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Purpose: To evaluate the effects of the association of lopinavir and ritonavir administered during the whole period of rat pregnancy., Methods: 62 Wistar rats of the EPM-1 variant weighing about 200 g were randomly divided into five groups: two controls (Ctrl = stress control, n = 10; and Ctr2 = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of lopinavir/ritonavir (Exp1 = 12.8/3.2 mg/kg b.w., n = 14; Exp2 = 38.4/9.6 mg/kg b.w., n = 14; Exp3 = 115.2/28.8 mg/kg b.w., n = 14) from 'day 0' up to the 20th day of pregnancy. Maternal body weight was recorded at the start of the experiment and on the 7th, 14th and 20th day thereafter. At term (20th day), upon laparotomy and hysterotomy, the rats were anesthetized and the amount of implantations, reabsorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed and the concepts were examined under a stereoscope microscope for external malformations., Results: An apparent dose-unrelated lethal effect of the antiviral association on the pregnant rats was observed; notwithstanding, the body weight gain of the surviving rats had no changes, independent of the considered group. It was noted that the quantitative and qualitative intrauterine content of living term rats was indistinguishable from that of the controls., Conclusion: There was some degree of deleterious effects of the administration of the lopinavir/ritonavir association on pregnant rats; such effects eventually led to maternal death. However, neither the surviving rats showed toxicity nor did their concepts present any detectable change which could be related to the drug association.

Purpose: To evaluate the morphological aspects in rats subjected to an association of the antiretroviral drugs zidovudine/lopinavir/ritonavir in different doses administered throughout the gestational period., Materials and Methods: Forty pregnant rats were randomly allocated into four groups: control (Ctrl) and experimental (Exp1, Exp2, and Exp3), which received zidovudine/lopinavir/ritonavir in the doses of 10/13.3/3.3, 30/39.9/9.9, and 90/119.7/29.7 mg/kg per day from the first to the 20th day of pregnancy, respectively. At term, the animals were euthanized and maternal and fetal organ samples were removed for morphological analysis., Results: No major changes were identified in the group treated with the lowest dosing compared with the control. In group Exp2, the authors found hepatocytes with eosinophilic cytoplasm, pyknotic nuclei, and vasodilation. The proximal convoluted tubules of maternal kidneys showed eosinophilic areas and hyperchromatic nuclei, as well as signs of vasodilation. In the group treated with the highest dose (Exp3); the morphological changes in the maternal kidneys and livers were similar and more pronounced than those found in Exp2. The maternal pancreas of groups Exp2 and Exp3 evidenced moderate and progressive signs of tissue damage. The morphological features of all fetal livers, kidneys, and pancreases were normal., Conclusion: High doses of zidovudine/lopinavir/ritonavir association during the entire rat pregnancy period can cause definite morphological changes in maternal liver, kidneys, and pancreas. On the other hand, the corresponding fetal organs were not affected.

Purpose: To evaluate the effects at term of a highly active antiretroviral drug association when administered for the whole period of rat pregnancy., Methods: Forty pregnant rats weighing about 200 g were randomly divided into four groups: a control group (Ctr = drug vehicle control, n=10) and three experimental groups, which were treated with an oral solution of zidovudine-stavudine (Explx = 10/1 mg/kg b.w., n=10; Exp3x = 30/3 mg/kg b.w., n=10; Exp9x = 90/9 mg/kg b.w., n=10) from "day 0" up to the 20th day of pregnancy. Maternal body weights were recorded at the start of the experiment and on the 7th, 14th and 20th day thereafter. At term (20th day) the rats were anesthetized and submitted to hysterotomy. Implantations, reabsorptions, living fetuses, placentae and intrauterine deaths were looked for and recorded. The collected fetuses and placentae were weighed and the concepts were examined by a stereoscopic microscope looking for external malformations., Results: No significant alterations due to the antiretroviral drug treatment could be detected regarding the number of implantations, fetuses, placentae, absorptions and malformations nor regarding maternal and fetal mortality., Conclusions: Administration of the association zidovudine/stavudine for the whole period of rat pregnancy did not interfere with the maternal, fetal and placental weight gain as well as abnormalities detectable by the employed methodology.

Purpose: To evaluate biochemical and morphological effects on rats submitted to three different doses of the association zidovudine and ritonavir administered throughout pregnancy., Methods: Forty pregnant EPM-1 Wistar rats weighing about 200 g were randomly divided into the control group (Ctr = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of zidovudine/ritonavir (Exp1 = 10/20 mg/kg bw, n = 10; Exp2 = 30/60 mg/kg bw, n = 10; Exp3 = 90/180 mg/kg bw, n = 10) from 'day 0' up to the 20th day of pregnancy. At term (20th day) the rats were anesthetized. Blood and fetal and maternal organ samples (livers and kidneys) were taken for morphological and biochemical analyses., Results: Upon histological examinations fetal livers and kidneys appeared normal. In contrast the maternal samples revealed structural alterations. Maternal kidneys of the three experimental groups exhibited progressive and dose-dependent histological alterations; liver alterations were detected only in Exp3. Blood levels of AST and ALT were not significantly different from the control group but urea and creatinine levels were lower in groups Exp3 and Exp1., Conclusions: The administration of zidovudine plus ritonavir throughout rat pregnancy can cause morphological as well as functional changes in maternal kidneys.

Purpose: To evaluate at term the effects of a highly active antiretroviral (HAAR) drug association administered during the entire period of rat pregnancy., Methods: Three groups (n = 10 each) of adult pregnant rats were treated with an oral solution of HAAR (Exp 1 = 10/5/20 mg/kg b.w.; Exp 2 = 30/15/60 mg/kg b.w.; Exp 3 = 90/45/180 mg/kg b.w.) from day "0" up to the 20th day of pregnancy. A fourth group served as a control. At term (20th day) the rats were killed under deep anesthesia and the number of implantations, resorptions, living fetuses, placentae and intrauterine deaths were recorded., Results: The highest HAAR doses caused lower maternal weight gain, lower litter weights, and lower placental weights compared to the control group., Conclusions: HAAR during the entire period of rat pregnancy can reduce maternal body weight gain and lower term placental weight.

The purpose of the study was to evaluate at term, the effects of the association of zidovudine/ritonavir administered during the entire period of rat pregnancy. Forty pregnant EPM-1 Wistar rats were divided randomly into four groups: one control (drug vehicle control, n=10) and three experimental treated with an oral solution of zidovudine/ritonavir (Exp 1 = 10/20 mg/kg bw, n = 10; Exp 2 = 30/60 mg/kg bw, n=10; Exp 3 = 90/180 mg/kg bw, n=10) from day 0 up to day 20 of pregnancy. Maternal body weights were recorded at the start of the experiment and at the 7th, 14th and the 20th day thereafter. At term (20th day) the rats were anesthetized and, upon laparotomy and hysterotomy, the number of implantations, resorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed, and the concepts were examined under a stereoscopic microscope for external malformations. The maternal body gain and the mean fetal weight at term were both significantly lower (p < 0.01 and p < 0.0001, respectively) in the experimental groups compared to the control. The recorded resorptions were higher in Exp 2 and Exp 3 groups than in the control group. The other parameters were not affected. The exposure of pregnant rats at term to a 1:2 association of zidovudine plus ritonavir resulted in a significant reduction in maternal body weight gain and increased rate of fetal resorption.

Since indinavir is currently used in combination with other antiretroviral agents, there is a scarcity of studies in the literature on its single-drug perinatal safety. Thus, we decided to examine the gross maternal and fetal effects of indinavir administered alone during the entire period of rat pregnancy. Forty pregnant animals were assigned at random to four groups (C = control) treated with the drug vehicle (distilled water); the experimental groups were treated with indinavir as follows: E1 = 40 mg/kg; E2 = 120 mg/kg; E3 = 360 mg/kg from "zero" up to the 20th day of gestation. Drug or vehicle were administered daily by gavage. Each group consisted of ten animals. At term-pregnancy, the rats were deeply anesthetized and blood samples were collected for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), creatinine and urea determinations. Fragments of maternal and fetal livers and kidneys were taken and routinely processed for histopathological study. Serum ALT activity in the E2 group was significantly higher (p < 0.01) than that of the other groups. The concentration of creatinine in blood was lower in the E2 and E3 groups than in group E1 (p < 0.01), whereas blood urea in group E3 was significantly lower than in the other groups (p < 0.01). Morphological (light microscopy) studies revealed that no significant effects of the drug could be detected regarding either maternal or fetal organs of the E1 and E2 groups. However, the maternal hepatocytes in the E3 group showed heterochromatic nuclei. In addition, there was some fatty infiltration, congested sinusoids and portal dilation. Maternal kidneys in the E2 and E3 groups revealed vascular dilation around the convoluted tubules. Regarding the biochemical determinations, the alterations observed were mild, without biological relevance, thus indicating that the treatment with indinavir during the entire gestation was essentially devoid of hepatic or renal effects which could result in altered metabolic parameters. It is concluded that indinavir was well tolerated in therapeutic and even in 9-fold higher doses. Notwithstanding, discrete morphological alterations occurred in the maternal compartment, but with no functional expression that could indicate deleterious effects on mothers and/or fetuses.

This experimental study aimed to evaluate the safety of nelfinavir when administered in normal up to high doses during the entire period of rat pregnancy. The renal and liver compartments of both mothers and fetuses were studied. For this purpose, three groups of pregnant rats were treated with nelfinavir (E1 = 40 mg/kg; E2 = 120 mg/kg; E3 = 360 mg/kg; no. = 10 in every group) from "zero" up to the 20th day of gestation. These doses were divided into two daily administrations by gavage. Controls (no. = 10) received distilled water in the same schedule. At term-pregnancy, the rats were deeply anesthesized and blood samples were collected for alanine and aspartate aminotransferases, creatinine and urea determinations. Fragments of maternal and fetal livers and kidneys were taken and processed for histopathological study. In all groups blood transaminases were within the normal limits, as were the levels of creatinine and urea, thus indicating that the treatment with nelfinavir during the entire gestation was essentially devoid of liver or kidney effects which could result in altered metabolic parameters. Morphological (light microscopy) studies revealed that no significant effects of the drug could be detected regarding either maternal or fetal organs of the E1 and E2 groups. However, the maternal hepatocytes in the E3 group showed heterochromatic nuclei. In addition, there was some fatty infiltration, congested sinusoids and portal dilatation. It is concluded that only doses of nelfinavir used during the entire gestation in doses well above the usual human doses could be considered to be potentially hepatotoxic for the pregnant rat.

Acetaminophen (paracetamol) is an analgesic-antipyretic drug virtually devoid of typical anti-inflammatory activity and hence free of some of the side-effects of aspirin and related agents (e.g. gastric erosion and bleeding complications). The worldwide use of paracetamol as a household analgesic, including during pregnancy, prompted us to investigate its potentially deleterious effects in that setting. Pregnant rats were treated with paracetamol (150, 500 or 1,500 mg/kg, once a day by gavage) from the first day up to term pregnancy. In the group treated with the lowest doses, no histological changes were noticed in maternal and fetal livers or kidneys when examined under light or electron microscopy. With the higher doses, however, various dose-dependent effects of paracetamol were observed, namely necrotic areas of the liver seen with light microscope and further confirmed by electron microscopy. The kidneys revealed degeneration and necrotic foci under light microscopy with ultrastructural derangements. Electronmicrographs of the liver revealed hepatocytes bearing translucent bodies as a consequence of a dilated smooth endoplasmic reticulum. There were signs of necrosis both in the hepatocytes (lysis of mitochondria and presence of lipid droplets) and renal tissue (mitochondrial cytolysis in convoluted tubules). Our data point out the fact that both maternal and fetal tissues can be adversely affected by paracetamol.

In view of the very important role played by ritonavir in the prevention of maternal-fetal HIV-vertical transmission, the aim of this experimental study was to evaluate its possible effects on several important obstetric parameters. Ritonavir was administered daily to three groups of pregnant rats (E1 = 20 mg/kg; E2 = 60 mg/kg; E3 = 180 mg/kg; n = 10 in every group) from 'zero' up to the 20th day of pregnancy. Controls (n = 10) were injected with the drug vehicle (propyleneglycol) in the same schedule. We evaluated the effects on fetal and maternal weight gain, placental weight, number of implantations and resorptions, malformations, fertility rate, and maternal and fetal death rates. Body weight gain of the E3 group was significantly lower than that of the other groups, most likely due to a toxic effect of the highest dose of ritonavir. Ritonavir did not affect the number of implantations. Group E3 had five resorptions and some reduction in fertility. The mortality rate was significantly affected by ritonavir (2/10 maternal deaths in E2 and 4/10 in E3). On the other hand, no alterations were observed in the fetuses, a finding which could be due at least in part to the protective action of placental P-glycoprotein.

The worldwide use of acetylsalicylic acid (ASA) as an analgesic-antipyretic drug, including during pregnancy, prompted us to investigate its potentially deleterious effects in that condition. Pregnant rats were treated with ASA (1, 10 or 100 mg/kg once a day) from the first day up to term pregnancy. No histological changes were noticed in maternal and fetal livers or kidneys when examined under light microscopy, but some definite dose-dependent effects of ASA were observed on electron microscopy examination. In livers and kidneys of pregnant rats treated with the highest doses of ASA we observed cytoplasmic derangement, mitochondrial cristolysis and abnormally shaped rough endoplasmic reticulum. Similarly, in foetal livers and kidneys from this group we observed degenerative cytoplasmic vacuoles and ballooned mitochondria with cristae derangement and myelin figures. Our data point out the fact that both maternal and foetal tissues can be importantly affected by ASA at the ultrastructural level, without overt signs of toxicity.