Changes of the biliary canalicular membrane lipid content can affect membrane fluidity and biliary lipid secretion in rats. The immunosuppressant cyclosporin A is known to cause intrahepatic cholestasis. This study investigated whether cyclosporin A influenced canalicular membrane fluidity by altering membrane phospholipids or transporter expression. In male Sprague–Dawley rats, a bile-duct cannula was inserted to collect bile, and sodium taurocholate was infused (100nmol/min per 100g) for 60min. During steady-state taurocholate infusion, cyclosporin A (20mg/kg) or vehicle was injected intravenously and then bile was collected for 80min. After killing the rats, canalicular membrane vesicles were prepared. Expression of canalicular membrane transporters was assessed by Western blotting and canalicular membrane vesicle fluidity was estimated by fluorescence polarization. Cyclosporin A reduced biliary lipid secretion along with a disproportionate reduction of lipids relative to bile acids. Cyclosporin A significantly decreased canalicular membrane fluidity along with an increase of the cholesterol/phospholipid molar ratio. Only expression of the transporter P-glycoprotein was increased by cyclosporin A. Because canalicular membrane transporter expression was largely unchanged by cyclosporin A despite a marked decrease of biliary lipid secretion, transporter activity may partly depend upon canalicular membrane fluidity.
Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.
Ninety-six patients treated successively for symptomatic cholelithiasis with extracorporeal shock wave lithotripsy (ESWL) and oral bile acid therapy consisting of ursodeoxycholic acid in daily dosages of 600 mg were prospectively followed for gallstone recurrence for a median of 13 months. Ultrasonography was performed to detect stone recurrence at 3, 6, and 12 months, and then yearly after the termination of therapy. Recurrent stones were found in 17 patients (18%). The cumulative probability of gallstone recurrence was 15.8% at 12 months, 26.1% at 24 months, and 30.7% at 36 months. The probability of stone recurrence over the entire period of observation was not dependent on stone number, whereas the median interval to detection of recurrence was significantly shorter in the patients with multiple stones (2 months) than in those with solitary stones (8 months) (p < 0.05). The rate of impaired gallbladder contractility was higher in patients with recurrence (8/15, 53.3%) when compared with those with no recurrence (15/72, 20.8%) (p < 0.01). Neither age, gender, or stone characteristics predicted stone recurrence. Only one patient with a recurrence reported biliary pain. Of the 15 patients with recurrent stones who opted for further nonsurgical treatment, complete stone disappearance was achieved in 10. Impaired gallbladder function may predict gallstone recurrence after ESWL.
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