Backtracking booze with Bayes--the retrospective interpretation of blood alcohol data.

1. A Bayesian method is described which allows the explicit estimation of errors produced in estimating drug concentrations at times for which samples are not available for analysis. 2.

Propranolol oxidation by human liver microsomes--the use of cumene hydroperoxide to probe isoenzyme specificity and regio- and stereoselectivity.

1. Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-450IID6) and the remaining seven were from extensive metaboliser (EM) phenotypes.

High mortality among recipients of bought living-unrelated donor kidneys.

Between June, 1984, and May, 1988, 130 patients from three renal units in the United Arab Emirates and Oman went of their own accord to Bombay, where they bought, through brokers, kidneys from living unrelated Indian donors for US$2600-3300. 131 transplants were done, and the 122 patients who survived the perioperative period returned to their original renal units for follow-up. Altogether there were 25 deaths (16 before the end of 3 months, 4 in the next 3 months, and 4 more by the end of the first year), which gave a patient survival rate of 81.

Ethics and commerce in live donor renal transplantation: classification of the issues.

Renal transplantation is now very successful. A shortage of kidneys continues to be a problem. Attempts to increase the supply have recently led to unethical practices, but the issues in the discussion of the ethics need clarification.

Abdominal carcinoid tumours in Sheffield.

The incidence, presentation, and treatment strategies of abdominal carcinoid tumours are discussed. In the Trent Region of the UK, carcinoid tumours have an incidence of 0.7 cases/100,000 population.

Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism--hypothesis testing.

1. The theory of methods of hypothesis testing in relation to the detection of bimodality in density distributions is discussed. 2.

Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism--histograms and probit plots.

1. The shape of histograms used to illustrate density distributions of indices of polymorphic drug metabolism was shown to be sensitive to the position of the cell divisions. 2.

Inhibition of lignocaine metabolism by beta-adrenoceptor antagonists in rat and human liver microsomes.

1. The inhibition of lignocaine metabolism by beta-adrenoceptor antagonists (beta-blockers) was investigated in rat and human liver microsomes. 2.

Histamine inhibition of mixed function oxidase activity in rat and human liver microsomes and in the isolated perfused rat liver.

The imidazole ring is a common structural feature of some xenobiotics that inhibit cytochrome P-450-catalysed reactions. Histamine is a 4-substituted imidazole and a preliminary study has shown it to be an inhibitor of rat liver microsomal drug oxidation. This work has now been extended.

Stereoselective metabolism of metoprolol in Caucasians and Nigerians--relationship to debrisoquine oxidation phenotype.

The relationship between debrisoquine oxidation phenotype and the stereoselective metabolism of metoprolol was investigated in populations of British Caucasians (n = 139) and Nigerian subjects (n = 117). The 0-8 h urinary S/R-metoprolol (S/R-M) ratio was related to the ability to metabolise metoprolol and debrisoquine in both ethnic groups. The median S/R-M ratio was significantly higher in Caucasians (1.

Timolol metabolism and debrisoquine oxidation polymorphism: a population study.

1. The metabolism of orally administered timolol (T) to its ring cleavage ethanolamine (TE) and glycine (TG) products was studied in 108 unrelated hypertensive patients. 2.

Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes.

The oxidation of the beta adrenoceptor antagonist metoprolol exhibits genetic polymorphism of the sparteine/debrisoquine (SP/DB) type. The alpha-hydroxylation of metoprolol is absent in poor metabolizers, whereas metoprolol O-demethylation is only partially impaired, suggesting that an enzyme or enzymes other than cytochrome P450-SP/DB contribute to the latter reaction. Using inhibition by the quinidine/quinine isomer pair as a marker for the activity of cytochrome P450-SP/DB, the role of this enzyme in the in vitro oxidation of the enantiomers of metoprolol by human liver microsomes was examined.

Irreversible binding and metabolism of propranolol by human liver microsomes--relationship to polymorphic oxidation.

Studies were performed to investigate the irreversible binding and oxidative metabolism of propranolol in human liver microsomes and the relationship of binding and metabolism to the polymorphic oxidation of debrisoquine. Incubation of microsomes with 14C-labelled propranolol in the presence of a NADPH-generating system gave rise to irreversible binding which increased linearly with time and became saturated at high substrate concentrations. The extent of binding was decreased by the exclusion of cofactors, boiling, anaerobic conditions, and the addition of reduced glutathione and SKF-525A.

The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus.

Fourteen non-insulin-dependent diabetics (9 female, 5 male), aged 46 to 64 years, uncontrolled by diet (fasting plasma glucose greater than or equal to 8 mmol/l), were treated with metformin, 1-3 g daily, and followed prospectively at 1 week, then at 2-weekly intervals for 6 months. The fasting plasma glucose fell significantly (p less than 0.01) after 1 week of therapy and HbA1 showed a significant reduction, 13.

Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices.

The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined. Pharmacokinetic determinants in addition to partial metabolic clearance down the polymorphic route were identified in each index. The ability of the various indices to discriminate bimodality in population data was assessed using a computer simulation.

Metoprolol and debrisoquin metabolism in Nigerians: lack of evidence for polymorphic oxidation.

The role of genetic polymorphism in the oxidative metabolism of metoprolol and debrisoquin was investigated in a population of 138 unrelated Nigerians. The debrisoquin/4-hydroxydebrisoquin 0-8 hour urinary ratio (D/HD) correlated significantly with the metoprolol/alpha-hydroxymetoprolol 0-8 hour urinary ratio (M/HM) (rs = 0.54; P less than 0.

Metoprolol oxidation by rat liver microsomes. Inhibition by debrisoquine and other drugs.

The oxidative metabolism of metoprolol has been shown to display genetic polymorphism of the debrisoquine-type. The use of in vitro inhibition studies has been proposed as a means of defining whether one or more forms of cytochrome P-450 are involved in the monogenically-controlled metabolism of two substrates. We have, therefore, tested the ability of debrisoquine and other substrates to inhibit the oxidation of metoprolol by rat liver microsomes.

Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol.

The contribution of debrisoquine polymorphism to the metabolism and action of beta-adrenoceptor antagonists (beta-blockers) varies widely between drugs. Oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The poor metabolizer phenotype is associated with an increased area under the plasma drug concentration vs.