The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Bezafibrate treatment: a new medical approach for PBC patients? A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.
Aim: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. Methods: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). Results: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. Conclusion: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis. The aim of this study was to assess the efficacy of ursodeoxycholic acid (UDCA) for primary biliary cirrhosis in a randomized, double-blind placebo-controlled trial.
                Consecutive patients (n=192) were randomized to receive 14-16 mg UDCA/kg/day or placebo. Patients underwent a complete history, physical examination, liver chemistries, immunological determinations and liver biopsy at entry and at the end of the trial, which lasted for at least 2 years. Patients were seen every 3 months and the median follow-up was 3.4 years (range 0.3 to 6.1 years).
                Patients receiving UDCA (99) or placebo (93) were comparable with regard to age, sex, biochemical parameters and liver histology. UDCA treatment was associated with decreases in alkaline phosphatase, gammaglutamyl transferase, alanine aminotransferase, and cholesterol levels, effects which were conspicuous after 3 months of treatment and remained similar during the follow-up. During the study 31 patients (10 receiving UDCA and 21 placebo) discontinued the trial because of noncompliance (n=11), voluntary withdrawal (n=19) or adverse effects (n=1). Treatment failure (death or liver transplantation) was observed in 17 patients receiving UDCA and in 11 patients receiving placebo. Times to death or liver transplantation and to clinical complications were not significantly different in patients receiving UDCA or placebo. Histological analysis indicates that UDCA improved portal inflammation and prevented histological stage progression. By contrast, histological stage as well as ductular proliferation and ductopenia progressed in patients receiving placebo.
                Although UDCA treatment did not significantly affect time to death or liver transplantation and to clinical complications, the effects on both cholestasis and liver histology suggest that UDCA is safe and may be useful for preventing the progression of primary biliary cirrhosis. The aim of this study was to evaluate the effects of the combination therapy with bezafibrate and ursodeoxycholic acid (UDCA) for primary biliary cirrhosis (PBC), compared to UDCA monotherapy. Sixteen patients with compensated PBC were divided randomly into two groups. Group A received treatment with bezafibrate and UDCA for 6 months, while group B received UDCA alone, treatment protocols were then exchanged for another 6 months. The laboratory data was followed every month. The mean levels of alkaline phosphatase (ALP) decreased significantly more in group A than in group B in the first half of the study. Then serum ALP levels were elevated in group A after exchanged the therapy, but fell down in group B. Serum levels of gamma-glutamyl transferase (GGT), immunoglobulin M and triglycerides values were significantly lower in group B than in group A, after changing therapies from monotherapy to combination therapy with bezafibrate and UDCA. The mean levels of ALP, GGT and triglycerides were significantly lower at the end of the combination therapy than those at the end of the monotherapy. The combination therapy with bezafibrate and UDCA significantly improves the laboratory data that specific for PBC in comparison with UDCA monotherapy. A new medical approach to primary biliary cirrhosis (PBC) has been desired. We investigated the feasibility of using combination ursodeoxycholic acid (UDCA)-bezafibrate therapy in patients with PBC nonresponsive to UDCA monotherapy.
                During a 6-month period, 22 PBC patients with elevated serum alkaline phosphatase (ALP) despite UDCA monotherapy received either UDCA at 600 mg/day (control group) or UDCA at 600 mg/day plus bezafibrate at 400 mg/day (bezafibrate group). Each patient underwent detailed clinical and biochemical evaluation.
                During treatment, changes in ALP level were greater in the bezafibrate group than in the control group (P< 0.01). During and at the end of treatment, serum ALP levels were significantly lower than those before treatment in patients receiving UDCA plus bezafibrate (P< 0.05). At the end of the 6 months, normalization of serum ALP was observed in 5 of 11 (45.4%) patients given bezafibrate and in 2 of 11 (18.1%) patients not given bezafibrate (P< 0.16). Bile acid proportions during the combination therapy did not change. Pruritus disappeared in 1 of 7 bezafibrate-group patients with this symptom.
                UDCA at 600 mg/day plus bezafibrate at 400 mg/day may be considered as a new therapeutic option for patients with PBC. In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis.
                We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction.
                Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, cholesterol, and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol.
                Ursodiol is a safe and effective treatment for primary biliary cirrhosis. Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the least-known hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (p < 0.001). Significant falls in serum alkaline phosphatase, aminotransferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with primary biliary cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with primary biliary cirrhosis. There is no satisfactory medical therapy for patients with primary sclerosing cholangitis. Ursodiol (ursodeoxycholic acid) benefits patients with primary biliary cirrhosis, another cholestatic liver disease.
                From May 1989 to July 1995, we enrolled 105 patients with well-documented primary sclerosing cholangitis in a randomized, double-blind study comparing ursodiol (13 to 15 mg per kilogram of body weight per day in divided doses) with placebo. The primary outcome was the time to treatment failure, defined as death; liver transplantation; histologic progression by two stages (of four) or progression to cirrhosis; the development of varices, ascites, or encephalopathy; sustained quadrupling of the serum bilirubin concentration; marked worsening of fatigue or pruritus; inability to tolerate the drug; or voluntary withdrawal from the study.
                We analyzed data on the 51 patients in each group with at least 3 months of follow-up; the median follow-up was 2.2 years. There was no significant difference between the groups in time to treatment failure (relative risk of treatment failure in the ursodiol group, 1.01; 95 percent confidence interval, 0.6 to 1.7). During the first two years of follow-up, treatment was unsuccessful in 17 of 32 patients (53 percent) in the placebo group and 16 of 31 (52 percent) in the ursodiol group. There were also no differences in time to treatment failure for patients with early-stage disease or in time to liver transplantation. Ursodiol, but not placebo, was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin levels at one and two years.
                In a group of patients with well-defined primary sclerosing cholangitis, ursodiol provided no clinical benefit. A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal.
                Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months.
                In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity.
                UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC. To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL.
                A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study.
                The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P < 0.05). No significant differences were observed in terms of improvement of liver enzymes related to cholestasis and cytolysis and of amelioration of pruritus. The Mayo score values increased less above the baseline values at 24 and 36 month-intervals in the UDCA/C group than in the UDCA group. Histological evaluation at baseline and at the end of the study was available for 15 patients with pre-cirrhotic stage. A significant reduction in histological grading score was observed in patients from the UDCA/C group, whereas no changes in these histological scores were observed in the UDCA group.
                The addition of colchicine to ursodeoxycholic acid in patients with symptomatic primary biliary cirrhosis results in a small but significant reduction of disease progress.
This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.