Basic aspects of selectivity of pantoprazole and its pharmacological actions.

Pantoprazole sodium is a substituted benzimidazole derivative which controls acid secretion by inhibition of gastric H(+)/K(+)-ATPase. The prodrug pantoprazole accumulates in the acidic space of the parietal cell where it is converted to the pharmacologically active principle, a thiophilic cyclic sulfenamide. The pH-dependent activation profile, i.

Helicobacter pylori augments the acid inhibitory effect of omeprazole on parietal cells and gastric H(+)/K(+)-ATPase.

Background: In duodenal ulcer patients, intragastric acidity during omeprazole treatment is significantly lower before Helicobacter pylori eradication than after cure.

Aims: To determine if H pylori enhances the acid inhibitory potency of omeprazole in isolated parietal cells and on H(+)/K(+)-ATPase.

Methods: Rat parietal cells and pig gastric membrane vesicles enriched in H(+)/K(+)-ATPase activity were incubated with H pylori and the H pylori fatty acid cis 9,10-methyleneoctadecanoic acid (MOA), and the inhibitory effects of omeprazole on parietal cell acid production, H(+)/K(+)-ATPase enzyme activity, and ATPase mediated proton transport were assessed.

Automated, fast and sensitive quantification of drugs in blood by liquid chromatography-mass spectrometry with on-line extraction: immunosuppressants.

We developed a universal LC-mass spectrometry assay with automated online extraction (LC/LC-MS) to quantify the immunosuppressants cyclosporine, tacrolimus, sirolimus and SDZ-RAD alone or in combination in whole blood. After protein precipitation, samples were loaded on a C18 extraction column, were washed and, after activation of the column-switching valve, were backflushed onto the C8 analytical column. [M+Na]+ ions were detected in the selected ion mode.

Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD.

Aims: The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels.

Methods: SDZ RAD was administered orally in different doses (0.

Helicobacter pylori reduces intracellular glutathione in gastric epithelial cells.

Helicobacter pylori infection has been associated with stimulation of gastric mucosal reactive oxygen species (ROS) production, and it was postulated that ROS production is due to neutrophil infiltration and activation. The aim of this study was to investigate the direct effect of H. pylori on ROS formation in gastric epithelial cells in vitro.

Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin.

In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metabolism and drug interactions of the acid and lactone forms of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hydroxy and ortho-hydroxy metabolites. Both substrates were metabolized mainly by CYP3A4 and CYP3A5.

Helicobacter pylori causes DNA damage in gastric epithelial cells.

Helicobacter pylori infection has been considered as a risk factor for gastric carcinoma. Strong evidence exists that reactive oxygen species (ROS) play an important role in carcinogenesis, and in vivo investigations have shown increased synthesis of ROS in the gastric mucosa of H.pylori-infected patients.

Role of vacA and cagA in Helicobacter pylori inhibition of mucin synthesis in gastric mucous cells.

The aim of this study was to investigate the effect of Helicobacter pylori on the function of gastric mucous cells. H. pylori (10(4) to 10(7) CFU/well) was incubated with the mucin-producing gastric cell line HM02 for 12 and 24 h.

Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin.

We compared the intestinal metabolism of the structurally related 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin and pravastatin in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6'beta-hydroxy (apparent K(m) = 11.2 +/- 3.

Growth characteristics and influence of antibiotics on rough/smooth phenotypic variants of Helicobacter pylori.

Helicobacter pylori shows a rather high variability of several biochemical markers including lipopolysaccharide structures. This study aimed to determine whether Helicobacter pylori has a potential for phenotypic variability and to describe its effects on bacterial pathogenesis. From colonies of three clinical strains of Helicobacter pylori with rough (R) colony morphology, spontaneous phenotypic variants with smooth (S) colony morphology were isolated that occurred with a frequency of 10(-2) to 10(-3), irrespective of growth conditions.

Simultaneous on-line extraction and analysis of sirolimus (rapamycin) and ciclosporin in blood by liquid chromatography-electrospray mass spectrometry.

We developed a sensitive and specific semi-automated liquid chromatography-electrospray mass spectrometric (HPLC-ESI-MS) assay for the simultaneous quantification of sirolimus and ciclosporin in blood. Following a simple protein precipitation step, the supernatants were injected into the HPLC system and extracted on-line. After column switching, the analytes were backflushed from the extraction column onto the analytical narrow-bore column and eluted into the ESI-MS system.

LC/ESI-MS allows simultaneous and specific quantification of SDZ RAD and cyclosporine, including groups of their metabolites in human blood.

An analytic technique using liquid chromatography (LC) coupled with electrospray-mass spectrometry (ESI-MS) has been developed for the simultaneous determination of the new immunosuppressant SDZ RAD (40-O-[2-hydroxy)ethylrapamycin) and cyclosporine (Cs), including their metabolites in blood. With the time-sparing, automated on-line extraction technique, the recovery of SDZ RAD averaged 95% and that of Cs, 94%. The calibration lines were linear from 0.

Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver.

In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A reductase inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6'beta-hydroxy [Michaelis-Menten constant (Km): 7.8 +/- 2.

Structural elucidation by electrospray mass spectrometry: an approach to the in vitro metabolism of the macrolide immunosuppressant SDZ RAD.

SDZ RAD [40-O-(2-hydroxyethyl)rapamycin] is a macrolide immunosuppressant that is currently under clinical investigation after organ transplantation. The elucidation of its metabolic pathway is essential to improve the understanding of its therapeutic potentials and safety. In this article we describe investigations on the structural identification of some major metabolites of the drug produced by human liver microsomes in vitro.

Stimulation of pepsinogen release from chief cells by Helicobacter pylori: evidence for a role of calcium and calmodulin.

To define the mechanisms by which Helicobacter pylori stimulates pepsinogen secretion, the in vitro release of pepsinogen was studied using a preparation of pig chief cell monolayers. Helicobacter pylori induced a time- and concentration-dependent release of pepsinogen into the medium, with about a three-fold increase in pepsinogen secretion over controls found after 45 min of incubation. 3x10(7) H.

Helicobacter pylori fatty acid cis 9,10-methyleneoctadecanoic acid increases [Ca2+]i, activates protein kinase C and stimulates acid secretion in parietal cells.

The effect of the Helicobacter pylori (H. pylori) fatty acid cis 9,10-methyleneoctadecanoic acid (MOA) on gastric acid secretion was studied in isolated guinea-pig parietal cells. MOA (1 and 3 micromol/l) stimulated basal and enhanced histamine- and dibutyryl cyclic AMP-stimulated acid secretion in parietal cells.

Effects of PGE2 and of different synthetic PGE derivatives on the glycosylation of pig gastric mucins.

The glycosylation of pig gastric mucins, discharged in response to prostaglandin (PG) E2 and to three synthetic PGE-derivatives (misoprostol, nocloprost, rioprostil) was compared. After a 20 h culture period in the absence or presence of 1 micromol/l of one of the PGs, mucins were isolated by gel chromatography and their glycosylation characterized by their linkage to a panel of lectins. For all tested PGs, a significantly increased lectin linkage to mucin glycoproteins of high molecular weight was detected; no significant effects were observed for low molecular weight glycoproteins.

The Helicobacter pylori fatty acid cis-9,10-methyleneoctadecanoic acid stimulates protein kinase C and increases DNA synthesis of gastric HM02 cells.

Protein kinase C (PKC) has been implicated in the control of epithelial proliferative activity and in the process of malignant transformation. Helicobacter pylori (H.p.

Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine.

Small intestinal metabolism and transport of sirolimus, a macrolide immunosuppressant with a low and highly variable oral bioavailability, were investigated using small intestinal microsomes and intestinal mucosa in the Ussing chamber. After incubation of sirolimus with human and pig small intestinal microsomes, five metabolites were detected using high performance liquid chromatography/electrospray-mass spectrometry: hydroxy, dihydroxy, trihydroxy, desmethyl and didesmethyl sirolimus. The same metabolites were generated by human liver microsomes and pig small intestinal mucosa in the Ussing chamber.

Automated simultaneous quantification of the immunosuppressants 40-O-(2-hydroxyethyl) rapamycin and cyclosporine in blood with electrospray-mass spectrometric detection.

A new analytical method to quantify 40-O-(2-hydroxyethyl)rapamycin (SDZ RAD) and cyclosporine (Cs) simultaneously in blood is presented. The combination of an on-line solid-phase extraction step with an HPLC system coupled to an electrospray mass spectrometer gave excellent specificity, sensitivity, and reproducibility. Aliquots of deproteinized blood samples were injected into the HPLC system and extracted on-line, using a conventional C18 guard column.

Pitfalls in monitoring tacrolimus (FK 506).

Tacrolimus (FK 506) is a new, potent immunosuppressive drug for primary and rescue therapy in liver and kidney transplantation. Therapeutic drug monitoring is essential for this drug because of its narrow therapeutic window. Blood levels are monitored routinely by enzyme linked immunoassay (ELISA) or by microparticle enzyme immunoassay (MEIA).