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Biomedical subjects

R Preisig

Publications and source records attributed to R Preisig.

At least 37 records · Page 2Linked to original sources
PubMed1985

[Foreign substances as indicators of liver function].

The need to use xenobiotics to quantify liver function is based on the fact that the serum levels of endogenous tracers (such as transaminases, alkaline phosphatase, bilirubin and bile acids) cannot be interpreted in pharmacokinetic terms, since information is lacking on volume of distribution and on rate of synthesis and of disposition. Methods are now available which allow practically non-invasive estimation of (minimal) hepatic perfusion by indocyanine green fractional clearance, of portosystemic shunt flow by finger pulse photometry following nitroglycerin administration, of microsomal capacity by the aminopyrine breath test (ABT) or caffeine clearance, and of cytosolic function by galactose elimination capacity (GEC). Assessment of inherited hydroxylation deficiency of the debrisoquine type is best performed with dextromethorphan, and of the acetylator phenotype with sulfadimidine. Recently, caffeine clearance in saliva has been studied extensively in this laboratory, and, on the basis of a constant relationship between caffeine concentrations in serum and saliva, overnight clearance measurements (requiring a saliva sample at bedtime and upon arising following a single oral dose of caffeine) have been shown to be closely related to ABT or GEC. This approach, which has been successfully used in children, may represent the first simple and innocuous test for quantifying of hepatic function in the pediatric age group. The clinical utility of these clearance tests is to assess severity of disease (or genetically determined impairment of function), thus yielding important clues to prognosis.

Aminopyrine↗
PubMed1984

Quasi-elastic light scattering studies of native hepatic bile from the dog: comparison with aggregative behavior of model biliary lipid systems.

Using quasi-elastic light scattering ( QLS ), we have characterized the macromolecular components in hepatic bile obtained from the dog and compared these results with data from model bile solutions containing the bile salt (BS) sodium taurocholate (TC), egg lecithin (L), and cholesterol (Ch). Native bile samples were obtained by direct catheterization of the common bile duct in a previously cholecystectomized dog fitted with a Thomas duodenal cannula. Hepatic bile was sampled during three secretory states: (A) unstimulated "fasting" bile, (B) "stimulated" secretion during an intravenous TC infusion, and (C) "secretin-stimulated" secretion. All three samples had comparable molar ratios of L/BS (0.21 +/- 0.03) and Ch/L (0.027 +/- 0.006) but differed in the total lipid concentration (BS + L + Ch): (A) 13.1 +/- 0.8, (B) 6.7 +/- 0.8, and (C) 3.0 +/- 0.4 g/dL. From the QLS autocorrelation functions measured on samples B and C, three macromolecular components (denoted 1 alpha, 1 beta, and 2) were resolved. Component 1 alpha (hydrodynamic radius R1 alpha = 10 +/- 2 A) is comparable in size to the micellar aggregates of model systems. Component 1 beta (R1 beta = 67 +/- 7 A) appears to reflect an average of biliary proteins. Component 2 (R2 = 650 +/- 15 A) is a trace component whose size and sedimentation behavior are compatible with those of the canalicular membrane vesicles postulated to be present in bile [ Godfrey , P. P., Warner, M. J., & Coleman , R. (1981) Biochem. J. 196, 11]. Serial dilution of the B and C bile samples with Tris buffer (0.15 M NaCl, pH 8.0) showed a remarkable similarity in the behavior of the 1 alpha component as compared to the mean hydrodynamic radius Rh of similarly diluted model bile solutions. When a critical dilution factor, d gamma, is reached, Rh increases abruptly from approximately 30 to approximately 400 A. Above a second dilution factor, d alpha, it then decreases to a value of approximately 150 A. Similar results were obtained on sample A but were shifted to higher dilutions. Such behavior is consistent with the presence of "mixed disk" micelles [ Mazer , N. A., Benedek , G. B., & Carey, M. C. (1980) Biochemistry 19, 601] in native bile which undergo a micelle-to-vesicle transition upon dilution. From the d gamma and d alpha values, estimates of the intermicellar bile salt concentrations were made for all three samples (range 1.4-6.2 mM) which agree well with previous experimental results on model and native bile. These studies offer compelling evidence for the existence of micellar aggregates in native bile whose size, structure, and equilibria are similar to those found in model bile solutions.

Animals↗
PubMed1984

Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man.

Inherited deficiency in mephenytoin hydroxylation was observed in a family study. It is important that the propositus was of the extensive metabolizer phenotype for the genetically controlled hydroxylation of debrisoquine. Thus, a genetic polymorphism of drug hydroxylation was suspected for mephenytoin. A population study of mephenytoin hydroxylation, combined with identification of extensive and poor debrisoquine hydroxylation phenotypes, was carried out in 221 unrelated normal volunteers. Twelve of them (5%) exhibited defective aromatic hydroxylation of mephenytoin, and 23 (10%) could be identified as poor metabolizers of debrisoquine. Amongst these 35 subjects with a drug hydroxylation deficiency, 3 (or 0.5%; 1 female, 2 males) displayed both defects simultaneously. A panel study of 10 extensive and 10 poor metabolizers of mephenytoin showed that the ability to perform aromatic hydroxylation of the demethylated mephenytoin metabolite nirvanol (5-phenyl-5-ethylhydantoin) was co-inherited with the mephenytoin hydroxylation polymorphism. Family studies suggested that poor metabolizer phenotypes of nirvanol and mephenytoin were most likely to have the homozygous genotype for an autosomal recessive allele of deficient aromatic drug hydroxylation. Intra-subject comparison of the debrisoquine and mephenytoin hydroxylation phenotypes in these subjects indicated that deficiency in the two drug hydroxylations occurred independently. Consequently, the co-inheritance of extensive and poor hydroxylation of mephenytoin and nirvanol, respectively, represents a new drug hydroxylation polymorphism in man.

Adult↗
PubMed1984

Evaluation of caffeine plasma levels by an automated enzyme immunoassay (EMIT) in comparison with a high-performance liquid chromatographic method.

A new enzyme immunoassay (EMIT) for the measurement of levels of caffeine in plasma was adapted to an automated centrifugal analyzer (Cobas Bio) and compared with a high-performance liquid chromatographic (HPLC) method. Precision of the EMIT test was similar to that of the HPLC method with intraassay coefficients of variation in the range of 2.0-4.1% (EMIT) and 1.5-3.3% (HPLC), respectively, depending on the concentration range tested. Day-to-day precision ranged from 2.7 to 5.6% for EMIT and was 3% for HPLC. Comparison of 69 patient samples assayed with both methods yielded the following equation: y = 1.06x + 1.25 mumol/L, r = 0.994 (X = HPLC, y = EMIT). Evaluation of the cross-reactivity of the three main human caffeine metabolites revealed no significant interference from theobromine and theophylline; however, there was significant interference (28%) by paraxanthine at a concentration range from 2.5 to 80 mumol/L. At low caffeine concentrations, up to 10 mumol/L, the level of this metabolite may be more than twice the corresponding caffeine concentration; therefore, the latter may be falsely elevated in the EMIT test. Despite this cross-reactivity, the new EMIT test proved to be suitable for use in a drug assay laboratory, as well as in the routine screening of outpatients for liver disease.

Caffeine↗
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

Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans.

Aromatic hydroxylation of 5-phenyl-5-ethylhydantoin (PEH) has been investigated in humans. Single oral doses of S-PEH (247 mumol) were given to seven extensive and seven poor hydroxylators of mephenytoin. Urinary recovery of PEH and 5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-PEH) indicated that all extensive metabolizer subjects excreted appreciable quantities of 4-OH-PEH, whereas all poor metabolizer subjects had only trace amounts of 4-OH-PEH in their urine. Four extensive metabolizer subjects received dual radiolabeled (S-[14C]PEH, R-[3H]PEH) pseudoracemic (494 mumol R-PEH, 494 mumol S-PEH) PEH and had serial urine and blood samples collected over 16 days. The urinary excretion rates of S-PEH and S-4-OH-PEH had half-lives of approximately 4.5 days whereas those of R-PEH and R-4-OH-PEH were approximately 10 days. The initial S/R ratio of 4-OH-PEH in urine was 14:1 whereas that of PEH was 1:1. Stereoselective hydroxylation in these four subjects was confirmed by the negligible recovery of 4-OH-PEH after oral administration of R-PEH (494 mumol). After racemic administration, the sum of S-and R-PEH plasma concentrations declined biexponentially with half-lives of the alpha- and beta-phases being consistent with the total plasma concentration reflecting the sum of the different rates of elimination of the two enantiomers. These results are consistent with the hypothesis that the same drug metabolizing enzymes are involved in the aromatic hydroxylation of S-mephenytoin and S-PEH.

Adolescent↗
PubMed1983

[Hepatitis B infection: studies on endemic disease in the closed ward of a psychiatric hospital].

Following the occurrence of 3 cases of icteric hepatitis in the period August 1980 to January 1981 in a closed male ward for mentally retarded patients in a psychiatric institution, the present study was undertaken to determine the type, investigate the source and reconstruct the sequence of viral infection, and to make recommendations for its containment. For this purpose, serologic markers for HAV and HBV (including anti HBcIgM) were determined and serum transaminase (AST) measured in March 1981 in all 24 patients (mean age 40) and in the 39 members of the medical, nursing and housekeeping staff (mean age 39). Subsequently, HAV and HBV serologies were repeated after 6 and 9 months respectively. The propositus (B.F.) and the two subsequent cases with overt hepatitis (F.P. and K.E.) showed the serologic constellation of positive HBs, HBe and anti HBcIgM, together with elevated AST levels (600, 800 and 200 I.U. respectively) at the time of clinical illness, consistent with an acute HBV infection. Since 7 (18%) among the staff members were immune to HBV (positive anti HBs and anti HBc) and the remainder sero-negative; the remaining 6, however, showed evidence of active viral replication (S. P. and K. E.), viral infection (F. P. and J. L.) or incomplete immune response (B.F. and G.H.). During the 9 months' follow-up their serologic status did not change, with the exception of 2 (F.P. and B.F.), in whom HBs disappeared. The incidence of anti HAV in patients was 42% and in the staff 44%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Portal-systemic spill-over of bile acids: a study of mechanisms using ursodeoxycholic acid.

Portal-systemic spill-over of unconjugated ursodeoxycholic acid (UDCA) was assessed in ten healthy subjects, six patients with mild chronic liver disease and eight patients with cirrhosis. Following oral administration of UDCA (1.5 mg/kg body weight), serum concentrations of unconjugated UDCA were measured during 2 h using a capillary gas-liquid chromatographic method. Peak time of UDCA varied from 15 to 30 min, but was not significantly different in the three groups studied. Peak concentration was increased up to two-fold in patients with mild, and up to three-fold in patients with cirrhotic liver disease. Since, in addition, plasma disappearance rate (k) was markedly impaired in cirrhotics (1.7 +/- SD 0.5%/min, compared to 2.8 +/- 0.6 in healthy controls), the calculated area under the curve (AUC) was on the average five-fold that in controls. In two healthy and four cirrhotic subjects, the data obtained after oral administration were compared with those after i.v. loading with the same UDCA dose. The k-values after the two routes of administration were practically identical. Calculated systemic availability was 50% in normals, 78-87% in cirrhotics, 90 and 136% in two patients with surgical porta-caval shunt. It is concluded that the portal-systemic spill-over of UDCA in patients with liver disease is increased primarily due to portal-systemic shunting. Since in the normal liver hepatic extraction of conjugated, endogenous bile acids is greater than 80%, diminished first-pass elimination is expected to augment systemic concentrations even more, particularly when measured after a meal.

Adult↗
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

[Positive diagnosis of Gilbert syndrome. Retrospective analysis of 59 cases with special reference to the nicotinic acid test].

The results of a retrospective analysis of 59 patients with Gilbert's syndrome are presented. All the patients were selected on the basis of repeatedly documented, predominantly unconjugated hyperbilirubinemia in the absence of liver or hemolytic disease. The peak incidence of Gilbert's syndrome was in the 15-30 years age group with males predominating almost fivefold. Scleral icterus or a laboratory finding of hyperbilirubinemia represented the major reasons for workup. Presenting symptoms such as fatigue, upper abdominal pain and fat intolerance were largely nonspecific. Whereas minimal values for total serum bilirubin concentrations were, at l.57 +/- 0.56 mg/dl (mean +/- S.D.), often within the normal range (less than 1.2), maximal values were always clearly elevated (2.05 +/- 0.65). The sex difference in bilirubin levels was also maintained in the Gilbert's syndrome, since mean values in women were lower than in men. As expected, neither liver scan nor histology yielded evidence of structural abnormalities. The results of liver function studies such as galactose elimination capacity, aminopyrine breath test, or fasting and postprandial serum bile acids, were all within normal limits. In contrast, the initial plasma disappearance of bromsulphthalein (BSP-k1) was reduced in 6 patients to a mean of 8.7% per min (normal value 12.6 +/- 1.6), which suggests that these subjects belong to the Gilbert type with diminished hepatic clearance of anionic dyes. The hematological investigations, including hemoglobin electrophoresis, Coombs tests and erythrocyte enzymes, yielded normal results. However, osmotic fragility was increased in 5 cases and erythrocyte survival reduced to less than 24 days in 9 cases (of 17 investigated). In 35 patients, a nicotinic acid test was performed in which total serum bilirubin rose within 3 hours from a mean of 1.66 +/- 0.7 to 3.51 +/- 0.75 mg/dl. Between the third and fifth hour bilirubin levels plateaued, yielding retention values of 98%, 92% and 92% respectively. These retention values may be considered in indirect estimate of bilirubin clearance. Retentions exceeding 70% after 5 hours correspond to bilirubin clearances of less than 20 ml/min, representing evidence in favour of the diagnosis of Gilbert's syndrome.

Acetylation↗
PubMed1982

[Drug hydroxylation disorders (debrisoquin type) in a random sample of the Swiss population].

The hydroxylation phenotype was determined in a sample of the Swiss population consisting of 222 normal unrelated subjects (131 women, 91 men). Following oral administration of a single dose of 19 mg debrisoquine, urine was collected for 8 hours. Urinary concentrations of parent compound and its major metabolite (4-hydroxydebrisoquine) were measured with GLC and their molar ratio ("metabolic ratio", MR) was calculated and plotted as a frequency distribution histogram. The frequency distribution of the MR was clearly bimodal, exhibiting two clusters of MR's of 0.1 to 1.0 and 20 to 100, respectively. Using probit analysis, the antimode was found at an MR of 12.6 Consequently, 22 subjects (16 women, 6 men), representing 10% of the population studied, were, with an MR of greater than 12.6, considered to be poor hydroxylators (PM). The families of two subjects, established as PMs in the population study, were also investigated. One family was found to be the first known pairing of homozygous PM parents with all 6 offspring exhibiting the PM phenotype. In both families the pattern was consistent with an autosomal recessive mode of inheritance for the two alleles E (extensive) and N (none) respectively. Clinical consequences of the PM phenotype known to date are summarized. Since some drugs typically used for longterm treatment (such as perhexiline, phenytoin, nortriptyline, guanoxan) are subject to the same hydroxylation pathway, PM patients are likely to be at higher risk of drug toxicity. This relationship has been well documented for perhexiline-induced neuropathy. Conversely, it is conceivable that with the use of prodrugs which have to be hydroxylated to the active compound, PM subjects might turn out to be "non-responders".

Adolescent↗
PubMed1981

[New aspects in the treatment of cholecysto-and choledolithiasis].

Since gallstone disease is one of the most frequent gastrointestinal disorders (average incidence 27% in males and 47% in females) it is mandatory for practicing physicians to keep abreast of recent progress in therapy. Thus, present treatment is based on the radiologic pattern of radiolucent (cholesterol) and radioopaque (calcium containing) stones. In the young patient, cholecystectomy is recommended for cholecystolithiasis regardless of type of stones, because this procedure is likely in most cases to provide optimal, definitive results at minimal risk. In the elderly, or when the operative risk is aggravated by accompanying disease, an attempt may be made to dissolve cholesterol stones by oral administration of cheno- or ursodeoxycholic acid. Following 18 months to 2 years of medication, the success rate for complete dissolution is approximately 50%.

Aged↗