Glucose and citrate reduce the permeability changes caused by indomethacin in humans

Nonsteroidal anti-inflammatory drug (NSAID)-induced increased intestinal permeability appears to be a prerequisite for NSAID enteropathy. It has been suggested that early metabolic events leading to the permeability changes may involve inhibition of glycolysis and the tricarboxylic acid cycle, in which case the coadministration of glucose and citrate (the substrates for these metabolic pathways) with indomethacin may afford some protection. The present study, using a combined intestinal absorption-permeability test including 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and [51Cr]ethylene-diaminetetraacetic acid (EDTA) as test probes and the differential urine excretion ratio of [51Cr]-EDTA/L-rhamnose, showed that indomethacin (50 + 75 mg) increased intestinal permeability. A formulation of indomethacin containing 15 mg glucose and 15 mg citrate to each milligram of indomethacin did not increase intestinal permeability significantly above baseline values. When given alone with indomethacin, neither glucose nor citrate (45 mg to each milligram of indomethacin) had any protective effects. Pharmokinetic studies showed that the effects of glucose and citrate cannot be explained on the basis of altered drug absorption. These results suggest a new approach to reducing the small intestinal side effects of NSAIDs.

Calcium fluxes modulate the radiation-induced bystander responses in targeted glioma and fibroblast cells

Bystander responses have been reported to be a major determinant of the response of cells to radiation exposure at low doses, including those of relevance to therapy. This study investigated the role of changes in calcium levels in bystander responses leading to chromosomal damage in nonirradiated T98G glioma cells and AG01522 fibroblasts that had been either exposed to conditioned medium from irradiated cells or co-cultured with a population where a fraction of cells were individually targeted through the nucleus or cytoplasm with a precise number of microbeam helium-3 particles. After the recipient cells were treated with conditioned medium from T98G or AG01522 cells that had been irradiated through either nucleus or cytoplasm, rapid calcium fluxes were monitored in the nonirradiated recipient cells. Their characteristics were dependent on the source of the conditioned medium but had no dependence on radiation dose. When recipient cells were co-cultured with an irradiated population of either T98G or AG01522 cells, micronuclei were induced in the nonirradiated cells, but this response was eliminated by treating the cells with calcicludine (CaC), a potent blocker of Ca2+ channels. Moreover, both the calcium fluxes and the bystander effect were inhibited when the irradiated T98G cells were treated with aminoguanidine, an inhibitor of nitric oxide synthase (NOS), and when the irradiated AG01522 cells were treated with DMSO, a scavenger of reactive oxygen species (ROS), which indicates that NO and ROS were involved in the bystander responses generated from irradiated T98G and AG01522 cells, respectively. Our findings indicate that calcium signaling may be an early response in radiation-induced bystander effects leading to chromosome damage. (c) 2006 by Radiation Research Society.

Radiation effects on the cytoskeleton of endothelial cells and endothelial monolayer permeability

Purpose: To investigate the effects of radiation on the endothelial cytoskeleton and endothelial monolayer permeability and to evaluate associated signaling pathways, which could reveal potential mechanisms of known vascular effects of radiation.

ROLE OF INTRACELLULAR AND EXTRACELLULAR CALCIUM IN HISTAMINE-RELEASE FROM RAT PERITONEAL MAST-CELLS

The present study provides evidence for a number of calcium pools important in histamine secretion from the mast cell. Firstly, calcium loosely bound to the cell membrane, and in rapid equilibrium with the extracellular environment, may be utilized for histamine release induced by most secretagogues. Secondly, all inducers are able to mobilize deeply buried or internal stores of calcium to initiate exocytosis. Finally, calcium bound to regulatory sites in the membrane may modulate the secretory process, Removal of calcium from the latter sites by brief treatment with chelating agents markedly enhances the secretory response in the absence of extracellular calcium, probably by facilitating the mobilization of bound stores of the ion, Saturation of these sites in the presence of excess calcium inhibits the release process and may restrict influx of the cation.