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Biomedical subjects

J Bircher

Publications and source records attributed to J Bircher.

At least 37 records · Page 2Linked to original sources
PubMed1990

Hepatic and extrahepatic disposition of propofol in patients undergoing coronary bypass surgery.

In order to clarify the relative contribution of the liver to the short term disposition of propofol, hepatic blood flow was measured during induction of anaesthesia with an i.v. bolus dose of propofol 2 mg kg-1. Total clearance of the drug was 2390 (SD 340) ml min-1, hepatic extraction 82% and hepatic clearance 1060 (260) ml min-1. During the 60-min period of observation, hepatic extraction of propofol increased from 79% to 92%. It is concluded that, within 1 h, only 44% of the administered dose is removed by the liver. Consequently, drug accumulation may occur with repeated dosing or infusion of propofol. The increase in extraction results presumably from slow release of propofol from the soy-bean emulsion.

Adult↗
PubMed1990

Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges.

Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases, were given ciprofloxacin (200 mg twice daily iv). Ciprofloxacin concentrations in serum and CSF were measured by HPLC. Single-dose pharmacokinetics were determined in three patients, and 60 and 600 min post-dose levels after repeated administration in six patients. CSF concentrations were maximal 60-120 min after the end of the infusion. The CSF elimination half-life was 260-430 min compared with 145-170 in serum. Post-dose levels at 60 min ranged from 0.042 to 0.223 mg/l (median = 0.110). Repeated administration did not lead to substantial increases in serum and CSF concentrations. With respect to MIC90 values reported for bacteria involved in CNS infections, the CSF concentrations of ciprofloxacin obtained under our experimental conditions would be considered subtherapeutic. Thus ciprofloxacin therapy of CNS infections may be inadequate when only minor impairment of the blood-CSF barrier exists.

Adult↗
PubMed1990

Low fractions of mono- and diconjugated bilirubin in patients with beta-thalassemia: an approach to characterize hepatic conjugation capacity.

Unconjugated and mono- and diconjugated bilirubin was determined by alkaline methanolysis and thin-layer chromatography in serum from 16 pediatric patients with homozygous beta-thalassemia (aged 1-23 years), in 14 age-matched controls, and in 26 healthy adults. Total bilirubin amounted to 21 +/- 20 mumol/L in patients with thalassemia compared with 7 +/- 4 mumol/L in healthy children and 11 +/- 3 mumol/L in healthy adults. The fractions of bilirubin conjugates in the various groups were 8 +/- 4% (patients with thalassemia), 18 +/- 5% (age-matched controls; p less than 0.001), and 16 +/- 5% (healthy adults; p less than 0.001). The low fraction of bilirubin conjugates in patients with thalassemia showed no correlation to any other physical or laboratory finding. It is concluded that subnormal values of bilirubin conjugates in thalassemia indicate defective bilirubin conjugation.

Adolescent↗
PubMed1989

Dose equivalence of midazolam and triazolam. A psychometric study based on flicker sensitivity, reaction time and digit symbol substitution test.

The pharmacodynamic potency of oral midazolam, a new ultrashort-acting hypnotic benzodiazepine, has been evaluated relative to a standard dose of triazolam, a well established oral benzodiazepine with a similar pharmacological profile. In a balanced design, double-blind cross-over study 6 healthy volunteers received 3.75, 7.5, and 15 mg midazolam and 0.25 mg triazolam orally, at 8 a.m., at weekly intervals. Drug effects were repeatedly measured over 8 h by a new psychometric method, the threshold amplitude for perception of flickering light (TPF) assessed at 5 and 30 Hz. Auditory reaction time, digit-symbol substitution test (DSST), and self-rating by subjects served as reference standards. Median midazolam doses equivalent to 0.25 mg triazolam, interpolated on dose-response curves for peak effects, were 5.2 mg (TPF 30 Hz), 6.4 mg (TPF 5 Hz), 6.5 mg (DSST), and 7.4 mg (reaction time), respectively. Alternative methods of data analysis gave similar results. Introduction of TPF as a highly reproducible and sensitive measure of the effect of benzodiazepines on the CNS offers new opportunities to compare the relative potencies of different benzodiazepines in man. Since clinical experience has shown 0.25 mg triazolam to be safe and effective, it is concluded that the corresponding single oral dose of midazolam is between 5 and 8 mg.

Adult↗
PubMed1989

Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis.

To evaluate the prognostic value of quantitative liver function tests in comparison with established prognostic variables, the data of 47 patients with liver cirrhosis were analysed. A total of 16 variables, comprising the galactose elimination capacity and the indocyanine green clearance, the Child-Pugh classification, and several clinical and biochemical variables were subjected to Kaplan-Meier life-table analysis and Cox proportional hazards regression analysis. As independent variables, poor prognosis was associated significantly with increasing Child-Pugh score (p less than 0.00001), whereas the galactose elimination capacity (p = 0.03) and the indocyanine green clearance (p less than 0.001) were less sensitive indicators. The regression analysis showed prognostic value in decreasing sequence for Child-Pugh classification, age, sex, history of upper GI haemorrhage, and alkaline phosphatase activity. The quantitative liver function tests evaluated in the present work have less prognostic value than routinely accessible variables.

Adult↗
PubMed1988

Increased systemic availability of albendazole when taken with a fatty meal.

We have studied the systemic availability of oral albendazole in 6 patients with echinococcosis either fasting or with breakfast. Albendazole sulphoxide, the pharmacologically active principle, was assayed by HPLC. Mean plasma concentrations and AUCs were 4.5 times higher when albendazole was given with breakfast than when administered in the fasting state. We conclude that therapy of echinococcosis with albendazole requires the drug to be taken with meals and that administration on an empty stomach might be more appropriate when intraluminal effects are desired, e.g. for intestinal parasites.

Adult↗
PubMed1988

Inadequate reporting of analytical quality control in the clinical pharmacological literature.

Quality control parameters were surveyed in the clinical pharmacological literature of 1984 and 1985, as published by the European Journal of Clinical Pharmacology, the British Journal of Clinical Pharmacology, and Clinical Pharmacology and Therapeutics. Papers which included newly developed methods gave details about precision and sensitivity in more than 60% and about accuracy and specificity in nearly 30%. Fewer than one-third of all articles containing analytical methods, described by citation only, gave information about precision and sensitivity in the originating laboratory, and accuracy and specificity were reported by less than 10% of them. These data represent an important deficiency in laboratory information in the clinical pharmacological literature.

Periodicals as Topic↗
PubMed1988

Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow.

Hepatic plasma flow was assessed with sorbitol (hepatic extraction = 0.96) at steady state. After infusion of 50 mg/min for 3 h, total and renal sorbitol clearances were calculated, and the extrarenal clearance was obtained by taking the difference between the two. In normal volunteers, the mean (+/- SD) extrarenal sorbitol clearance was 10.6 +/- 2.1 ml/min.kg. In patients with various liver diseases, it was correlated more closely to the fractional clearance of indocyanine green (r = 0.83, n = 57) than the galactose elimination capacity (r = 0.66, n = 55). Hepatic vein catheterization showed that the hepatic extraction of sorbitol was always much higher than the extraction of indocyanine green; there was no evidence for extrahepatic, extrarenal sorbitol elimination. On the basis of these findings, sorbitol is kinetically superior to indocyanine green and, although the noninvasively determined extrarenal sorbitol clearance at steady state may not be equal to total hepatic plasma flow, it may at least be regarded as a measure of parenchymal liver plasma flow.

Adult↗
PubMed1988

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↗
PubMed1987

Bioavailability determination of lidocaine by capillary gas chromatography ammonia chemical ionization mass spectrometry.

A method was developed to measure bioavailability of lidocaine by simultaneous peroral and intravenous dosing. Lidocaine hydrochloride corresponding to 125 mg base was given perorally. Simultaneously, 30 mg of deuterated lidocaine-d3 were injected intravenously. Blood samples were taken at intervals for 270 min. Plasma samples were spiked with mepivacaine hydrochloride as internal standard, alkalinized to pH 11.7 and extracted with diethyl ether. The extracts were analysed by capillary GC ammonia CI MS using a 15 m X 0.32 mm i.d. glass capillary column coated with SE-54. The ion source pressure was 0.4 Torr of ammonia as reagent gas. Quasimolecular ions were monitored at m/z 235, 238 and 247 for lidocaine, lidocaine-d3 and mepivacaine, respectively. Calibration curves were linear from 0.2 to 5.0 nmol lidocaine ml-1 plasma. Interday reproducibility of this method was 6.9% for lidocaine-d3 (n = 16; 1.90 +/- 0.13 nmol ml-1). Bioavailability of lidocaine in 5 normal volunteers ranged from 26 to 36% (mean 31 +/- SD 5%) and in a cirrhotic with an end-to-side portacaval shunt it approached 100%, as anticipated. The method is well suited for determination of bioavailability of lidocaine after simultaneous administration of rather small and safe doses both intravenously and perorally.

Administration, Oral↗
PubMed1987

Paracetamol as a test drug to determine glucuronide formation in man. Effects of inducers and of smoking.

A simple, noninvasive procedure was developed to monitor glucuronidation and sulphation in patients using paracetamol as the test drug. Urinary paracetamol and its metabolites were determined by UV absorption and electrochemical detection after separation by HPLC. The metabolite to paracetamol ratio (M/P) was used as an approximation of the partial clearance due to metabolite formation. In 14 healthy volunteers, all nonsmokers without medication, M/P was 18 +/- 5 for glucuronides and 12 +/- 4 for sulphate esters. The test was validated in patients treated with enzyme inducers. In 10 patients with epilepsy given phenytoin 0.3 g/day, and in 10 patients with tuberculosis treated with rifampicin 0.6 g/day, the M/P value for glucuronidation was significantly increased to 41 +/- 11 and 35 +/- 7, respectively. In contrast, M/P values for sulphation were not significantly different from untreated controls. In 9 heavy smokers (about 40 cigarettes/day) M/P values for glucuronidation were also significantly increased to 33 +/- 11. However, in 4 moderate smokers (about 10 cigarettes/day) no significant increase was found. The results suggest that in man glucuronidation of paracetamol is inducible both by phenobarbital- and 3-methylcholanthrene-type inducers. Monitoring the ratios of various urinary paracetamol conjugates/paracetamol may be useful as a new tool for the evaluation of factors determining glucuronide and sulphate ester formation in man.

Acetaminophen↗
PubMed1987

Non-invasive evaluation of portal-systemic shunting in man by D-sorbitol bioavailability.

Portal-systemic shunting is an important circulatory abnormality in patients with cirrhosis. This study explores the potential of the natural polyol D-sorbitol as test compound for non-invasive assessment of shunting. Ten normal subjects, 10 patients with cirrhosis and 12 cirrhotics with surgical portacaval shunts were studied after oral and intravenous administration of a 2 g dose of sorbitol. As measured by the H2 breath test, removal from the intestinal lumen was complete in both groups. Bioavailability of sorbitol, calculated as ratio of the areas under the plasma concentration/time curve after p.o. and i.v. administration, was zero in normal subjects, 0.29 +/- 0.15 in cirrhotic patients, and 0.38 +/- 0.11 in patients with portacaval shunts. Calculation of bioavailability on the basis of urinary outputs of sorbitol gave similar results. It is concluded that the bioavailability of sorbitol reflects portal-systemic shunting, although the relatively low figures suggest some degree of sorbitol metabolism by enterocytes.

Adult↗
PubMed1987

Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert's syndrome.

A group of eleven subjects with Gilbert's syndrome was characterized by conventional tests and determination of bilirubin and its conjugates in plasma by alkaline methanolysis and thin layer chromatography. After a 1 g dose of paracetamol h.s. the drug and its metabolites were measured by high performance liquid chromatography (HPLC) in the overnight 8-h urine sample. The amounts of paracetamol and of its metabolites recovered in urine were almost identical with those found in the control group (n = 10). The glucuronide:paracetamol ratio, which is considered to be an index of glucuronidation, was not correlated with the fraction of bilirubin present in plasma as glucuronides. These data do not suggest that in subjects with Gilbert's syndrome therapeutic doses of paracetamol are associated with an increased risk for hepatic or systemic toxicity.

Acetaminophen↗
PubMed1986

Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.

Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.

Adult↗