Search PubMed⌕ Search

Biomedical subjects

K F Sewing

Publications and source records attributed to K F Sewing.

249 records · Page 14Linked to original sources
PubMed1967

Histamine in the plasma and gastric juice of cats during infusions of [14C] histamine.

1. In anaesthetized cats with gastric fistulae, the relation was investigated between the rate of gastric secretion and the histamine contents of the plasma and the gastric juice during intravenous infusions of [(14)C]histamine for 3 hr.2. In the first hour only, some endogenous histamine appeared in the gastric juice.3. There was no quantitative relation between the histamine that was infused and that which appeared in the gastric juice.4. There was no correlation between the rate of gastric secretion and the concentration of histamine in either plasma or gastric juice.5. It was concluded that the secretion of histamine into the gastric juice was not essential to gastric secretion.

Animals↗
PubMedDate not supplied

Influence of atropine, metiamide and vagotomy on cAMP of resting and stimulated gastric mucosa.

In normal rats the effect of atropine and metiamide was studied on cAMP levels of resting and histamine-, pentagastrin-, carbachol- and insulin-stimulated gastric mucosa. In vagotomized rats gastric mucosal cAMP levels were investigated under basal conditions and after insulin. Atropine and metiamide did not alter cAMP levels of resting gastric mucosa. Truncal vagotomy caused an increase in gastric mucosal cAMP, which was not affected by insulin. All gastric secretagogues caused a significant rise in gastric mucosal cAMP levels, which was not antagonized by atropine. Metiamide effectively blocked the rise in cAMP concentration after histamine and pentagastrin, but not that evoked by cholinergic stimulation. The results are consistent with the view that the in vivo rise of gastric mucosal cAMP after carbachol or insulin is not due to a direct cholinergic action. From the spectrum of inhibitory actions of metiamide it looks as if the increase in rat gastric mucosal cAMP concentration after histamine and pentagastrin administration is mediated by H2-receptor stimulation.

Animals↗
PubMedDate not supplied

Cyclosporin metabolism in transplant patients.

The immunosuppressant cyclosporin, a cyclic undecapeptide, is metabolized to more than 30 metabolites. Cytochrome P450IIIA enzymes located in liver and small intestine are responsible for the biotransformation of cyclosporin and its metabolites and are the site of several drug interactions. It is still under discussion, whether the cyclosporin metabolites are involved in the immunosuppressive and/or toxic activities of cyclosporin. While isolated metabolites show not more than 10-20% of the activity of the mother compound in vitro, metabolite combinations have additive and synergistic effects. Isolated metabolites show no toxic effects in rat models while there is an association between metabolite blood concentrations and cyclosporin toxicity in several clinical studies. Possible mechanisms for the toxic effect of cyclosporin metabolites are covalent binding to macromolecules in liver and kidney, alteration of the cytochrome P450 pattern in liver and kidney, increased endothelin production in the kidney and synergistic effects of cyclosporin combinations on mesangial cells. Liver dysfunction leads to an alteration of the metabolite patterns and to increased concentrations of cyclosporin metabolites in blood. In conclusion there is evidence that cyclosporin metabolites may contribute to cyclosporin toxicity and high metabolite blood concentrations in patients should not be tolerated.

Animals↗
PubMedDate not supplied

Isolation of two immunosuppressive metabolites after in vitro metabolism of rapamycin.

Rapamycin was incubated with human liver microsomes and an NADPH regenerating system, the metabolites were purified by semipreparative HPLC, and their structures were elucidated by direct chemical ionization and FAB-MS. At least six fractions were isolated containing rapamycin metabolites, indicating that rapamycin is metabolized by the human liver cytochrome P-450 system. One of these metabolites was identified as 41-O-demethyl-rapamycin. A second metabolite was hydroxylated in a yet unknown position. These two metabolites retained immunosuppressive activity in a phytohemagglutinin-stimulated human lymphocyte assay with IC50S of 1 and 1.5 nmol/liter, respectively. Rapamycin was metabolized by rat small intestinal microsomes to at least two metabolites, indicating extra-hepatic metabolism of rapamycin.

Animals↗
PubMedDate not supplied

Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat.

The hepatic cytochrome P-450 responsible for metabolism of the structurally related macrolides FK506 and rapamycin in humans was identified using in vitro studies. FK506 and rapamycin metabolism was significantly correlated with nifedipine oxidation in human liver microsomes of eight different individuals. Immunoinhibition with anti-P450 3A4 abolished almost all FK506 and rapamycin metabolite formation. Inactivation of P450 3A4 by incubation of human liver microsomes with triacetyl oleandomycin (50 microM) or gestodene (10 microM) inhibited metabolism of FK506 and rapamycin. In liver microsomes from dexamethasone-treated rats FK506 and rapamycin metabolism was increased compared to liver microsomes from uninduced, phenobarbital-, or 3-methylcholanthrene-induced rats. FK506 and rapamycin were metabolized by reconstituted recombinant human liver P450 3A4. It is concluded that in human and rat liver FK506 and rapamycin are metabolized primarily by cytochrome P-450 3A4.

Animals↗