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Biomedical subjects

G Karlaganis

Publications and source records attributed to G Karlaganis.

At least 37 records · Page 2Linked to original sources
PubMed1984

Urinary bile acid and bile alcohol excretion does not reflect the genetic polymorphism of debrisoquine hydroxylation.

Excretion of the major urinary bile alcohol 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24,25- pentol , and of cholic, chenodeoxycholic, deoxycholic and lithocholic acid was measured in 24 h urine collections of 10 extensive and seven poor metabolizers of debrisoquine. There was no significant difference of the excretion of these cholesterol metabolites between the two groups, indicating that cholesterol hydroxylation to bile alcohols and bile acids is probably not controlled by the same genes responsible for the 'debrisoquine-type' hydroxylation polymorphism.

Adult↗
PubMed1984

Identification of 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi, 25 xi,26-hexol and partial characterization of the bile alcohol profile in urine.

The nature of the bile alcohols present in urine of an infant with neonatal cholestasis has been investigated. Urine was extracted with Sep-Pak C18 cartridges and a glucuronide fraction was isolated by ion exchange chromatography on Lipidex-DEAP. Following enzymatic hydrolysis and purification on Lipidex-DEAP, the bile alcohols were isolated by high performance liquid chromatography. Fourteen compounds were studied by a combination of microchemical reactions and capillary column gas-liquid chromatography-mass spectrometry. Both C26 and C27 bile alcohols were present. Among the former, three additional isomers of the previously identified 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,25 xi-pentol were detected. A new C26 bile alcohol, 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,25 xi,26 -hexol, was identified, and a 27-norcholestane-pentolone with hydroxyl groups at C-24 and C-25 and a keto group in the ring system was partially characterized. The C27 bile alcohols consisted of cholestanepentols, -tetrolones, and -pentolones. 5 beta-Cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol (5 beta-bufol), one of its isomers and an isomer of cholestane-3,7,12,24,26-pentol were present. Two cholestanetetrolones and two cholestanepentolones having the keto group in the ring system were partially characterized. The hydroxyl groups in the side chain of the tetrolones were at C-24,26 and C-25,26, respectively, whereas the pentolones had hydroxyl groups at C-24,25 and C-25,26, respectively. The excretion of glucuronidated bile alcohols in urine is suggested to reflect an alternative metabolism of intermediates in the normal biosynthesis of bile acids.

Cholestanols↗
PubMed1983

In vivo hydroxylation of 3H-acetanilide--evaluation of a new radiospirometric method in the rat.

The proposed in vivo methodology for the investigation of hydroxylation rates consists of of the i.v. administration of tritiated substrates and the collection of tritiated water (HTO) from exhaled air as a measure of HTO accumulation in body water. Specifically, HTO was assessed in exhaled water after i.v. administration of 3H-acetanilide. Over a wide range the half lives of accumulation of HTO in exhaled water (T50) were almost identical with the half lives of elimination of 3H-acetanilide in blood, evaluated by an inverse isotope dilution method (r = 0.96, N = 18). Average T50 amounted to 29 min in controls, was reduced to 20 min after enzyme induction by phenobarbital or 3-methylcholanthrene, and prolonged to 45, 46 and 66 min after bile duct ligation, portacaval shunt and a single dose of ethanol, respectively. It is concluded that the chosen pharmacokinetic approach corrects for the NIH-shift and the results adequately reflect changes in acetanilide hydroxylation related to enzyme induction or inhibition and to liver pathology.

Acetanilides↗
PubMed1983

Precursor of 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24,25-pentol in man.

Cholesterol was shown to be the precursor of 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24,25-pentol which is the major bile alcohol in human urine. 4-[14C]-Labelled cholesterol and beta-sitosterol were administered to patients with primary biliary cirrhosis. Urine was extracted with Amberlite XAD-2 and sterol glucuronides and bile acid conjugates were isolated by ion exchange chromatography on Lipidex-DEAP. Following hydrolysis and further purification on Lipidex-DEAP, the C26 bile alcohol and methyl esters of cholic and chenodeoxycholic acids were isolated by HPLC. The specific radioactivity of the C26-pentol was the same as that of cholic acid after administration of [14C]-cholesterol. In contrast, little if any radioactivity could be detected in the C26-pentol after administration of labelled beta-sitosterol.

Bile Acids and Salts↗
PubMed1983

Zellweger's cerebro-hepato-renal syndrome--variations in expressivity and in defects of bile acid synthesis.

Two siblings with Zellweger's cerebro-hepato-renal syndrome are reported. The two children both had multiple anomalies associated with Zellweger's syndrome such as characteristic facial appearance, cerebral dysfunction, muscular hypotonia, liver abnormalities, failure to thrive, marasm and early death. One of the children, a girl, lacked several anomalies that were present in her brother. In one of the children bile acid analysis was performed by use of gas chromatography-mass spectrometry. 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) and varanic acid, both precursors of cholic acid, were found. The defect bile acid synthesis may be due both to liver mitochondrial abnormalities and to the absence of liver peroxisomes, conditions known to occur in Zellweger's syndrome.

Abnormalities, Multiple↗
PubMed1983

Monohydroxy bile salt sulfates: tauro-3 beta-hydroxy-5-cholenoate-3-sulfate induces intrahepatic cholestasis in rats.

The biologic effects of sulfation of tauro-3 beta-hydroxy-5-cholenoate and of taurolithocholate were compared. Equimolar amounts (100 nmol/min X 100 g body wt) of the following were administered intravenously to male Sprague-Dawley rats over a 180-min period: taurolithocholate, [14C]taurolithocholate-3-sulfate, tauro-3 beta-hydroxy-5-cholenoate, [14C]tauro-3 beta-hydroxy-5-cholenoate-3-sulfate, its combination with taurocholate, and a saline-albumin solution (control). Sulfation of taurolithocholate and of tauro-3 beta-hydroxy-5-cholenoate only prevented the cholestatic effect of the former. Bile flow during infusion of [14C]tauro-3 beta-hydroxy-5-cholenoate-3-sulfate was reduced by 80% at the end of the experiment. A dose-dependent bile flow reduction was demonstrated. Recovery of the administered bile acid was 3% in urine, 13% in serum, 23% in the liver tissue, and 52% in bile, respectively. Excretion of biliary cholesterol and phospholipids was significantly reduced during the first hour of infusion. Coadministration of taurocholate abolished the cholestatic effect and enhanced the renal excretion of the sulfated bile salt. These data suggest that (a) the cholestatic effect of tauro-3 beta-hydroxy-5-cholenoate-3-sulfate is comparable with or may even exceed the effect of taurolithocholate and (b) although sulfation renders some bile salts more water soluble, it does not prevent the cholestatic effect of all monohydroxy bile salts.

Animals↗
PubMed1982

Urinary excretion of bile alcohols in normal children and patients with alpha 1-antitrypsin deficiency during development of liver disease.

Healthy infants and children were found to excrete bile alcohol glucuronides in urine. Following isolation and hydrolysis, the bile alcohols were estimated by capillary gas-liquid chromatography. The daily urinary excretion of the major compound, 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 xi, 25 xi-pentol (a C26 bile alcohol), ranged from 0.1 to 1.1 mumol/24 h per m2 body surface area for healthy infants and children. Two groups of patients with alpha 1-antitrypsin deficiency (phenotype PiZ) were also studied during infancy and childhood, and biochemical liver function tests and liver morphology were compared to the excretion of bile alcohols. The highest excretion of the C26 bile alcohol in urine was found in patients with alpha 1-antitrypsin deficiency and juvenile cirrhosis (2.1-8.4 mumol 24 h-1 m-2) regardless of preceding neonatal cholestasis. Patients with alpha 1-antitrypsin deficiency, neonatal cholestasis and subsequent fibrosis or normal liver morphology excreted bile alcohols within the normal range. The C26 bile alcohol constituted an average of 36% of the total bile alcohols in forty-three urine samples. This percentage was about the same in the three groups studied. The findings suggest that determination of urinary bile alcohols may be a valuable non-invasive diagnostic tool for patients with or at risk of developing liver cirrhosis.

Adolescent↗
PubMed1981

N-Acetyl-procainamide kinetics in the elderly.

Plasma and saliva N-acetyl-procainamide (NAPA) concentrations were measured by high-power liquid chromatography (HPLC) after intravenous infusion of 750 mg to 14 elderly patients (x age = 69 yr). The plasma NAPA disappearance curve can best be described by a two-compartment body model. Mean total body clearance was 10.6 1/hr, Vdss 125.8 1, and terminal half-life (t 1/2) 8.8 hr. A nonrenal clearance of 2.72 1/hr was calculated, that is, 19% of the expected total body clearance with normal kidney function. Saliva concentrations show huge inter- and intraindividual variability and are probably not usable for NAPA monitoring in older patients.

Acecainide↗
PubMed1980

[Steady-state plasma and saliva concentrations of procainamide and N-acetyl-procainamide after a sustained release preparation].

With ordinary procainamide tablets a dosing interval of 3-4 hours must be chosen to achieve therapeutically useful plasma concentrations during the entire interval. The concentrations of procainamide and its N-acetylated metabolite, NAPA, have been studied in the plasma of 10 normal volunteers and 11 patients who were given a new sustained release preparation at 8 hour intervals. Blood samples were taken between two doses on the fourth day of treatment. Procainamide showed levels within the accepted therapeutic range during the entire dosing interval. A dose of 4.5 g per day per 70 kg body-weight is necessary in order to achieve adequate levels. NAPA concentrations did not fluctuate during the dosing interval and mean steady-state concentrations were influenced predominantly by the degree of renal function. Saliva to plasma concentration ratio, measured in four patients, showed huge inter- and intraindividual variability. Therefore, saliva concentrations measurements of procainamide and NAPA are of little clinical use.

Acecainide↗
PubMed1980

Plasma concentrations of mebendazole during treatment of echinococcosis: preliminary results.

High oral doses of mebendazole are used experimentally for the treatment of human alveolar and cystic echinococcosis. In order to assess bioavailability of this drug 1.5 g doses were given to 3 volunteers. Measurable plasma concentrations of 17 to 134 nmol/l were found only if mebendazole was given together with a fatty meal. In a patient with cholestasis plasma concentrations were higher than in the 3 normal subjects. In patients on long term treatment the increase in plasma concentration after administration of a 1 g dose varied between 0 and 500 nmol/l. It is concluded that systemic availability of mebendazole is enhanced by concomitant food intake. In view of the large intra- and interindividual variation in plasma concentration, monitoring plasma levels during long term therapy appears advisable.

Administration, Oral↗
PubMed1980

Autoradiographic evidence for hepatic lobular concentration gradient of bile acid derivative.

Using an iodinated bile-acid analog with hepatic uptake and transport characteristics similar to conventional bile acids, the hepatic lobular gradient concept of Goresky was studied utilizing autoradiography. 125I-labeled cholylglycylhistamine (125I-CGH) was infused into the portal veins of male Sprague-Dawley rats and the livers were fixed for light microscopic autoradiography at 1 and 5 min after infusion. In two animals, sequential samples of bile were collected to assess the transport characteristics of 125I-CGH. By 1 min, virtually all (98%) of the injected 125I-CGH was taken up and retained by hepatocytes after perfusion fixation. Less than 15% of the label was lost during subsequent tissue processing. 125I-CGH appeared in bile within minutes, reaching maximum levels at 7 min. Quantitative autoradiography demonstrated that the first six to nine periportal hepatocytes were, by far, the most active (P less than 0.0005) in sequestering the bile-acid analog than were the remaining cells in the lobule. This study, therefore, provides the first autoradiographic evidence of a hepatic lobular concentration gradient for the uptake of a bile-acid analog.

Animals↗
PubMed1980

Analysis of serum bile acids by capillary gas--liquid chromatography--mass spectrometry.

A method for quantitative analysis of serum bile acids by capillary gas--liquid chromatography--mass spectrometry is described. The main features of this method are a Grob-type barium carbonate/polyethyleneglycol 20,000 glass capillary column, an all-glass capillary interface, use of the lipophilic anion exchanger DEAP-Sephadex-LH-20 for purification of the serum extract, and chenodeoxycholic-11,12-d2 acid as internal standard. Linearity of the response (ratio of intensities of the fragment ions diagnostic for the bile acid to be measured and for the internal standard) was demonstrated for four different bile acids. The method is sufficiently sensitive for measurement of bile acids in serum of healthy humans.

Bile Acids and Salts↗
PubMed1979

A highly specific 125I-radioimmunoassay for cholic acid conjugates.

Several modifications of the immunization procedure permitted development of a highly specific radioimmunoassay (RIA) for cholic acid conjugates. Antiserum was produced in guinea pigs using cholic acid-thyroglobulin complex as immunogen. 125-I-Cholyglycylhistamine was prepared as radioactive ligand according to a modification of the method of Spenney et al. (Spenney, J.G., Johnson, B.J., Hirschowitz, B.I., Mihas, A.A. and Gibson, R. (1977) Gastroenterology 72, 305--311). The association constant of the antisera to taurocholic acid was 1.8 x 10(7) l/mol, the working range of the assay between 9.5--890 pmol. Cross-reactivities of the antiserum to bile acids other than cholic acid species were less than 3%, which is lower than for any published bile acid RIA. Concentrations of cholic acid conjugates in sera obtained from 17 healthy fasting volunteers ranged from 0.4--1.9/mumul/l.

Animals↗
PubMed1979

Determination of bile acids in serum by capillary gas-liquid chromatography.

A glass capillary column and an appropriate relatively simple procedure for sample preparation have been developed for determination of serum bile acids. Sample preparation involved extraction with Amberlite XAD-2, solvolysis of sulfates, enzymatic hydrolysis with cholylglycine hydrolase, methylation and silylation. Because of complete chromatographic separation of bile acid trimethylsilylether derivatives from cholesterol on the capillary column, an additional step for elimination of cholesterol could be omitted. Trimethylsilylether derivatives were separated on a 20 meter x 0.3 mm i.d. glass capillary column covered with a crystal layer of barium carbonate and coated with polyethyleneglycol 20,000 as liquid phase according to Grob, K. and Grob, G. (1976) J. Chromatogr.125, 471--485, and Grob, K., Grob, G. and Grob, Jr., K., (1977) Chromatographia 10, 181--187. Overall recovery of the major human conjugated bile acids ranged from 86 to 89%. Reproducibility of bile acid determination was satisfactory in both normal and pathological serum with elevated bile acid concentrations (coefficient of variation 7.6 to 10.0%). The mean concentrations of cholic, deoxycholic, chenodeoxycholic and lithocholic acid in the serum of healthy subjects were 0.9, 1.0, 1.7 and 0.2 mumol/l in males, and 1.0, 0.8, 1.4 and 0.2 mumol/l in females.

Adolescent↗
PubMed1979

Hepatic handling of a gamma-emitting bile salt derivative, 123I-cholylglycylhistamine, in the dog.

The hepatic handling of the bile salt derivative 123I-cholylglycylhistamine has been compared with that of the physiologic bile salt taurocholate in boxer dogs equipped with a Thomas duodenal cannula. After intravenous injection of trace amounts, 123I-cholylglycylhistamine and 14C-taurocholate disappeared from plasma with nearly identical disappearance rate constants. Excellent scintiscans of the liver were obtained with the Anger camera after injection of 3 mCi of 123I-cholylglycylhistamine. Monitoring of radioactivity over a hepatic region of interest revealed rapid uptake of 123I-cholylglycylhistamine by the liver, which reached a maximum 5.7 +/- 0.4 min after injection. The biliary excretion rates of the compounds closely paralleled each other, reaching their maximum within 15 min after injection. Cumulative biliary excretion within 45 min was 58.5 +/- 2.9% and 61.4 +/- 5.0% of the dose for 123I-cholylglycylhistamine and 14C-taurocholate, respectively. Modification of the side chain and gamma-labelling of bile salts may provide scintigraphic agents for the study of the biliary system, which in the behaviour closely resemble the physiologic parent compounds.

Animals↗
PubMed1979

Radioimmunological determination of serum 3 beta-hydroxy-5-cholenoic acid in normal subjects and patients with liver disease.

A radioimmunoassay for the determination of 3 beta-hydroxy-5-cholenoic acid in human serum has been developed, using 3 beta-hydroxy-5-cholenoyl-thyroglobulin as immunogen and 3 beta-hydroxy-5-cholenoylglycyl-125I histamine as radioactive ligand. The association constant was 6.3 X 10(8) l/mol. Cross reactivity with other bile acids of human serum was not detectable, but was 5.6% with cholesterol. Serum sample preparation included extraction of 3 beta-hydroxy-5-cholenoic acid from serum, solvolysis of sulfates, hydrolysis of conjugates, and separation from cholesterol by thin-layer chromatography. Serum concentrations of 3 beta-hydroxy-5-cholenoic acid were 0.23 +/- SD 0.12 mumol/l and 0.21 +/- SD 0.09 mumol/l in healthy males and females, respectively. In patients with primary biliary cirrhosis the serum concentration of 3 beta-hydroxy-5-cholenoic acid and the quotient 3 beta-hydroxy-5-cholenoic acid over total 3 alpha-hydroxy-bile acids (measured enzymatically) were significantly higher (P less than 0.02) than in patients with chronic active hepatitis or alcoholic cirrhosis. Analysis of 17 sera with elevated concentration of 3 beta-hydroxy-5-cholenoic acid by radioimmunoassay and capillary gas-liquid chromatography showed a close correlation (r = 0.91, slope = 0.97) between the results of the two methods.

Adult↗
PubMed1978

Rate of drug metabolism in man measured by 14CO2-breath analysis.

Exhalation of 14CO2 in breath has been used to assess the rate of hepatic demethylation of (14C-dimethyl)aminopyrine, but due to the complexity of aminopyrine metabolism the pharmacokinetics of the procedure are insufficiently understood. Therefore, studies were performed in five individuals after oral administration of (14C-methoxy)glycodiazine, a model substance with relatively simple kinetic properties. Plasma concentrations of the drug and urinary output of its metabolites measured by high pressure liquid chromatography were analysed by a two-compartment open model. The terminal disappearance of 14CO2 from breath was practically identical with the terminal disappearance of glycodiazine from plasma, which could be correlated with the plasma clearance of free glycodiazine. The mean transit time of 14C-atoms from plasma to breath was 3 h. These results contribute to the pharmacokinetic basis for use of 14C-demethylation breath tests. In particular, they are consistent with the hypothesis that 14CO2-breath analysis may be used to assess certain pharmacokinetic parameters of appropriately labelled test compounds. These parameters may not necessarily be a direct reflection of the rate of demethylation.

Adult↗