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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 127 records · Page 7Linked to original sources
PubMed1990

Microprocessor-assisted solvent transfer system for effective contact dissolution of gallbladder stones.

Dissolution of cholesterol gallbladder stones by manual lavage with methyl tert-butyl ether (MTBE) via a percutaneous indwelling gallbladder catheter is reviewed. The procedure is labor intensive and requires several hours, is associated with escape of solvent into the biliary tract, and is incomplete since residue remains. To solve these problems, a microprocessor-assisted solvent transfer (MST) system was developed. The system consists of a three-lumen catheter, dual peristaltic pumps, a pressure transducer, and a microprocessor controller which regulates pump rate according to the measured intraluminal gallbladder pressure. The two pumps simultaneously infuse and aspirate from the gallbladder via two of the catheter lumens; intraluminal pressure is monitored using the third lumen. An increase in intraluminal pressure above a set limit causes infusion to cease while aspiration continues, thus lowering the pressure and preventing overflow of gallbladder contents into the biliary tract. In vitro evaluation showed that the system's response was 156 fold faster than the natural rate of gallbladder emptying. The time required for gallstone dissolution by MTBE was measured in vitro using the MST system and found to be 48 +/- 23 (M +/- SE) min at 100 mL/min flow, 15 +/- 5 min at 150 mL/min flow, 12 +/- 4 min at 200 mL/min flow, and 6 +/- 1.4 min at 250 mL/min flow. No residual debris remained with flow rates greater than 150 mL/minute. These in vitro studies suggest that the MST system is capable of rapid, complete, and fully automatic contact dissolution of cholesterol gallbladder stones using MTBE or similar lipid solvents.

Cholelithiasis↗
PubMed1990

The effect of colestipol dose on postprandial serum bile acid concentration: assessment by an enzymic bioluminescence procedure.

A dose-response study was performed with three doses of colestipol, using postprandial serum bile acid levels to assess bile acid sequestering activity in 40 volunteers with asymptomatic hyperlipidaemia. Subjects who entered the study had total serum cholesterol concentrations greater than 220 mg/dl and triglyceride concentrations less than 200 mg/dl. They were randomly assigned to one of four parallel treatment groups: (a) placebo b.d., (b) colestipol (as Colestid hydrochloride granules) 2.5 g b.d., (c) colestipol 5 g b.d., and (d) colestipol 7.5 g b.d. Subjects were maintained on a constant repeating solid diet throughout the 6-day study period, and colestipol was ingested 30 min before breakfast and dinner. No drug was administered on Days 1-3; baseline (pre-treatment) serum bile acid concentration profiles were determined on Day 3. The above treatments were given on Days 4-6, and total serum bile acid concentrations were determined at 30- or 60-min intervals for 10 h on Days 4 and 6. Serum bile acids were measured using a bioluminescence procedure which enzymically measures total 3 alpha hydroxy bile acids. Serum bile acid concentrations were significantly decreased from the pretreatment period by 5.0 and 7.5 g/day as compared to 2.5 g/day or placebo. Differences from the pre-treatment period in the area under the serum bile acid time curve revealed the same trends in the data as analysis of percentage difference (Day 6 vs pre-treatment period) in serum bile acid concentrations. These results indicate that postprandial serum bile acid concentrations are influenced by colestipol in a dose-related manner, with doses of 5 and 7.5 g b.d. having a significantly greater effect than 2.5 g b.d. The dose of 7.5 g b.d. had an identical effect on serum bile acid patterns as a dose of 5.0 g t.d.s., which was previously reported. Our findings also show that changes in serum bile acid concentrations may be used to follow the immediate effects of bile acid sequestration in hypercholes terolaemic subjects, and that the bioluminescence enzyme technique is sufficiently sensitive to detect such changes.

Bile Acids and Salts↗
PubMed1990

Nonsurgical treatment of gallstone disease.

Gallstones can now be treated nonsurgically as well as surgically. The current view is that only symptomatic gallstones should be treated; of these, only cholesterol gallstones can be treated nonsurgically. Cholesterol gallstones in a functioning gallbladder will dissolve slowly when the secretion of unsaturated bile is induced by the ingestion of ursodiol or chenodiol, which are naturally occurring bile acids. Stone dissolution can be accelerated by increasing the surface area via extracorporeal shock wave lithotripsy, which fragments stones rapidly and safely, enhancing their dissolution rate. A technique is being developed in which a catheter is inserted into the gallbladder via either a percutaneous transhepatic or endoscopic route and an organic solvent such as methyl tert-butyl ether is instilled, dissolving the stones rapidly without major side effects. Gallstones will eventually recur in about half of the patients treated by these nonsurgical approaches, because the gallbladder is left in place and the fundamental pathogenic abnormalities associated with this common disease are not corrected. However, the rate of recurrence of symptomatic gallstone disease is lower.

Bile Acids and Salts↗
PubMed1990

Bile acid secretion, bile flow and biliary lipid secretion in humans.

The transport of bile acids through the hepatocyte and the effect of this flux of molecules on bile flow, biliary lipid secretion and bile acid biosynthesis are reviewed. Efficient hepatic clearance of bile acids involves several active systems and passive uptake. Formation of coenzyme A derivatives prevents reflux of lipophilic dihydroxy bile acids. Biotransformation of bile acids during hepatocyte transport involves both type I and type II biotransformations. The major type II biotransformation is reamidation of unconjugated bile acids, but sulfation and glucuronidation also occur. The only major type I biotransformation is oxidoreduction, which converts iso- or 3 oxo bile acids to the preferred 3 alpha-hydroxy form and 7 oxo bile acids to their corresponding 7 alpha-hydroxy derivatives. Secretion of bile acids into the canaliculus is concentrative and induces osmotic flow of plasma water and solutes across the paracellular junctions between the space of Disse and the canaliculus. Bile flow in man is characterized by its low volume and by a paucity of bile acid-independent flow when compared with that of other mammals. Bile acid secretion also induces biliary lipid secretion, but some lipid secretion appears to be bile acid independent. The lipid vesicles secreted in human bile have a much higher cholesterol/phospholipid ratio than those of other mammals. During flow down the biliary tree, vesicles are solubilized by bile acid micelles, and Ca++ ions are complexed by bile acid monomers and micelles. However, the biochemical mechanisms and factors regulating biliary lipid secretion in man are poorly understood.

Bile↗
PubMed1990

Bile sampling, processing and analysis in clinical studies.

Obtaining a proper bile sample for investigative purposes is of utmost importance to obtain valid results. Bile can be collected by direct aspiration of the gallbladder, by duodenal intubation or by T-tube drainage. The optimal method of collection depends on the investigative question, as well as on the resources available to the investigator. The procedures for obtaining, processing and analyzing human bile (gallbladder and hepatic) are summarized, pointing out the disadvantages and pitfalls that may occur.

Bile↗
PubMed1989

Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect.

Canalicular transport of bilirubin diglucuronide, dibromosulfophthalein and several glutathione conjugates is deficient in mutant TR- rats. In contrast, transport of cholyltaurine (taurocholate), a conjugated bile acid, is normal. Previous studies using normal rats have shown that C23 nor-dihydroxy bile acids are conjugated with sulfate or glucuronide during hepatic transport in contrast to the natural C24 bile acids, which are amidated with glycine or taurine. Studies were performed to test the hypothesis that (a) in the TR- rat, nordeoxycholate would be conjugated with glucuronate or sulfate just as in the normal rat, and (b) that such conjugates would have defective biliary secretion. [C23-14C]Nordeoxycholate was administered intravenously to bile fistula rats (TR- and normal), and the biliary recovery of metabolites was assessed by chromatography and mass spectrometry. In both groups of rats, the major biotransformation product of nordeoxycholate was the side chain (23-ester) glucuronide. Conjugation on the nucleus with sulfate and glucuronide at the 3-position (ethereal linkage) also occurred, as well as amidation at the C23 carboxylic acid group. In the mutant rats, biliary secretion of the 3-sulfate and 3-glucuronide conjugates was less than 10% and 1%, respectively, of that of normal rats, whereas biliary secretion of the 23-ester glucuronide and the 23-taurine amidate, as well as unchanged nordeoxycholate, was not decreased. Canalicular secretion of nor-bile acid 3-ether glucuronides and 3-sulfates appears to involve the "bilirubin transport system," which is deficient in mutant rats. Canalicular secretion of unconjugated, amidated or esterified nordeoxycholate is mediated via another pathway, probably the "bile acid transport system."(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Current concepts of biliary secretion.

Biliary secretion is reviewed. Bile acids pass along the biliary tract and small intestine without undergoing passive absorption because of their hydrophilicity and size. Active ileal absorption leads to the development of a large circulating pool of molecules and thus dissociates biliary secretion from bile acid biosynthesis (which is synonymous with cholesterol degradation). Man differs from most vertebrates in having little bile acid-independent flow; bile acid-dependent flow is also less in man than many other vertebrates. The hypercholeretic effects of certain bile acids are reviewed; the most likely explanation is cholehepatic shunting of the unconjugated, lipophilic species. Biliary lipid secretion involves bile acid-stimulated microtubule-dependent movement of phospholipid-cholesterol-rich vesicles from the Golgi to the canaliculus. Bile acid biotransformation during hepatic transport involves reconjugation (with glycine or taurine) of C24 bile acids (deconjugated during enterohepatic cycling), conjugation with glucuronate of lipophilic C23-nor bile acids, reduction of oxo groups, and epimerization of iso-(3 beta-hydroxy) bile acids. Glucose and amino acids enter bile from plasma as secondary solutes and are absorbed efficiently in the biliary ductular system. The biliary system is almost freely permeable to plasma Ca2+; in bile, Ca2+ is bound to bile acid monomers and micelles. Alteration of biliary lipid secretion by orally administered bile acids is a major first step in the medical treatment of calculous biliary disease.

Animals↗
PubMed1989

Medical dissolution of gallstones by oral bile acid therapy.

The rationale, safety, and efficacy of cholesterol gallstone dissolution by orally administered ursodiol, chenodiol, or a combination of the two agents are summarized herein. Bile must be supersaturated in cholesterol for gallstones to form, and desaturation of bile by orally administered bile acids induces gradual stone dissolution. The mechanism of action of the two agents differs, but both cause a decreased input of cholesterol into the metabolic pool. Ursodiol is free of side effects, and the combination with chenodiol is equally efficacious and also has few side effects. Chenodiol, although an effective desaturation agent, causes diarrhea, mild reversible hepatic injury, and a small increase in the plasma cholesterol level. Extracorporeal shock-wave lithotripsy decreases gallstone size markedly and thereby increases the speed of dissolution by orally administered bile acids. Medical therapy with oral bile acids is appropriate for patients who present with small cholesterol stones and for patients with larger cholesterol gallstones who cannot or will not have surgery. Oral bile acids may also be valuable in the treatment of gallstone recurrence before it has become symptomatic or to prevent recurrence after prior successful dissolution of recurrent stones.

Administration, Oral↗
PubMed1989

Effect of the bile-acid sequestrant colestipol on postprandial serum bile-acid concentration: evaluation by bioluminescent enzymic analysis.

Chronic ingestion of bile-acid sequestrants has been shown to decrease the serum cholesterol concentration and coronary events in hypercholesterolaemic patients. To develop improved sequestrants, a rapid, convenient method for testing the bile-acid binding efficacy of sequestrants is needed. Serum bile-acid concentrations could be used to detect bile-acid binding by an administered sequestrant, since the serum bile-acid concentration is determined largely by the rate of intestinal absorption in healthy individuals. To test this, serum bile-acid concentrations were measured at frequent intervals over 24 h in five otherwise healthy hypercholesterolaemic subjects during the ingestion of three standard meals, with or without the addition of 5 g colestipol granules administered 30 min before each meal. Total serum bile-acid concentration was measured with a previously reported bioluminescent enzymic assay, that uses a 3 alpha-hydroxysteroid dehydrogenase, an oxido-reductase, and a bacterial luciferase co-immobilized on to Sepharose beads. Bile acids in 1 ml of serum were isolated by solid-phase extraction chromatography with reversed-phase C18 cartridges. Colestipol lowered the postprandial elevation of serum bile acids by one half, with a subsequent decrease in the cumulative area under the curve. The data suggest that measurement of serum bile-acid concentrations by bioluminescence is a rapid, simple way to document the efficacy of bile-acid sequestrants.

Adolescent↗
PubMed1989

Interventional radiology in the gallbladder.

This article is a pictorial review of the current status of interventional radiology of the gallbladder. The indications and technical aspects of various procedures are presented. Specifically discussed are: (1) needle puncture for percutaneous biopsy, withdrawal of bile for culture, or imaging of the biliary tract; (2) catheter insertion for decompression or abscess drainage; and (3) gallstone management via contact dissolution, fragmentation and basketing, or contact lithotripsy. The management of vagal hypotension and bile leak, the major complication of these procedures is also discussed.

Catheterization↗
PubMed1989

Role of bile acid conjugation in hepatic transport of dihydroxy bile acids.

The effect of conjugation and side chain length on dihydroxy bile acid unidirectional hepatic uptake and efflux was studied using the isolated perfused rat liver which was perfused prograde or retrograde in single pass fashion. Deoxycholic acid (DC) and its C23 (nor) derivative nor-DC, as well as the synthetically prepared taurine conjugate of DC, were administered at a constant dose of 1 mumol/min/kg (body weight), upon which a bolus tracer dose of labeled bile acid was superimposed. Analysis of radioactivity recovery in perfusate indicated that unidirectional uptake of all three bile acids was equally rapid, but that only nor-DC showed considerable and continuing efflux into the perfusate; this involved mostly the unchanged acid. Nor-DC was not amidated but was metabolized to mostly ester glucuronides and hydroxylated derivatives; the biotransformation products did not reflux and were secreted into bile; similarly, DC was amidated with taurine; its taurine conjugate did not efflux and was secreted into bile. When nor-DC-taurine was infused, it did not efflux and was secreted rapidly into bile. When the liver was perfused retrograde fashion to increase concentrations of bile acids pericentral cells, only nor-DC showed efflux, which again involved only the unchanged acid. All bile acids were partly 7 alpha-hydroxylated, the magnitude being greater during retrograde perfusion presumably because slower cellular transport exposed bile acid to hydroxylation enzymes for a longer period. It is concluded that bile acid conjugation, whether by esterification with CoA formation adn subsequent amidation or by esterification with glucuronate, restricts the movement of lipophilic dihydroxy bile acids to the hepatocyte and canalicular lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Basal and bile salt-stimulated bile flow and biliary lipid excretion in ponies.

The role of bile salt in biliary lipid excretion was studied in 3 healthy ponies with chronic external biliary fistulas. After endogenous bile salt pool depletion, micelle-forming taurocholate or taurochenodeoxycholate was infused to replace excreted bile salt. Enterohepatic circulations were held open (total biliary diversion) throughout each study. Results indicated that biliary lipid excretion in ponies (113 +/- 21 nmol/min/kg of body weight) is approximately 10 times less than that reported in rodents. Although the lipid composition (4.4% cholesterol, 5.6% phospholipid, and 90% bile salt) was within the predicted range for a single phase of micellar (or vesicular) liquid in solution, it was supersaturated with cholesterol because of low absolute concentrations of bile salt and phospholipid. Ponies, like guinea pigs, were determined to have a high bile salt-independent secretion of biliary lipid with little (or no) coupling to endogenous bile salt output. However, bile salt excretion induced by higher taurocholate infusion rates (ie, those greater than the physiologic range of 61 to 125 nmol/min/kg) was positively correlated with an increase in biliary phospholipid excretion, but not cholesterol excretion, thus indicating that a threshold intracellular bile salt concentration may be associated with enhanced biliary phospholipid excretion in ponies. The apparent cholerectic effects of endogenous bile salts, taurocholate, and taurochenodeoxycholate (that is, the increment in bile flow per increment in bile salt recovered) were greater in ponies than reported for any other mammal.

Animals↗
PubMed1988

Defective bile acid amidation: predicted features of a new inborn error of metabolism.

Biochemical and clinical features are predicted for an as yet unreported inborn error of metabolism, in which bile acids cannot be conjugated with glycine or taurine. Unconjugated cholic acid will be secreted into bile, be absorbed from the intestine, and become the predominant bile acid in bile and plasma. Other bile acids will be esterified with glucuronate and secreted into bile, but undergo little enterohepatic circulation. Cholestasis will not be present; the bile acid pool will be diminished and lipid absorption, especially that of fat-soluble vitamins, will be impaired. A secretory diarrhoea may occur, caused by increased bile acid concentrations in the colon. Awareness of this possible syndrome should aid in its identification; oral administration of bile acids conjugated with glycine or taurine should correct the metabolic and clinical abnormalities.

Bile Acids and Salts↗
PubMed1988

Tissue taurine content and conjugated bile acid composition of rhesus monkey infants fed a human infant soy-protein formula with or without taurine supplementation for 3 months.

The concentrations of taurine in a number of brain regions and in other tissues of rhesus monkeys fed a taurine-free human infant formula for 3 months are substantially lower than in similar monkeys fed the same formula supplemented with taurine. Activities of enzymes involved in taurine biosynthesis were not different in the two groups except for liver cysteinesulfinic acid decarboxylase, which was greater in the monkeys fed formula alone. There was no difference in the biliary bile acid composition, but the proportion of bile acids conjugated with taurine was significantly greater in the monkeys fed formula supplemented with taurine. These results indicate that the effects of a taurine-deficient diet on infant primates are widespread.

Animals↗
PubMed1988

Inhibition of Na+/H+ exchange in the rat is associated with decreased ursodeoxycholate hypercholeresis, decreased secretion of unconjugated urodeoxycholate, and increased ursodeoxycholate glucuronidation.

In the perfused rat liver, ursodeoxycholate in high dose produces an HCO3- -rich hypercholeresis which we have shown previously to be inhibited by replacement of perfusate Na+ with Li+ or by addition of amiloride (or amiloride analogues). In the present studies, we have determined whether such inhibition is associated with altered ursodeoxycholate biotransformation. Under control conditions, ursodeoxycholate infusion produced a 3.7-fold increase in bile flow and a 9.2-fold increase in biliary HCO3- output. By thin-layer chromatography, ursodeoxycholate radioactivity in bile was present in unconjugated form (15%) or as glycine or taurine amidates. Glucuronide conjugates of ursodeoxycholate accounted for less than 1% of biliary bile acids. Li+/Na+ substitution decreased ursodeoxycholate-stimulated bile flow and HCO3- secretion by greater than 90%, but decreased recovery of ursodeoxycholate and metabolites by only 25%. Amiloride or amiloride analogues decreased ursodeoxycholate-stimulated choleresis and HCO3- output by 38%-76%, yet did not cause decreased recovery of ursodeoxycholate and metabolites. Inhibition of the hypercholeresis was associated with a decrease in unconjugated ursodeoxycholate to less than 2% of total biliary bile acids, a striking increase in ursodeoxycholate glucuronides, and a reciprocal decrease in glycine and taurine amidates. With Li+/Na+ substitution, the predominant metabolites were a mixture of the 24-ester and the 3-aketal (ethereal) glucuronide (29%), and amidation with glycine appeared to be selectively inhibited; with amiloride or its analogues, only the 3-ethereal glucuronide was formed (20%-60% of biliary bile acids), and both taurine and glycine amidation were inhibited. Thus, maneuvers that decrease Na+/H+ exchange inhibit ursodeoxycholate hypercholeresis and cause replacement of unconjugated ursodeoxycholate in bile by its glucuronide. The secretion of unconjugated ursodeoxycholate, a lipophilic bile acid, appears to be necessary for hypercholeresis induced by high-dose ursodeoxycholate infusion.

Amiloride↗
PubMed1988

Common bile duct calculi: updated experience with dissolution with methyl tertiary butyl ether.

The authors describe their experience with methyl tertiary butyl ether (MTBE) in a larger series of patients than previously reported in order to acquaint physicians with both its effectiveness for dissolution of common bile duct calculi and the limitations of its use. Ten patients with 13 biliary calculi underwent percutaneous stone dissolution treatment with the experimental cholesterol solvent, MTBE. Three stones completely dissolved within 30 minutes, seven were reduced in size, and three were visibly unaffected. All stones not completely dissolved were easily extracted by means of a stone basket except for one in a patient taken to surgery. Although MTBE perfusion is an effective technique for management of biliary calculi, practitioners should be aware that its use is quite time consuming and its odor difficult to control.

Aged↗
PubMed1988

Gallbladder and bile duct stones: percutaneous therapy with primary MTBE dissolution and mechanical methods.

The authors describe percutaneous treatment of gallbladder or bile duct stones in 18 patients who were poor surgical candidates or in whom conventional therapy failed. Dissolution was performed in most cases with methyl tert-butyl ether (MTBE) because of its potent dissolution properties; other solvents used included monooctanoin or chelating solutions. Gallbladder stones were eliminated in 11 of 13 patients (six of seven with dissolution alone, four of four with dissolution and basket extraction, one with basket removal alone). In five patients with stones in the common bile duct (n = 3), cystic duct remnant (n = 1), and intrahepatic bile ducts (n = 1), stones were eliminated with dissolution alone in two and with dissolution plus basket extraction in one. In two patients percutaneous therapy failed due to complications (vagal hypotension with bile peritonitis and transient respiratory arrest) that occurred during catheter placement. Preliminary results suggest that MTBE is effective for dissolution of many gallbladder stones and some bile duct stones. Noncholesterol solvents and adjuvant mechanical maneuvers are valuable adjuncts to achieve complete stone elimination.

Bile Duct Diseases↗