Effect of ursodeoxycholic acid administration on biliary lipid composition and bile acid kinetics in cholesterol gallstone patients

The effect of ursodeoxycholic acid (UDCA) on bile lipid composition and bile acid kinetics was evaluated in seven cholesterol gallstone patients following one month of UDCA administration (12 mg/kg/day). UDCA administration induces a significant reduction in the cholesterol saturation index (SI). After UDCA treatment, UDCA becomes the predominant biliary bile acid while chenodeoxycholic, cholic, and deoxycholic acid are significantly reduced. UDCA pool significantly increases, and chenodeoxycholic, cholic, and total bile acid pools significantly decrease. The reduction in bile lithogenicity during UDCA administration suggests that UDCA may be useful for cholesterol gallstone treatment in man.     

Effect of ursodeoxycholic acid on biliary bile acid and bile lipid composition in gallstone patients

In five patients with radiolucent gallstones, the effect of ursodeoxycholic acid (Urso) in doses of 250, 500, 750, 1,000, and 1,250 mg per day on biliary lipid and bile acid composition was studied. Biliary cholesterol decreased from 8.8 +/- 0.8 mole% to 4.4 +/- 0.2 mole% at 500 mg Urso per day (7.1 mg per kg) and to 4.2 +/- 0.3 mole% at 750 mg Urso per day (10.7 mg per kg). Administration of 1,000 or 1,250 mg Urso per day produced no further decrease of biliary cholesterol. The biliary content of phospholipids and total bile acids remained unchanged. During Urso treatment, the relative amounts of glyco-Urso and tauro-Urso in bile increased. Glyco-Urso reached a plateau at 49.1 +/- 2.1% of total bile acids during treatment with 1,000 mg Urso per day, and tauro-Urso increased up to 4.3 +/- 1.5% of total bile acids at 250 mg Urso per day. Simultaneously cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid decreased. The data indicate that Urso treatment reduces biliary cholesterol efficiently already at a dose of 500 mg per day; biliary bile acid composition changes up to 1,000 mg Urso per day. Doses greater than 1,000 mg per day produced no additional alterations in bile composition.     

Effect of chronic administration of tauro-hyodeoxycholic acid on biliary bile acid composition and on biliary lipid secretion in humans

BACKGROUND: Tauro-hyodeoxycholic acid is a hydrophilic bile acid of potential interest for treating cholestatic liver diseases. Bile acid pool is enriched with this bile acid during acute administration in patients with interrupted enterohepatic circulation. The aim of our study was to check the effect of chronic administration of tauro-hyodeoxycholic acid on biliary lipid composition and secretion in man with intact enterohepatic circulation. METHODS: We studied 7 dyspeptic patients before and during taurohyodeoxycholic acid 750 mg/day given for 6-8 weeks. We measured bile acid composition in duodenal aspirate, and biliary lipid secretion was also measured in 5 of these patients using a duodenal perfusion technique. RESULT: Tauro-hyodeoxycholic was undetectable in duodenal aspirate in all patients before treatment, and was 2%, 4%, 5%, 7%, 7%, 8% and 13% of biliary bile acid during treatment in individual patients. The proportion of cholic, deoxycholic, chenodeoxycholic ursodeoxycholic and lithocholic acid was similar before and during treatment. Bile acid duodenal output remained unchanged during taurohyodeoxycholic by comparison with pretreatment with median difference -0.3 mmol (95% confidence interval 1.6 mmol). The corresponding difference for duodenal cholesterol and phospholipid output was 0.1 mmol (0.2 mmol) and 0.2 mmol (0.6 mmol). CONCLUSIONS: By contrast with acute administration in patients with interrupted enterohepatic circulation, chronic administration of tauro-hyodeoxycholic to man with intact enterohepatic circulation has little effect on biliary lipid composition and secretion.     

Effect of 3-hydroxy-3-methylglutaric acid administration on bile lipid composition in humans

The effects of the lipid-lowering agent 3-hydroxy-3-methylglutaric acid (HMGA) on serum lipids and on biliary lipid composition were evaluated in a double-blind, placebo-controlled study in normolipidemic volunteers. After 4 weeks of HMGA administration (1 g three times a day orally) serum total cholesterol showed a significant decrease with regard to both pretreatment values and corresponding values of controls. The bile lipid molar percentage composition and the cholesterol saturation index showed no modification after HMGA and did not differ from the values obtained in the placebo group. These findings indicate that HMGA exerts no adverse effects on bile lipid composition in humans, differing from other hypolipidemic drugs currently in clinical use, which increase the bile cholesterol saturation index.     

Effect of acute administration of bile acids on fatty acid composition of biliary phosphatidylcholine in man

Little is known on variations in fatty acid composition of biliary phosphatidylcholine (PC) during acute administration of particular bile acids (BAs) in man. Bile was collected hourly for 5 h in 6 T-tube patients (prereplacement period). Thereafter particular BAs were infused into the duodenum at a rate of 1 g/h for 5 h and bile collected hourly (replacement period). Each patient received two BAs at an interval of 3 days, following a cross-over design. Three patients received deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) and a second 3 patients cholic acid (CA) and chenodeoxycholic acid (CDCA). Bile acid pool contained mainly the two primary BAs in the prereplacement period and more than 80% administered BAs in the replacement period. Hydrophobic and detergent BAs (DCA and CDCA) increased the secretion rates and the percentage of biliary PC species with arachidonic acid and stearic acid; in contrast less detergent BAs (UDCA and CA) did not significantly alter fatty acid composition of biliary PC. Thus, very hydrophobic and detergent BAs would seem to promote the preferential secretion into the bile of lecithin species present in the liver cell plasma membranes, rich in arachidonic and stearic acid.     

Changes in bile acid composition and effect on cytolytic activity of fecal water by ursodeoxycholic acid administration: a placebo-controlled cross-over intervention trial in healthy volunteers

BACKGROUND: Ursodeoxycholic acid (UDCA) has been shown to affect membrane-damaging effects of bile acids in vitro and fecal bile acid composition in rats. This study evaluates the effect of UDCA on fecal bile acid composition and on cytolytic activity of fecal water in man to clarify the potential chemopreventive role of UDCA for colorectal cancer. METHODS: In this placebo-controlled crossover intervention trial, the effect of 900 mg/day UDCA orally in 15 healthy volunteers was studied. At the end of each 4-week period, 72 h feces were collected. Total and individual bile acids in feces were determined by gas chromatography and soluble bile acids were analyzed by high-performance liquid chromatography. Cytolytic activity of fecal water was measured using an erythrocyte lysis assay. RESULTS: In feces, the percentages of primary bile acids-cholic acid (CA) and chenodeoxycholic acid (CDCA)-and of secondary bile acid-deoxycholic acid (DCA) - decreased after supplementation with UDCA, whereas those of UDCA and LCA increased from 2.7 +/- 0.4% to 23.7 +/- 2.6%, P < 0.0001 and from 26.2 +/- 1.2% to 49.4 +/- 1.8%, P < 0.0001 respectively. The concentrations of these two bile acids in fecal water also increased after UDCA administration from 7.8 +/- 1.9 micromol/l to 47.0 +/- 6.7 micromol/l (UDCA), P < 0.0001 and from 2.5 +/- 0.6 micromol/l to 18.3 +/- 4.1 micromol/l (LCA), P < 0.002, respectively. Cytolytic activity of fecal water was not affected by UDCA. CONCLUSION: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.     

Effect of varying doses of chenodeoxycholic acid on bile lipid and biliary bile acid composition in gallstone patients: A dose-response study

In a dose-response study, a formulation of chenodeoxycholic acid (chenic acid) with complete bioavailability was fed at doses of 0,250, 500, 750 mg for randomized 6-week periods to 13 patients with radiolucent gallstones. The proportion of chenic acid in biliary bile acids increased in direct relation to dose. Lithocholic acid also increased, but ursodeoxycholic acid showed no significant change. Bile saturation decreased with increasing dose, but response was variable and achieved significance only at 750 mg/day. Cholesterol saturation was negatively correlated with the proportion of chenic acid in biliary bile acids: When biliary bile acids contained greater than 70% chenic acid (and ursodeoxycholic acid), bile became unsaturated, on the average. The data suggest that a dose of at least 10–15 mg/kg may be necessary to obtain desaturation in many gallstone patients.Supported in part by NIH grants AM 16770 and 15887.     

Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7 alpha-hydroxylation rates in vivo

The rates of cholesterol 7 alpha-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7 alpha-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7 alpha position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7 alpha-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7 alpha-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoprotein-cholesterol but exerted no change on 7 alpha-hydroxylation rates.(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 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.     

Effect of cicloxilic acid on bile lipid composition in patients with gallstones: a multicenter trial

24 gallstone patients were treated with cicloxilic acid, an agent endowed with choleretic activity, at the dose of 240 mg/day for 1 month. 24 comparable patients on placebo treatment acted as controls. Bile lipid composition was determined and the saturation index calculated before and after treatment, on samples collected by duodenal siphonage after caerulein stimulation, in both groups. In the cicloxilic group there was little or no change in bile salts and phospholipids, whereas biliary cholesterol concentration was significantly reduced (p less than 0.05) and consequently the lithogenic index lowered (from 1.5 to 1.2, p less than 0.01). Cicloxilic acid can have a place in gallstone disease therapy in association with the litholytic bile acids or in the prevention of gallstone formation in high-risk populations.     

The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study

OBJECTIVES: In 30% of patients with primary biliary cirrhosis (PBC) ursodeoxycholic acid (UDCA) causes full biochemical normalization, while 70% are incomplete responders. The only differences between the two groups are the significantly higher cholestasis indices in the incomplete responders. In these patients we investigated whether the strongly choleretic sulindac together with UDCA is superior to UDCA monotherapy. DESIGN AND METHODS: Twenty-three patients with PBC incompletely responding to UDCA monotherapy were entered in the open label study for 12 months. Eleven patients (stage II, seven; III, two; and IV, two) received UDCA (10-15 mg/kg/day) plus sulindac (100-300 mg/day) (Group I). Twelve patients (stage I, six; II, four; III, one; and IV, one) were treated with UDCA alone (Group II). Liver biochemistry, analysis of antimitochondrial, antinuclear, smooth muscle, and liver-kidney-microsomal antibodies, ultrasonography and gastroscopy were done in regular intervals. RESULTS: In Group I all liver indices, IgG, IgM and IgA significantly improved although pretreatment data and stages of the disease tended to be higher than in Group II. In five patients of Group I liver histology improved slightly. Sulindac was well tolerated. The biochemical indices did not further improve on UDCA monotherapy. CONCLUSIONS: Sulindac in combination with UDCA further improves liver biochemistries in patients with PBC who responded incompletely to UDCA alone.     

Effect of long term lactulose ingestion on secondary bile salt metabolism in man: potential protective effect of lactulose in colonic carcinogenesis.

This study investigated whether colonic absorption of secondary bile acids, especially deoxycholate in patients with adenomas could be decreased by oral lactulose. Bile acid metabolism was studied using bile sampling and 14C-deoxycholate kinetics in patients with colonic adenomatous polyps before and after four and 12 weeks of lactulose, 60 g/day. The results indicate that lactulose decreased the deoxycholate pool size from a mean of 22.0 (SD: +/- 13.8) to 14.3 (+/- 7.6) mumol/kg (p less than 0.025). Deoxycholate absorption fell from 3.8 (+/- 2.3) to 2.9 (+/- 1.4 mumol/kg/d (ns). The biliary bile acid composition decreased significantly in deoxycholate after four and 12 weeks with a rise in primary bile acids. There was a highly significant correlation between the %-change in DCA input and the %-change in DCA pool size (r = 0.89). Intestinal transit measured by the pellet method (4.1 +/- 1.9 to 2.4 +/- 0.6 day; p less than 0.01) and faecal pH decreased, while stool frequency and weight rose significantly. Significant correlations between the %-change in gut transit time and the %-change in DCA pool size or %-change in DCA input were absent. The results show that it is possible to lower colonic secondary bile acid absorption by long term lactulose feeding. This effect can be mediated by accelerated transit and the acidification of the colonic contents.     

Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation

Reperfusion therapy has become a practical and effective strategy in the salvage of ischemic myocardium. The direct enhancement of cardiac cellular tolerance against ischemic and reperfusion injury should further improve patient outcome in acute coronary syndromes (ACS). This approach has been explored for many decades, and although we await mortality-weighted randomized clinical trials, the infusion of glucose-insulin-potassium (GIK) has shown promise in protecting post-infarct myocardium. The current dogma is that this cardioprotective effect of GIK acts via the modulation of cardiac and circulating metabolites to provide the heart with an optimal metabolic milieu to resist ischemia and reperfusion injury. This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine. We contend that the mitogen insulin, itself, promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart. To advance this viewpoint, we will present clinical data that support a dose-dependent effect of insulin's beneficial action in the management of acute myocardial infarction. Furthermore, we present experimental data that identify cell-survival programs that are directly activated by the administration of insulin. Finally, as intravenous insulin therapy is both labor intensive and associated with metabolic perturbations, we propose that the development of pharmaco-therapeutic agents that target downstream cell-survival insulin-activated signaling molecules may be an alternate approach to promote cardioprotection during ACS.     

Antithrombin-III-Hamilton, Ala 382 to Thr: an antithrombin-III variant that acts as a substrate but not an inhibitor of alpha-thrombin and factor Xa

Antithrombin-III-Hamilton has been shown to be a structural variant of antithrombin-III (AT-III) with normal heparin affinity but impaired protease inhibitory activity. The molecular defect of AT-III-Hamilton is the substitution of Thr for Ala at amino acid residue 382. The plasma of affected individuals contains approximately equal quantities of normal AT-III and AT-III-Hamilton. When AT-III was isolated from the plasma of the propositus by heparin-Sepharose chromatography, it had identical mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to normal plasma-derived AT-III, under both reducing and nonreducing conditions. However, the AT-III-Hamilton species, separated from the propositus' normal AT-III by a combination of heparin-Sepharose and thrombin-Sepharose chromatography, had increased mobility on reductive SDS-PAGE compared with AT-III from the propositus isolated by heparin-Sepharose chromatography alone. Under nonreducing conditions this AT-III-Hamilton species had decreased mobility compared with AT-III from the propositus (or normal AT-III) isolated only by heparin-Sepharose chromatography. When incubated with either human alpha-thrombin or human factor Xa, this AT-III-Hamilton species was unreactive. Approximately 50% of the AT-III from the propositus isolated by heparin-Sepharose chromatography, when incubated with either human alpha-thrombin or factor Xa, did not form complex but was cleaved, presumably at the reactive center Arg393-Ser394. To further substantiate the biological behavior of this variant, AT-III-Hamilton polypeptides were synthesized in a cell-free system. This recombinantly produced AT-III-Hamilton, when incubated with either human alpha-thrombin or factor Xa, was cleaved by both these proteases, but did not show any complex formation. The results indicate that AT-III-Hamilton does not form a stable covalent inhibitory complex with these serine proteases but can be cleaved at the reactive center. Thus, the inhibition of serine proteases by their natural inhibitors (the serpins) involves at least two separate, but interrelated events; hydrolysis at the reactive center followed by complex formation. AT-III-Hamilton is capable of only the first of these events.