indinavir-sulfate and Abnormalities--Drug-Induced

Assess possible adverse effects of the chronic use of indinavir during pregnancy in a rat model.. 40 pregnant EOM-1 albino rats were randomly allocated into four groups of 10 animals each: a control (Ctr) group (without any handling) and three experimental groups (Exp 1, Exp 2 e Exp 3) which received indinavir 9, 27 e 81 mg/kg, respectively). Rats were treated by gavage once daily. The treatment period extended from day 0 until the 20th day of pregnancy. Body weights were recorded on days 0, 7, 14 and 20. At term, the rats were sacrificed, and the implantation sites, number of live and dead fetuses and placentas, resorptions, fetal and placental weights were recorded. The fetuses were evaluated for external abnormalities under a stereomicroscope.. Weight gain during pregnancy did not differ significantly between the groups. Average weight gains between the 7th and 20th day were 7.95-42.70 g; 7.22-45.27 g; 7.12-46.26 g and 8.05-42.29 g in groups Ctr, Exp 1, Exp 2 and Exp 3, respectively. All other parameters assessed did not differ significantly between groups.. Chronic use of various dosages of indinavir during pregnancy was not associated significant adverse outcomes.

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Female; Fetal Development; HIV Protease Inhibitors; Indinavir; Placentation; Pregnancy; Random Allocation; Rats; Rats, Wistar

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.. 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.. 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.. 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.

Topics: Abnormalities, Drug-Induced; Animals; Anti-HIV Agents; Crown-Rump Length; Didanosine; Drug Therapy, Combination; Embryo, Mammalian; Female; HIV Protease Inhibitors; Indinavir; Organ Culture Techniques; Pregnancy; Rats; Rats, Sprague-Dawley; Zalcitabine; Zidovudine

Indinavir is an antiviral agent used for the treatment of HIV infection. We studied its developmental toxicity in rats.. Pregnant animals were treated orally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of gestation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a control group of 17 rats was treated with the vehicle accordingly. Developmental landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was examined by electron microscopy.. Fetal examination on day 21 of pregnancy showed no treatment-related effects on number, weight, and viability of the fetuses; however, an increased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testis. The most striking finding was unilateral anophthalmia, observed in 7 pups (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. Electron microscopy of liver samples showed hepatocellular inclusions of lipids and myelin figure-like structures in maternal livers and infiltration with granulocytes in offspring livers.. Further studies on reproductive toxicity, including combinations of three or more antiretroviral agents as used therapeutically, are needed to determine the hazards of such a treatment.

Topics: Abnormalities, Drug-Induced; Animals; Anophthalmos; Body Weight; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Embryonic and Fetal Development; Female; Fetus; HIV Protease Inhibitors; Indinavir; Liver; Male; Microscopy, Electron; Microsomes, Liver; Ossification, Heterotopic; Pregnancy; Rats; Rats, Wistar; Ribs; Spine