Ursodeoxycholic Acid In Bile Research Articles

Dihydroartemisinin-Ursodeoxycholic Bile Acid Hybrids in the Fight against SARS-CoV-2.

Here, we propose the molecular hybridization of dihydroartemisinin (DHA) and ursodeoxycholic bile acid (UDCA), approved drugs, for the preparation of antiviral agents against SARS-CoV-2. DHA and UDCA were selected on the basis of their recently demonstrated in vitro activity against SARS-CoV-2. A selection of DHA-UDCA-based hybrids obtained by varying the nature of the linkage and the bile acid conjugation point as well as unconjugated DHA and UDCA were tested in vitro for cytotoxicity and anti-SARS-CoV-2 activity on Vero E6 and Calu-3 human lung cells. The hybrid DHA-t-UDCMe, obtained by conjugation via click chemistry on a gram scale, was identified as a potential candidate for SARS-CoV-2 infection treatment due to significant reduction of viral replication, possibly involving ACE2 downregulation, no cytotoxicity, and chemical stability.

Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis

The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK-8], and KCl) that occurs after BDL. Prostaglandin (PG) E 2-induced contraction remained normal in the placebo and UDCA-treated groups but was impaired in the CDCA-treated group. Treatment with UDCA also prevented the expected increase in the levels of H 2O 2, lipid peroxidation, and PGE 2 content in the placebo-treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE 2 to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress. (H epatology 2003;37:1442-1450.)

Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis

Background. Ursodeoxycholic acid is currently used for the treatment of primary biliary cirrhosis at 13–15 mg/kg/day, but liver tests of some patients do not return to normal at this dose. Studies reported here were designed to test whether a higher dose of ursodeoxycholic acid than is currently used would induce still greater biliary enrichment of ursodeoxycholic acid and whether such enrichment would lead to still further improvement in liver tests in patients with early primary biliary cirrhosis. Methods. A total of 20 patients with histologically proven primary biliary cirrhosis were enrolled. Patients had early stage primary biliary cirrhosis as serum bilirubin levels were normal and the Mayo risk score 4.2±0.5. Group 1 received 600, 1200 and 1800 mg/day of ursodeoxycholic acid; group 2 received 900, 1500 and 2100 mg/day. The order of periods was randomized. Each treatment period lasted 3 months followed by a further 3 months during which a standard dose of ursodeoxycholic acid was given. At the end of each treatment period, liver tests were evaluated, and biliary bile acid pattern of duodenal bile was determined using high pressure liquid chromatography. Results. Biliary bile acid became enriched in ursodeoxycholic acid in direct relationship to dosage (r=0.84, p<0.001). At doses of 1800 mg/day (25–35 mg/kg/day), biliary ursodeoxycholic acid averaged 69±6.6%. A progressive decrease of alanine aminotransferase (p<0.0001), aspartate aminotransferase (p<0.001) and alkaline phosphatase (p<0.02) was observed with increasing concentrations of ursodeoxycholic acid in bile. Biochemical liver tests showed a stronger correlation with biliary concentrations of ursodeoxycholic acid than with the administered dose. Conclusions. In early primary biliary cirrhosis, higher dose ursodeoxycholic acid appears to be more effective than doses currently recommended.

Influence of cholestasis on absorption of ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. Absorption of UDCA is slow and incomplete. In the present study the effect of cholestasis on absorption was evaluated in 10 patients with pancreatic carcinoma and extrahepatic biliary drainage. At days 3 and 10 after insertion of the biliary drain, all patients received 750 mg UDCA in three divided doses. On both occasions intestinal absorption of UDCA was determined to evaluate the influence of cholestasis. Serum bilirubin was used as indicator of cholestasis. Biliary output of UDCA served as measure of absorption and was determined by gas-liquid chromatography. At days 4 and 11 bile consisted of less than 2% of UDCA, indicating that UDCA excretion was complete within 24 hr and no accumulation of UDCA had occurred. After insertion of the drain, serum bilirubin decreased from 12.2 +/- 2.4 mg/dl at day 3 to 5.4 +/- 0.9 mg/dl at day 10. Biliary secretion of bile acids increased from 2.0 +/- 0.3 to 3.1 +/- 0.4 mmol/day, whereas percentage of ursodeoxycholic acid in bile did not significantly increase (41.1% vs 42.1%). Absorption of UDCA increased from 39.8 +/- 5.0% to 61.1 +/- 6.2% of the administered dose, indicating an improvement of the absorption rate after decrease of cholestasis by 53.65% (P < 0.05). In conclusion, in severe cholestasis absorption of orally administered UDCA is markedly reduced. This may have implications in the treatment of patients with cholestatic disease.

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

Objective: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. Methods: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. Results: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) ( p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p ≤ 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. Conclusion: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Ursodeoxycholic Acid Therapy in Cystic Fibrosis—Associated Liver Disease: A Dose–Response Study

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose-response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2-mo periods in a replicated Latin-square design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% +/- 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration

We describe a detailed study of the effects of ursodeoxycholic acid administration on bile acid composition of the serum and bile of patients with primary biliary cirrhosis. Gas chromatography-mass spectrometry was used to analyze bile acids from 10 patients with primary biliary cirrhosis before and during ursodeoxycholic acid administration (500 mg/day, corresponding to approximately 8 mg/kg body wt), after group separation of the unconjugated and conjugated fractions by lipophilic anion exchange chromatography. These studies were directed at assessing whether the beneficial role of ursodeoxycholic acid in primary biliary cirrhosis was the consequence of a shift in the hydrophobic/hydrophilic balance of the bile acid pool and whether the hypercholeresis might result from the cholehepatic circulation of unconjugated ursodeoxycholic acid in bile. In basal conditions, the unconjugated bile acids accounted for only 5.5% and 2.5%, respectively, of the total bile acids of serum and bile; cholic acid was the major component of the conjugated fraction of serum and bile (56.0% ± 4.0%, mean ± S.E.M.), and ursodeoxycholic acid was present in only trace amounts. The conjugated fraction contained many unusual bile acids (representing 16.5% ± 1.3% of total) including C 25 bile acids, iso-chenodeoxycholic acid and several oxo-bile acids. After ursodeoxycholic acid administration biochemical indices of liver function all improved, but the proportions of the unconjugated bile acids in serum and bile did not significantly change. Ursodeoxycholic acid became the predominant biliary bile acid of conjugated bile acid fraction (33.4% ± 1.4%) and significant decreases occurred (p < 0.05) in biliary levels of cholic acid (28.3% ± 2.3%) and the unusual bile acids (9.2% ± 0.8%), but no changes occurred in the proportions of chenodeoxycholic acid (from 19.4% ± 2.7% to 19.4% ± 1.3%) and deoxycholic acid (from 5.4% ± 1.4% to 6.8% ± 1.3%). The proportions of biliary lithocholic acid increased significantly after ursodeoxycholic acid administration (from 0.7% ± 0.1% to 2.9% ± 0.9%; p < 0.05). In serum, ursodeoxycholic acid concentrations attained levels of 64 μmol/L. Serum lithocholic acid concentrations increased, whereas cholic and chenodeoxycholic acids decreased. Relative percentages of individual biliary bile acids in the unconjugated fraction were similar to the conjugated fraction before and after ursodeoxycholic acid treatment. The proportions of biliary unconjugated ursodeoxycholic acid did not change significantly after its administration (from 0.6% to 0.9% of the total). These data provide little support for a significant shift in the hydrophilicity of the circulating bile acid pool after ursodeoxycholic acid administration. However, because the detergency and hepatotoxicity of a bile salt appears to correlate well with the retention index determined by reverse-phase liquid chromatography, the qualitative changes observed in the biliary pool (i.e., a displacement of cholic acid by ursodeoxycholic acid), suggests that a relative lowering of the hepatotoxicity index of the bile acid pool occurs after ursodeoxycholic acid therapy. Furthermore, our findings indirectly suggest that a hypercholeresis related to the biliary secretion of unconjugated ursodeoxycholic acid does not play a role in the beneficial effects of ursodeoxycholic acid therapy in primary biliary cirrhosis.

Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration

We describe a detailed study of the effects of ursodeoxycholic acid administration on bile acid composition of the serum and bile of patients with primary biliary cirrhosis. Gas chromatography-mass spectrometry was used to analyze bile acids from 10 patients with primary biliary cirrhosis before and during ursodeoxycholic acid administration (500 mg/day, corresponding to approximately 8 mg/kg body wt), after group separation of the unconjugated and conjugated fractions by lipophilic anion exchange chromatography. These studies were directed at assessing whether the beneficial role of ursodeoxycholic acid in primary biliary cirrhosis was the consequence of a shift in the hydrophobic/hydrophilic balance of the bile acid pool and whether the hypercholeresis might result from the cholehepatic circulation of unconjugated ursodeoxycholic acid in bile. In basal conditions, the unconjugated bile acids accounted for only 5.5% and 2.5%, respectively, of the total bile acids of serum and bile; cholic acid was the major component of the conjugated fraction of serum and bile (56.0% +/- 4.0%, mean +/- S.E.M.), and ursodeoxycholic acid was present in only trace amounts. The conjugated fraction contained many unusual bile acids (representing 16.5% +/- 1.3% of total) including C25 bile acids, iso-chenodeoxycholic acid and several oxo-bile acids. After ursodeoxycholic acid administration biochemical indices of liver function all improved, but the proportions of the unconjugated bile acids in serum and bile did not significantly change.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: A dose-response study

The effect of ursodeoxycholic acid administration on liver function tests and on bile acid metabolism was investigated in 18 patients with chronic active hepatitis. Three different doses of ursodeoxycholic acid—250 mg, 500 mg and 750 mg—were administered daily to each patient for consecutive 2-mo periods. The order of doses was randomly assigned according to a replicated Latin-square design. A significant decrease in serum transaminases and γ-glutamyl transpeptidase occurred with the lowest dose of ursodeoxycholic acid, which corresponded to 4 mg/kg body wt/day, and no further significant decrease with the higher doses was seen. Biliary bile acid composition was determined by high-performance liquid chromatography and gas chromatography-mass spectrometry. At entry the relative proportions of major bile acids were similar, to those observed in normal individuals. During treatment the mean percentage of ursodeoxycholic acid in bile (22% with the 250 mg dose, 32% with the 500 mg dose and 34% with the 750 mg dose) was lower than values previously reported for patients with gallstones and normal liver function. The major bile acids were cholic, chenodeoxycholic and deoxycholic acids. A number of unusual bile acids were identified by gas chromatography-mass spectrometry, but these accounted for only 3% to 5% of the total and did not change during ursodeoxycholic acid therapy. No correlation between the improvement in liver function tests and the percentage of ursodeoxycholic acid in bile existed. These data suggest that even a slight enrichment of bile with ursodeoxycholic acid, as is attained with 250 mg/day, is effective in improving biochemical markers of liver function in patients with chronic active hepatitis. (HEPATOLOGY 1991;13:339–344).

Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: A dose-response study

The effect of ursodeoxycholic acid administration on liver function tests and on bile acid metabolism was investigated in 18 patients with chronic active hepatitis. Three different doses of ursodeoxycholic acid--250 mg, 500 mg and 750 mg--were administered daily to each patient for consecutive 2-mo periods. The order of doses was randomly assigned according to a replicated Latin-square design. A significant decrease in serum transaminases and gamma-glutamyl transpeptidase occurred with the lowest dose of ursodeoxycholic acid, which corresponded to 4 mg/kg body wt/day, and no further significant decrease with the higher doses was seen. Biliary bile acid composition was determined by high-performance liquid chromatography and gas chromatography-mass spectrometry. At entry the relative proportions of major bile acids were similar to those observed in normal individuals. During treatment the mean percentage of ursodeoxycholic acid in bile (22% with the 250 mg dose, 32% with the 500 mg dose and 34% with the 750 mg dose) was lower than values previously reported for patients with gallstones and normal liver function. The major bile acids were cholic, chenodeoxycholic and deoxycholic acids. A number of unusual bile acids were identified by gas chromatography-mass spectrometry, but these accounted for only 3% to 5% of the total and did not change during ursodeoxycholic acid therapy. No correlation between the improvement in liver function tests and the percentage of ursodeoxycholic acid in bile existed. These data suggest that even a slight enrichment of bile with ursodeoxycholic acid, as is attained with 250 mg/day, is effective in improving biochemical markers of liver function in patients with chronic active hepatitis.

Effects of ursodeoxycholic acid on gallbladder contraction and cholecystokinin release in gallstone patients and normal subjects

It has been previously suggested that treatment with ursodeoxycholic acid leads to decreased gallbladder emptying. The proposed mechanism is decreased release of cholecystokinin through negative feedback control by an increased amount of intraduodenal bile acids. In the present study we examined cholecystokinin release and gallbladder contraction after oral administration of a commercial fatty meal (Sorbitract; Dagra, Diemen, The Netherlands) using ultrasonography in eight normal subjects and eight gallstone patients before and after 1 and 4 weeks of treatment with ursodeoxycholic acid (10 mg kg−1 · day−1). Fasting gallbladder volume increased in 15 of 16 subjects during treatment (P < 0.01). Minimal volume did not change. Therefore, both absolute and relative gallbladder emptying increased during therapy. Maximal decrement of gallbladder volume in milliliters and percentage as well as integrated gallbladder contraction during 90 minutes in milliliters and percentage were significantly increased after 1 and 4 weeks of treatment with ursodeoxycholic acid when compared with data before therapy. Gallstone patients tended to have larger fasting and residual gallbladder volumes than normal subjects, whereas parameters for the amount of bile expelled (maximal decrement of gallbladder volume and integrated gallbladder contraction in milliliters and percentage) did not differ. Release of cholecystokinin did not change during treatment and did not differ significantly between patients and normal subjects. Mean relative percentage of ursodeoxycholic acid in bile during treatment in 13 subjects consenting to have duodenal intubation was 47% (range 31%–60%). Changes of fasting gallbladder volume after institution of bile acid treatment correlated significantly (r = 0.74, P < 0.01) with changes of cholesterol saturation index but not with relative percentage of ursodeoxycholic acid in bile. This study indicates that gallbladder emptying does not decrease during treatment with ursodeoxycholic acid. Moreover, there is no evidence of decreased cholecystokinin release.

Development of Bile Secretory Function in the Neonatal Guinea Pig

Maturation of hepatic bile formation and lipid secretion were examined in neonatal guinea pigs in an attempt to explain the earlier observation that the neonate (15 days old) is less susceptible to lithocholate-induced cholestasis than the adult. Bile flow and bile acid secretion were lowest at 12 h postpartum and increased to attain a maximum at 15 days. Thereafter, values decreased to a level which was not significantly different from that at 3 days of age. Bile acid analysis indicated the presence of chenodeoxycholic acid, 7-ketolithocholic acid and ursodeoxycholic acid in bile at all ages. But, at 15 days ursodeoxycholic acid was a major contributor to total bile acid secretion. Phospholipid and cholesterol secretion increased between the 1st and the 3rd day of age but decreased markedly at 15 days. This indicated an uncoupling of biliary lipid secretion and endogenous bile acids which was related in part to the nature of the bile acids secreted. Serum bile acid levels were markedly increased at 15 days of age. This hypercholanemia may reflect a rapid expansion of the bile acid pool including an enhanced bile acid secretion which could explain in part the resistance to the lithocholate cholestasis by increasing the secretory capacity for the toxic bile acid.

Sulphated bile acids in duodenal juice of healthy infants and children compared with sulphated bile acids in paediatric patients with various gastroenterological diseases.

The bile acid pattern in the first 10 minute fraction of intestinal juice after injection of pancreozymin (2 U/kg bw) was studied in 32 gastroenterologically healthy children and 26 paediatric patients with various diseases of the liver or intestine. The sulphated and non-sulphated portions of monohydroxy, dihydroxy, and trihydroxy bile acids were evaluated in relation to the total concentration of bile acids as well as the ratios of the individual acids to each other in esterified and unesterified form. In healthy patients, the extent of sulphation was not age dependent. The quantity of potentially toxic monohydroxy and dihydroxy bile acids did not determine the percentage of sulphation, which was induced only by the severity of cholestasis. Ursodeoxycholic bile acids were usually esterified with sulphuric acid to a remarkably high degree. Less sulphated bile acids were detected in patients with coeliac disease than in the control group.

Ursodeoxycholic acid therapy and biliary lipids--a dose-response study.

The effects of four different doses of ursodeoxycholic acid (250, 500, 750, and 1000 mg daily) on biliary lipids were studied in 24 patients with radiolucent gallbladder stones. There was a significant increase in the proportion of ursodeoxycholic acid in bile after all doses, being greatest with 750 and 1000 mg daily. Unsulphated lithocholic acid was also increased in the bile after therapy, while the other major bile acids were reduced. The cholesterol content of bile was reduced by all doses, and this change was most marked after 1000 mg (from 10.9 +/- 1.4 to 5.6 +/- 0.5 mol%, P < 0.01). Biliary cholesterol saturation improved significantly only after 750 and 1000 mg daily.

Clinical studies on dissolution of gallstones using ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA), 7beta hydroxy epimer of chenodeoxycholic acid (CDCA), has been used as a choleretica for 20 years in Japan. Recent report showing increased excretion of UDCA in bile after CDCA administration may suggest the possibility that UDCA has similar effects to CDCA on bile cholesterol unsaturation and on gallstone dissolution. The present paper describes the clinical usefulness of UDCA for gallstone patients during the past two years. Seventy-four gallstone patients with functioning gall-bladders, 19 men and 55 women with a mean age of 48 years, have been treated for 6 months or more. UDCA, supplied in tablets (Ursosan), was given 450 mg per day. The disappearance or the reduction of stone size or number, or both (dissolution effect) was recognized in 32 out of 74 patients (43%). In case of radiolucent stones, the overall effective rate was estimated for 24 of 46 patients (52%). There may be no significant difference in dissolution effect between CDCA and UDCA treatment, however, the merit of UDCA treatment seems to have its few side effects.