The in vivo and in vitro Developmental Toxicity and Teratogenicity of the Anti-AIDS Drugs (Human and Experimental Animal Studies)

摘要

This study gives an overview about the modes of human immunodeficiency virus transmission, women and AIDS and the in vivo and in vitro developmental toxicity and teratogenicity studies of the anti-AIDS drugs (antiretrovirals), in humans and experimental animals, with especial highlights dedicated to zalcitabine effects on mice fetuses. In earlier human studies, management of AIDS positive pregnant women with antiretrovirals revealed exposure of their infants to such drugs with evidence of adverse events. However, recent publications present conflicting data about associations between antiretrovirals and adverse pregnancy outcomes. Animal embryos exposed in vivo to antiretrovirals exhibited significantly increased pregnancy losses, drugs incorporation into the DNA of fetal organs, external abnormalities, skeletal defects, developmental toxicity, carcinogenicity, reduced weight, anemia, deaths and significant mitochondrial damage. The in vitro antiretrovirals exposure of animal cells or organs resulted in cytotoxicity, growth retardation, chromosomal aberrations, mutations, sister chromatid exchange and other genotoxic effects. Zalcitabine orally (600 or 800 or 1000 mg kg~(-1)) applied to pregnant mice for five consecutive days, from day 9-13 of gestation evoked significant elevation in the number of resorption sites and dead fetuses, haematomas formation, significant reduction of body weight and length, mild to severe limb abnormalities, histopathological changes in fetal ovaries, hearts, spinal cords, brains and eyes and ultrastructural changes in ovaries. The in vitro exposure of mouse fibroblasts to zalcitabine revealed significant increase of abnormal metaphases and chromosomal abnormalities per metaphase. The study concluded that in utero or in vitro exposures to retrovirals revealed adverse outcomes in human and experimental animals.