The acquired immunodeficiency syndrome (AIDS) is a devastating disease which has now reached epidemic proportions in the United States. The causative agent, the human immunodeficiency virus (HIV), can be transmitted by several routes. Of these, the route of maternal-fetal transmission is the most important contributor to the increase in incidence of HIV infection in children. It is estimated that by 1992 AIDS is likely to be one of the five leading causes of mortality in the 1-4 year age group. Currently only one drug, zidovudine (ZDV or azidothymidine), a dideoxynucleoside (ddNS), has been approved for use in the treatment of adult AIDS patients. Several other dideoxynucleosides (ddNSs) are currently undergoing phase I or II trials. However, none of these drugs are currently approved for administration to HIV infected pregnant women. The long-term objective of the proposed project is to test the hypothesis that administration of anti-HIV drugs to HIV positive pregnant women may either reduce the incidence of maternal-fetal transmission of the HIV or retard the onset and course of AIDS in the offspring. Before testing this hypothesis, studies need to be conducted in a representative animal model to ascertain if anti-HIV drugs can cross the placenta and if so whether they are capable of accumulating in the fetus.
The specific aims of this project, therefore,are: 1 .To determine the transplacental pharmacokinetics of four dideoxynucleosides of varying lipophilicity, namely zidovudine (ZDV), dideoxycytidine (DDC), dideoxyinosine (DDI) and didehyro-dideoxythymidine (D4T) in a chronically catheterized maternal-fetal macaque (Macaca nemestrina) model. 2.To determine the mutual interaction between ZDV and DDC, DDI or D4T with respect to their transplacental pharmacokinetics in the above macaque model. 3.To determine the transplacental pharmacokinetics of the above listed dideoxynucleosides in the (in vitro) isolated perfused human placenta model. 4.To determine the ability of the in vitro perfused human placenta to predict the in vivo transplacental pharmacokinetics of the ddNSs in the macaque.
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