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Biomedical subjects

R Preisig

Publications and source records attributed to R Preisig.

At least 19 recordsLinked to original sources

[What does the alcoholic patient need from his family physician?].

Chronic alcoholics are all too often not recognized in general practice. Diagnosis is only possible if the doctor assumes potential alcoholism in all his patients. Because of the tendency of the patient and often his family to deny alcohol dependence, diagnosis is only possible by taking psychiatric, somatic and psychosocial aspects into consideration in addition to an independent history. Questionnaires may be helpful. The severity of the dependence on alcohol is not a predictor of success in therapy. In practice, three types of alcoholics may be distinguished: (1) patients with stable social relationships; (2) patients with stable social relationships and severe anxiety or depression with alcohol abuse as an inadequate self medication; (3) patients who are not able to maintain stable relationships. The latter are unlikely to be successfully treated by a family physician. A careful classification of patients according to these simple criteria may reduce the rate of treatment failures. Therapy by the family physician is initiated with an extensive somatic, psychiatric and psychosocial work-up, and maintained by counseling and care. An important factor is close collaboration between physician and social worker. Disulfiram may be a powerful adjunct to the therapy of the family physician if supervised by a trustee. In our departments we work with alcoholics in a joint consultation service involving an internist and a psychiatrist. Two thirds of the patients who consent to supervised disulfiram remain in the program for a year. 3 months after initiation of the treatment, gamma-glutamyltransferase, ASAT, ALAT and MCV are normalized. A follow-up 5 years after treatment indicated the efficacy of this treatment.

Alcoholism

Microsomal liver function declines steadily after kidney grafting: a three to five year follow-up.

We have previously shown that the functioning hepatocyte mass (galactose elimination capacity, GEC) and microsomal liver functions (non-renal clearances of unbound prednisolone and cyclosporin A) are impaired in renal allograft recipients (N = 28) one month and one year after successful transplantation. To assess the natural history of these hepatic functional derangements, we reinvestigated 21 patients with stable renal function three to five years following grafting. GEC remained with 6.07 +/- 0.86 mg/min x kg significantly (P less than 0.001) below that in healthy controls (7.52 +/- 0.78 mg/min x kg), but did not significantly change during follow-up (5.93 +/- 0.96 and 6.26 +/- 0.94 mg/min x kg at 1 year and 1 month, respectively). In contrast, the non-renal clearance of unbound prednisolone declined steadily during follow-up averaging 4.98 +/- 0.71 ml/min x kg at three to five (compared to 5.83 +/- 1.51 and 6.80 +/- 1.73 ml/min x kg at one year and one month, respectively). These values were lower (P less than 0.01) than those observed in healthy control subjects (7.56 +/- 1.59 ml/min x kg). The total body clearance of cyclosporin A decreased similarly with time averaging 4.5 +/- 1.2 ml/min x kg at three to five years (compared to 4.9 +/- 1.2 and 5.9 +/- 2.1 ml/min x kg at 1 year and 1 month, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral

Chronic rejection and extrahepatic biliary tract obstruction 8 years after orthotopic liver transplantation using the gallbladder-conduit technique.

A case of delayed biliary obstruction and cholangitis, occurring in the setting of chronic allograft rejection, 8 years after liver transplantation using the gallbladder-conduit, is presented. Extrahepatic biliary obstruction may be seen in the late follow-up of liver grafting and rejection phenomena may play a significant role in the development of such obstruction.

Adult

Use of quantitative liver function tests--caffeine clearance and galactose elimination capacity--after orthotopic liver transplantation.

To establish the potential value of quantitative tests of liver function following orthotopic liver transplantation (OLT), a total of 100 determinations of caffeine clearance (CafCl) and galactose elimination capacity (GEC) were made in ten OLT recipients early in the post-operative course (days 2, 4, 6, 8 and 12) and later when clinically stable (3-12 months). Values were compared with a reference range in six normal volunteers in whom it was shown that the standard doses of caffeine (125 mg) and galactose (0.5 g per kg body weight) could be given together without interference. In orthotopic liver transplantation recipients initial GEC and CafCl measurements showed no correlation with peri-operative blood loss, donor ischaemia time, initial bile flow or survival. Throughout the early post-operative period, there were wide inter- and intra-individual variations in both CafCl (17-fold range from 0.16 to 2.7 ml.min-1.kg-1) and GEC (2.4-fold range from 5.1 to 12 mg.min-1.kg-1), but the only correlation of test values with standard liver function tests results was between GEC and gamma-glutamyltranspeptidase. However, GEC values fell by 19% during periods of acute rejection and there was an inverse correlation of GEC with white cell count probably related to sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

[Ambulatory, disulfiram-(Antabuse)-assisted management of the alcoholic patient].

The treatment of patients suffering from alcoholism is notoriously difficult. Ambulatory supportive therapy using disulfiram and supervised by the practicing physician has many advantages. Foremost among these is the maintenance of the patient within his working and social environment. For achievement of longterm abstinence, psychological aspects (patients motivation and agreement, understanding care by the physician) may be more important than the aversive effects of disulfiram. Although disulfiram is generally a safe drug, careful preliminary work-up represents the key to proper assessment of risk versus benefit.

Alcoholism

Impaired liver function in stable renal allograft recipients.

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.

Cyclosporins

Increased urinary excretion of bile alcohol glucuronides in patients with primary biliary cirrhosis.

The bile alcohol glucuronides in urine of 12 patients with primary biliary cirrhosis (PBC), 10 patients with chronic active hepatitis (CAH), and 6 healthy volunteers were analyzed by capillary gas-liquid chromatography-mass spectrometry. In all subjects studied, the major urinary bile alcohol was found to be 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol (C26 pentol). In PBC patients, the excretion of C26 pentol (main isomer) was significantly increased above values observed in healthy volunteers (mean +/- SD = 5.2 +/- 3.5 mumol/24 h, range 1.0-13.4; versus 0.6 +/- 0.3, range 0.4-1.0). In addition, PBC patients excreted increased amounts of other bile alcohols such as isomers of C26 pentol, pentahydroxylated C27 bile alcohols (5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol) and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol) and a hexahydroxylated C26 bile alcohol (27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25,26-hexol). In CAH patients, the excretion of the C26 pentol main isomer ranged from 0.3 to 2.0 mumol/24 h (mean +/- SD = 0.7 +/- 0.5) and did not significantly differ from that in healthy volunteers. Moreover, the bile alcohol profile was comparable to those found in healthy volunteers and PBC patients. These findings show that total urinary bile alcohol glucuronide excretion is significantly increased in primary biliary cirrhosis. A PBC-specific urinary bile alcohol profile, however, does not exist.

Adult

The 30-minute aminopyrine breath test: optimization of sampling times after intravenous administration of 14C-aminopyrine.

In a retrospective analysis of 78 well-defined patients, the procedure of the aminopyrine breath test was evaluated. After intravenous administration of 14C-aminopyrine (1.5 microCi, 1 mg) 14CO2 was sampled at 15-min intervals for 1 h. Samples taken at 15, 30, 45 and 60 min were similarly able to distinguish between patients with mild liver disease and patients with enzyme induction. The results of the aminopyrine breath test at each sampling time were highly correlated with the galactose elimination capacity and the fractional clearance of indocyanine green. It is concluded that sampling at 30 min represents a satisfactory compromise between practicality and accuracy of the test.

Adult

[Cardiovascular and metabolic changes in the antabuse-alcohol reaction: basis for the diagnosis of degree of severity].

The clinical symptoms and signs, certain metabolic aspects (including ethanol, acetaldehyde and glucose concentrations in plasma) and hemodynamic parameters (cardiac rate, blood pressure and cardiac output) were assessed in 16 ambulatory alcoholics (3 female, 13 male, average age 46 years) following pretreatment with disulfiram (total dose 1.2 to 2.4 g) and oral administration of 0.2 g ethanol 94% per kg body weight. Since the only selection criterion for inclusion was a diagnosis of alcohol dependence (DSM III, 303.9), the group was heterogeneous and exhibited a variety of concomitant diseases such as alcoholic liver disease in 9, chronic bronchitis in 5 and arterial hypertension in 3. Whereas peak plasma alcohol concentrations were comparable (median: 0.33 mg/ml; range: 0.19 to 0.40) in all subjects, peak acetaldehyde levels varied over 40-fold (median 5.1 micrograms/ml; range: 0.2 to 8.8). In consequence, there were marked interindividual differences in cardiovascular reaction, in contrast to the virtually constant finding of flush, palpitations and dyspnoea. Since the decrease in peripheral vascular resistance (to a median of 46% of control) was only in part compensated by increased cardiac output (median: 161%), both systolic and diastolic blood pressures were reduced by 30 and 45 mm Hg respectively. In 4 patients systolic pressure fell to shock levels (less than 70 mm Hg). The presumed toxic effect of acetaldehyde is again supported by close correlations between acetaldehyde plasma concentrations and the changes in blood pressures and peripheral resistances. We were able to demonstrate that disulfiram-induced inhibition of hepatic microsomal function - measured with the aminopyrine breath test - predicts the expected acetaldehyde peak levels following ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde

Polymorphic debrisoquine and mephenytoin hydroxylation in patients with pulmonary hypertension of vascular origin after aminorex fumarate.

During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.

Adult

Perhexiline-induced lipidosis in the dark Agouti (DA) rat. An animal model of genetically determined neurotoxicity.

Perhexiline maleate, an antianginal compound, may cause severe adverse effects such as weight loss, hepatic dysfunction and peripheral neuropathy in a small proportion of patients. Since present evidence suggests that poor debrisoquine hydroxylators are at risk, we designed an experimental study comparing its neurotoxic effects in dark Agouti (DA) rats, with poor hydroxylation of debrisoquine with that in Sprague Dawley (SD) rats, which are vigorous hydroxylators. Light and electron microscopic investigations revealed neurotoxic changes in DA rats after cumulative doses which did not cause any changes in SD rats. Although there was no evidence of hepatic disturbance, morphological examination disclosed a heavy lipid deposition in neurons of dorsal root and sympathetic ganglia in DA rats. This was correlated with increased plasma and tissue concentrations of the drug. The lipid accumulation was similar to that observed in man with perhexilene-induced neuropathy. Our results suggest that perhexilene neurotoxicity in the DA rat is related to a genetically determined impairment of hydroxylation. The DA rat may serve as an animal model for investigating the potential neurotoxicity of drugs which are metabolized by hydroxylation of the debrisoquine type.

Animals

Effect of dietary caffeine on airway reactivity in asthma.

The potential influence of dietary caffeine on bronchoprovocation challenges with carbachol was examined in 7 patients with asymptomatic asthma. In a double-blind fashion placebo or caffeine (6 mg/kg body weight; equivalent to approximately 4 cups of coffee) solved in orange juice was administered, and carbachol challenges were performed. The average peak serum concentration achieved 60 min after dosing was 7.6 +/- SD 2.1 mg/l. These caffeine levels did not produce any appreciable attenuation of the bronchoconstrictor response to carbachol inhalations. It thus appears that dietary caffeine is barely a cause of erroneous interpretations of bronchoprovocation challenges with carbachol.

Administration, Oral

[Quantification of the drug-metabolizing enzyme system in liver diseases: a comparison between antipyrine saliva clearance and the aminopyrine breath test].

The metabolic activity of the hepatic cytochrome P450 system was studied in 53 ambulatory subjects. 18 of these were cirrhotics and 23 had non-cirrhotic liver disease, documented by biopsy, serologic, ultrasound or computerized tomography findings, and characterized by quantitative liver function tests, such as galactose elimination capacity and indocyanine green fractional clearance. For comparison, 12 normal control subjects were also included. All subjects were given 10 mg/kg body weight antipyrine and saliva concentrations determined with an HPLC-method at 24 and 48 hours after dosing. Antipyrine saliva clearance (ASC) was calculated according to a two-point method (Cl1), and compared with a one-point method (Cl2) using the 24 h sample only. These subjects also underwent an aminopyrine breath test (ABT), breath samples being collected at regular intervals during 60 minutes following injection of a tracer dose of 1.5 muCi (14C-dimethylamino)antipyrine. Cl1 and Cl2 correlated strongly (r = 0.93). On the basis of smaller variations (particularly in control subjects), better definition of disease severity and convenience and time saving, Cl2 is to be preferred. Comparison of Cl2 with ABT showed that both procedures apparently quantify overlapping enzymatic activities. However, the relationship between Cl2 and ABT values, albeit highly significant (r = 0.72), suggests that only about half of the variables are subject to the same determinant. In addition, a positive intercept of the regression line extrapolated to the Cl2 axis points to quantitatively important extrahepatic breakdown of antipyrine. The results suggest that, in view of the wide variation in normal values (presumably in part influenced by exogenous pollutants), ASC only provides an approximation of hepatic metabolic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Administration, Oral

Fasting plasma caffeine concentration. A guide to the severity of chronic liver disease.

Fasting plasma caffeine concentrations (FPCC) were measured in 86 outpatients being examined for suspected or known liver disease. Seven patients (8%) who avoided caffeine consumption had nonmeasurable FPCC; they were dropped from further consideration. The remaining 79 subjects were divided into 4 diagnostic groups: surgical shunt (n = 11); alcoholic, posthepatitic, or primary biliary cirrhosis (n = 29); miscellaneous liver disease (n = 23); and normal liver (n = 16). FPCC was highest (mean, 17.8 mumol/l) in the shunt group, followed by the cirrhosis (12.3), miscellaneous liver diseases (4.6), and normal liver (2.1) groups. FPCC seemed to reflect severity of functional impairment, further supported by highly significant correlations with quantitative liver function tests, such as aminopyrine breath test (Rs = -0.89; n = 66), indocyanine green disappearance (Rs = -0.85; n = 65), and galactose elimination capacity (Rs = -0.70; n = 75). A careful dietary history showed no significant difference in caffeine consumption among the groups. It is suggested that in regular coffee drinkers FPCC might serve as a simple and convenient guide to the severity of functional impairment in chronic liver disease.

Adult

[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

[Bile acid concentration in serum after a test meal in hepatobiliary diseases. A comparison with quantitative liver function tests].

The concentration of bile acids in serum was measured by an enzymatic-fluorometric method under fasting conditions and 2 hours after a standardized meal in 26 patients with chronic liver disease (chronic hepatitis, liver cirrhosis, primary biliary cirrhosis) and compared with other tests of liver function. Postprandial bile acids and transaminases were false negative in only 12% and are thus the most sensitive tests after the BSP-retention test (3% false negative results). In comparison, fasting bile acids proved to be a relatively insensitive screening test for liver disease (38% false negative results). Postprandial bile acids were more closely correlated with BSP retention and BSP disappearance rate constant (Ki) than fasting bile acids. In view of these findings postprandial serum bile acid concentrations should be preferred to fasting bile acid concentrations in screening for liver disease and monitoring liver function.

Adult