Abstract
to evaluate the effect of administration of three different doses of the zidovudine/lamivudine/ritonavir combination on the liver and kidneys of pregnant rats and their concepts from a morphological and physiological standpoint. 40 pregnant EPM-1 Wistar rats were randomly divided into 4 groups: 1 control (Ctrl: drug vehicle control, n=10) and 3 experimental groups: Exp1x, Exp3x and Exp9x. An oral solution of the zidovudine/lamivudine/ritonavir combination was administered to the experimental groups from the day 0 to day 20 of pregnancy: Exp1x=10/5/20 mg/kg; Exp3x=30/15/60 mg/kg; Exp9x=90/45/180 mg/kg. On the 20th pregnancy day the rats were anesthetized and blood was taken directly from the ventricular chambers for further biochemical determinations: aspartate-(AST) and alanine-(ALT) aminotransferases (Calorimetric method), urea nitrogen (BUN) by an enzymatic-kinetic method, and creatinine by a kinetic-calorimetric method. Maternal and fetal liver and kidney samples were taken, fixed in 10% formaldehyde and processed histologically for paraffin embedding. Five µm-thick fragments of maternal and fetal livers and kidneys were stained with hematoxilyn-eosin, being analyzed by light microscopy. To interpret the results, the well-known pattern of normality for livers and kidneys was considered on the basis of the following structures: hepatocytes, portal structure, hepatic veins, renal corpuscles, renal tubules and loop of Henle. Regarding the fetal livers, we also considered the erythrocytes in their different stages of development as well as the megacariocytes. If there was a change in the established staining pattern for liver and kidney structures, changes in nuclear morphology, rupture of some cytoplasmic organelles, and presence of vascular congestion, this was considered to be due to the drug doses. Results were submitted to analysis of variance (ANOVA) and to the Tukey-Kramer multiple comparisons test (p<0.05). no morphological changes were observed in the maternal livers of the Ctrl, Exp1x and Exp3x groups. In the maternal liver of the Exp9x group, hepatocytes showed signs of atrophy and apoptosis (eosinophilic cytoplasm and pycnotic nuclei) and marked sinusoid capillary vasodilation (congestion) was observed. The maternal kidneys of the Ctrl and Exp1x groups were normal, with renal corpuscles, convoluted tubules and typical loops of Henle. In contrast, the Exp3x and Exp9x groups showed vascular congestion and small glomeruli rich in cells containing hyperchromatic nuclei which were more intense in Exp9x. Regarding the fetal organs, no morphological or physiological changes were observed. A significant increase of AST (305.70±55.80, p<0.05) and creatinine (0.50±0.09, p<0.05) was observed in group Exp9x. our results show that the administration of the zidovudine, lamivudine and ritonavir combination to pregnant rats at high doses caused morphological and physiological changes in the maternal liver and kidneys. On the other hand, there were no changes in fetal organs.
Highlights
An oral solution of the zidovudine/lamivudine/ritonavir combination was administered to the experimental groups from the day 0 to day 20 of pregnancy: Exp1x=10/5/20 mg/kg; Exp3x=30/15/60 mg/kg; Exp9x=90/45/180 mg/kg
Five μm-thick fragments of maternal and fetal livers and kidneys were stained with hematoxilyn-eosin, being analyzed by light microscopy
We considered the erythrocytes in their different stages of development as well as the megacariocytes
Summary
Departamento de Obstetrícia da Universidade Federal de São Paulo, Escola Paulista de Medicina – UNIFESP – São Paulo (SP), Brasil. 1 Professora Doutora do Departamento de Obstetrícia e Ginecologia da Universidade José do Rosário Vellano – UNIFENAS – Alfenas (MG), Brasil. 2 Professor Doutor do Serviço de Clínica Médica da Universidade José do Rosário Vellano – UNIFENAS – Alfenas (MG), Brasil. 3 Professora Associada e Livre-Docente do Departamento de Obstetrícia da Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brasil. 4 Médico Assistente do Hospital Universitário da Faculdade de Medicina da Universidade de São Paulo – USP São Paulo (SP), Brasil – Pós-Graduando (Mestrado) do Departamento de Obstetrícia e Ginecologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – USP – São Paulo (SP), Brasil. 5 Professora do Departamento de Ginecologia e Obstetrícia da Universidade Gama Filho – UGF – Rio de Janeiro (RJ), Brasil. 6 Professora Doutora do Departamento de Obstetrícia e Pediatria da Faculdade de Medicina do ABC – FMABC – Santo André (SP), Brasil. 7 Professor Titular do Departamento de Obstetrícia da Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brasil. Análise morfológica e fisiológica dos fígados e rins de ratas prenhes e seus fetos tratados pela associação zidovudina, lamivudina e ritonavir durante toda a prenhez n=10) and 3 experimental groups: Exp1x, Exp3x and Exp9x.
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