Biomedical subjects
A Lanzini
Publications and source records attributed to A Lanzini.
Best-buy regimen of ursodeoxycholic acid for patients with gallstones.
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 ursodeoxycholic 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 (4.6-17.0 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 10 mg/kg/day for mealtime UDCA. The effect of the 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-related side effects and at minimum treatment costs.
Effect of ursodeoxycholic acid (UDCA) on pancreatic enzyme secretion and gallbladder emptying.
We have used a duodenal perfusion technique to study the effect of chronic administration of ursodeoxycholic acid (UDCA) on postprandial pancreatic enzyme secretion and gallbladder emptying. Duodenal output and hepatic secretion rate of bile acid were also measured. Six gallstone subjects were studied during an evening meal and an overnight fast before and during UDCA administration (675 mg/day for 6 weeks). During the first postprandial hour, the duodenal trypsin output was reduced from 253 to 164 IU/kg/h (p less than 0.05), and mean gallbladder ejection fraction from 38 to 20% (p less than 0.05). The peak response to the meal was delayed from 30 to 50 min for trypsin output (NS) and from 25 to 45 min for gallbladder ejection fraction (p less than 0.05). Area under the curve during the first postprandial hour was decreased for trypsin output from 225 to 119 IU/kg (p less than 0.025), and for gallbladder ejection fraction from 43 to 19% (NS); but areas for the second postprandial hour were increased, so that total values were unchanged. We conclude that the pattern of response for both end organs during chronic UDCA is better described as an attenuated response to food, rather than as a simple reduction in response; and that, since the effects were unaccompanied by any quantitative changes in hepatic bile acid secretion rate, they were probably mediated via the qualitative change in biliary bile acid composition known to accompany chronic UDCA administration.
Review article: bile acid therapy.
Over the past 3 years there has been a renewed interest in bile acid therapy not only because of the promising results obtained by combining this therapy with extracorporeal shock-wave lithotripsy for rapid gallstone dissolution, but also because of its novel use as a treatment for primary biliary cirrhosis. This article reviews the use of bile acids for both these indications.
Hepatic biliary lipid secretion and gall bladder biliary lipid mass in gall stone patients: effect of ursodeoxycholic acid.
We have carried out overnight measurements of hepatic secretion rate and duodenal output of biliary lipids using a duodenal perfusion technique. We correlated these measurements with the fasting state mass of biliary lipids within the gall bladder on the following morning using a combined nasoduodenal intubation and isotope scanning technique. We studied six gall stone subjects before and during treatment with ursodeoxycholic acid 675 mg/day. Lipid mass within the gall bladder correlated with the corresponding overnight hepatic secretion rate for all three biliary lipids. During ursodeoxycholic acid treatment, there was an increase in gall bladder bile acid mass without significant change in cholesterol or phospholipid mass. We conclude that the mass of individual biliary lipids within the fasting gall bladder is influenced by overnight hepatic biliary lipid secretion rate; and that the effect of ursodeoxycholic acid (675 mg/day) on cholesterol saturation index of fasting gall bladder bile is mediated via an increase in bile acid mass rather than through a decrease in cholesterol mass within the gall bladder.
Effect of chronic ursocholic acid administration on bile lipid composition and bile acid pool size in gallstone patients.
We assessed the effect of chronic (4-6 weeks) administration of ursocholic acid (UCA) (15 mg/kg/day), a natural bile acid with poor detergent capacity, on biliary lipid composition of gallbladder bile (n = 26) and bile acid pool size (n = 5) in gallstone patients. During treatment the biliary molar percentage UCA increased from trace values to 28% (p less than 0.001). This effect was accompanied by an increase in molar percentage deoxycholic acid from 16% to 33% (p less than 0.001). Total bile acid pool size remained unchanged during UCA administration; cholic acid and chenodeoxycholic acid pool sizes decreased from 1.0 to 0.6 mmol (p less than 0.05) and from 1.6 to 0.9 mmol (p less than 0.05), respectively. The molar percentage cholesterol of gallbladder bile decreased from 9.8% to 7.0% (p less than 0.001) during UCA, but bile remained supersaturated with cholesterol in 21 patients. The weak effect on biliary lipid composition and the increase of potentially toxic deoxycholic acid in bile suggest that UCA is unlikely to replace ursodeoxycholic and chenodeoxycholic acid for medical treatment of gallstones.
Assessment of the motor functions of the gallbladder.
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Quantitative measurement of biliary excretion and of gall bladder concentration of drugs under physiological conditions in man.
Gall bladder storage of hepatic bile prevents complete recovery of biliary excretion of drugs to be obtained under physiological conditions in man. The aim of this study was to develop and validate a method for simultaneous measurement of gall bladder storage of a cholephilic drug, and of its duodenal excretion and t1/2 in bile. Duodenal perfusion using polyethylene glycol as intestinal recovery marker for measurement of drug duodenal excretion, with an iv bolus of 99mTc HIDA for measurement of drug mass within the gall bladder was used. Gall bladder volume was measured by ultrasonography. T1/2 in bile was measured by relating drug duodenal excretion to that of bile acid used as an endogenous bile marker. The use of bile acid as biliary marker was validated in two subjects receiving simultaneous iv infusion of indocyanine green. Seven healthy subjects were studied using a beta-lattam antibiotic, Cefotetan 1 g iv, as test drug. Median values during the study period (seven hours) were 51.1 mg for Cefotetan duodenal excretion, 45.2 mg for gall bladder mass and 2.8 mg/ml for concentration within the gall bladder. T1/2 of the drug in bile was 100 minutes. This technique enables measurement of mass and concentration of drugs within the gall bladder to be carried out, in addition to measurements of t1/2 of drugs in bile. These measurements may have specific application for assessment of potential efficacy of antibiotics in biliary tract infections, as well as general application for assessment of biliary excretory kinetics of drugs.
Maintenance of hepatic bile acid secretion rate during overnight fasting by bedtime bile acid administration.
We have tested the hypothesis that the greater clinical efficacy of bedtime administration of bile acid in gallstone dissolution is due to prevention of the reduction in hepatic bile acid secretion that normally accompanies overnight interruption of the enterohepatic circulation, thus also reducing the secretion of supersaturated hepatic bile. We measured the hepatic bile acid secretion rate by combining duodenal perfusion of a nonabsorbable recovery marker (polyethylene glycol) with continuous intravenous infusion of a hepatic bile marker (indocyanine green). We studied 6 subjects with gallstones before and during administration of ursodeoxycholic acid (UDCA, 675 mg) at bedtime. Duplicate pretreatment studies revealed good reproducibility. Mean values for hepatic bile acid secretion rate were uninfluenced by chronic UDCA administration before the acute bedtime dose, but during the 4-h period after acute administration of UDCA the total bile acids secreted increased by a mean value of 2.2 mmol (p less than 0.01). Before treatment, nine of the 78 hourly samples were secreted at a hepatic bile acid secretion rate of less than 5 mumol/kg.h in the 6 patients studied, compared with only one hourly sample during UDCA administration. Super-saturated hepatic bile was secreted for a mean of 9.5 h before treatment, and for 1.2 h during UDCA treatment (p less than 0.005). We conclude that if UDCA is administered at bedtime, this maintains the hepatic bile acid secretion rate overnight, thus reducing secretion of supersaturated hepatic bile, in addition to the well-established effect of UDCA on cholesterol secretion.
Effect of ursodeoxycholic acid on biliary lipid coupling and on cholesterol absorption during fasting and eating in subjects with cholesterol gallstones.
The aim of this study was to determine the effect of chronic ursodeoxycholic acid administration on coupling of bile acids with cholesterol and phospholipid in hepatic bile, and on cholesterol absorption in the duodenum. A range of bile acid secretion rates was obtained during an evening meal and an overnight fast. Duodenal perfusion of polyethylene glycol as a nonabsorbable recovery marker and of [3H]cholesterol and [14C]lecithin as absorbable recovery markers was combined with continuous intravenous infusion of indocyanine green as a hepatic bile marker. Six subjects with gallstones were studied before and during chronic administration of ursodeoxycholic acid (675 mg/day). Duplicate pretreatment studies revealed good reproducibility for biliary lipid coupling and cholesterol absorption. During ursodeoxycholic acid administration there was a significant alteration not only in bile acid/cholesterol coupling (p less than 0.001), but also in bile acid/phospholipid coupling (p less than 0.001). Mean cholesterol absorption decreased from 25% to 15% (p less than 0.001) during ursodeoxycholic acid administration. These effects of chronic ursodeoxycholic acid administration on biliary lipid coupling are similar to those reported for acute administration, and are thus consistent with an effect caused by bile acid lipid-solubilizing capacity.
Simultaneous quantitative measurements of absolute gallbladder storage and emptying during fasting and eating in humans.
We have carried out simultaneous, quantitative measurements of absolute gallbladder (GB) storage and emptying in 6 subjects with gallstones, using a modified duodenal perfusion technique that incorporates technetium 99m-labeled diethyl phenylcarbamomethyl iminodiacetate (99mTc-HIDA) as a GB bile marker in addition to indocyanine green as a hepatic bile marker. The technique was validated by measuring duodenal recovery of 99mTc-HIDA (mean +/- SEM, 101% +/- 4%), and also by studying 2 subjects who had undergone cholecystectomy. During the first hour following an evening meal, cumulative GB ejection of 99mTc-HIDA in the 6 subjects with gallstones was 43% +/- 12%. This was accompanied by GB storage of most hepatic indocyanine green (70% +/- 5%) during each 10-min interval of that hour. During subsequent overnight fasting, storage of hepatic indocyanine green (89% +/- 2%) was accompanied by ejection of 99mTc-HIDA from the GB in 33 of the 66 hourly intervals. Since 'simultaneous' filling and emptying cannot occur through the cystic duct, the results suggest frequent alternations in absolute GB storage and emptying, a phenomenon more analogous to a bellows than to the conventional concept of a simple pump.
Bile acid binding to dietary casein: a study in vitro and in vivo.
1. Studies were carried out in vitro using an ultracentrifugation method to quantify bile acid binding to the different components of a Lundh test meal, and to determine what factors influence bile acid binding to one of the components (casein). We validated the ultracentrifugation method by showing good agreement with the equilibrium dialysis method. Studies were carried out in vivo on jejunal aspirate from 10 ileal resection patients in order to determine whether bile acid binding to casein could be demonstrated, and whether this influenced aqueous-phase bile acid and fatty acid concentrations. 2. In vitro, the Lundh test meal was found to adsorb bile acid. The protein content of the meal (casein) alone accounted for this binding, which was abolished by use of casein hydrolysate. The binding to casein was a saturable process. Both binding affinity and binding capacity were significantly greater for taurocholate at pH 4.5 than at pH 6.5, and for dihydroxylated than for trihydroxylated bile acid, suggesting that hydrophobic bonding was involved. 3. In vivo, jejunal samples aspirated at pH greater than 6 from 10 ileal resection patients showed 25% binding of bile acid to protein. On substitution of amino acids for casein, mean binding was reduced to 16% (P less than 0.05), residual binding being attributed to endogenous protein. This was associated with an increase in fatty acid solubilization from 28% to 60% (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)
Biliary excretory kinetics of cefotetan in healthy volunteers.
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Cefotetan in the treatment of internal medicine infections in diabetic patients.
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Gallstone recurrence after medical dissolution. An overestimated threat?
We assessed gallstone recurrence rate in 42 patients diagnosed as having complete gallstone dissolution on bile acid therapy. By contrast with most previous studies, this diagnosis was based on ultrasound as well as on radiology, and only patients having their first gallstone recurrence were included in the study. Patients were followed for periods varying from 6 months to 7 years (median 30 months). Eleven patients had recurrences, giving an overall recurrence rate of 26%. A life analysis table was constructed by an actuarial method to compensate for the different lengths of follow-up in individual patients. Corrected recurrence rates by life table analysis were 15%, 21%, 25%, 36%, 45%, 45% and 45% at 1, 2, 3, 4, 5, 6 and 7 years respectively; for the same time intervals, cumulative recurrence rate overestimated the risk of gallstone recurrence (14%, 22%, 31%, 50%, 61%, 79% and 92%). We conclude that previous figures for recurrence rate have been an overestimate; but recurrence rate remains substantial over the first 5 years, and then levels off.
Quantification of temocillin biliary excretion and gallbladder bile concentration in healthy subjects.
The techniques of duodenal perfusion with polyethylene glycol as a nonabsorbable marker, and cholescintiscan using 99Tc HIDA as a gallbladder bile marker, were used to measure the total duodenal output and gallbladder bile concentration of temocillin after administration of an intravenous bolus injection to each of 6 healthy subjects. We carried out 8 studies. 3 with 0.5g temocillin and 5 with 1g temocillin. The plasma half-life of temocillin was 177 (+/- 25) minutes [mean (+/- SD)] and 196 (+/- 29) minutes with the 0.5g and 1g doses, respectively. Urinary excretion accounted for 38% of the total dose given during the study period of 6 hours, and total biliary excretion was recorded as 2.2% of the given dose for both doses. The mean concentration of temocillin in gallbladder bile was 314.7 (+/- 273.2) mg/L after the 0.5g dose and 474.5 (+/- 307.3) mg/L after 1g dose. It was concluded that temocillin is highly concentrated in the normal gallbladder in man.