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Biomedical subjects

T Manabe

Publications and source records attributed to T Manabe.

618 records · Page 35Linked to original sources
PubMedDate not supplied

Effect of short-term pancreatico-biliary duct obstruction with intraductal hypertension on subcellular organelle fragility and pancreatic adenylate energy metabolism in rats: protective effect of a new protease inhibitor, E-3123.

Blockage of the rat pancreatico-biliary duct (PBDO) for 4 hours and secretin infusion (0.2 CU [Clinical Unit]/kg/hr) caused significant rises in portal serum amylase, cathepsin B levels, pancreatic water content, and pancreatic amylase content as well as lysosomal and mitochondrial fragility. Impaired pancreatic adenylate energy charge levels were also noted. These changes tended to continue for 12 hours after the release of PBDO and disappeared after 24 hours. All the changes induced by PBDO with secretin infusion were no longer observed at 48 hours. The administration of a new potent protease inhibitor, E-3123 at a dose of 5 mg/kg/hr during PBDO markedly attenuated all the parameters examined, exerting a significant protective effect on acinar cells in this model. These results indicate the important roles of subcellular organelle fragility and impaired pancreatic energy metabolism in the pathogenesis of pancreatic injuries induced by common channel obstruction with intraductal hypertension, and also indicate the possible usefulness of E-3123 in the treatment of acute pancreatitis such as gallstone pancreatitis.

Adenylyl Cyclases↗
PubMedDate not supplied

Pharmacokinetics of RU44403, an active form of newly developed angiotensin-converting enzyme inhibitor (RU44570) in the rat.

Trandolapril (RU44570) is an ethyl ester prodrug of trandolprilat (RU44403) having angiotensin I-converting enzyme (ACE) inhibitory activity. Disposition of RU44403 was investigated by oral or intravenous administration of RU44570 (0.1, 1, and 3 mg/kg p.o. or 1 mg/kg i.v.) and RU44403 (0.94 mg/kg p.o.) to rats. Orally dosed RU44403 was scarcely absorbed from the gastrointestinal tract (3% of dose), whereas its prodrug was found to be rapidly absorbed (32.1-45.7% of dose) and completely transformed to RU44403, giving maximum plasma concentration within 0.5 hr. Regardless of both dose level and route of administration, almost similar plasma concentrations of RU44403 were observed in the terminal phase following doses of RU44570, resulting in prolonged elimination half-life, 89.01, 63.29, and 62.64 hr for 0.1, 1, and 3 mg/kg p.o. and 63.52 hr for 1 mg/kg i.v., respectively. Furthermore, oral AUC0-infinity of 0.1 mg/kg RU44403 was not dose proportional, suggesting nonlinear pharmacokinetic profile. To elucidate the factors causing the nonlinear disposition, a dissociation constant of the active metabolite in plasma was determined using a one-compartment model in which free RU44403 in plasma was the sole form available for elimination from the compartment. The value of the constant was 0.024 nM, which was closely similar to that of the high-affinity binding site of plasma protein determined by the ultrafiltration method in vitro. Also, both values were comparable with an inhibitor constant of RU44403 to ACE in plasma that was obtained by Henderson's plot for a kinetic analysis of the tight binding of an enzyme and inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

The association of sialyl Lewis(a) antigen with the metastatic potential of human colon cancer cells.

BACKGROUND: The vascular endothelium plays a critical role in cancer metastasis by directing circulating cancer cells into extravascular tissues and by expressing cell adhesion molecules. The authors investigated the interaction between a cell line derived from human colon cancer and cultured murine endothelial cells, in vitro, and in vivo. MATERIALS AND METHODS: Variant cell lines with high (WiDr-HA) or low (WiDr-LA) levels of cell surface sialyl Lewis(a) antigen (s-Le(a)) were isolated from the heterogeneous WiDr cells (WiDr-P) in order to characterize the biological behavior of colon cancer cells having elevated cell surface contents of s-Le(a). RESULTS: A correlation was found to exist between the degree of s-Le(a) expression, and the attachment of cancer cells to activated human umbilical vein endothelial cells, or to F-2 cells isolated from murine vascular endothelial cells. The adhesion of WiDr-P and WiDr-HA to F-2 cells was inhibited by the addition of anti-s-Le(a) antibody (Ab). WiDr-P and WiDr-HA both demonstrated the capacity to metastasize to the liver, by the inoculation of cancer cells to the spleen, while WiDr-LA did not do so. The number of metastatic nodules of WiDr-HA was significantly higher than that of WiDr-P. Treatment with anti-s-Le(a) Ab inhibited the metastasis of WiDr-P and WiDr-HA to the liver, but not with anti-s-Le(x) Ab. CONCLUSIONS: These findings suggest that s-Le(a) plays an important role in cell adhesion molecules, in the metastasis of colon cancer.

Animals↗