Discrimination between the venous equilibrium and sinusoidal models of hepatic drug elimination in the isolated perfused rat liver by perturbation of propranolol protein binding.

To discriminate between two widely used models of hepatic drug elimination, the venous equilibrium and sinusoidal models, we examined the effect of altering perfusate protein binding on the hepatic elimination of the highly cleared drug, propranolol, by the isolated perfused rat liver. We investigated specifically the relationship between the unbound fraction of drug perfusing the liver and the steady-state unbound drug concentration in hepatic venous effluent (i.e.

Effect of increased bile flow and bile acid secretion on the hepatic elimination of sodium valproate in the cat.

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.

Circadian temperature variation in healthy aged and in Alzheimer's disease.

Circadian temperature variation was monitored in healthy older adults and in health-, age-, and sex-matched Alzheimer's dementia patients. Oral and rectal temperatures were analyzed for mean level, amplitude, and phase using cosinor analyses. Mean 24-hour temperature level was not altered by dementia.

Human antroduodenal motility, pyloric closure, and domperidone.

The action of the peripheral dopamine antagonist, domperidone, on human antroduodenal coordination, has been studied in a double-blind study. Thirty dyspeptic patients without antroduodenal pathology were studied at upper alimentary endoscopy, being studied for two 10-minute periods before and after receiving intravenous domperidone (20 mg) or placebo. Antral and proximal duodenal contractions were recorded with Fogarty balloon catheters and pyloric closure recorded as the fall in impedance measured across four small electrodes maintained at the pylorus.

Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics.

The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n = 6 subjects) or ranitidine (300 mg/day, n = 6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life.

Simultaneous high-performance liquid chromatographic analysis of omeprazole and its sulphone and sulphide metabolites in human plasma and urine.

Omeprazole, a substituted benzimidazole which suppresses gastric acid secretion, and its sulphone and sulphide metabolites were simultaneously measured in human plasma and urine using a selective, reversed-phase, high-performance liquid chromatographic method with a sensitivity of 5 ng/ml for omeprazole, 30 ng/ml for omeprazole sulphone, and 50 ng/ml for omeprazole sulphide. The coefficients of variation for within-day assays were 4.4, 7.

Timing of pyloric closure in man. Studies with impedance electrodes.

The timing of pyloric closure was studied at upper alimentary endoscopy in 20 subjects without antroduodenal pathology. Antral and duodenal contractions were recorded with balloon catheters and pyloric closure detected as a fall in impedance measured across two pairs of silver wire electrodes mounted around the shaft of the duodenal catheter 0.5 cm proximal to the balloon.

Group modification of affective verbalizations in a psychiatric population.

An operant group procedure significantly increased the frequency of here-and-now affect, feedback and empathy statements made by psychiatric patients when compared with non-reinforced patients and with base-line performances. Transfer effects were also noted when randomly selected patients from these original groups were 'seeded' into new groups during a non-reinforced session one week after training. Self-disclosure, measured by a modification of Jourard's scale, showed pre-post increases, but the expected interaction with reinforcement was non-significant (P less than 0.

Placental transfer and renal elimination of cimetidine in maternal and fetal sheep.

The placental transfer and renal elimination of cimetidine were studied at steady state in near-term pregnant sheep. In seven nonanesthetized sheep, maternal dosage produced mean steady-state plasma concentrations of 776 +/- 217 ng/ml in the mother and 32 +/- 15 ng/ml in the fetus. Total cimetidine clearance was 41.

Gliadin subfraction skin test for the diagnosis of coeliac disease.

Skin hypersensitivity to a gliadin subfraction (Fraction 3) was tested in patients with coeliac disease, patients with inflammatory bowel disease, and controls. Those with coeliac disease showed substantially greater hypersensitivity than controls, but there was no significant difference between the frequency of hypersensitivity in patients with coeliac disease and in those with inflammatory bowel disease. Fraction 3 did not provide a sufficiently specific skin reaction to be of use in the diagnosis of coeliac disease.

Sleep apnea: relationship to age, sex, and Alzheimer's dementia.

The relationship of sleep apnea to age, sex, and Alzheimer's dementia was investigated in 45 elderly subjects and 10 young males, all nonobese, normotensive, nonsmoking, with no sleep complaints and no medical problems other than Alzheimer's disease. Mean apnea/hypopnea index [(AH)I] was significantly greater in elderly males than in young males or elderly females. Mean (AH)I and percentage of subjects with an (AH)I greater than 5 in the Alzheimer groups were not significantly different from age and sex-matched controls.

Hepatotoxicity of sodium valproate.

Repeated clinical and biochemical evaluations of liver function were performed on 60 patients taking sodium valproate. No clinical evidence of liver disease was found. Biochemical abnormalities were frequently found, but they were far more common in patients treated with multiple anticonvulsants than in patients on valproate alone.

H2-receptor antagonists and hepatic drug disposition.

The effect of four H2-receptor antagonists (cimetidine, burimamide, oxmetidine, and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The first three drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100-ml, recycling, constant flow circuit for 4 hr.

High dose of antacid (Mylanta II) reduces bioavailability of ranitidine.

To investigate the effect of antacid on the bioavailability and disposition of ranitidine six healthy volunteers were studied on two occasions one week apart. In the first study the received ranitidine 150 mg with 60 ml water, and in the second study they received ranitidine 150 mg plus 30 ml of an aluminium/magnesium hydroxide mixture (Mylanta II) and 30 ml water. Giving antacid reduced both the maximum plasma ranitidine concentration and the area under the curve by one-third; elimination of the drug was not changed.

Placental transfer of ranitidine during steady-state infusions of maternal and fetal sheep.

The placental transfer of ranitidine was studied at pharmacokinetic steady state in anesthetized, full-term, pregnant sheep. Ranitidine was administered to the ewe in three preparations and to the fetus in three other sheep. In all experiments, dose size was based on the combined maternal-fetal weight.

Fetal bile salt metabolism: placental transfer of dihydroxy bile salts in sheep.

The bidirectional placental transfer of sodium [11,12-di-3H]chenodeoxycholate and sodium [14C]deoxycholate was studied in conscious pregnant sheep near term. In fetal-to-maternal studies, radiolabeled bile salt was injected into the fetal portal vein, and the daily excretion of radiolabel in maternal hepatic bile was measured over 3-4 days. In maternal-to-fetal studies, the mother received daily injections of radiolabeled bile salt, and the accumulation of label in the fetal pool was measured after 6-9 days.

High-pressure liquid chromatographic determination of cimetidine in plasma and urine.

An assay is described for the determination of the H2-receptor antagonist, cimetidine, in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analysed by high-pressure liquid chromatography (HPLC) using a reversed-phase prepacked plastic column housed in a radial compression module. The metabolite, cimetidine sulfoxide, was identified but could not be quantitated due to interference from the solvent front.

The developing liver: the steady-state disposition of propranolol in pregnant sheep.

The steady-state disposition of the beta-adrenoreceptor blocking drug, propranolol, and its metabolite, 4-hydroxypropranolol, was studied in the anesthetized pregnant sheep near term. Following infusion of propranolol to the mother, steady-state plasma concentrations were obtained at three dosage levels in each of the eight animals studied. Blood samples were obtained from : (i) maternal facial artery and hepatic vein; (ii) umbilical vein, and (iii) fetal carotid artery, portal vein, and right hepatic vein.