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Toxicology and carcinogenesis studies of mixtures of 3'-azido-3'-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV) (Cas Nos. 30516-87-1, 134678-17-4, 129618-40-2, 159989-65-8) in B6C3F1 Mice (transplacental exposure studies).

Abstract

BACKGROUND:

Antiretroviral drugs are used to treat patients positive for the human immunovirus HIV-1, and increasingly treatments include a combination of such drugs. The noninfected children of women who are pregnant and receiving such treatment may also be exposed to the drugs by transplacental exposure. We studied the long-term effects of such transplacental exposure in mice by exposing pregnant mice to combinations of four such antiretroviral drugs for seven days and then observing their pups for two years following birth. The four drugs studied were 3′-azido-3′-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV).

METHODS:

Four different sets of exposure studies were performed: exposure to AZT; to AZT plus 3TC; to AZT, 3TC, and NVP; or to AZT, 3TC, and NFV. In each of these studies, groups of pregnant females were given one of three concentrations of the drug combinations seven times though a tube directly into their stomachs, and after birth their pups were maintained with no further exposure for two years. The offspring of another group of pregnant females not treated with the drugs served as controls. At the end of the study, tissues from more than 40 sites were examined for every animal.

RESULTS:

Survival of pups whose mothers were exposed to AZT or AZT plus 3TC was similar to their controls, while the survival rates for offspring of mice exposed to AZT, 3TC, and NVP or AZT, 3TC, and NFP were lower than for controls. In most cases the body weights of pups from mothers exposed were slightly less than those of the controls. There were slight increases in the incidences of thyroid gland tumors and skin tumors in the female pups of mothers exposed to AZT alone and of lung tumors in female pups of mothers exposed to AZT plus 3TC. For offspring of mothers exposed to AZT, 3TC, and NVP there were increased incidences of skin tumors in both male and female pups, and more so in the males.

CONCLUSIONS:

We conclude that exposure to the combination of AZT, 3TC, and NVP during pregnancy caused an increase in skin tumors in the male offspring and possibly also to the female offspring. Exposure to AZT alone during pregnancy may have been related to thyroid gland or skin tumors in female offspring, and exposure to AZT plus 3TC may have been related to lung tumors in female offspring.

PMID:
23385634
[PubMed - indexed for MEDLINE]
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