taurochenodeoxycholic-acid and Cholelithiasis

Tauroursodeoxycholic acid has been proposed for the treatment of hepatobiliary disease, but data on the enrichment of biliary tauroursodeoxycholic acid pool and on changes of biliary lipids after administration of the compound are scarce. We studied the composition of biliary lipids in a series of 33 patients with radiolucent stones, before and after treatment with tauroursodeoxycholic acid, 3.5 - 16.6 mg/kg/day for 4 - 6 weeks. Duodenal bile was collected with the Entero-Test after gallbladder contraction. Tauroursodeoxycholic acid administration produced the following dose-dependent effects: a linear decrease of cholesterol saturation (r = 0.59, p < 0.001); a non-linear increase of the percent of ursodeoxycholic acid in bile (r = 0.59, p < 0.001); a non-linear increase of the fraction of ursodeoxycholate conjugated with taurine. At the dose of 11 mg/kg per day, cholesterol saturation was 80%, ursodeoxycholic acid represented about 45% of biliary bile acids, and about half of UDCA was conjugated with taurine. Biliary bile acids were repeatedly measured in 6 patients during long-term treatment with 9.7 - 12.1 mg/kg. The fraction of tauroursodeoxycholic acid decreased progressively from 67.6% +/- 10.5 to 29.1% +/- 5. Tauroursodeoxycholic acid is as effective as ursodeoxycholic acid on a molar basis in reducing biliary cholesterol saturation and in enriching bile with ursodeoxycholate. Moreover, tauroursodeoxycholic acid administration is associated with higher concentrations of tauroconjugates in the bile than those previously reported by feeding the free bile acid.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Dose-Response Relationship, Drug; Female; Humans; Lipid Metabolism; Male; Middle Aged; Taurochenodeoxycholic Acid

Out of 34 patients enrolled and randomized, 31 completed the 6 months study period. Fifteen were treated with TUDCA, and 16 with UDCA. Dosage for both drugs was 10 mg/kg body weight daily. Superiprisingly, TUDCA was not found to be more active than UDCA in dissolving, totally or partially, the gallbladder stones; indeed, total dissolution was more frequent in the UDCA group. Since the two groups were similar as to number and size of the stones, the better results with UDCA cannot be attributed to the characteristics of the calculosis but must be ascribed to the molecule used. Both drugs induced an improvement in dyspeptic symptoms, but from this point of view, too, UCDA was more effective than TUDCA (p < 0.01). Finally, tolerability was also significantly better for UDCA, although TUDCA was altogether acceptable.

Topics: Adolescent; Adult; Aged; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Female; Humans; Male; Middle Aged; Single-Blind Method; Solubility; Taurochenodeoxycholic Acid

The hydrophilic bile salt ursodeoxycholate is frequently used to dissolve cholesterol gallstones. We have now quantitated crystallization as a function of bile salt hydrophobicity, phospholipid content, cholesterol saturation and total lipid concentration (TLCo).. Crystallization in supersaturated model biles with low phospholipid contents (left two-phase-micelles and crystal-containing-zone) was assessed during 21 days by microscopy and chemical measurement of crystal mass. For model biles with higher phospholipid contents (central three-phase-micelles, vesicles and crystal-containing-zone), lipid distribution into various phases was determined by combined ultracentrifugation-filtration-dialysis methodology (Biochim. Biophys. Acta 1532 (2001) 15-27).. In the left two-phase zone, crystal numbers and masses were highest in case of more hydrophilic bile salt composition (TUDC 100%>TC/TUDC 70%/30%>TC 100%>TC/TDC 70%/30%>TDC 100%) and decreased with increasing phospholipid contents, lower TLCo and lower cholesterol saturation index (CSI). In contrast, in the presence of vesicles (three-phase zone), crystallization decreased at increasing bile salt hydrophilicity, with concomitant increased vesicular cholesterol solubilization.. Presence of vesicular phases is a prerequisite for inhibition of cholesterol crystallization by tauroursodeoxycholate.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Hydrophobic and Hydrophilic Interactions; Micelles; Phosphatidylcholines; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid

Precipitation of cholesterol crystals is an essential step in gallstone formation. In the present study we found much faster and more extensive precipitation of various cholesterol crystal shapes in whole model biles containing the hydrophobic bile salt taurodeoxycholate than in biles containing the relatively hydrophilic taurocholate. Addition of taurodeoxycholate to isolated cholesterol-phospholipid vesicles also induced more crystallization than taurocholate. Crystallization behaviour in whole model biles and in vesicles after addition of corresponding bile salts was very similar. The very hydrophilic bile salts tauroursodeoxycholate and taurohyodeoxycholate never induced crystallization from vesicles, and crystallization in corresponding whole model biles did not occur. These bile salts also reduced crystallization dose dependently after addition of taurodeoxycholate to vesicles. Ultracentrifugation experiments suggested a higher vesicular cholesterol-phospholipid bile salts. These findings indicate that bile salt hydrophobicity influences shape of cholesterol crystals and extent of crystallization, possibly by modulating the vesicular cholesterol-phospholipid ratio.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Humans; In Vitro Techniques; Models, Biological; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid

The appearance of gallstone opacification during oral bile acid administration indicates that stones are no longer susceptible to dissolution and represents, therefore, a definitive treatment failure. Ursodeoxycholic acid (UDCA) has been imputed to facilitate gallstone opacification; however, data regarding the comparative occurrence of gallstone opacification during UDCA and chenodeoxycholic acid (CDCA) administration are not yet available. Our objectives were to evaluate the frequency of acquired opacification in gallstone patients taking UDCA and in gallstone patients taking CDCA, to verify whether or not gallstone opacification is a peculiar side effect of UDCA treatment and, further, to evaluate gallstone opacification in gallstone patients receiving tauro-UDCA (TUDCA) to verify whether the administration of the more soluble tauroconjugate might prevent the deposition of calcium salts on the stone surface.. 106 gallstone patients on UDCA, 125 gallstone patients on CDCA, and 31 gallstone patients on TUDCA were evaluated. Before treatment, all patients had radiolucent gallstones as assessed by oral cholecystography; further cholecystographic evaluations were performed every 6 months during treatment.. The frequency of gallstone opacification was 13.2% (14/106) in UDCA patients, 8.8% (11/125) in the CDCA patients, and 12.9% (4/31) in the TUDCA patients. The differences were not statistically significant (p = NS). Sex, stone size, dose of bile acid, and duration of treatment were not significantly related to an increased frequency of gallstone calcification in any of the treatment groups. The frequency of gallstone opacification appeared to be higher in older patients.. 1) UDCA rich bile is not a major predisposing factor for acquired gallstone opacification; 2) the administration of TUDCA does not prevent gallstone opacification; 3) opacification could be related to the natural history of gallstone disease.

Topics: Adolescent; Adult; Aged; Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Female; Humans; Male; Middle Aged; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Unconjugated bile salts currently available for gallstone dissolution are poorly effective. We evaluated in vitro the litholytic potency of taurine-amidated bile salts against human cholesterol gallstones.. Seventy radiolucent gallstones with similar size and composition (cholesterol content, 70.1 +/- 0.9%) from a single patient were incubated in model biles composed of 100 mM of either taurochenodeoxycholate (TCDC), taurocholate (TC), taurohyodeoxycholate (THDC) or tauroursodeoxycholate (TUDC) and of 45 mM egg yolk lecithin in saline buffered with tris/HCl (at pHs 7 and 8) or phosphate (at pHs 4 and 6). Biles (total lipids, 10 g/dl; cholesterol saturation, 99%) were incubated at 37 degrees C for 40 days. Gallstones were periodically weighed and returned to the dissolution vials, and the biliary cholesterol concentration was monitored.. Model biles remained optically clear during the initial 48 h of incubation. Then, biles containing THDC and TUDC, but not those with TC and TCDC, became progressively turbid until, after several days, a white precipitate surrounded the residual stone. Abundant liquid crytalline droplets were observed at polarizing microscopy in biles containing TUDC and THDC. Gallstone dissolution was closely related to cholesterol solubilization and decreased in the order TCDC > THDC > or = TC > TUDC, being highest at pH 8. At the physiologic pH of 7 THDC was more litholythic than TC.. In vitro, the litholytic potency of bile salts on cholesterol gallstones primarily depends on their hydrophobicity. THDC is a new potential gallstone-dissolving agent, deserving in vivo studies.

Topics: Cholagogues and Choleretics; Cholelithiasis; Cholesterol; Drug Combinations; Drug Evaluation, Preclinical; Humans; Hydrogen-Ion Concentration; Phosphatidylcholines; Taurochenodeoxycholic Acid; Taurodeoxycholic Acid

In vitro dissolution of the gallstones was studied in order to evaluate the effect of proteolytic enzyme (Pronase E) and bile acids (CA, CDCA, UDCA and TCA) on the dissolution of the calcium bilirubinate gallstones with ethylene diamine-tetraacetic acid (EDTA 4Na) solution. In this study, the slices and the whole concrement of the calcium bilirubinate gallstones were dissolved with an admixture of the chemical agents. It was shown that a pretreatment with 0.5-1.0% solution of Pronase E made the slices susceptible to the dissolution with EDTA 4Na (1.0%). Although, the addition of Pronase E to an admixture of CA and EDTA 4Na did not increase the efficacy of the slices dissolution, it seemed to be effective in the dissolution of the whole concrement. Regarding to the effect of the bile acids on the slices dissolution, each bile acid was not significantly different from the others when it was used as a 25mM admixture with EDTA 4Na. One hundred milimoles solution of TCA had 2-fold activity of a 25mM solution in the dissolution of both the slices and the whole concrement when it was used in combination with EDTA 4Na. The results suggest that a pretreatment of the calcium bilirubinate gallstones with Pronase E is of great advantage in dissolution therapy. It is also suggested that TCA (100mM in EDTA 4Na), which can be applied in human beings without any serious side effect, is helpful in the treatment of calcium bilirubinate gallstones in clinical cases.

Topics: Bile Acids and Salts; Bilirubin; Chenodeoxycholic Acid; Cholelithiasis; Edetic Acid; Humans; In Vitro Techniques; Pronase; Taurochenodeoxycholic Acid

Topics: Adult; Chenodeoxycholic Acid; Cholelithiasis; Female; Humans; Male; Middle Aged; Taurochenodeoxycholic Acid

Bile acids are capable of disrupting the gastric and esophageal mucosal barriers and are known to differ in their ability to injure these mucosae. Two bile acids, chenodeoxycholic and its 7-B epimer, ursodeoxycholic, that are being used to dissolve gallbladder stones were evaluated for their damaging effects on experimental preparations of the esophageal (rabbit) and gastric (dog) mucosa. Damage was assessed by measuring indices of mucosal barrier function, including net acid flux, potential difference, and tissue resistance, before and after exposure to the taurine conjugates of these bile acids. In both the esophageal and gastric mucosa, tauroursodeoxycholic acid caused significantly less disruption of barrier function than taurochenodeoxycholic acid. These results demonstrate that minor differences in conjugated bile acid structure can cause major changes in the effects of bile acids on the upper gastrointestinal mucosa and that ursodeoxycholic acid may be the preferred bile acid for oral ingestion to dissolve gallbladder stones.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Dogs; Esophagus; Gastric Mucosa; Mucous Membrane; Rabbits; Taurochenodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diffusion; Glycine; Glycochenodeoxycholic Acid; In Vitro Techniques; Kinetics; Solubility; Taurine; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid; Water; X-Ray Diffraction

Chenodeoxycholic acid (cheno) and ursodeoxycholic acid (urso) dissolve cholesterol gallstones in humans. In the present study conjugation of biliary bile acids with glycine and taurine and their effects on biliary cholesterol saturation were investigated during treatment with cheno, urso, and cheno-urso. Ten patients were included in this study, and every patient served as his own control. Each of the treatment periods lasted for 3 mo. During treatment with cheno or urso, daily doses of 11.9-15.6 mg/kg were administered, while during treatment with cheno-urso each bile acid was administered at one-half the dose. In the control period biliary bile acids consisted of 31.8 +/- 2.8% glycocheno, 10.9 +/- 1.2% taurocheno, 1.0 +/- 0.1% glycourso, and 0.3 +/- 0.1% taurourso. During the three treatment periods dihydroxy bile acids in bile and glycine conjugation of these dihydroxy bile acids increased significantly (P < 0.05). During treatment with urso the amounts of glycourso in bile were positively correlated to the dose of urso administered (P < 0.05). No correlation existed between urso dose and the amounts of taurourso in bile. Biliary cholesterol was 9.0 +/- 1.0 mol% in the control period and decreased during treatment with cheno, urso, and chenourso to 5.2 +/- 0.5, 3.7 +/- 0.3, and 3.8 +/- 0.3 mol%, respectively. Cholesterol saturation index corrected for the biliary content of glycourso and taurourso was 1.2 +/- 0.1 in the control period and decreased during treatment with cheno, urso, and cheno-urso to 0.8 +/- 0.1, 1.0 +/- 0.1 and 0.7 +/- 0.1, respectively. Thus urso treatment led to the lowest biliary content of cholesterol, but cheno-urso treatment led to significantly lower cholesterol saturation indices than urso treatment (P < 0.05).

Topics: Aged; Anticholesteremic Agents; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Therapy, Combination; Female; Glycochenodeoxycholic Acid; Glycocholic Acid; Humans; Male; Middle Aged; Solubility; Taurochenodeoxycholic Acid; Taurocholic Acid; Ursodeoxycholic Acid