National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/RDGT97003-01abs

Abstract for RDGT97003 on AZT and Nitazoxanide Combination

Reproductive/Developmental and General Toxicity Study of AZT (CAS No. 30516-87-1) and Nitazoxanide (CAS No. 5598-09-4) Combinations in Swiss CD-1 Mice

Report Date: Aug. 24, 1999


Summary

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.

Table 1: Summary of Significant Treatment–Related Toxicological Parameters in the Reproductive/ Developmental and General Toxicity Study of AZT and Nitazoxanide
Body Weights
Treatment Regimen Males Females–A Females–B
AZT Alone – no change – decrease in body weight – no change
Nitazoxanide Alone – no change – no change – no change
AZT + Nitazoxanide – no change – decrease in body weight – decrease in body weight during the lactation period
Clinical Pathology
Treatment Regimen Males Females–A Females–B
AZT Alone – mild decrease in RBC, HGB, and HCT
– mild increase in MCV and RDW
– mild neutropenia
– mild decrease in RBC, HGB, and HCT
– mild increase in MCV and RDW
– mild neutropenia
– mild increase in MCV and RDW
Nitazoxanide Alone – no significant changes – no significant changes – no significant changes
AZT + Nitazoxanide – anemia
– increased MCV
– increased RDW
– neutropenia
– anemia
– increased MCV
– increased RDW
– neutropenia
– increased MCV
– increased RDW
– reticulocytosis

Histopathology
Treatment Regimen Males Females–A (Liver only)
AZT Alone Spleen
– hematopoietic cell proliferation (minimal to mild)

 
Nitazoxanide Alone Spleen
– hematopoietic cell proliferation (low incidence)

 
AZT + Nitazoxanide Spleen
– hematopoietic cell proliferation (minimal to moderate)
Bone Marrow
– cellular depletion (low incidence)
Liver
– centrilobular atrophy of hepatocytes (minimal to mild)
– centrilobular necrosis of hepatocytes (low incidence)
Note: Histopathological evaluations were performed only on gross lesions in Female–B mice.
Reproductive/Developmental
Treatment Regimen Females–A Fetuses Females–B Pups
AZT Alone – reduced pregnancy rate in high dose group
– reduced live litter size – increased number of resorptions
– slight decline in fetal weight per litter
– decreased percent of pups/litter surviving to postnatal Day 4 (200 mg group only)
Nitazoxanide Alone – reduced pregnancy rate in high dose group – decreased number of litters delivered in high dose group
AZT + Nitazoxanide – dose–related reduction in pregnancy rate
– dose–related decline in live litter size (only 1 litter in highest dose combination group)
– increased number of resorptions
– prominent decline in fetal weight per litter
– decreased number of live born pups per litter
– decreased percentage of pups/litter surviving to postnatal Day 4
– reduced pup weight

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