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inhibit mt DNA replication during a short exposure in a cell culture will be inadequate to predict serious problems in a clinical setting.


Lilly Rat Studies

Despite failing to produce any significant histological or biochemical abnormalities in dogs given FIAU at 3 mg/kg/day for 90 days or in monkeys given 25 mg/kg/day for 30 days, Eli Lilly completed a report in July 1994 describing a study conducted from September 23 through December 2, 1993, in which they set out to produce in rats the toxic syndrome seen in the PPPC clinical trial. Rats (five rats of each sex receiving each dose) were treated with FIAU three times per day, with total daily dosages of 255 or 510 mg/kg/day (a dosage 1,000 times greater than that administered to humans) for a period of 10 weeks. Originally, the study was designed to last only 2 weeks, but since the animals tolerated the high doses better than expected, the study was extended first to 1 month and finally to 10 weeks. The FIAU was administered by gavage as an aqueous acacia suspension.

All rats survived the 10-week period, but clinical signs started to appear during the last 4 weeks. Significant differences in body weight gain and food utilization efficiency were seen in all animals, but the male rats were more severely affected than the females. Decreased body weight gain was attributed primarily to the decreased efficiency of food utilization. Hematologic parameters were assessed on days 27 and 70. 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. gamma-glutamyltransferase activity was increased (about 33 percent) in both males and females at the higher dose level. It is noteworthy, however, that no significant increases in ALT or AST were observed in either test group. Dose-related decreases in glucose (both doses, both sexes), total protein (both doses, males; high dose, females), and albumin (both doses, males; high dose, females) were recorded. There were moderate increases in plasma lactate ( versus 16 mg/dl) in animals of both sexes at both dose levels.

Mitochondrial parameters were assessed from liver samples obtained at day 70. Citrate synthase activity was significantly higher than that of control rats in both males ( percent of the control at both doses) and females ( percent of the control at the lower dose; percent of the control at the higher dose) treated with FIAU. On the other hand, cytochrome oxidase activity was significantly lower than that of control rats, in both males ( percent of the control at both doses) and females ( percent of the control at the lower dose; percent of the control at the higher dose) treated with FIAU.

DNA was isolated from liver, heart, spleen, jejunum, and epididymal sperm about 24 hours following the last treatment with FIAU. The FIAU concentration in cellular DNA was assessed by radioimmunoassay and was normalized to the thymidine concentration in each

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