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Continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2-3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2-3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4-5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD.

The mechanisms for the lower toxicity of fenitrothion as compared with methylparathion were investigated in male rats. The difference in the acute toxicity of the insecticides could be the more rapid decomposition of fenitrothion and fenitrooxon in rat liver than that of methylparathion and methylparaoxon. In particular, the decomposition of fenitrothion by hepatic microsomes was accelerated by increasing the insecticide concentration as the substrate. The oxygen analogues of both insecticides, fenitrooxon and methylparaoxon, were not detected in the brain after the administration of their parent compounds. From these results, it is concluded that the lower toxicity of fenitrothion as compared with methylparathion could be due to the greater rate of the decomposition of fenitrothion to its less toxic metabolites, rather than to the relative rate of penetration of the oxygen analogues into brain.

The purpose of this study was to characterize the protective effect of N G -nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on oxidative stress-induced endothelial cell injury. Intracellular oxidative stress was induced by 1-chloro-2,4-dinitrobenzene, a glutathione (GSH) depleting agent, and the leakage of intracellular lactate dehydrogenase was measured as a marker of cell injury. Addition of l-chloro-2,4-dinitrobenzene (100-500 μM) induced leakage of lactate dehydrogenase from endothelial cells, and the leakage of lactate dehydrogenase was strongly attenuated by L-NAME, but not by N G -methyl-L-arginine, also an inhibitor of nitric oxide synthase. However, cell injury induced by the Ca 2+ ionophore ionomycin was not affected by L-NAME or N G -methyl-L-arginine. Moreover, neither L-NAME nor N G -methyl-L-arginine affected GSH depleting agent-induced or H 2 O 2 -induced cell injury in a rat foetal lung fibroblast cell line which lacks nitric oxide synthase. These results suggest that the protective effect of L-NAME is likely to be related to nitric oxide synthase, while the inhibition of nitric oxide production may not be involved in the protective effect of L-NAME, since N G -methyl-L-arginine did not affect endothelial cell injury.

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

6.35 1.4 (1.3-1.4) ( 3 H)GR113808 0.16 0.90 (0.68-1.1) 5-HT 1A ( 3 H)8-OH-DPAT HeLa 0.78 >4900 5-HT 1B ( 3 H)5-HT HeLa 4.14 >5600 5-HT 1D ( 3 H)5-HT

Two novel triterpene glycosides, achyranthosides E and F, were isolated as methyl esters from the root of Achyranthes fauriei, an antiinflammatory medicinal plant. Their structures were characterized as oleanolic acid glucuronides having unique substituents composed of C6H9O5 and C9H15O7, respectively, at the C-3 position of glucuronic acid. These compounds are active components which can inhibit the excess recruiting of neutrophiles to injured tissues 1,000 times more potently than sialyl Lewis X.