Reproductive, Developmental and General Toxicity Study of 3'-Azido-3'-Deoxythymidine (CAS No. 30516-87-1) and 2',3'-Dideoxyinosine (CAS No. 69655-05-6) Combinations in Swiss MiceReport Date: April 18, 1994
The toxicity of AZT/ddI was evaluated in Swiss mice treated orally by gavage with 100 and 200 mg/AZT/day and 250, 500, and 1000 mg/ddI/day. Male mice (10/group) were dosed from study day 5 until the day prior to sacrifice on study day 25 or 26. Prior to dosing (study days 0-4), the male mice were cohabited with a group of female mice (20/dose group), hereafter referred to as females (b). The sperm-positive female (b) mice were dosed on days 6 through 15 of gestation and sacrificed on scheduled day 4 or 5 of lactation. A second group of female mice (20/dose group), hereafter referred to as females (a), were dosed from study day 0 throughout mating on study days 9 to 13 until sacrifice on day 18 of gestation. Adult mice were evaluated for clinical signs, body weight, hematology, gross necropsy, and histopathology evaluations, and organ/body weights and sperm function (males only). Offspring were evaluated for viability, external anomalies, and weight.
Administration of ddI alone to male mice did not produce significant evidence of measurable toxicity. The most significant alteration encountered in male mice treated with AZT alone was a mild dose-related anemia. Administration of combinations of AZT and ddI to male mice did not exacerbate the anemia produced by AZT alone. The mild anemia in male mice was accompanied by histopathological evidence of hematotoxicity in the form of bone marrow depletion and extra medullary hematopoieses in the spleen. Significant manifestations of toxicity were not detected in the mortality data, clinical observations, in-life body weights, terminal body weights, sperm count and vaginal cytology evaluation parameters, or organ/body weight data evaluated in male mice treated with AZT alone or combinations of AZT and ddI.
Administration of ddI alone did not produce measurable toxicity in female mice. The most significant alterations detected in female (a) mice treated with AZT alone was a mild anemia and neutropenia. Hematological alterations detected in female (b) mice treated with AZT alone were limited to slight elevations in MCV, MCH, and reticulocyte values. AZT and ddI administered in combination to female (a) and female (b) mice did not exacerbate the hematological toxicity induced by AZT administration alone.
Minimal maternal toxicity manifested by diminished body weights and/or body weight gains resulted from the administration of AZT alone. Developmental toxicity in the form of increased resorptions, diminished litter size, and diminished fetal weights also resulted from the administration of AZT alone. Administered in combination, AZT and ddI did not exacerbate the maternal or developmental toxicity produced by AZT alone.