The toxicity of combinations of AZT (200 or 400 mg) and NZT (250, 500, or 1000 mg) was evaluated in Swiss (CD-1) mice treated by oral gavage. Doses of AZT were equivalent to approximately 2 and 4 times the therapeutic dose in humans. Doses of nitazoxanide were approximately 1.5, 3, and 6 times the human therapeutic dose. Male mice (10 or 18/dose group) were dosed from study day 5 until the day prior to sacrifice on study day 25 or 26. Females were divided into two groups designated females–A and females–B. The females–A (20/group) were dosed from day 0 to sacrifice. They were cohabited with treated males on days 9–13 to test for effects on mating behavior, fertilization, and implantation, and Caesarean sections were performed on days 28–32. The females designated as females–B (20/group) were cohabited with untreated males on days 0–4. Sperm–positive females–B were dosed during organogenesis on days 6–15 of presumed gestation and sacrificed on day 4 of lactation.
Summarized in Table 1 are the most significant effects of treatment with AZT and nitazoxanide. Administration of AZT alone resulted in slight hematopoietic toxicity manifested by mild declines in RBC, HGB, and/or HCT values. Hematopoietic cell proliferation in the spleen accompanied the mild alterations in erythrocyte parameters. Administration of nitazoxanide alone did not result in consistently significant alterations in hematology parameters, clinical chemistry parameters, mortality, body weights, or histopathological lesions.
Administration of AZT in combination with nitazoxanide resulted in prominent hematotoxicity, and the severity of the anemia was far greater than that induced by AZT alone. The anemia in male mice was accompanied by hematopoietic cell proliferation in the spleen and a low incidence of cellular depletion of the bone marrow. In female–A mice, centrilobular atrophy of the liver and necrosis– of hepatocytes, believed to be secondary to hypoxia, accompanied the anemia. The anemia was characterized as nonregenerative and macrocytic.
Treatment with AZT alone resulted primarily in an increased number of resorptions, reduced live litter size, reduced pregnancy rate, and slightly lower fetal weights per litter. Treatment with nitazoxanide alone resulted in a decreased pregnancy rate and a decreased number of litters delivered in the high dose group. Fertility was further reduced in groups treated with combinations of AZT and nitazoxanide, with dose–related reductions in pregnancy rates, live litter size, and numbers of litters delivered. Groups treated with combinations of AZT and nitazoxanide also had an increased number of resorptions, decreased percentage of pups per litter surviving to postnatal day 4, and lower fetal weights per litter and pup weights.