Serous papillary cystic ovarian borderline tumor: case report.

A case of a 30-year-old patient with a serous papillary borderline tumor of the right ovary who underwent a simple mono-lateral salpingo-oophorectomy is presented. Conservative surgery allowed a subsequent pregnancy with spontaneous delivery 27 months later.

Changes in biliary lipid secretion and cholic acid kinetics induced by diet, diet plus simvastatin and diet plus ursodeoxycholic acid in obese subjects.

The aim of this work was to evaluate and compare the effects of a low calorie diet (1026 kcal), simvastatin and ursodeoxycholic acid administration on biliary lipid secretion and cholic acid kinetics in dieting obese subjects. We studied 6 obese subjects before and after four weeks of a hypocaloric diet alone, after four weeks of diet plus ursodeoxycholic acid (900 mg/day) and after four weeks of diet plus simvastatin (40 mg/day), according to a Latin square design. The cholesterol saturation index was increased after diet alone, significantly reduced with diet plus ursodeoxycholic acid (p < 0.01), and unchanged during simvastatin administration. While the cholesterol output was reduced by all three regimens, diet plus ursodeoxycholic acid caused a significantly greater decrease than diet alone (p < 0.01). Cholic acid synthesis and bile acid secretion were decreased by diet and diet plus simvastatin (p < 0.05), but neither was affected by ursodeoxycholic acid. For cholic acid, all three treatments, but especially diet alone and diet plus simvastatin (p < 0.05), reduced the pool size; all three regimens also increased the turnover rate, but this was significant only for ursodeoxycholic acid (p < 0.01). Our study shows that, in obese patients, a hypocaloric diet reduces cholesterol-holding biliary lipid output and consequently increases the cholesterol saturation index. The addition of simvastatin to a hypocaloric dietary regimen reduces cholesterol secretion, but without variation in bile acid and phospholipid output thus the cholesterol saturation index remains unchanged. When ursodeoxycholic acid is added to the dietary regimen, it reduces cholesterol secretion, while maintaining bile acid output and, thus, lowers the cholesterol saturation index. Unlike simvastatin, ursodeoxycholic acid prevents the drop in cholic acid synthesis induced by a low calorie diet.

Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters.

BACKGROUND/AIMS: The effectiveness of ursodeoxycholic acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic acid but with similar detergency. METHODS: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of taurochenodeoxycholic acid was evaluated in bile fistula rats after intraduodenal coinfusion. RESULTS: 6-Fluoro-ursodeoxycholic acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taurochenodeoxycholic acid. CONCLUSIONS: The results suggest that 6-fluoro-ursodeoxycholic acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.

Bioavailability study of a new, sinking, enteric-coated ursodeoxycholic acid formulation.

A new enteric-coated ursodeoxycholic acid (UDCA) formulation which sinks in the stomach and releases the drug only at a pH > or = 6.5 was developed. In 12 healthy subjects we measured, using a specific enzyme immunoassay, the serum levels of UDCA after a single oral dose of 450 mg of UDCA in three different formulations; enteric coated sinking tablet, stomach-floating enteric coated hard gelatin capsule and conventional gelatin capsule. The drug was given after a meal. Results are expressed as mean +/- SD. The area under the curve [AUC, mumol l-1 (8 h)] following oral administration of enteric-coated, sinking UDCA (39.0 +/- 8.5) was significantly higher than that obtained after both conventional UDCA (30.5 +/- 4.9) and floating enteric coated UDCA (29.3 +/- 3.4). Moreover, the maximum UDCA serum concentration (Cmax) was significantly higher with the enteric coated sinking UDCA formulation when compared to the other two formulations, while the time of maximum UDCA serum concentration (tmax) occurred later. These results may be explained by the hypothesis that the sinking tablet is expelled in the latter phase of gastric emptying along with the solid content. It therefore reaches the intestine at the highest alkalization phase caused by sustained biliary and pancreatic secretions. When released, the protonated insoluble UDCA is promptly solubilized by the alkaline pH thus giving a higher UDCA concentration gradient which facilitates its passive absorption. On the other hand, the floating capsule reaches the intestine too early, still in presence of an acidic pH; and in this condition UDCA is almost insoluble and consequently may be malabsorbed.(ABSTRACT TRUNCATED AT 250 WORDS)

New 6-substituted bile acids: physico-chemical and biological properties of 6 alpha-methyl ursodeoxycholic acid and 6 alpha-methyl-7-epicholic acid.

New analogs of ursodeoxycholic acid and 7-epicholic acid containing a 6 alpha-methyl group were synthesized, and their physico-chemical properties were studied and compared with those of their natural analogs. The 6 alpha-methyl group slightly increases the lipophilicity and slightly lowers the critical micellar concentration with respect to the corresponding natural analogs. Simulated bile 50% enriched with 6 alpha-methyl ursodeoxycholic acid, with a total bile acid/phospholipid ratio of 10/1, demonstrated a higher cholesterol-holding capacity and a faster cholesterol gallstone dissolution rate with respect to ursodeoxycholic acid, while 6 alpha-methyl-7-epicholic acid and 7-epicholic acid were much less efficient in these processes. The 6 alpha-methyl analogs were highly stable toward 7-dehydroxylation when incubated with human stool in anaerobic conditions. Their transport, metabolism, and effect on biliary lipid secretion were evaluated both in rats and hamsters after acute intravenous and intraduodenal infusion at a dose of 10 mumol/min per kg. In both species, 6 alpha-methyl ursodeoxycholic acid is efficiently secreted in bile, with a cumulative recovery similar to that of ursodeoxycholic acid. The only metabolites of 6 alpha-methyl ursodeoxycholic acid identified were its glycine and taurine amidated forms. 6 alpha-Methyl-7-epicholic acid was efficiently secreted into bile when infused intravenously, and to a lesser extent when infused intraduodenally, in both rats and hamsters; it was secreted in bile as amidate and also as free acid. When 6 alpha-methyl ursodeoxycholic acid, 6 alpha-methyl-7-epicholic acid, ursodeoxycholic acid, and 7-epicholic acid were chronically administered to hamsters (for 3 weeks, at a dose of 50 mg/kg per day) their accumulation in gallbladder bile was, respectively, 25.1%, 4.0%, 15.2%, and 3.4% of the total bile acids. In conclusion, of the two analogs, only 6 alpha-methyl ursodeoxycholic acid shows potential as a cholesterol gallstone-dissolving agent. In this regard, its most important properties are moderate lipophilicity, good metabolic stability, and better conservation in the enterohepatic circulation, with respect to ursodeoxycholic acid.

Hepatic uptake and intestinal absorption of bile acids in the rabbit.

The existence of transporters for bile acids (BA) in liver and intestine has been well documented, but information is still needed as to their respective transport capacity. In the present investigation, we compared the hepatic and intestinal transport rates for BA, using perfused livers and intestines. The livers and intestines were separately perfused and dose-response curves (0.25-10 mM) for tauroursodeoxycholate, taurocholate and taurodeoxycholate were obtained. The intestinal and mesenteric concentration and bile acid pattern were also evaluated in six non-fasting rabbits. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid ileal absorption showed saturation kinetics in the intestine as in the liver; the maximal uptake velocity for each bile acid in the liver was tenfold higher than the respective maximal transport velocity in the intestine; the Km values obtained in the liver were of the same order of magnitude, i.e. in the millimolar range. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid transport differences in the liver paralleled those in the intestine. Although the intestine was not homogeneously filled, the bile acid concentration in the ileal content fell into the range of the Km for the three studied bile acids, while the portal blood total bile acid concentration was inferior to the observed Kms of liver uptake. Therefore, both the hepatic and intestinal systems do not operate at their maximal transport rates at the prevailing concentrations in portal blood and luminal content, and the hepatic transport occurs at its highest efficiency (below the Km values) in physiological conditions.

Improved intestinal absorption of an enteric-coated sodium ursodeoxycholate formulation.

A new enteric-coated formulation of sodium ursodeoxycholate was prepared and administered to man. The barrier film disintegrates and releases the drug only at pH > or = 5.5. The sodium salt of glycoursodeoxycholate was also prepared and encapsulated like ursodeoxycholate. Serum levels of ursodeoxycholate and glycoursodeoxycholate were measured by specific enzyme immunoassay after oral administration of their sodium salts in an enteric-coated formulation at equimolar doses of 475 and 540 mg. The same subjects also received in separate experiments ursodeoxycholic acid, sodium ursodeoxycholate, and glycoursodeoxycholic acid in gelatin capsules. The mean area under the curve (mumol/L.hr) following administration of enteric-coated sodium ursodeoxycholate (45 +/- 8) was significantly higher than that of either ursodeoxycholic acid (26 +/- 5; P < 0.01) or sodium ursodeoxycholate (25 +/- 6; P < 0.001) administered in a conventional gelatin capsule. No differences were found when glycoursodeoxycholic acid was administered as an enteric-coated sodium salt or in acid form in gelatin capsules. Ursodeoxycholic was administered at a dose of 10 mumol/min/kg over 1 hr to bile fistula rats both intraduodenally (i.d.) and intravenously (i.v.). The experiment included administration of the sodium salt in solution and the acid as a suspension. A similar experiment was performed with glycoursodeoxycholic acid. The ratio of the amount recovered from bile in the i.d. to that in the i.v. experiment is almost 1 for the sodium salt of ursodeoxycholate in solution, while it drops to 0.55 for ursodeoxycholic acid. No differences were found between i.v. and i.d. administration when glycoursodeoxycholic acid was administered in acid form and as a soluble sodium salt.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of ursodeoxycholic acid on biliary lipids.

The advent of bile acid therapy has shed some light on the mechanisms involved in determining bile lipid secretion. The administration of cholelytic bile acids results in a lowering of cholesterol percent molar and saturation index due to a reduction in cholesterol secretion. Studies carried out after administration of bile acids showed initially that biliary cholesterol secretion rates were dependent on the hydrophobic/hydrophilic balance of the prevailing bile acid present in bile. However, more detailed investigations showed that some bile acids (cholic and chenodeoxycholic acids) did not follow this rule because of the presence of other mechanisms involved in determining biliary cholesterol secretion and a possible link between cholesterol synthesis and biliary cholesterol secretion. Several different human models have been used in more recent studies to arrive at a better understanding of the mechanisms involved in determining bile lipid secretion: obese patients, obese patients in rapid weight loss, patients with non-familial hypercholesterolemia and primary biliary cirrhosis. The findings in these studies indicate how modifications in biliary lipid secretion can easily be induced when there are changes in the relative amounts of bile acids. These changes may bring about modifications in intestinal absorption, liver synthesis, and secretion of cholesterol and bile acids that could possibly lead to the formation of lithogenic bile and subsequently to cholesterol gallstones.

Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis.

Ursodeoxycholic acid has been proposed for the treatment of primary biliary cirrhosis. The aim of this study was to evaluate the effect of ursodeoxycholic acid administration on bile acid metabolism in patients with early-stage primary biliary cirrhosis. Biliary bile acid composition, primary bile acid pool sizes, synthesis, and fractional turnover rate were measured before and after four weeks of ursodeoxycholic acid administration (600 mg/day) in nine patients with biopsy-proven primary biliary cirrhosis (stages I-III). Molar percentages of chenodeoxycholic, cholic, and deoxycholic acids in bile were significantly decreased by ursodeoxycholic acid administration, while its biliary concentration increased to 34.2% at the end of the same four-week period. The cholic and chenodeoxycholic acid pools decreased, although not significantly, while the deoxycholic acid pool was reduced by 60% (from 0.7 +/- 0.12 to 0.29 +/- 0.07 mmol, P < 0.002). Primary bile acid synthesis was slightly increased, and fractional turnover rate was significantly increased. The conversion rate of cholic to deoxycholic acid was measured and found to be significantly increased (P < 0.05) after ursodeoxycholic acid administration; however, serum levels of both free and conjugated deoxycholic acid were significantly decreased (from 23.2 +/- 9.7 to 3.8 +/- 1.9 mumol/liter, P < 0.001). We conclude that in patients with primary biliary cirrhosis, ursodeoxycholic acid administration replaces endogenous bile acids in the enterohepatic circulation by increasing bile acid fractional turnover rate without significant increments of their hepatic synthesis.

Determination of free and amidated bile acids by high-performance liquid chromatography with evaporative light-scattering mass detection.

A simple reverse phase high-performance liquid chromatographic method for a simultaneous analysis of free, glycine- and taurine-amidated bile acids is described. The resolution of ursodeoxycholic, cholic, chenodeocycholic, deoxycholic, and lithocholic acids, either free or amidated with glycine and taurine, is achieved using a C-18 octadecylsilane column (30 cm length, 4 micron particle size) with a gradient elution of aqueous methanol (65----75%) containing 15 mM ammonium acetate, pH 5.40, at 37 degrees C. The separated bile acids are detected with a new evaporative light-scattering mass detector and by absorbance at 200 nm. A complete resolution of the 16 bile acids, including the internal standard nor-deoxycholic acid, is obtained within 55 min. Using the light-scattering mass detector, amidated bile acids and, for the first time, free bile acids can be detected with similar detection limits in the order of 2-7 nmol. The new detector improves the baseline and the signal-to-noise ratio over the UV detection as it is not affected by impurities present in the samples with higher molar absorptivity than bile acids or by the change in the mobile phase composition during the gradient. The method fulfills all the standard requirements of precision and accuracy and the linearity of the mass detector is over 5 decade the detection limit. The new method has been used for the direct analysis of bile acid in stools and bile with only a preliminary clean-up procedure using a C-18 reverse phase extraction.

Functional properties of dilute Hb solutions studied without tonometric techniques.

The authors found that, by continuously bubbling pure nitrogen within a dilute Hb solution, the latter releases its oxygen with an intensity which is quite proportional to the duration of bubbling. Such a procedure can be employed instead of the common tonometric technique, to measure functional properties of Hb. In fact, not only dissociation curves can be obtained, but also a correct evaluation of the affinity changes upon pH variations (Bohr effect). The results obtained by this technique are not far from those recently reported by using tonometry, although the method is less precise and still not suitable for routine purposes. Nevertheless, it can be substantially improved.

Functional behaviour of dilute solutions of Hb-Kempsey: beta 99 (G-1) Asp--Asn.

The authors report that a diluted solution of Hb-Kempsey, beta 99 (G-1) Asp-Asn, can be chromatographically separated from the coexistent Hb-A and functionally examined if progressively depleted in O2 by bubbling pure nitrogen in the solution. Next, at fixed times, the O2 saturations of Hb are compared with the pO2s measured. Hb-Kempsey has a p50 of 1 torr, with an n-value of 1 and a Bohr effect of -0.2. Normal Hb-A of the same patient, examined with identical methods, presents: p50 = 4.5 torr; n = 2.7; Bohr effect = -0.412. Therefore, Hb-Kempsey is strongly hyperaffinic, does not display any heme-heme interaction, and has a half-normal Bohr effect.