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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 217 records · Page 12Linked to original sources
PubMed1980

Monooctanoin, a dissolution agent for retained cholesterol bile duct stones: physical properties and clinical application.

A commercial emulsifying agent consisting largely of glyceryl-l-monooctanoate (monooctanoin) was found to be an excellent cholesterol solvent. In vitro, the agent dissolved mixed cholesterol gallstones more than twice as fast as sodium cholate solutions, which have been previously used for dissolution of retained cholesterol bile duct stones by T-tube infusion. To test clinical efficacy, the solvent was infused, via T-tube, into 12 patients with retained bile duct stones. Some or all of the stones disappeared in 10 patients during biliary tract infusion of monooctanoin for 4--21 days. Stones from the 2 patients whose stones did not disappear were removed surgically and in vitro were found to be insoluble in monooctanoin. Monooctanoin infusions were well tolerated. This digestible solvent appears to be a useful substance for direct physical dissolution of retained bile duct stones by T-tube infusion.

Adult↗
PubMed1979

Cholesterol solubility in organic solvents.

The 37 degree cholesterol solubilities in over 50 solvents, including the homologous n-alkanols through dodecanol and homologous ethyl carboxylates through the undecanoate, and the 37 degree beta-sitosterol solubilities in the n-alkanols through decanol are reported. Additionally, solubility data for cholesterol at 7, 17, and 27 degrees in the alcohol series were obtained. These measurements allowed the calculation of heats of solution for cholesterol in the alkanols, which range from 7.5 kcal for methanol to 4.3 kcal for decanol and which tend to decrease, although irregularly, with increasing alkanol chain length. A solubility maximum in all of these series for both solutes was observed between a chain length of six and seven. A surprisingly irregular, odd-even alternating solubility pattern was noted for cholesterol in the alkanols at all four temperatures. Experimental evidence indicated that this pattern was due to solvent-induced crystalline changes, presumably solvate formation, in each alkanol solvent through C10. Overall, the solubility studies screened solvents for their utility in dissolving cholesterol and, thus, cholesterol gallstones. To these ends, some limited dissolution experiments were performed, which indicated that the solution rate is directly related to the measured solubility in organic solvents. The dissolution behavior is thus different from micellar bile salt solutions, in which a significant interfacial barrier controls kinetics.

Cholesterol↗
PubMed1979

Colonic absorption of unconjugated bile acids: perfusion studies in man.

Colonic absorption of three major unconjugated bile acids--cholate, chenodeoxycholate, and deoxycholate--was measured under steady-state conditions using a technique of colonic perfusion in healthy volunteers. Aqueous solutions at pH 8.0 and varying in concentration from 1 mM to 10 mM were used. The rate of chenodeoxycholate absorption averaged nine times that of cholate absorption; deoxycholate absorption was somewhat less than that of chenodeoxycholate absorption, averaging six times that of cholate. At concentrations below 5 mM, the rate of absorption of bile acids was directly proportional to concentration, so that "clearance" could be calculated. Clearance values for a 1-mM solution (ml/min/colon, mean +/- SE) were: chenodeoxycholate, 9.84 +/- 1.0; deoxycholate, 7.0 +/- 1; and cholate, 0.82 +/- 0.10. Since absorption was proportional to concentration in the lumen, and was more rapid for the dihydroxy acids, the major mechanism of absorption was thought to be passive nonionic diffusion. Maximal rates of bile acid absorption were calculated from a 1-mM solution and found to be as high as 4.2 g/day for chenodeoxycholate, 3.2 g/day for deoxycholate, and 0.5 g/day for cholate, and the rate would be still greater for more concentrated solutions. Colonic absorption may contribute significantly to conservation of the dihydroxy bile acid pool, especially in conditions of bile acid malabsorption.

Bile Acids and Salts↗
PubMed1979

Biliary lipid secretion in hypercholesterolemia.

A report on the effects of primary bile acid ingestion alone or in combination with plant sterols on serum cholesterol levels, biliary lipid secretion, and bile acid metabolism. Biliary bile acid and cholesterol secretion were measured in four patients with type IIa hypercholesterolemia before and after randomized treatment periods. During these periods either a bile acid mixture (cholic-chenodeoxycholic 2:1, a proportion similar to that endogenously synthesized in health), at a level of 20 mg/kg, or the same mixture plus sitosterols, 200 mg/kg, was fed. Serum cholesterol and the cholesterol saturation of fasting-state bile was also measured. Pretreatment biliary lipid secretion was within normal limits. Bile acid kinetic measurements were also recorded before treatment and showed that cholic acid synthesis was disproportionately decreased relative to that of chenodeoxycholic acid, a finding previously reported by others. Administration of the bile acid mixture increased biliary bile acid secretion in 3 of 4 patients, but did not influence biliary cholesterol secretion. The combination of sitosterol-bile acid, however, caused a relative decrease in cholesterol secretion in bile, and fasting-state bile became unsaturated in all patients. No change in fecal neutral sterol excretion occurred during the beta-sitosterol-bile acid regimen, suggesting that simultaneous bile acid feeding blocks the compensatory increase in cholesterol synthesis known to be induced by beta-sitosterol feeding in hypercholesterolemic patients. Serum cholesterol levels also fell modestly during the sitosterol-bile acid regimen, the decrease averaging 15%. We conclude that the abnormally low rate of bile acid synthesis in patients with type IIa hyperlipoproteinemia does not influence biliary lipid secretion; that increasing the input of the two primary bile acids into the enterohepatic circulation does not increase biliary cholesterol secretion or lower serum cholesterol levels in such patients; and that the usual increase in cholesterol synthesis induced by beta-sitosterol feeding does not occur if bile acids are administered simultaneously.

Adult↗
PubMed1979

Separation of individual sulfated bile acid conjugates as calcium complexes using reversed-phase partition thin-layer chromatography.

A method for separating individual monosulfated primary bile acid conjugates by reversed-phase partition thin-layer chromatography on octadecyl-bonded silica gel is described. The solvent system is acetonitrile containing calcium, probably as calcium carbamate. Excellent resolution of the 3- and 7-monosulfated glycine conjugates, as well as 3- and 7-monosulfated taurine conjugates of cholic and chenodeoxycholic acids is reported. A convenient class separation of sulfated from nonsulfated primary bile acid conjugates by adsorption thin-layer chromatography on low-polarity silica gel is also described.

Bile Acids and Salts↗
PubMed1979

Effect of molecular structure on bile acid-induced alterations in absorptive function, permeability, and morphology in the perfused rabbit colon.

An in vivo intestinal perfusion system was used to study the effects of different bile acids on fluid secretion, mucosal permeability, and mucosal morphology in the rabbit colon. To define the structure-activity relationships of the bile acids, nine unconjugated bile acids were used, varying only in the number (two or three) or position (3, 7, or 12 or various combinations) of hydroxy or keto nuclear substituents. Results showed that bile acids with two hydroxy groups in the alpha configuration at the 3,7 position, 3,12 position, or 7,12 position induced fluid secretion, increased mucosal permeability, and produced mucosal damage as assessed by light and scanning electron microscopy and quantitated by DNA loss during perfusion. Replacement of hydroxy groups by keto groups or a change from alpha to beta configuration for the hydroxylic substituent in the 7 position abolished all three activities. Trisubstituted derivatives, whether hydroxy or keto, did not affect fluid secretion permeability or cause mucosal damage. These studies indicate that of the major primary and secondary bile acids in man, only deoxycholic and chenodeoxycholic acids alter colonic structure and function in the rabbit. They show further that the cathartic effects of bile acids have specific structural requirements; and they show that bile acid-induced secretion was invariably associated with increased mucosal permeability and epitheliolysis.

Animals↗
PubMed1979

Triolein breath test: a sensitive and specific test for fat malabsorption.

In order to develop a simple and accurate screening test for steatorrhea, the authors compared quantitative stool fat excretion with breath excretion of 14CO2 after the ingestion of 14C-labeled trioctanoin, tripalmitin, or triolein. The study group included 24 nonobese subjects without steatorrhea but with diarrhea secondary to irritable bowel syndrome and 40 subjects with steatorrhea. The triolein breath test provided the most reliable discrimination, with 100% sensitivity and 96% specificity. The trioctanoin and tripalmitin breath tests were sensitive, but lacked specificity (69% and 58% false-positive results, respectively). Three of the 12 obese patients with irritable bowel syndrome had false-positive triolein breath results. In detecting steatorrhea, the triolein breath test was moderately superior to the measurement of serum carotene and to qualitative stool fat. Thus, the triolein breath test appears to be a sensitive, specific, noninvasive, and relatively simple screening test for the detection of steatorrhea.

Adult↗
PubMed1978

Bile acid conjugation in the chimpanzee: effective sulfation of lithocholic acid.

To characterize the hepatic biotransformation in the chimpanzee of the primary bile acid chenodeoxycholic acid (chenic) and its major bacterial metabolite lithocholic acid (lithocholic) a mixture of trace amounts of 14C-lithocholic and 3H-chenic was injected intravenously into two animals with a bile fistula; the chemical form of radioactivity appearing in bile was inferred using thin layer chromatography. About 80% of chenic, and 70% of lithocholic was recovered in 90 min. Chenic was completely conjugated in bile, appearing predominantly as chenyltaurine (52%) and chenylglycine (37%). An unidentified conjugate (about 11%) was also found. Lithocholic was excreted completely as taurine and glycine conjugates, but the majority (63%) of conjugates was sulfated. Sulfation increased progressively with time, and lithocholylglycine was sulfated more than lithocholyltaurine. We conclude that the chimpanzee is similar to man in that the secondary bile acid lithocholic is efficiently sulfated. The chimpanzee thus differs from the baboon and rhesus monkey which sulfate lithocholic poorly. However, the chimpanzee differs from man and is similar to the baboon and rhesus monkey in showing preferential conjugation of bile acids with taurine. The results imply that hepatotoxicity caused by chenic, which is well documented in the rhesus monkey and baboon and has been related to defective lithocholic sulfation, should not occur in the chimpanzee.

Animals↗
PubMed1978

Chenotherapy for gallstone dissolution. II. Induced changes in bile composition and gallstone response.

Changes in bile saturation and biliary bile acid composition in patients with gallstones who received chenodeoxycholic ("chenic") acid, cholic acid, or placebo were measured. Chenodeoxycholic induced bile desaturation; this effect was attributable solely to a decrease in the proportion of cholesterol. By gas chromatography, chenodeoxycholic acid increased substantially in the biliary bile acids of patients receiving it, and by mass spectrometry, no unusual bile acids were detected in appreciable amounts. Changes in bile saturation and biliary bile acid composition were then related to chenodeoxycholic acid dosage, and all of these variables were, in turn, related to gallstone response. In general, patients whose gallstones dissolved ingested a higher dose of chenodeoxycholic acid or had bile that contained a higher proportion of this acid and it was more unsaturated, but there were many exceptions, casting doubt on the value of a single analysis of fasting-state bile for predicting gallstone dissolutions. The major factor influencing response, provided dosage is adequate, appears to be gallstone type. Nonetheless, the proportion of chenodeoxycholic acid in biliary bile acids can probably be used to infer patient compliance.

Bile↗
PubMed1978

Chenotherapy for gallstone dissolution. I. Efficacy and safety.

Clinical experience with chenodeoxycholic acid therapy for dissolving gallstones is reported, with particular attention to determinants of response. Of 12 patients receiving 15 mg/kg/day or more, ten responded (83%); only 15 of 40 patients (38%) receiving less than 15 mg/kg/day responded. Large solitary stones and stones in gallbladders that visualized poorly after oral cholecystography had a lower response rate. Radiopaque stones did not respond in 18 patients. Five of ten patients with stones in the common bile duct responded. Small, dose-related elevations in SGOT were the only biochemical abnormality observed. Liver biopsy specimens showed no notable abnormality. Diarrhea was an infrequent problem. Stones recurred in three of 15 patients during six to 48 months of observation without treatment. Chenodeoxycholic acid, when given in adequate dosage, continues to appear promising as medical therapy for asymptomatic radiolucent gallstones in radiologically visualizing gallbladders.

Chenodeoxycholic Acid↗
PubMed1978

Dissolution kinetics of cholesterol in simulated bile II: influence of simulated bile composition.

Normal human gallbladder bile and gallbladder bile of patients undergoing chenodeoxycholic acid therapy were simulated by using appropriate combinations of taurine and glycine conjugates of cholic, chenodeoxycholic, and deoxycholic acids. Also, the total bile acid concentration and the total bile acid to lecithin ratio were varied over physiological ranges. Dissolution rates of cholesterol monohydrate pellets (model gallstone) in these solutions were 90--99% interfacially controlled. Even under conditions favorable for dissolution, i.e., high bile acid concentration and high bile acid to lecithin ratio, the interfacial resistances were extremely large. These results are of the same order of magnitude as those found in the limited studies with actual gallbladder bile and suggest that the bile acids, lecithin, and the electrolytes are the primary determinants of the interfacial resistance for cholesterol dissolution. Furthermore, the kinetics of dissolution were always much faster with the chenodeoxycholic acid-rich compositions than with the corresponding normal compositions. This finding suggests, therefore, that in addition to desaturating bile with respect to cholesterol, the feeding of chenodeoxycholic acid further facilitates cholesterol gallstone dissolution by reducing the interfacial resistance of the process.

Bile↗
PubMed1978

Determinants of fasting and postprandial serum bile acid levels in healthy man.

The relationship between serum levels of conjugates of cholic acid measured by radioimmunoassay, bile acid absorption, and hepatic clearance was studied in order to define the determinants of fasting and postprandial serum bile acids in healthy man. Acute or chronic interruption of the enterohepatic circulation caused a significant decrease in basal serum levels of cholyl conjugates, while liquid or solid meals caused a marked and reproducible increase in serum cholyl conjugates. A temporal correlation was demonstrated postprandially or after intravenous cholecystokinin between intestinal transit of bile acids and simultaneous changes in levels of serum cholyl conjugates. Finally, the plasma disappearance of intravenously injected cholylglycine was shown to be unaffected by serum levels of endogenous cholyl conjugates. These data are consistent with the interpretation that, in the presence of normal hepatic function, the major determinant of serum bile acids is their rate of intestinal absorption.

Adult↗
PubMed1978

Diurnal serum levels of primary conjugated bile acids. Assessment by specific radioimmunoassays for conjugates of cholic and chenodeoxycholic acid.

The serum levels of conjugates of chenodeoxycholic acid (chenyl conjugates) and of cholic acid (cholyl conjugates) were determined by specific radioimmunoassays during a 24-hour period, which included three liquid meals and an overnight fast, in five healthy volunteers, five patients with previous cholecystectomy, five patients with documented bile acid malabsorption because of ileal resection, and four pregnant women. In healthy subjects, fasting-state levels of chenyl conjugates, when compared with those of cholyl conjugates, were higher; postprandially, levels of chenyl conjugates rose to a peak sooner (30 minutes vs 60 minutes) and to higher levels (5.2 +/- 1.3 muM vs 2.0 +/- 0.5 muM, M +/- SE). In cholecystectomised patients, the integrated areas under the curve for both bile acids were similar to those of the healthy controls, but postprandial peaks were less marked. In patients with bile acid malabsorption, postprandial rises of chenyl conjugates were lower but remained relatively constant throughout the day, whereas cholyl conjugate levels diminished progressively with each successive meal, consistant with depletion of the cholyl, but not the chenyl, pool. In three of four pregnant women, the postprandial rise of chenyl conjugates was disproportionately less compared with that of healthy controls. These results confirm the dynamic complexity of serum bile acid levels in man and indicate that the major circulating primary bile acids are chenyl conjugates. They support previous proposals that jejunal absorption of chenyl conjugates is important in the normal enterohepatic circulation of bile acids; and they suggest an abnormality in the enterohepatic circulation in pregnancy.

Chenodeoxycholic Acid↗
PubMed1978

Familial and nonfamilial benign recurrent cholestiasis distinguished by plasma disappearance of indocyanine green but not cholylglycine.

To determine whether a defect in uptake of organic anions is present in patients with benign recurrent cholestasis, the plasma disappearance of simultaneously injected indocyanine green and cholyglycine-1-14C was measured in eight patients with asymptomatic benign recurrent cholestasis, four with the familial type, as well as 22 healthy control subjects. Evans blue was also simultaneously injected to permit correction for variation in blood volume and speed of mixing. Uptake of indocyanine green was decreased in all three patients with nonfamilial benign recurrent cholestatsis, but normal or increased in the four patients uith the familial form of the disorder. By contrast, cholyglycine-1-14C uptake was abnormal in one patient with each type of the disorder. Thus, patients with nonfamilial benign recurrent cholestasis have a defect in indocyanine green uptake, and patients with benign recurrent cholestasis are heterogeneous with respect to organic anion uptake.

Cholestasis↗