alterations.
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From page 101... ...
On July 2, 1993, the group at Cornell, who had been advised of the adverse effects seen in patients treated with FlAU in the PPPC clinical trial, reinitiated posttreatment observations on the surviving woodchucks; the observations were continued until February 1994, when the remaining animals were euthanized and postmortem evaluations were performed. A significant difference in body weights between the group treated with FlAU at a high dose and the placebo-treated animals was observed; the groups receiving FlAU weighed less (3.4 versus 3.8 kg)
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From page 102... ...
Furthermore, both WHV infected and uninfected animals receiving FIAU are reported by the investigator as exhibiting elevations in transaminase activity, particularly AST as the animals became moribund. Kidney insufficiency was also observed in FIAU-treated animals; elevations in blood lactic acid concentrations were found in the final stages of FIAU toxicity.
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From page 103... ...
The reproductive capacity of the woodchuck (one breeding cycle annually yielding one or two offspring) unfortunately precludes its use as a routine species for animal toxicity testing, but the data to date suggest that it might be a powerful addition to preclinical testing for anti-HBV drugs.
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