Best-Buy Regimen of Ursodeoxycholic Acid for Patients with Gallstones A . LANZINI, D. FACCHINETTI, M. G. PIGOZZI, L. BETTINI &
G . MUIESAN Dept. of Clinical Medicine, University of Brescia, Spedali Civili, Brescia, Italy
Lanzini A, Facchinetti D, Pigozzi MG, Bettini L, Muiesan G. Best-buy regimen of ursodeoxycholic acid for patients with gallstones. Scand J Gastroenterol 1991, 26, Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
55 1-556
Bedtime administration has been advocated as a strategy for reducing minimum effective dose, side effects, and costs of chenodeoxycholic acid treatment of cholesterol gallstones, but little information is available for ursodcoxycholic acid (UDCA). We prospectively determined the minimum effective dose of bedtime UDCA in 44 patients with radiolucent gallstones treated with a range of UDCA doses (4.617.0 mg/kg/day). The average minimum effective dose for reducing the cholesterol saturation index (SI) of gallbladder bile to a value of 0.8 was 8.4 mg/kg/ day for bedtime UDCA. The greater potency of the bedtime regimen was confirmed in seven individual patients by comparison with a mealtime regimen. Cholesterol SI was reduced from 1.25 during placebo to 0.73 during 7 mg/kg/day for bedtime UDCA and to 0.81 during lOmg/kg/day for mealtime UDCA. The effect of thc bedtime regimen was not enhanced by a repeated-release tablet formulation of UDCA by comparison with UDCA in 15 patients. We conclude that the bile acid dose is reduced during bedtime UDCA administration by comparison with mealtime UDCA in individual patients and that the best-buy regimen is 8.4 mg/kg/day UDCA given at bedtime for patients with gallstones as a group. With this dose, gallstone dissolution can be supported by unsaturated gallbladder bile at minimum risk of dose-rclated side effects and at minimum treatment costs.
Key words: Bile acid; gallstones; ursodeoxycholic acid Albert0 Lanrini, M . D . , Ph. D . , Clinica Medica, 1 Medicina, Spedali Ciuili, 25100 Brescia, Italy
Oral administration of the bile acids chenodeoxycholic (CDCA)( 1-3) and ursodeoxycholic (UDCA)(4-7) reduces the cholesterol saturation index (SI) of fasting gallbladder bile and dissolves cholesterol gallstones. UDCA is generally preferred to CDCA for gallstone dissolution because, in contrast to the latter bile acid (8, 9), it does not cause diarrhea and hypertransaminasemia (10). On the other hand, UDCA is more expensive than CDCA and causes acquired gallstone calcification (11-13) in about 10% of the patients, a dose-related side effect (13). Northfield and colleagues (14, 15) have proposed the bedtime regimen as a strategy for reducing the minimum effective dose of CDCA to desaturate gallbladder bile with cholesterol and for minimizing side effects and treatment costs.
The minimum effective dose for bedtime UDCA is still unknown, and it may be lower than the 10 mg/kg/day UCDA dose reported by Maton et al. (5) for the mealtime regimen. The main aim of our study was to identify the minimum effective dose of bedtime UDCA for desaturating gallbladder bile with cholesterol in a large group of patients with radiolucent gallstones ( n = 44) treated with a range of UDCA doses. We have also checked whether a reduced UDCA dose (7 mg/kg/day) given at bedtime is as potent as the conventional 10 mg/kg/day UDCA given at mealtime for reducing the SI of gallbladder bile in individual patients (n = 7). An additional aim of our study was to test the hypothesis that a repeated-release formulation of UDCA (RR-UDCA) may further enhance the
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
552
A. Lanzini et a\.
effect of the bedtime regimen on the cholesterol square design to receive placebo, 10 mg/kg/day SI of gallbladder bile by comparison with equi- U D C A at mealtime, and 7 mg/kg/day UDCA at molar U D C A in individual patients ( n = 15). bedtime. RR-UDCA versus UDCA. To check whether UDCA is released by this tablet formulation along bedtime RR-UDCA administration enhances the a p H gradient, and it is likely t o be absorbed in effect of bile acid treatment by comparison with the enterohepatic circulation (16) and secreted by bedtime U D C A , nine patients were randomized the liver more gradually than U D C A in gelatin in accordance with a double-blind Latin-square capsules. RR-UDCA may therefore prevent design to receive placebo, ‘low’ bedtime doses of more efficiently than bedtime U D C A the secreUDCA (7 mg/kg/day), and equimolar bedtime tion of supersaturated hepatic bile that occurs doses of RR-UDCA (Gipharmex). Six additional during nocturnal fasting (17, 18) at a low bile acid patients were studied in accordance with the same secretion rate. experimental design during administration of ‘high’ bedtime doses of U D C A and RR-UDCA (14 mg/kg/day) and during placebo treatment. PATIENTS A N D METHODS In all subjects gallbladder bile samples were We studied 44 patients (30 women and 14 men) collected by means of nasoduodenal intubation with radiolucent gallstones participating to sep before and during each regimen given for at least functioning gallbladder. Mean age was 44 ? 2 6 weeks. years (k SEM; range, 20-73 years), and mean body mass index was 23.5 & 0.6 kg/m2 (range, Clinical procedure The patients fasted in the morning; a double17.631.6 kg/m’). Pretreatment liver function test results were within the normal limits for our lumen nasoduodenal tube (Anpro AN 20, USA) laboratory in each individual patient and did not was then advanced under fluoroscopic control to change during the study. The study protocol was position the distal end in the second duodenal in accordance with the Helsinki Declaration, and portion. Gallbladder contraction was induced informed consent was obtained from each patient. with intravenous cerulein (Farmitalia, Italy) infusion (20 pg/IOO mI normal saIine/2O min). Gallbladder-bile-rich duodenal fluid was collected by siphonage, and the darkest fluid retained and Study design Minimum effective dose of bedtime UDCA . The stored at -20°C until analysis. cholesterol SI of fasting gallbladder bile was measured before and during U D C A adminis- Laboratory methods Bile acid, cholesterol, and phospholipid contration (Gipharmex, Milan, Italy) in 44 patients with radiolucent gallstones participating to sep- centration in duodenal aspirate was measured arate prospective studies involving comparison enzymatically as previously described (17). of different bile acid regimens. For the present report, results of cholesterol SI obtained during Calculation und expression of results Body mass index was calculated in accordance bedtime administration of U D C A were pooled and related to bile acid dose, to derive the mini- with the following formula: body weight (kg)/ mum effective dose (see Calculations and ex- high (m)2. The cholesterol SI of fasting gallbladder bile pression of results). When expressed on a body weight basis, U D C A dose ranged from 4.6 to was calculated in accordance with the equation of Thomas & Hofmann (19) based on the cholesterol 17.0 mg/kg/day in individual patients. Bedtime versus meultime UDCA. To check solubility lines of Hegardt & Dam (20). The minimum effective dose of bedtime U D C A whether the U D C A dose can be reduced by bedtime administration, seven patients were ran- was defined in accordance with the criteria of domized in accordance with a double-blind Latin- Maton et al. (5) as the mean bile acid dose giving
Best-Buy Regimen of UDCA
a cholesterol SI of 0.8 on the regression line relating bile acid dose to cholesterol SI of fasting gallbladder bile. Statistical methods Results were expressed as mean values standard error of the mean (SEM). Statistical significance was tested with the t test for paired observations, and p values < 0.05 were accepted to indicate significant differences. Regression analysis was carried out by the least-square method.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
*
RESULTS
Minimum effective dose of bedtime UDCA (Fig. 1)
The mean value for cholesterol SI of fasting gallbladder bile was 1.27 2 0.06 before treatment. During treatment there was an inverse relationship between bedtime UDCA dose and cholesterol SI of fasting gallbladder bile in the 44 patients studied. This relationship was statistically significant ( n = 44, y = 1.089 - O.O34x, r = -0.384, p < 0.05) (Fig. l), and the average minimum effective dose for bedtime UDCA to reduce cholesterol SI to a value of 0.8 was 8.4mg/kg/ day. 2.57 Cholesterol
SI
Mealtime versus bedtime UDCA (Fig. 2 ) Fig. 2 shows the effect on cholesterol SI of gallbladder bile of a reduced dose of UDCA (7.2 0.4 mg/kg/day) given at bedtime compared with that of the conventional dose of UDCA (10.4 ? 0.3 mg/kg/day) given at mealtime in individual patients. The cholesterol SI was 1.25 k 0.08 during placebo treatment and decreased to 0.81 0.07 (p < 0.001) and to 0.73 0.06 0, < 0.001) with mealtime and bedtime UDCA, respectively. The cholesterol SI was >1 during mealtime UDCA treatment in one patient, and was
G . MUIESAN Dept. of Clinical Medicine, University of Brescia, Spedali Civili, Brescia, Italy
Lanzini A, Facchinetti D, Pigozzi MG, Bettini L, Muiesan G. Best-buy regimen of ursodeoxycholic acid for patients with gallstones. Scand J Gastroenterol 1991, 26, Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
55 1-556
Bedtime administration has been advocated as a strategy for reducing minimum effective dose, side effects, and costs of chenodeoxycholic acid treatment of cholesterol gallstones, but little information is available for ursodcoxycholic acid (UDCA). We prospectively determined the minimum effective dose of bedtime UDCA in 44 patients with radiolucent gallstones treated with a range of UDCA doses (4.617.0 mg/kg/day). The average minimum effective dose for reducing the cholesterol saturation index (SI) of gallbladder bile to a value of 0.8 was 8.4 mg/kg/ day for bedtime UDCA. The greater potency of the bedtime regimen was confirmed in seven individual patients by comparison with a mealtime regimen. Cholesterol SI was reduced from 1.25 during placebo to 0.73 during 7 mg/kg/day for bedtime UDCA and to 0.81 during lOmg/kg/day for mealtime UDCA. The effect of thc bedtime regimen was not enhanced by a repeated-release tablet formulation of UDCA by comparison with UDCA in 15 patients. We conclude that the bile acid dose is reduced during bedtime UDCA administration by comparison with mealtime UDCA in individual patients and that the best-buy regimen is 8.4 mg/kg/day UDCA given at bedtime for patients with gallstones as a group. With this dose, gallstone dissolution can be supported by unsaturated gallbladder bile at minimum risk of dose-rclated side effects and at minimum treatment costs.
Key words: Bile acid; gallstones; ursodeoxycholic acid Albert0 Lanrini, M . D . , Ph. D . , Clinica Medica, 1 Medicina, Spedali Ciuili, 25100 Brescia, Italy
Oral administration of the bile acids chenodeoxycholic (CDCA)( 1-3) and ursodeoxycholic (UDCA)(4-7) reduces the cholesterol saturation index (SI) of fasting gallbladder bile and dissolves cholesterol gallstones. UDCA is generally preferred to CDCA for gallstone dissolution because, in contrast to the latter bile acid (8, 9), it does not cause diarrhea and hypertransaminasemia (10). On the other hand, UDCA is more expensive than CDCA and causes acquired gallstone calcification (11-13) in about 10% of the patients, a dose-related side effect (13). Northfield and colleagues (14, 15) have proposed the bedtime regimen as a strategy for reducing the minimum effective dose of CDCA to desaturate gallbladder bile with cholesterol and for minimizing side effects and treatment costs.
The minimum effective dose for bedtime UDCA is still unknown, and it may be lower than the 10 mg/kg/day UCDA dose reported by Maton et al. (5) for the mealtime regimen. The main aim of our study was to identify the minimum effective dose of bedtime UDCA for desaturating gallbladder bile with cholesterol in a large group of patients with radiolucent gallstones ( n = 44) treated with a range of UDCA doses. We have also checked whether a reduced UDCA dose (7 mg/kg/day) given at bedtime is as potent as the conventional 10 mg/kg/day UDCA given at mealtime for reducing the SI of gallbladder bile in individual patients (n = 7). An additional aim of our study was to test the hypothesis that a repeated-release formulation of UDCA (RR-UDCA) may further enhance the
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
552
A. Lanzini et a\.
effect of the bedtime regimen on the cholesterol square design to receive placebo, 10 mg/kg/day SI of gallbladder bile by comparison with equi- U D C A at mealtime, and 7 mg/kg/day UDCA at molar U D C A in individual patients ( n = 15). bedtime. RR-UDCA versus UDCA. To check whether UDCA is released by this tablet formulation along bedtime RR-UDCA administration enhances the a p H gradient, and it is likely t o be absorbed in effect of bile acid treatment by comparison with the enterohepatic circulation (16) and secreted by bedtime U D C A , nine patients were randomized the liver more gradually than U D C A in gelatin in accordance with a double-blind Latin-square capsules. RR-UDCA may therefore prevent design to receive placebo, ‘low’ bedtime doses of more efficiently than bedtime U D C A the secreUDCA (7 mg/kg/day), and equimolar bedtime tion of supersaturated hepatic bile that occurs doses of RR-UDCA (Gipharmex). Six additional during nocturnal fasting (17, 18) at a low bile acid patients were studied in accordance with the same secretion rate. experimental design during administration of ‘high’ bedtime doses of U D C A and RR-UDCA (14 mg/kg/day) and during placebo treatment. PATIENTS A N D METHODS In all subjects gallbladder bile samples were We studied 44 patients (30 women and 14 men) collected by means of nasoduodenal intubation with radiolucent gallstones participating to sep before and during each regimen given for at least functioning gallbladder. Mean age was 44 ? 2 6 weeks. years (k SEM; range, 20-73 years), and mean body mass index was 23.5 & 0.6 kg/m2 (range, Clinical procedure The patients fasted in the morning; a double17.631.6 kg/m’). Pretreatment liver function test results were within the normal limits for our lumen nasoduodenal tube (Anpro AN 20, USA) laboratory in each individual patient and did not was then advanced under fluoroscopic control to change during the study. The study protocol was position the distal end in the second duodenal in accordance with the Helsinki Declaration, and portion. Gallbladder contraction was induced informed consent was obtained from each patient. with intravenous cerulein (Farmitalia, Italy) infusion (20 pg/IOO mI normal saIine/2O min). Gallbladder-bile-rich duodenal fluid was collected by siphonage, and the darkest fluid retained and Study design Minimum effective dose of bedtime UDCA . The stored at -20°C until analysis. cholesterol SI of fasting gallbladder bile was measured before and during U D C A adminis- Laboratory methods Bile acid, cholesterol, and phospholipid contration (Gipharmex, Milan, Italy) in 44 patients with radiolucent gallstones participating to sep- centration in duodenal aspirate was measured arate prospective studies involving comparison enzymatically as previously described (17). of different bile acid regimens. For the present report, results of cholesterol SI obtained during Calculation und expression of results Body mass index was calculated in accordance bedtime administration of U D C A were pooled and related to bile acid dose, to derive the mini- with the following formula: body weight (kg)/ mum effective dose (see Calculations and ex- high (m)2. The cholesterol SI of fasting gallbladder bile pression of results). When expressed on a body weight basis, U D C A dose ranged from 4.6 to was calculated in accordance with the equation of Thomas & Hofmann (19) based on the cholesterol 17.0 mg/kg/day in individual patients. Bedtime versus meultime UDCA. To check solubility lines of Hegardt & Dam (20). The minimum effective dose of bedtime U D C A whether the U D C A dose can be reduced by bedtime administration, seven patients were ran- was defined in accordance with the criteria of domized in accordance with a double-blind Latin- Maton et al. (5) as the mean bile acid dose giving
Best-Buy Regimen of UDCA
a cholesterol SI of 0.8 on the regression line relating bile acid dose to cholesterol SI of fasting gallbladder bile. Statistical methods Results were expressed as mean values standard error of the mean (SEM). Statistical significance was tested with the t test for paired observations, and p values < 0.05 were accepted to indicate significant differences. Regression analysis was carried out by the least-square method.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
*
RESULTS
Minimum effective dose of bedtime UDCA (Fig. 1)
The mean value for cholesterol SI of fasting gallbladder bile was 1.27 2 0.06 before treatment. During treatment there was an inverse relationship between bedtime UDCA dose and cholesterol SI of fasting gallbladder bile in the 44 patients studied. This relationship was statistically significant ( n = 44, y = 1.089 - O.O34x, r = -0.384, p < 0.05) (Fig. l), and the average minimum effective dose for bedtime UDCA to reduce cholesterol SI to a value of 0.8 was 8.4mg/kg/ day. 2.57 Cholesterol
SI
Mealtime versus bedtime UDCA (Fig. 2 ) Fig. 2 shows the effect on cholesterol SI of gallbladder bile of a reduced dose of UDCA (7.2 0.4 mg/kg/day) given at bedtime compared with that of the conventional dose of UDCA (10.4 ? 0.3 mg/kg/day) given at mealtime in individual patients. The cholesterol SI was 1.25 k 0.08 during placebo treatment and decreased to 0.81 0.07 (p < 0.001) and to 0.73 0.06 0, < 0.001) with mealtime and bedtime UDCA, respectively. The cholesterol SI was >1 during mealtime UDCA treatment in one patient, and was
