Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: a comparison with ursodeoxycholic acid alone.

Chenodeoxycholic acid (CDC) and ursodeoxycholic acid (UDC) have distinct physicochemical and metabolic properties which, being complementary, should favor more rapid removal of cholesterol from gallstones when both bile acids are administered together. To see if the combination is more effective and well tolerated, we have compared 5 mg/kg of CDC plus 5 mg/kg of UDC with a 10-mg/kg dose of UDC alone in 120 patients with radiolucent, sonographically confirmed gallstones and characteristics favoring complete dissolution. Ursodeoxycholic acid was chosen as the reference because it dissolves stones faster and is better tolerated than CDC. To minimize the influence of stone size, the major determinant of dissolution, patients were divided, on admission, into two groups according to the maximum stone diameter: 50 had stones less than or equal to 5 mm, 70 had stones greater than 5 mm but less than 15 mm. The effects of treatment on stone dissolution evaluated by cholecystography and ultrasonography at 6, 12, and 24 mo, were analyzed by the actuarial life-table method. In the group with smaller stones, significantly more patients had obtained complete dissolution after treatment with the combination (52%) than after treatment with UDC alone (24%) at 6 mo. After longer periods, results were still better with the combination, although the differences from UDC alone became smaller. In the patients with larger stones, rates of complete and partial dissolutions were higher after treatment with the combination (51% vs. 24% with UDC) at 6 mo and again the differences had become smaller after longer treatment. Although not statistically significant, stone calcification occurred more often with UDC (7 cases) than with the combination (1 case). We conclude that CDC plus UDC is preferable to UDC alone because it dissolves stones more quickly, with a lower incidence of stone calcification, and may result in reduced cost of treatment.

Varying nuclear staining intensity of hepatitis B virus DNA in human hepatocellular carcinoma.

An in situ hybridization technique with biotinylated hepatitis B virus (HBV)-DNA probes was used to localize HBV-related DNA sequences in cells of human hepatocellular carcinoma (HCC). Formalin fixed, paraffin-embedded liver biopsies of 11 patients with HCC studied; nuclear HBV-DNA hybridization was observed in 7 of the patients. Sensitivity and specificity of the method were determined by examining appropriate controls. The number of cells exhibiting nuclear fluorescence and intensity of fluorescence varied from tumor to tumor. In two instances liver tissue adjacent to HCC exhibited nuclear staining. HBV-DNA nuclear staining did not correlate with tumor localization of HBsAg or HBcAg, nor with type or with differentiation of the tumor. The use of biotinylated HBV-DNA probes offers a powerful and reproducible technique to localize HBV-related DNA sequences even in formalin-fixed, paraffin-embedded tumor tissue, and also to compare the presence of HBV-DNA with that of viral antigens stained in parallel sections. The frequent localization of HBV-DNA in nuclei of HCC cells fortifies the important epidemiologic association between infection and HCC. The random cellular localization of HBV-DNA sequences in HCC suggests that HBV-DNA may be incorporated, or perhaps replicated, unequally in tumor cells.

Hepatocellular carcinoma in Italy: report of a clinical trial with intravenous doxorubicin.

Sixty-six patients with hepatocellular carcinoma (HCC) in various stages of hepatic involvement were studied prospectively. Of these, 50 (75%) had associated cirrhosis and 19 (28%) had serum hepatitis B surface antigen (HBsAg). Six (9%) patients were eligible for tumor resection, 34 were selected for doxorubicin chemotherapy (60 mg/m2, i.v., given every 3 weeks, up to a maximum dose of 550 mg/m2), and 26 were followed up without treatment. Untreated patients survived 1-18 months (median 1) after diagnosis. Surgically treated patients survived 1-14 months (median 4.5). In the doxorubicin group, six patients died soon after the first course of treatment, leaving 28 patients to be evaluated. Seven (24.5%) responded to therapy, surviving 2-26 months (median 8.0). Twenty-one (75.5%) did not respond to chemotherapy and had a median survival of 3.5 months (range: 2-12). Initial performance status and the degree of hepatic impairment were found to be covariates of prognostic significance. The type and severity of drug-related side-effects appeared to be comparable to those reported by others. In accordance with previous reports, our patients with HCC often had non-resectable tumors or responded poorly to chemotherapy. The association between this tumor and cirrhosis might partially account for treatment failure.

A combination of chenodeoxycholic acid and ursodeoxycholic acid is more effective than either alone in reducing biliary cholesterol saturation.

The effects on biliary lipids of 10 mg per kg per day of chenodeoxycholic acid (CDCA), 10 mg per kg per day of ursodeoxycholic acid (UDCA), and their equimolar combination (5 mg per kg per day of each), all administered for 45 to 60 days, were investigated in 18 patients with gallstones in a double-blind study with a balanced latin square design. The molar percentage of cholesterol in bile (initial value 9.7 +/- 2.2) was significantly lower after UDCA (5.4 +/- 1.3) and the combination (5.2 +/- 1.2) than after CDCA (7.2 +/- 1.7). Nevertheless, when the ability to solubilize cholesterol was calculated, taking into account the percentage of biliary UDCA, then the differences in cholesterol saturation induced by UDCA alone and the combination also became considerable (saturation index: 0.94 +/- 0.12 as compared to 0.81 +/- 0.12). The total bile acid pool increased significantly after treatment with CDCA and the combination, but not after UDCA. Lithocholic acid was increased significantly only by treatment with CDCA. Diarrhea was observed in five patients with hypertransaminasemia and in four patients after CDCA, whereas both UDCA and the combination were well-tolerated. We conclude that the administration of a combination of equimolar doses of CDCA and UDCA can be recommended for medical treatment of gallstones since it has greater effects on bile cholesterol saturation than either alone, is better tolerated than CDCA, and is less expensive than UDCA.

Gallstone dissolution after 6 months of ursodeoxycholic acid (UDCA): effectiveness of different doses.

In order to compare the effects on gallstone dissolution of three different doses of UDCA (4, 8 and 12 mg/kg/day), a controlled trial was carried out with seventy-one patients. The dissolution rate was higher in the group treated with the highest dose. Stone size was the major factor affecting the outcome of treatment, with a significantly higher success rate in patients with gallstones less than 10 mm than with stones greater than 10 mm.

Effect of dihydroxydibutylether (DHBE) on bile flow and composition in rats with ethynylestradiol-induced cholestasis.

Administration of dihydroxydibutylether (DHBE, Dis-Cinil) to rats with ethynylestradiol(EE)-induced cholestasis provoked an increase in bile flow and output of bile acids and phospholipids. Since EE-induced cholestasis is related to the condition observed in humans, a clinical trial of DHBE in cholestatic syndromes seems worthwhile.