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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 235 records · Page 13Linked to original sources
PubMed1978

Tolerance to lactose among lactase-deficient American Indians.

To determine the amount of lactose that could be tolerated in a meal, 59 lactase-deficient American Indians, ranging in age from 5 to 62, were given graded doses of lactose. The diagnosis of lactase deficiency had beeen documented previously by showing increased breath hydrogen after an oral lactose load (2 g per kg, maximum 50 g). With this load, 88% of the subjects had symptoms. On 6 consecutive mornings, each subject was given a breakfast that contained graded doses of lactose ranging from 0 to 18 g. The order of the breakfasts was randomized and the contents were double-blinded. Symptoms, which were assessed by a "blinded" observer, were present after 9% of the breakfasts at all dosage levels, including the lactose-free breakfast. Thus, under the conditions of this study, a modest amount of lactose, equivalent to that present in 1 to 1 1/2 glasses of milk, when taken with a meal, is well tolerated by the lactase-deficient American Indian.

Adolescent↗
PubMed1978

Clinical value of the bile acid breath test. Evaluation of the Mayo Clinic experience.

The Mayo Clinic experience with more than 200 bile acid breath tests was analyzed retrospectively to assess its clinical value. In patients with suspected bacterial overgrowth, the result of the bile acid breath test was compared with that of culture of aspirates of small bowel, and the test was found to have a sensitivity of 0.70 and a specificity of 0.90 (1.0 highest possible value). Although in one-third of the patients with a positive small-bowel culture the bile acid breath test failed to demonstrate the presence of bacterial overgrowth, analysis of the data according to the Bayes theorem showed that, compared with a routine evaluation without a small-bowel culture, the availability of breath test results will double the probability with which the clinician can be certain about the presence or absence of bacterial overgrowth. The test result appeared to influence the diagnosis in 83% and the management in 74% of the 163 patients in whom it was performed because of suspected bacterial overgrowth. In patients with suspected malabsorption of bile acids, on the other hand, the test that was performed without determination of fecal bile acid excretion appeared to be rather insensitive, and only rarely was information gained that was not already known from a routine workup of the patient.

Bacterial Infections↗
PubMed1978

Nocturnal gallbladder storage and emptying in gallstone patients and healthy subjects.

Nocturnal hepatic bile is supersaturated with cholesterol, and increased storage of this "lithogenic" bile in gallstone patients might explain why they more frequently have supersaturated fasting state gallbladder bile than patients without gallstone disease. To test this possibility, we measured the fraction of nocturnal hepatic bile stored in the gallbladder in 5 patients whose gallstones had been previously dissolved by chenodeoxycholic acid, in 5 control subjects without gallstone disease matched for age, sex, and weight, and in 5 young healthy males. We developed a new method based on the use of indocyanine green as a bile marker. The hourly rate of input into the duodenum of indocyanine green was measured during its constant, prolonged intravenous infusion. When gallbladder storage occurred, indocyanine green input was less than the infusion rate; when gallbladder emptying occurred, input exceeded the infusion rate. The method was validated by showing that duodenal output of indocyanine green was identical to intravenous input of indocyanine green in 2 cholecystectomized patients. When the method was applied, emptying of the gallbladder with meals was documented, and calculations showed that more than half of the bile secreted at night bypassed the gallbladder in both gallstone patients and control subjects. No difference in "cholecystodynamics" was observed between gallstone patients, matched control subjects, and young healthy men. Our results validate a method for quantitating gallbladder storage and emptying in men, but fail to support the speculation that an important pathogenetic step in gallstone formation is increased storage of supersaturated nocturnal bile in the gallbladder.

Adult↗
PubMed1977

[Enterohepatic circulation of bile acids and biliary lipid secretion].

The enterohepatic circulation of bile acids in man is reviewed. The chemistry of biliary bile acids is summarized and related to the formation of primary bile acids in the liver and secondary bile acids in the intestinal lumen. New findings showing that lithocholic acid is absorbed in man are presented, and the recent experiments showing that lithocholic acid is extensively sulfated are reviewed. The consistent hepatotoxicity of chenodeoxycholic acid in the rhesus monkey, which contrasts with its non-toxicity in man, is explained by the inability of the rhesus monkey to sulfate abosrbed lithocholic acid; this accumulates in the enterohepatic circulation of the monkey causing liver damage. In man, absorbed lithocholic acid is rapidly sulfated, and the sulfated conjugates are excreted fecally without enterohepatic cycling. The physical chemistry of bile is highlighted, and it is shown that the saturation of bile with cholesterol depends on the amount of bile acids passing through the liver: at low bile acid flow rates, such as occurs during overnight fasting, bile is supersaturated in both gallstone and healthy persons. Chenodeoxycholic acid decreases cholesterol secretion into bile, renders bile unsaturated during most of the day and night, and thus induces gallstone dissolution.

Animals↗
PubMed1977

Dissolution kinetics of cholesterol in simulated bile I: Influence of bile acid type and concentration, bile acid-lecithin ration, and added electrolyte.

A physical model approach was utilized to investigate cholesterol monohydrate dissolution kinetics in simulated bile. The static pellet method and the Berthoud theory were employed to assess the contributions of the diffusion-convection mass transfer resistance and those of the interfacial resistance to the overall kinetics. For almost all situations studied, the interfacial resistance was the dominant rate-determining factor. The effects of four bile acids and their concentrations, the bile acid-lecithin ratio, and the added electrolytes and their concentrations on the interfacial resistance were examined. The results were correlated with those obtained with human bile samples, and the indications were that the kinetics of cholesterol dissolution in bile may be explainable on the basis of the principal bile acids, lecithin, and the electrolytes in the bile.

Bile↗
PubMed1977

Dissolution rates of model gallstones in human and animal biles and importance of interfacial resistance.

Cholesterol monohydrate dissolution kinetics in human gallbladder bile were studied to determine the magnitudes of the in vitro dissolution rates, the rate resistances in human gallbladder bile, and the extent that the interfacial resistance is the rate-determining factor. Dissolution rate studies also were conducted using human duodenal bile and animal bile for comparison. The dissolution rate resistance, R, ranged from 10(4) sec/cm for chicken bile to 10(4)-10(6) sec/cm for human bile. Interfacial resistance was the rate-determining factor for essentially all results. Where chemical composition data were obtained, the R values for the human bile samples were consistent with predictions made from the simulated bile studies. In two human gallbladder specimens having low bile acid-lecithin molar ratios (i.e., 2.9 and 2.3), very high R values of 1.9 X 10(5) and 4.1 X 10(5) sec/cm were found. These values were in good agreement with the findings in the simulated bile studies and suggest that stone dissolution in patients with low bile acid-lecithin ratios may proceed very slowly, even when the bile is highly undersaturated with respect to cholesterol.

Animals↗
PubMed1977

Cholesterol gallstone dissolution rate accelerators I: Exploratory investigations.

Various compounds that might function as cholesterol gallstone dissolution accelerators were studied. The dissolution rates of cholesterol monohydrate pellets in synthetic bile (116 mM sodium cholate-32 mM lecithin) containing the agent at various concentration levels were determined. In the absence of any dissolution rate accelerator, the dissolution kinetics for cholesterol previously were found to be interfacial resistance controlled, and the rates were around 20 times less than the diffusion-controlled rates in the present experiments. Primary, secondary, and tertiary amines and quaternary ammonium compounds were effective accelerators. When the alkyl chain lengths were long enough and/or when the agent concentrations were high enough, the dissolution rates generally approached diffusion-controlled rates. Steroidal amines generally had good activity. Anionic and nonionic surfactants had little or negative activity.

Amines↗
PubMed1977

Effect of varying doses of chenodeoxycholic acid on bile lipid and biliary bile acid composition in gallstone patients: a dose-response study.

In a dose-response study, a formulation of chenodeoxycholic acid (chenic acid) with complete bioavailability was fed at doses of 0, 250, 500, 750 mg for randomized 6-week periods to 13 patients with radiolucent gallstones. The proportion of chenic acid in biliary bile acids increased in direct relation to dose. Lithocholic acid also increased, but ursodeoxycholic acid showed no significant change. Bile saturation decreased with increasing dose, but response was variable and achieved significance only at 750 mg/day. Cholesterol saturation was negatively correlated with the proportion of chenic acid in biliary bile acids: When biliary bile acids contained greater than 70% chenic acid (and ursodeoxycholic acid), bile became unsaturated, on the average. The data suggest that a dose of at least 10-15 mg/kg may be necessary to obtain desaturation in many gallstone patients.

Adult↗
PubMed1977

24-Nor-5beta-chol-22-enes derived from the major bile acids by oxidative decarboxylation.

The preparation of 24-nor-5beta-chol-22-enes from formyloxy-5beta-cholanic acids by oxidative decarboxylation with lead tetraacetate is described. NMR data is presented with other physical constants for the norcholenes derived from cholic, chenodeoxycholic, ursodeoxycholic, hyodeoxycholic, and deoxycholic acids. The facile synthesis of these norcholenes demonstrates the applicability of the formyloxy protecting group to oxidative decarboxylations in the bile acid series.

Bile Acids and Salts↗
PubMed1977

Desaturation of bile and cholesterol gallstone dissolution with chenodeoxycholic acid.

The feeding of one of the major biliary bile acids, chenodeoxycholic acid, at a dose of 10 to 15 mg/kg per day causes the circulating bile acid pool to become greatly enriched in this bile acid. When chenodeoxycholic acid composes more than 70% of the biliary bile acids, the amount of cholesterol secreted in bile falls, and bile becomes unsaturated in cholesterol. If cholesterol gallstones are present and are exposed to this unsaturated bile, they will dissolve in 4 to 24 months in the majority of patients. Extensive clinical experience indicates that such medical therapy is safe, despite unequivocal toxicity of chenodeoxycholic acid in several nonhuman primates. When therapy is stopped, bile resaturates, and stones may recur. Since cholecystecomy is a rapid, safe, effective, and usually permanent treatment for all gallstones, the value of medical therapy remains uncertain at present, except for patients in whom surgery is inadvisable. Nonetheless, the demonstration that chenodeoxycholic acid ingestion will desaturate bile and induce gallstone dissolution would appear to be an important pharmacological advance.

Adult↗
PubMed1977

Bile acids, diarrhea, and antibiotics: data, speculation, and a unifying hypothesis.

The primary bile acid, chenodeoxycholic acid, and the secondary bile acid, deoxycholic acid, when present at a concentration of greater than 3 mM, induce salt and water secretion from the human colon and cause a marked increase in the permeability of the human colon to molecules of a molecular weight of 200-500 daltons. Scanning electron microscopy indicates that this action may be associated with tissue damage in some species. In the healthy individual, the primary bile acids, cholic and chenodeoxycholic acid, are dehydroxylated in the colon and are simultaneously precipitated from solution; at pH less than 7, deoxycholic and lithocholic acid are insoluble. In patients with bile acid diarrhea resulting from bile acid malabsorption, dehydroxylation is decreased, and the concentration of bile acids in the colon is markedly elevated. The major secretory bile acid in solution is chenodeoxycholic acid. Administration of cholestyramine, a resin that binds bile acid, reduces the elevated concentration of chenodeoxycholic acid and abolishes the diarrhea. These facts can be used to develop a unifying hypothesis which proposes that elevated concentrations of primary bile acids in the colon play a role in diarrhea and pseudomembranous colitis induced by clindamycin.

Anti-Bacterial Agents↗
PubMed1977

Binding properties in vitro of antacids for conjugated bile acids.

The binding properties of various commercial antacids for pure conjugated bile acids in an aqueous solution or the bile acids present in human gallbladder bile were characterized. Aluminum hydroxide was a potent binding agent, similar in affinity and capacity to cholestyramine. With aluminum hydroxide, dihydroxy bile acid conjugates were bound more strongly than trihydroxy bile acid conjugates, and glycine conjugates were bound more strongly than taurine conjugates; pH had no effect per se on binding. Magnesium hydroxide and aluminum phosphate bound bile acids much more weakly. Aluminum hydroxide warrants exploration in therapeutic situations in which bile acid binding is sought.

Aluminum↗