Protective Effects of Norursodeoxycholic Acid Versus Ursodeoxycholic Acid on Thioacetamide-induced Rat Liver Fibrosis.

BACKGROUND/OBJECTIVES: Effects of norursodeoxycholic acid (norUDCA) and ursodeoxycholic acid (UDCA) on liver fibrosis progression and liver fibrosis reversal in thioacetamide (TAA)-treated rats were studied. METHODS: Advanced liver fibrosis was induced by TAA treatment (200 mg/kg, i.p.) for 12 weeks. In the second experiment resolution of liver fibrosis was assessed after 8 weeks of TAA withdrawal. During 8 last weeks of each trial, fibrotic rats were daily administered with UDCA (80 mg/kg) and norUDCA (equimolar to 80 mg/kg of UDCA) by oral gavage. Liver fibrosis was assessed by Sirius red staining, liver hydroxyproline and serum fibrosis markers determination. RESULTS: The TAA treatment resulted in advanced fibrosis and increase in liver hydroxyproline content and serum fibrosis markers. These signs of fibrosis were less pronounced in rats after TAA withdrawal. Treatment with of norUDCA significantly decreased the total and relative liver hydroxyproline contents in rats with fibrosis reversal, whereas UDCA did not change these parameters. Both compounds decreased serum TGFß and type IV collagen contents, whereas other serum markers did not differ from the placebo group. In the fibrosis progression model the square of connective tissue was decreased by norUDCA. Serum type IV collagen and procollagen III-NT contents in these experiments were lowered by both UDCA and norUDCA, whereas rest of serum fibrosis markers were diminished only by norUDCA. CONCLUSIONS: Both norUDCA and UDCA showed therapeutic and prophylactic antifibrotic effect in rats with TAA-induced liver fibrosis. For most of tested parameters norUDCA was more effective than UDCA, especially in the experiment with liver fibrosis regression.

Ursodeoxycholic acid dose-dependently improves liver injury in rats fed a methionine- and choline-deficient diet.

AIM: The data on the beneficial effect of ursodeoxycholic acid (UDCA) in non-alcoholic steatohepatitis (NASH) are controversial. The difference of opinion is connected with UDCA dosage to be used. Therefore, we evaluated the dose-dependent efficacy of UDCA in experimental NASH. METHODS: Male Wistar rats were fed the methionine- and choline-deficient (MCD) diet for 10 weeks. Rats were administrated UDCA (10, 20, 40 and 80 mg/kg bodyweight intragastrically) after 6 weeks of the MCD diet. RESULTS: Animals fed the MCD diet developed severe steatohepatitis. Treatment with UDCA dose-dependently decreased liver damage, but only high-dose UDCA (80 mg/kg) significantly diminished ultrastructural changes in addition to preventing steatosis, ballooning and inflammatory changes in the liver. The activities of serum marker enzymes and the content of liver triglyceride and blood glucose were increased in MCD diet-fed rats, but decreased in all the UDCA-treated groups. Serum insulin concentration was decreased whereas the quantitative insulin sensitivity check index did not changed in MCD diet-fed groups. Serum tumor necrosis factor-α content was strongly increased after MCD diet and normalized in the UDCA-treated rats, with the most pronounced effect in the highest dose groups, 40 and 80 mg/kg. The contents of endogenous ethanol in blood and intestinal mucus were increased in MCD diet-fed rats which were significantly lowered by UDCA (40 and 80 mg/kg per day). CONCLUSION: The present data demonstrate a beneficial effect of UDCA that manifested by the decrease of liver steatosis, inflammatory signs and serum tumor necrosis factor-α content especially of the highest 40 and 80 mg/kg day doses.

Ursodeoxycholic acid treatment in preterm infants: a pilot study for the prevention of cholestasis associated with total parenteral nutrition.

In a prospective, double-blind, placebo-controlled trial, the efficacy and safety of ursodeoxycholic acid (UDCA) was evaluated in preterm infants, in terms of its potential impact on fat absorption, advancement of enteral feeding, development of cholestasis, growth, nutritional status, and metabolic status. Although fecal fat excretion slightly decreased and achievement of full enteral feeding was earlier in the UDCA group, these differences were not significant. Interestingly, whereas serum gamma-glutamyl transferase activity increased during the parenteral nutrition period in the placebo group, we observed a constant and significant decrease in the UDCA group. This observation warrants further investigation to determine the utility of prophylactic UDCA in preventing cholestasis in infants with prolonged parenteral nutrition.

Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy.

AIM: To evaluate the predictive value of clinical symptoms and biochemical parameters for prematurity in intrahepatic cholestasis of pregnancy (ICP). METHODS: Sixty symptomatic patients with ICP were included in this retrospective analysis. Preterm delivery was defined as delivery before 37 wk gestation. Predictors of preterm delivery were disclosed by binary multivariate logistic regression analysis. RESULTS: Mean time of delivery was 38.1 +/- 1.7 wk. No stillbirths occurred. Premature delivery was observed in eight (13.3%) patients. Total fasting serum bile acids were higher (47.8 +/- 15.2 vs 41.0 +/- 10.0 mumol/L, P < 0.05), and pruritus tended to start earlier (29.0 +/- 3.9 vs 31.6 +/- 3.3 wk, P = 0.057) in patients with premature delivery when compared to those with term delivery. Binary multivariate logistic regression analysis revealed that early onset of pruritus (OR 1.70, 95% CI 1.23-2.95, P = 0.038) and serum bile acid (OR 2.13, 95% CI 1.13-3.25, P = 0.013) were independent predictors of preterm delivery. CONCLUSION: Early onset of pruritus and high levels of serum bile acids predict preterm delivery in ICP, and define a subgroup of patients at risk for poor neonatal outcome.

Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells.

We investigated the effects of UDCA on sphingomyelinase (SMase) in Caco 2 cells cultured in monolayer and polarized conditions. Alkaline SMase activity was high in polarized cells whereas, acid and neutral SMase activities were high in monolayer cells. In polarized cells, UDCA increased alkaline SMase expression and caspase 3 activity but had no effect on acid and neutral SMases. In monolayer cells, UDCA reduced both acid and neutral SMase activities, inhibited cell proliferation, but had little effect on alkaline SMase and caspase 3 activities. In conclusion, UDCA differentially affects SMase activity, cell proliferation, and apoptosis in colonic cells depending on the cell conditions.

Evaluation of oral budesonide in the treatment of active distal ulcerative colitis.

Budesonide, a topical corticosteroid, has proven useful for the management of Crohn's disease. Its efficacy is similar to prednisone but it has fewer side effects. A new pH-modified release capsule (Budenofalk) is probably efficacious in distal ulcerative colitis. The aim of the present study was to establish the pharmacokinetics, pharmacodynamics, and safety of two dosage regimens of budesonide capsules and to obtain efficacy information. Budenofalk 9 mg daily was administered as a single dose 9 mg in 8 patients and as three 3 mg doses in 7 patients with active distal ulcerative colitis for 8 weeks. Symptoms were assessed at three timepoints during the study: baseline, 4 and 8 weeks after start of treatment. Endoscopic evaluation and budesonide concentration in mucosal biopsy specimens was performed at 0 and 8 weeks. A pharmacokinetic profile and pharmacodynamic profile (cortisol, lymphocytes and neutrophils) was performed at day 5. In the 9 mg o.d. group, higher peak concentrations and systemic availability was found compared to the 3 mg t.i.d. group. Cortisol suppression was more pronounced after 9 mg o.d. than after 3 mg t.i.d. Lag-time, AUC and pharmacodynamic effects were comparable (14% mean decrease lymphocyte count and 26% mean increase neutrophil count). Mucosal biopsy specimens in the distal colon revealed significant budesonide levels with both regimens. After 8 weeks, 71% in the 9 mg o.d. group and 38% in the 3 t.i.d. group responded. The endoscopic index improved from 10 +/- 2 to 2 +/- 3 (p <0.001) with 9 mg o.d. and from 9 +/- 2 to 4 +/- 4.7 (p = 0.02) with 3 mg t.i.d. The pharmacokinetic and pharmacodynamic profiles found in this study indicate that Budenofalk reaches the distal part of colon and rectum, but further studies to validate the budesonide assay in the mucosa and comparison with a control group are necessary. This limited study suggests that Budenofalk is effective in distal colitis and side effects are rare. Based on these observations a large clinical trial using 9 mg o.d. is indicated to confirm efficacy and assess further possible side effects.

Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives.

OBJECTIVE: Contraception is recommended for female patients during ursodeoxycholic acid (UDCA) treatment for the potential teratogenic effect of this bile acid, and the aim of our study was to determine whether this treatment affects the bioavailability of ethinylestradiol (EE2). METHODS: In this double-blind, randomised study, we measured EE2 pharmacokinetics in eight healthy volunteers randomly allocated to receive oral contraceptive (30 microg EE2 and 75 microg gestodene) plus either UDCA (8-10 mg/kg per day) or placebo for 21 days during the first of three consecutive menstrual cycles. After a washout period during the second cycle, the subjects received the alternative treatment during the third menstrual cycle. Serum EE2 and UDCA were measured using radioimmunoassay and gas chromatography-mass spectrometry, respectively. RESULTS: The profile for serum EE2 concentration was similar during UDCA (mean maximum serum concentration 177 pg/ml, SEM 59) and during placebo treatment (153 pg/ml, SEM 62), and mean area under the curve (AUC) was 1374 pg/h per ml (SEM 580) and 1320 pg/h per ml (SEM 551) during the two regimens, respectively. The point estimates and 90% confidence intervals of UDCA/placebo ratios for EE2 AUC and for maximum serum concentration were 1.1 (0.8-1.5) and 1.2 (1.0-1.4), respectively. Mean serum triglycerides concentration increased from 58.3 mg/dl (SEM 6.8) at enrolment to 91.4 mg/dl (SEM 10.7) during placebo (P < 0.01) and to 88.6 mg/dl (SEM 13.7) during UDCA treatment (P < 0.05). During UDCA treatment, serum enrichment with this bile acid and with the metabolite iso-UDCA was 29% (16%) and 3% (2%), respectively. CONCLUSION: Co-administration with UDCA does not affect the bioavailability of EE2 in healthy volunteers, indicating that contraceptive efficacy is not affected.

The protective effect of ursodeoxycholic acid in alloxan-induced diabetes.

The purpose of this work was to study the effect of ursodeoxycholic acid (UDCA) on the morphological and functional alterations in pancreatic islet beta-cells in rats with diabetes induced by alloxan (150 mg kg(-1), i.p.). UDCA (40 mg kg(-1), i.g.) was administered daily from the fifth to the 35th day after the alloxan treatment. The treatment of diabetic rats with UDCA improved the pancreatic morphology disturbed by the alloxan treatment: UDCA increased the number of pancreatic islets and beta-cells, the beta-/alpha-cell ratio and decreased the number of alpha-cells. As the morphometric data suggest, the treatment of diabetic animals with UDCA significantly increased the area of beta-cell cytoplasmatic granules stained by paraldehyde-fuchsin. The concentration of blood glucose in diabetic rats was gradually decreased after the UDCA treatment, and at the end of the experiment reached the control value. The treatment with UDCA raised the serum insulin level in diabetic rats about 2.5-fold, but this concentration was significantly lower as compared to the control group. The content of lipid peroxidation end-products, hydroxyalkenals and malondialdehyde, was significantly elevated in the alloxan-treated rats, whereas the treatment with UDCA normalized these parameters. The present data indicate that UDCA acts as an effective antidiabetic agent in alloxan-induced diabetes and its beneficial effects in diabetic rats can be related to the antioxidant properties of UDCA.