Assessment of developmental toxicity of antiretroviral drugs using a rat whole embryo culture system.
BACKGROUND
Previous guidelines for HIV-infected pregnant women have recommended zidovudine (ZDV) monotherapy during the second and third trimesters of pregnancy to prevent fetal HIV infection. New guidelines suggest that women should continue or be offered combination antiretroviral therapy (including protease inhibitors) during pregnancy. Nevertheless, little animal or human toxicity data underlie these recommendations.


METHODS
We used an in vitro rat whole embryo culture system to assess the embryo toxicity of various nucleoside analogues, namely, ZDV, dideoxyinosine (ddI), and 2', 3'-dideoxycytidine (ddC), and the HIV-1 protease inhibitor, indinavir, both alone and in combination.


RESULTS
Although human fetal concentrations of these compounds are unknown, no gross abnormalities were detected after incubation with these agents, either alone or in combination at concentrations that would be expected to be achievable in human maternal serum (1-50 microM). ZDV in combination with ddC at >100 microM, resulted in severe growth retardation and morphologic abnormalities not seen with either agent singly.


CONCLUSIONS
We conclude that the combination of ZDV/ddC results in severe concentration-dependent embryo toxicity. No growth retardation or gross morphologic abnormalities were found for any of the agents, either singly or in combination, at clinically relevant concentrations.
Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, USA. m.fujinaga@ic.ac.uk
M
M
Fujinaga
M
M
Schulte
M
M
Holodniy
D000014:Abnormalities, Drug-Induced; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D018568:Crown-Rump Length; D016049:Didanosine / Q000633:toxicity; D004359:Drug Therapy, Combination; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D017320:HIV Protease Inhibitors / Q000633:toxicity; D019469:Indinavir / Q000633:toxicity; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016047:Zalcitabine / Q000633:toxicity; D015215:Zidovudine / Q000633:toxicity
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D015215:Zidovudine; D019469:Indinavir; D016047:Zalcitabine; D016049:Didanosine