Effect of six antiretroviral drugs (delavirdine, stavudine, lamivudine, nelfinavir, amprenavir and lopinavir/ritonavir in association) on albino pregnant rats (Rattus norvegicus Albinus, Rodentia, Mammalia): biological assay.

OBJECTIVE: To compare the chronic effects of antiretrovirals (lamivudine, stavudine, delavirdine, nelfinavir, amprenavir and an association of lopinavir/ritonavir) on albino pregnant rats. DESIGN: Review. SETTING: Department of Obstetrics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil. METHODS: This was a comparative retrospective study formed by 18 groups of 10 pregnant rats each, which were nearly three months of age and weighed 200 g. All of them were medicated every day using a stomach probe, while the control group was given 1 mL of distilled water. The study groups received lamivudine (at 5, 15 and 45 mg/kg/day); stavudine (at 1, 3 and 9 mg/kg/day); nelfinavir (at 40, 120 and 360 mg/kg/day); amprenavir (at 46, 138 and 414 mg/kg/day); lopinavir/ritonavir (at 12.8/3.2, 38.4/9.6 and 115/28.8 mg/kg/day) and delavirdine (at 20 and 60 mg/kg/day). These represented 1, 3 and 9 times the human therapeutic dose, except for the last drug, for which the 9-times dose was not used. Maternal, litter and placental weights, implantation and reabsorption numbers, major external fetal malformations and fetal and maternal deaths were evaluated. The Kruskal-Wallis test was used to compare quantitative variables and the chi-square test was used to compare qualitative variables. RESULTS: At all three doses, stavudine increased the maternal weight (p=0.001), while lamivudine at 3- and 9-times doses reduced it (p<0.001). Amprenavir at all of the doses, and lopinavir/ritonavir at 3- and 9-times doses, caused higher rates of maternal death (p<0.001). Regarding the fetuses, none of the antiretroviral drugs studied were harmful with regard to implantation, reabsorption, teratogenity and mortality (p>0.05). Stavudine at all doses reduced the litter weights (p<0.001); however, lamivudine at the usual and 3-times doses, delavirdine at 3-times dose, and amprenavir at 3-times dose increased the litter weight (p<0.001). CONCLUSION: In the maternal compartment, we observed lethal toxicity in the pregnant rats that received amprenavir and ritonavir/lopinavir; and maternal weight change with lamivudine and stavudine. In the fetal compartment, adverse effects were observed in relation to litter weight from stavudine, lamivudine, delavirdine and amprenavir.

Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial.

Preeclampsia is an important cause of maternal and perinatal morbidity and mortality. Previous studies have tested calcium supplementation and aspirin separately to reduce the incidence of preeclampsia but not the effects of combined supplementation. The objective of this study was to investigate the effectiveness of aspirin combined with calcium supplementation to prevent preeclampsia in women with chronic hypertension. A double-blind, placebo-controlled randomized clinical trial was carried out at the antenatal clinic of a large university hospital in São Paulo, SP, Brazil. A total of 49 women with chronic hypertension and abnormal uterine artery Doppler at 20-27 weeks gestation were randomly assigned to receive placebo (N = 26) or 100 mg aspirin plus 2 g calcium (N = 23) daily until delivery. The main outcome of this pilot study was development of superimposed preeclampsia. Secondary outcomes were fetal growth restriction and preterm birth. The rate of superimposed preeclampsia was 28.6% lower among women receiving aspirin plus calcium than in the placebo group (52.2 vs 73.1%, respectively, P=0.112). The rate of fetal growth restriction was reduced by 80.8% in the supplemented group (25 vs 4.8% in the placebo vs supplemented groups, respectively; P=0.073). The rate of preterm birth was 33.3% in both groups. The combined supplementation of aspirin and calcium starting at 20-27 weeks of gestation produced a nonsignificant decrease in the incidence of superimposed preeclampsia and fetal growth restriction in hypertensive women with abnormal uterine artery Doppler.

Effects of combined zidovudine/lopinavir/ritonavir therapy during rat pregnancy: morphological aspects.

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.

Administration of lopinavir/ritonavir association during rat pregnancy: maternal and fetal effects.

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.

Effects of daily intake of zidovudine-stavudine on rat pregnancy outcome: biological essay.

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.

Effects of the association zidovudine plus ritonavir on the liver and kidneys of pregnant rats. Morphological and biochemical aspects.

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.

Chronic action of association of zidovudine, lamivudine and ritonavir on pregnant rats. A biologic assay.

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.

Extended administration of the association of zidovudine plus ritonavir during rat pregnancy: maternal and fetal effects.

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.

Morphological and biochemical appraisal of the liver and renal effects of indinavir on rat pregnancy.

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.

Effects of lopinavir-ritonavir combined therapy during the rat pregnancy. Morphological and biochemical aspects.

OBJECTIVE: To evaluate the biochemical and morphological effects in rats subjected to three different dose associations of the protease inhibitors lopinavir and ritonavir administered throughout the entire period of pregnancy. STUDY DESIGN: The animals were treated throughout pregnancy with daily oral doses of lopinavir+ritonavir starting at the day one of pregnancy, and were divided into four groups: E1, 13.3+3.3 mg/kg; E2, 39.9+9.9 mg/kg; E3, 119.7+29.9 mg/kg and C, control (drug vehicle, propyleneglycol). The animals were then sacrificed and maternal blood and fetal and maternal organ samples were taken for morphological and biochemical analysis. RESULTS: No major changes were identified in the group treated with the lowest dose as compared with the control. In the group E2, we found hepatocytes with signs of atrophy, eosinophilic cytoplasm, picnotic nuclei and vasodilatation. 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 (group E3), in the maternal kidneys and livers, the morphological changes were similar to those found in E2, although more prominent. Regarding the fetal organs, the single abnormality observed was some liver vasodilation in the group E3 (highest dose). The treatment with lopinavir+ritonavir caused discrete, yet significant, alterations of aspartate aminotransferase activity, blood urea nitrogen and creatinine plasma levels. CONCLUSIONS: Our results showed that the administration of a combination of lopinavir plus ritonavir to pregnant rats can cause morphological as well as functional changes in maternal and fetal liver and kidneys and, in higher than therapeutic doses, might be toxic to those animals.

A morphological and biochemical appraisal of the liver and renal effects of lamivudine on rat pregnancy.

No data exist on the perinatal safety of lamivudine alone, as it is used in combination with other antiretroviral agents. Until now, only preliminary data on the lamivudine-zidovudine combination have been available, thus we decided to examine the gross maternal and fetal effects of lamivudine administered alone during the entire period of rat pregnancy. Forty pregnant animals were assigned at random to four groups (C1 = control; E1 = 5 mg/kg; E2 = 15 mg/kg; E3 = 45 mg/kg) from day 0 up to the 20th day of gestation. These doses were divided into two daily administrations by gavage. Controls (n = 10) received distilled water in the same schedule. At term-pregnancy, the rats were deeply anesthetized 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 treatment with lamivudine 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. Maternal kidneys in the E3 group revealed vascular dilation around the convoluted tubules. It is concluded that only doses of lamivudine used during the entire gestation in doses well above the usual human doses could be considered to be potentially hepatotoxic for the pregnant rat.

Safety of nelfinavir use during pregnancy. An experimental approach in rats.

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.

Long-term acetaminophen (paracetamol) treatment causes liver and kidney ultra-structural changes during rat pregnancy.

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.

Morphological and morphometric changes in the cervix uteri of the rat at term pregnancy induced by hyaluronidase.

Intracervix injection of hyaluronidase during pregnancy has been proposed to accelerate cervix ripening. We evaluated the morphological and morphometric changes of the uterine cervix of pregnant rats, caused by the action of this enzyme. Ten female rats were equally divided between an experimental group (G II) and a control group (G I). On the 20th day of pregnancy, under light microscopy, a greater thinning of the superficial muciferous epithelium, with lamina propria rich in blood vessels and in eosinophils was found in G II. The histometric count of G II showed a smaller number of collagen fibers (average 248 vs 552 in the control group) and a greater concentration of eosinophils (average 18.20 vs 9.20 in the control group). The Student's t-test showed a significant difference in collagen fibers (p < 0.0001) and in eosinophils (p < 0.0007). The action of this enzyme caused a predominance of flaccid connective tissue, a lower concentration of collagen fibers and an increased concentration of eosinophils, confirming its utilization in cervix ripening.

Effect of chronic ritonavir administration on pregnant rats and their fetuses.

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.

Liver and kidney ultrastructural changes caused by acetylsalicylic acid treatment during pregnancy in rats.

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.

[A comparative study of the sodium, potassium, urea, creatinine, and uric acid concentrations in the human amniotic fluid between weeks 15-20 and 38-42]. / Estudo comparativo das dosagens de sódio, potássio, uréia, creatinina e ácido úrico no líquido amniótico entre 15-20 semanas e 38-42 semanas.

UNLABELLED: The amniotic fluid physiology is a dynamic process involving maternal and fetal compartments and depends on gestational age. PURPOSE: To analyze the concentration of sodium, potassium, urea, creatinine, and uric acid in the amniotic fluid of normal pregnant women in the second and third trimester. Also, to evaluate the influence of maternal age, race, parity, and fetal sex on those elements. METHOD: Fifty samples obtained by genetic amniocentesis (15-20 weeks, group I) and fifty obtained by elective cesarean section (38-42 weeks, group II) were analyzed. According to the variables we used the following statistical tests: Analysis of variance; Test t Student: Chi-square test; Mann-Whitney test (a 0.05 pounds). RESULTS: In group II, urea, creatinine and uric acid levels were significantly higher than in group I. The sodium level was significantly lower in group II compared with group I. The potassium concentration did not show any significant difference in both groups. There was no significant interference of maternal age, race, parity and fetal sex in any of the five studied variables. CONCLUSION: These findings were emphasized for prenatal diagnosis purposes and analysis of renal function. The authors suggest future comparisons of obtained "normal" data with pathological situations.

Semi-continuous lactic fermentation of whey by Lactobacillus bulgaricus.

Semi-continuous tests of lactic fermentation of whey by Lactobacillus buigaricus were carried out using a mixture of hydrolysed milk and vitamins. The volume of the Inoculum varied from 20% to 50% of the reactor working volume. A Monod-like equation correlates the lactic acid productivity and the volume fraction of inoculum.

Maternal and fetal liver enzymes of mid-to-term pregnant rats chronically treated with magnesium sulphate.

1. Pregnant rats were injected daily with 150 mg/kg body weight magnesium sulphate (MgSO4) starting at the 5th day of gestation and sacrificed at the 13th, 15th, 19th or 21st day of pregnancy. 2. Maternal liver enzymes of glycolysis (HK, PFK, PK, LDH), pentose shunt pathway (G-6-PD) and glutamate metabolism (Ala-T, Asp-T) were unaltered by the treatment. 3. Fetal liver PK, LDH, G-6-PD, Ala-T and Asp-T activities were strongly activated by MgSO4 to levels in some instances as high or even higher than those found in the adult rat liver. 4. Results support recent evidence that MgSO4 induces precocious maturation of certain morphofunctional features of the fetal rat liver. 5. Data presented herein cannot account for the strong deleterious effects of the drug on rat pregnancy. Instead, such effects would be better explained by the direct cell toxicity of MgSO4.

Patterns of mid-to-term placental enzymes in rats treated with magnesium sulphate.

1. Pregnant rats were injected daily with 150 mg/kg b.w. of magnesium sulphate (MgSO4) starting at the 5th day gestation and sacrificed at the 13th, 15th, 19th or the 21st day of pregnancy. 2. The profiles of LDH, G-6-PD, HK and Ala-T activities in mid-to-term placentae were not changed by the drug. 3. Placental PK was strongly activated by MgSO4 in 13-19 day pregnant rats, whereas Asp-T was more severely depressed at the final phase of pregnancy. 4. Although mild to moderate changes in the flow of substrates should be predictable by the results, it seems unlikely that these could account for the reported deleterious effects of MgSO4 on rat offsprings.