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C M Rodrigues

Publications and source records attributed to C M Rodrigues.

33 records · Page 2Linked to original sources
PubMed1998

Unusual case of severe cholestasis of pregnancy with early onset, improved by ursodeoxycholic acid administration.

An exceptional case of early onset and prolonged postpartum course of intrahepatic cholestasis of pregnancy is described. Contrary to other drugs tested, ursodeoxycholic acid administered after the 29th week of gestation improved pruritus and decreased bile acid levels both in serum and amniotic fluid. Labour was induced at 36 weeks, and a female weighing 2.050 g and with an Apgar score of nine was born. Ursodeoxycholic acid, by decreasing the passage of bile acids to the foetus, may have improved the outcome of the pregnancy.

Adult↗
PubMed1998

Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in an high incidence area: Portugal.

OBJECTIVE(S): The present work was conducted to clarify the relevance of usual liver function tests, and define the most predictive serum bile acid profile for diagnosis of intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: This study comprised 20 healthy nonpregnant women and 77 pregnant women in the last trimester of pregnancy, from which 38 were normal pregnancies, and 39 suffered from ICP. Liver function tests were evaluated by routine laboratory techniques, conjugated bile acids were analysed by high-performance liquid chromatography, and unconjugated forms were measured by an enzymatic-fluorimetric assay. RESULTS: During the third trimester in normal pregnancy, increased concentration of conjugated species affected all primary bile acids, although only significantly for glycocholic acid. Moreover, deoxycholic acid proportion decreased when compared with healthy nonpregnant women. Important ICP-induced changes in serum profiles of amidated bile acids were observed, involving both a marked increase in cholic acid concentration and a shift towards a higher proportion of taurine-conjugated species. Among routine liver tests, alanine aminotransferase and conjugated bilirubin were the most common indicators of ICP. CONCLUSION(S): In the early diagnosis and follow-up of ICP, the most predictive and accurate markers (efficiency 100%) were: (i) TBA concentration in serum >11.0 micromol(-1): (ii) cholic/chenodeoxycholic acid ratio >1.5 and cholic acid percentage >42%: (iii) glycine/taurine bile acid ratio <1.0 or glycocholic acid concentration >2.0 micromol(-1). Accurate diagnosis based on sensitive biochemical markers followed by appropriate treatment may improve both pregnancy outcome and newborn prognosis.

Adolescent↗
PubMed1998

Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production.

BACKGROUND: The hydrophilic bile salt ursodeoxycholate (UDCA) inhibits injury by hydrophobic bile acids and is used to treat cholestatic liver diseases. Interestingly, hepatocyte cell death from bile acid-induced toxicity occurs more frequently from apoptosis than from necrosis. However, both processes appear to involve the mitochondrial membrane permeability transition (MPT). In this study, we determined the inhibitory effect of UDCA on deoxycholic acid (DCA)-induced MPT in isolated mitochondria by measuring changes in transmembrane potential (delta psi m) and production of reactive oxygen species (ROS). In addition, we examined the expression of apoptosis-associated proteins in mitochondria isolated from livers of bile acid-fed animals. MATERIALS AND METHODS: Adult male rats were maintained on standard diet supplemented with DCA and/or UDCA for 10 days. Mitochondria were isolated from livers by sucrose/percoll gradient centrifugation and MPT was measured using spectrophotometric and fluorimetric assays. delta psi m and ROS generation were determined by FACScan analysis. Cytoplasmic and mitochondrial protein abundance were determined by Western blot analysis. RESULTS: DCA increased mitochondrial swelling 25-fold over controls (p < 0.001); UDCA reduced the swelling by > 40% (p < 0.001). Similarly, UDCA inhibited DCA-mediated release of calcein-loaded mitochondria by 50% (p < 0.001). delta psi m was significantly decreased in mitochondria incubated with DCA but not with UDCA. delta psi m disruption was followed closely by increased superoxide anion and peroxides production (p < 0.01). Coincubation of mitochondria with UDCA significantly inhibited the changes associated with DCA (p < 0.05). In vivo, DCA feeding was associated with a 4.5-fold increase in mitochondria-associated Bax protein levels (p < 0.001); combination feeding with UDCA almost totally inhibited this increase (p < 0.001). CONCLUSION: UDCA significantly reduces DCA-induced disruption of delta psi m, ROS production, and Bax protein abundance in mitochondria, suggesting both short- and long-term mechanisms in preventing MPT. The results suggest a possible role for UDCA as a therapeutic agent in the treatment of both hepatic and nonhepatic diseases associated with high levels of apoptosis.

Animals↗
PubMed1997

Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei.

BACKGROUND & AIMS: Bile acids exert cellular and molecular effects in the liver, but little is known about tissue concentrations. The aim of this study was to characterize bile acid composition in human and rat liver tissue and hepatocyte nuclei and examine the effects of experimental cholestasis and bile acid administration. METHODS: Bile acids were measured by gas chromatography-mass spectrometry. RESULTS: Liver tissue concentrations of sham-operated rats were 130.8 +/- 21.3 nmol/g, representing 2%-4% of the bile acid pool; cholic and delta 22-beta-muricholic acids were the major bile acids identified. Concentrations increased 7-8-fold with bile duct ligation; deoxycholate and hyodeoxycholate disappeared. Lithocholate concentrations were higher in ligated rats (6.4 +/- 0.4 vs. 3.9 +/- 0.5 nmol/g for sham-operated). Total bile acid concentrations in human liver tissue were 61.6 +/- 29.7 nmol/g and comprised mainly chenodeoxycholic and cholic acids. Concentrations were higher during ursodeoxycholate or tauroursodeoxycholate administration (157.2 +/- 45.6 and 161.6 +/- 43.4 nmol/g, respectively), and liver tissue was enriched 30% in ursodeoxycholate at the expense of hydrophobic bile acids. Bile acids were identified in rat hepatic nuclei (50-110 pmol/4 x 10(7) nuclei), accounting for < 0.1% of liver tissue levels. CONCLUSIONS: Human and rat liver tissue bile acid concentrations are low, increase with bile acid administration or bile duct ligation, and account for only a small fraction of the bile acid pool.

Adult↗
PubMed1996

Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis.

The metabolism of tauroursodeoxycholic acid orally administered and its effects on the bile acid pool of patients with asymptomatic/mildly symptomatic primary biliary cirrhosis is described. Patients were randomly assigned 500, 1000, or 1500 mg/day of tauroursodeoxycholate for six months. Biliary and serum bile acids were measured before and during treatment by gas chromatography-mass spectrometry and by high performance liquid chromatography. During tauroursodeoxycholate administration, the proportion of total ursodeoxycholate in bile reached mean (SEM) 34.4 (4.5)%, 32.8 (2.8)%, and 41.6 (3.0)% with doses of 500, 1000, and 1500 mg/day, respectively. Significant decreases in the proportions of chenodeoxycholate and cholate resulted. The glycine/taurine ratio of the biliary bile acid pool decreased from 1.9 at baseline, to 1.1 with the highest dose. Ursodeoxycholate in bile was conjugated with glycine and taurine, indicating that tauroursodeoxycholate undergoes significant deconjugation and reconjugation during its enterohepatic recycling. The proportion of lithocholate in bile remained unchanged. Fasting serum conjugated ursodeoxycholate concentration positively correlated with the tauroursodeoxycholate dose, and the increased proportion of ursodeoxycholate was accompanied by substantial decreases in the endogenous bile acids. Compared with previously published data for ursodeoxycholic acid therapy, these findings indicate that the shift toward a more hydrophilic bile acid pool is greater and potentially more favourable with tauroursodeoxycholate, and this is because of the reduced intestinal biotransformation of tauroursodeoxycholate.

Administration, Oral↗
PubMed1996

Clinical pharmacokinetics of therapeutic bile acids.

The pharmacokinetics of chenodeoxycholic and ursodeoxycholic acids are reviewed in this article. Chenodeoxycholic acid is well absorbed by the intestine, whereas the absorption of ursodeoxycholic acid is incomplete. They are extracted efficiently by the liver, conjugated with glycerine and taurine, secreted in bile, and then undergo enterohepatic circulation with the endogenous bile acids. Therapeutic bile acids are metabolised by intestinal bacteria to lithocholic acid which is mainly excreted with faeces. Since the large majority of bile acid is confined within the enterohepatic circulation (resulting in low serum concentrations) their volume of distribution is relatively high. Despite the high hepatic extraction, the clearance of therapeutic bile acids is relatively low because of the highly efficient enterohepatic recirculation. Elimination of therapeutic bile acids mainly occurs in the faeces either unmodified or after biotransformation. At present the main clinical indication for therapeutic bile acids is ursodeoxycholic acid treatment for chronic cholestatic liver disease. In these patients, ursodeoxycholic acid is efficiently absorbed but its hepatic uptake and biliary secretion are impaired, thus leading to reduced biliary enrichment and high serum concentrations of this exogenous bile acid. In patients with cystic fibrosis-associated liver disease, bile acid malabsorption also occurs, thus indicating the need for higher dosages. The volume of distribution and clearance of ursodeoxycholic acid reduced in the presence of liver disease. Also in this case, elimination mainly occurs with the faeces but, in the presence of severe cholestasis, renal clearance may become relevant. Sulphation or conjugation with glucose and N-acetylglucosamine facilitate urinary excretion.

Absorption↗
PubMed1996

Formation of delta 22-bile acids in rats is not gender specific and occurs in the peroxisome.

We recently demonstrated that the formation of delta 22-bile acids is a quantitatively major pathway for normal bile acid synthesis in the adult male Sprague-Dawley rat. This pathway is specific for 7 beta-hydroxy bile acids and, when ursodeoxycholic acid is administered, delta 22-ursodeoxycholic acid appears as a major metabolite in the liver tissue, bile, intestinal contents, and plasma. The aims of this study were, therefore, to determine whether this metabolic pathway was gender specific, and to establish that the peroxisome is a site of formation of delta 22-bile acids. Bile acids were determined by gas chromatography-mass spectrometry in liver tissue, jejunum, and plasma of adult female rats and in animals fed a diet containing 0.4% and 1% ursodeoxycholic acid. Bile acid metabolism in female rats was found to be similar to that of male rats, and delta 22-beta-muricholic acid, rather than beta-muricholate, was likewise confirmed as the major muricholic acid synthesized. Ursodeoxycholic acid administration resulted in the appearance of delta 22-ursodeoxycholic acid as a major metabolite. When adult male Sprague-Dawley rats were treated with clofibrate, a drug that induces peroxisomal proliferation, liver weight increased 40-60% and total bile acid synthesis decreased markedly, but the relative composition of individual bile acids was unchanged. When ursodeoxycholic acid was added to the diet, the proportion of delta 22-bile acids relative to the corresponding saturated analogues increased significantly compared with untreated rats, indicating that clofibrate had "amplified" the pathway for formation of delta 22-bile acids. When UDCA was incubated in vitro with a peroxisomal-enriched fraction from normal adult male rat liver, delta 22-ursodeoxycholic acid was formed in proportions comparable to that observed in vivo when this bile acid was given orally. These studies establish that the pathway for the formation of delta 22-bile acids is not gender specific and mainly occurs in hepatic peroxisomes.

Animals↗
PubMed1995

delta 22-Ursodeoxycholic acid, a unique metabolite of administered ursodeoxycholic acid in rats, indicating partial beta-oxidation as a major pathway for bile acid metabolism.

We describe for the first time the identification of 3 alpha, 7 beta-dihydroxy-5 beta-chol-22-en-24-oic acid (delta 22-UDCA) in the plasma, bile, intestinal contents, and liver tissue of Sprague-Dawley rats after intravenous and oral administration of ursodeoxycholic acid (UDCA). Infusion of [2,2,4,4-2H4]UDCA confirmed delta 22-UDCA to be a specific metabolite of UDCA. Definitive confirmation of this unique and major metabolite was established by liquid secondary ionization mass spectrometry and gas chromatography-mass spectrometry by comparison of the retention index and mass spectrum with an authentic standard of delta 22-UDCA. When rats were fed a diet containing 1.0% UDCA, high concentrations of delta 22-UDCA were found in the plasma (40.3 +/- 11.8 mumol/L) and liver tissue (300.9 +/- 64.2 nmol/g of tissue), and these represented 36% and 57%, respectively, of the UDCA concentration. In animals fed 0.4% and 1.0% UDCA, the mass of delta 22-UDCA in the jejunum was high (7.5 +/- 0.9 and 6.6 +/- 0.6 mg, respectively), accounting for 50-60% of the total UDCA, but diminished markedly along the intestine, accounting for < 3% of the total UDCA in the colon. Although delta 22-UDCA was not found in biological samples from control rats, delta 22-beta-muricholic and delta 22-omega-muricholic acids were normal constituents of plasma and intestinal contents and were major muricholate isomers in liver tissue and bile. Synthesis of delta 22-bile acids appears to be highly specific toward bile acids possessing a functional 7 beta-hydroxyl group. We presume that, in common with pathways for endogenous bile acid synthesis, partial side-chain oxidation of UDCA occurs in the peroxisome with formation of alpha/beta unsaturation; since UDCA has only a 5-carbon side chain, release of propionic or acetic acid is not possible, beta-oxidation proceeds no further, and delta 22-UDCA is formed. While the mechanism of formation and physiological significance of delta 22-bile acids remain to be established, our data indicate that partial beta-oxidation is a quantitatively important pathway for endogenous bile acid synthesis and for UDCA metabolism in this species.

Animals↗
PubMed1995

Tauroursodeoxycholate increases rat liver ursodeoxycholate levels and limits lithocholate formation better than ursodeoxycholate.

BACKGROUND & AIMS: To explain the greater hepatoprotective effect of tauroursodeoxycholic acid vs. ursodeoxycholic acid, the absorption, hepatic enrichment, and biotransformation of these bile acids (250 mg/day) were compared in rats. METHODS: Bile acids were determined in intestinal contents, feces, urine, plasma, and liver by gas chromatography-mass spectrometry. RESULTS: The concentration of ursodeoxycholate in the liver of animals administered tauroursodeoxycholic acid (175 +/- 29 nmol/g) was greater (P < 0.05) than in animals administered ursodeoxycholic acid (79 +/- 19 nmol/g). Hepatic lithocholate was substantially higher after ursodeoxycholic acid administration (21 +/- 10 nmol/g) than after tauroursodeoxycholic acid administration (12 +/- 1 nmol/g). A concomitant reduction in the proportion of hydrophobic bile acids occurred that was greatest during tauroursodeoxycholic acid administration. In the intestinal tract, the mass of ursodeoxycholate and its specific metabolites was greater in rats administered tauroursodeoxycholic acid (27.2 mg) than those administered ursodeoxycholic acid (13.2 mg). In feces, the proportion of lithocholate was 21.9% +/- 4.9% and 5.4% +/- 4.0% after ursodeoxycholic acid and tauroursodeoxycholic acid administration, respectively. CONCLUSIONS: Compared with ursodeoxycholic acid, tauroursodeoxycholic acid induces a greater decrease in the percent composition of more hydrophobic bile acids within the pool, limits lithocholate formation, and increases hepatic ursodeoxycholate concentration. These differences are explained by increased hepatic extraction and reduced intestinal biotransformation and not by enhanced absorption of the amidated species.

Absorption↗
PubMed1995

The site-specific delivery of ursodeoxycholic acid to the rat colon by sulfate conjugation.

BACKGROUND & AIMS: Because ursodeoxycholate has been shown to act as a tumor-suppressive agent in the colon, the absorption and metabolism of its sulfate conjugates were examined in rats to show that sulfation would facilitate the site-specific delivery of ursodeoxycholate to the colon. METHODS: Bile acids were measured in intestinal contents, feces, urine, plasma, and liver tissue after oral administration of ursodeoxycholate and its C-3, C-7, and C-3,7 sulfate derivatives. RESULTS: Ursodeoxycholate was found in the jejunum after administration of all bile acids, but the mass was greatest for ursodeoxycholic acid administration. In the colon, lithocholic acid, normally found in negligible amounts, became the major bile acid after ursodeoxycholate administration. In contrast, reductions in mass and proportions of lithocholate and deoxycholate occurred after administering the C-7 sulfates. The fecal lithocholate/deoxycholate ratio, a risk marker for colon cancer, increased markedly after administration of ursodeoxycholate and its C-3 sulfate, but did not change after administering the C-7 sulfates. Unlike ursodeoxycholate or its C-3 sulfate, which increased liver concentrations of lithocholate and ursodeoxycholate, the C-7 sulfates had the opposite effect, which was consistent with poor absorption. CONCLUSIONS: Sulfation of ursodeoxycholate, specifically at the C-7 position, protects the molecule from bacterial degradation and inhibits its intestinal absorption, thereby facilitating delivery to the colon.

Animals↗
PubMed1995

Posttranscriptional regulation of mRNA levels in rat liver associated with deoxycholic acid feeding.

We investigated the effects of bile acid feeding on the mRNA levels and transcriptional activity of genes involved in various facets of hepatic cell function. Rats were maintained for 10 days on standard diet supplemented with combinations of 1 and 0.4% deoxycholic acid and ursodeoxycholic acid. Significant reductions in mRNA levels for liver fatty acid binding protein, albumin, the asialoglycoprotein receptor, connexins 32 and 26, and cytochromes P-450IIB1 and P-450IIE1 were associated with 1% deoxycholic acid feeding. Conversely, the 1% deoxycholic acid-fed animals exhibited increased mRNA levels for cholesterol 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl-CoA reductase, multidrug resistance, procollagens, extracellular matrix, protooncogenes, tumor suppressors, and cyclins. The 0.4% deoxycholic acid-fed animals exhibited increased mRNA levels for c-jun, H-ras, p53, cyclins D1 and D3, fibronectin, and procollagens alpha 1(I) and alpha 1(III). Transcriptional rate changes could not account for the observed changes in steady-state mRNA levels. Ursodeoxycholic acid feeding had no significant effect on gene expression and almost completely inhibited the changes associated with 1% deoxycholic acid when coadministered. The results indicate that dietary ingestion of deoxycholic acid profoundly affects hepatic gene expression in the rat, and regulation occurs primarily at the posttranscriptional level.

Animals↗
PubMedDate not supplied

Performance characteristics of reversed-phase bonded silica cartridges for serum bile acid extraction.

The quantitative extraction of bile acids and their conjugates from serum was investigated using different commercially available reversed-phase bonded silica cartridges. Serum was diluted with 0.1 M sodium hydroxide or 0.5 M triethylamine sulphate, pH 7.0, and heated at 64 degrees C for 20-30 min prior to application to the cartridge. Bile acids were adsorbed to the bonded silica particles, and recovered by elution with a small volume of methanol. Dilution of serum with triethylamine sulphate gave quantitative extraction of bile acids from serum using Bond-Elut C18 cartridges, but the milder conditions of the applied sample compared with dilution with sodium hydroxide permitted re-use of the cartridges with no loss in performance, and gave relatively clean extracts. Large variations in the recovery of bile acids were observed using sorbents from different manufacturers. These studies highlight the need to evaluate critically the performance characteristics of solid-phase cartridges when the manufacturer or batch lot is changed.

Adsorption↗
PubMedDate not supplied

Mechanism of charged pollutants removal in an ion exchange membrane bioreactor: drinking water denitrification.

The mechanism of anionic pollutant removal in an ion exchange membrane bioreactor (IEMB) was studied for drinking water denitrification. This hybrid process combines continuous ion exchange transport (Donnan dialysis) of nitrate and its simultaneous bioreduction to gaseous nitrogen. A nonporous mono-anion permselective membrane precludes direct contact between the polluted water and the denitrifying culture and prevents secondary pollution of the treated water with dissolved nutrients and metabolic products. Complete denitrification may be achieved without accumulation of NO3(-) and NO2(-) ions in the biocompartment. Focus was given to the effect of the concentration of co-ions, counterions, and ethanol on the IEMB performance. The nitrate overall mass transfer coefficient in this hybrid process was found to be 2.8 times higher compared to that in a pure Donnan dialysis process without denitrification. Furthermore, by adjusting the ratio of co-ions between the biocompartment and the polluted water compartment, the magnitude and direction of each individual anion flux can be easily regulated, allowing for flexible process operation and control. Synthetic groundwater containing 135-350 mg NO3(-) L(-1) was treated in the IEMB system. A surface denitrification rate of 33 g NO3(-) per square meter of membrane per day was obtained at a nitrate loading rate of 360 g NO3(-) m(-3)d(-1), resulting in a nitrate removal efficiency of 85%.

Bioreactors↗
PubMedDate not supplied

Sterilization approval and follow-through in Brazil.

The purpose of this study was to examine the factors that affect approval for and completion of sterilization in Rio de Janeiro. Of 2,186 new female family planning clients, 1,256 requested sterilization and 925 were approved for surgery. Among the approved women, 639 scheduled surgery and, of these, 595 were sterilized within three months of approval. While approval is dependent mainly on demographic variables, especially age and parity, follow-through by a woman is related to her education and income. The steps that a woman must complete to obtain a sterilization also affect whether she ultimately undergoes surgery. Almost no women were scheduled for sterilization during their initial clinic visit. Women who were not scheduled because they lacked certain documentation were more likely to follow through than women who, in addition to lacking documentation, were asked to switch from an inefficient contraceptive method (or no method) to a more modern one. The lessons to be learned from this study provide useful information to programs in other countries that are concerned about maintaining high standards but do not want to discourage women in their efforts to be sterilized.

Adult↗