ting and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol per se. The hepatotoxicity of lithocholic acid is characterized biochemically and morphologically as cholestatic.
Man has the capacity to form sulfate conjugates of lithocholic acid. Variation in this capacity among individuals has not been well established and a recent published report suggests that patients who develop chenodiol-induced serum aminotransferase elevations are poor sulfators of lithocholic acid (see ADVERSE REACTIONS and WARNINGS).
General Clinical Results:
Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Gallstone Study (NCGS) involving 305 patients in each treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2% and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28 to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n = 86) achieved complete confirmed dissolutions.
Observed stone dissolution rates achieved with chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patients with small {less than 15 mm in diameter} radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones. (See FLOATABLE VERSUS NONFLOATABLE STONES, below). Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of chenodiol, doses that are too low are associated with increased cholecystectomy rates (see ADVERSE REACTIONS).
Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in all clinical trials and are dose-related (refer to ADVERSE REACTIONS and WARNINGS sections for full information).
Floatable versus Nonfloatable Stones
A major finding in clinical trials was a difference between floatable and nonfloatable stones, with respect to both natural history and response to chenodiol. Over the two-year course of the National Cooperative Gallstone Study (NCGS), placebo – treated patients with floatable stones (n = 47) had significantly higher rates of biliary pain and cholecystectomy than patients with nonfloatable stones (n = 258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750 mg/day) compared to placebo was associated with a significant reduction in both biliary pain and the cholecystectomy rates in the group with floatable stones (27% versus 47% and 1.5% versus 19%, r |
