Biomedical subjects

A Fujimura

Publications and source records attributed to A Fujimura.

At least 73 records · Page 4Linked to original sources

PubMed2000

Failure of probucol to prolong survival in salt-loaded stroke-prone spontaneously hypertensive rats.

We examined the effect of probucol, a lipid-lowering agent with strong antioxidant properties, on neurological events and survival in stroke-prone spontaneously hypertensive rats (SHRSP). Rapid onset of stroke was induced by maintaining the animals on 1% NaCl solution in place of drinking water. Probucol (10 or 30 mg/kg/day), both of which doses are therapeutic in humans was given by gastric gavage once daily to salt-loaded SHRSP. Animals receiving vehicle were used as controls. Probucol did not influence the elevation of blood pressure. Although probucol did not improve the survival rate of salt-loaded SHRSP, 30 mg/ kg/day of probucol slightly but significantly delayed the development of neurological events (p=0.0235 by generalized Wilcoxon test). However, a high dose of probucol (100 mg/kg/day) did not change the survival or neurological events of salt-loaded SHRSP. These results suggest that probucol may be protective against the development of neurological events, but is not preventive for the progression of stroke in SHRSP.

Animals↗

PubMed2000

Acute effect of cadmium-metallothionein on glucose and amino acid transport across the apical membrane of the rabbit proximal tubule perfused in vitro.

Acute as well as chronic exposure of cadmium (Cd) leads to proximal tubule injury. The exact cellular mechanism of this disorder and whether there is a contribution of cadmium-metallothionein (Cd-MT), a binding protein of Cd, remain unclear. We perfused isolated S2 segments of rabbit nephron, and the deflections of transmural voltage (DeltaV(t)) and apical membrane voltage (DeltaV(a)) on elimination of glucose or alanine from the perfusate were measured for the parameters of activity of Na(+)-glucose and Na(+)-amino acid cotransporters. The effects of Cd-MT or CdCl(2) to either bath or lumen for 10 min on these parameters were examined. We also measured the lumen-to-bath [(14)C]glucose flux. Addition of Cd-MT to lumen suppressed glucose- or alanine-dependent DeltaV(t) and DeltaV(a), as well as baseline V(t) and basolateral membrane voltage (V(b)), at approximately 10 min. [(14)C]glucose flux was inhibited by Cd-MT to lumen. The effects of Cd-MT to bath and CdCl(2) to either lumen or bath were 100-fold less potent than that of Cd-MT to lumen. Luminal Cd-MT immediately suppressed the glucose-dependent DeltaV(a), whereas the baseline V(a) and V(t) were unchanged. The early effect of luminal Cd-MT was simulated by addition of 10(-4) M phloretin. Addition of 10(-4) M ouabain to the bath simulated the later effect of Cd-MT. The protection of SH group by dithiothreitol prevented the early effect of Cd-MT, but not the later effect. We concluded that Cd-MT initially acts directly on Na(+)-glucose and Na(+)-amino acid cotransporters from the lumen by attacking SH group, followed by the later inhibition of Na(+)-K(+)-ATPase after entering the cell from the apical membrane.

Alanine↗

PubMed1999

Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines in vitro.

We tested the effect of tamoxifen alone and tamoxifen plus 5-fluorouracil (5-FU) on proliferation of two different types of gastric cancer cell lines using the WST-1 method. A high dose of tamoxifen suppressed the proliferation of KATOIII cells (poorly differentiated adenocarcinoma), but MKN28 cells (well-differentiated adenocarcinoma) were not affected. The combination of the two drugs resulted in a synergistic anti-proliferative activity on KATOIII cells. On the other hand, in the combination therapy, tamoxifen stimulated MKN28 cells to proliferate in a dose-dependent manner. TGF-beta1 secretion was not changed in KATOIII cells by tamoxifen plus 5-FU treatment but was down-regulated in MKN28 cells. Both cancer cell lines were judged as intracellular estrogen receptor (ER) negative. These data suggest that the anti-proliferative effects of tamoxifen plus 5-FU on KATOIII cells were not dependent on ER expression or TGF-beta1 secretion. On the other hand, their proliferative effects on MKN28 cells might be, in part, caused by the reduced secretion of TGF-beta1.

Adenocarcinoma↗

PubMed1999

Chronopharmacology for deoxyspergualin: toxicity and efficacy in the rat.

BACKGROUND: Deoxyspergualin (DSG), a potent immunosuppressive drug, has been clinically used as a rescue therapy for acute graft rejection. However, DSG has severe adverse effects that limits its use. Here, we examined the optimized therapeutic protocol for DSG using chronopharmacological profiles of it. METHODS: First, a dosing time-dependent difference in the toxicity and efficacy of DSG was determined using a heterotopic heart transplantation model. Second, chronokinetics of DSG were examined to reveal the mechanism for dosing time-dependent differences in the effect. RESULTS: In rats treated with DSG at the active period, bone marrow suppression and damage of small intestine were significantly severe. However, no significant difference was found in cardiac allograft survival and pharmacokinetics according to the timing of drug administration. CONCLUSIONS: The toxicity of DSG varied with the dosing time, whereas its efficacy did not. The chronopharmacological approach may provide merits for immunosuppressive therapy with DSG in clinical organ transplantation.

Animals↗

PubMed1999

Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model. Comparative study with cyclosporine.

Cholestatic effects have been reported for cyclosporine (CsA), but information is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid composition as compared with CsA, using a continuously bile-drained rat model. Adult male Wistar rats received TCR (0.4 mg/kg, 1 mg/kg, and 4 mg/kg) or CsA (2.5 mg/kg, 10 mg/kg, and 25 mg/kg) by intramuscular injection (i.m.) daily for 10 days. On day 7, the common bile duct of all rats was cannulated, then bile was continuously collected for the following 3 days. Bile flow, bile acid secretion rate (BASR), and biliary lipids secretion were measured for each of the groups. TCR increased bile acid-dependent flow (BADF) but with no statistical significance. However, this agent did not influence total bile flow and biliary lipids secretion, while bile acid-independent flow (BAIF) was significantly reduced and bile acid synthesis (mainly cholic acid, CA, synthesis) was increased. In contrast, CsA was cholestatic, showing a tendency to reduce both BADF and BAIF. BASR was dose-dependently suppressed, especially in chenodeoxycholic acid (CDCA). Furthermore, biliary lipids secretions were also significantly decreased under a higher dose of CsA. TCR increased BADF with no influence on total bile flow, having a stimulating effect on CA production, although CsA dose-dependently diminishes CDCA production and consequently reduced bile secretion. Our results suggest that TCR is a less effective agent on cholestasis as compared to CsA.

Animals↗

PubMed1999

Changes in fecal fat excretion from allo-intestine transplanted rats after discontinuance of immunosuppressive agents.

We have previously shown in a rat model of segmental small bowel transplantation, that an ileal graft was more favorable for lipid absorption than a jejunal graft. In the present study, we investigated changes in the lipid absorption of allo-ileal grafts after the withdrawal of an immunosuppressant (methyldeoxyspergualin; given for 1 or 2 weeks at 2.5mg/kg per day) and compared the findings with the results of histological examinations. Heterotopic segmental small bowel transplantation (SBT) was performed using cuff anastomoses in the inbred rat strain combination DA (RT1a) and LEW (RT1). Orthotopic SBT was performed as reconstruction SBT. Reconstruction after resection of the original intestinal tract of the recipient was performed on the seventh day after heterotopic segmental ileal grafting. For the histological evaluation of graft rejection, we performed biopsies in the heterotopic model and autopsies in the orthotopic model. Fecal fat excretion from the orthotopically reconstructed recipients was measured by Folch's method. One- and 2-week use of methyldeoxyspergualin allowed the heterotopic allografts to remain intact histologically for 16.8+/-5.6 and 25.3+/-3.3 (mean+/-SD) days, respectively, whereas the grafts were rejected at 7.3+/-1.1 days when the immunosuppressive drug was not used. All the recipients in the orthotopic group had died by 19 days after reconstruction. After discontinuance of the immunosuppressive agent, fat excretion in feces in the surviving orthotopic grafted rats had increased markedly prior to histologically assessed heterotopic graft rejection. Evaluation of fecal lipid excretion may be a useful parameter for detecting graft rejection in rats.

Animals↗

PubMed1999

Chronotherapy of high-dose 1,25-dihydroxyvitamin D3 in hemodialysis patients with secondary hyperparathyroidism: a single-dose study.

BACKGROUND: A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. METHODS: Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 microg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. RESULTS: A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration-time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Pre-dose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. CONCLUSION: The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone-lowering effect of the drug does not vary with dosing time.

Area Under Curve↗

PubMed1999

Experimental small bowel transplantation using newborn intestine in rats: II. Revascularization of newborn intestine is independent of vascular endothelial growth factor.

BACKGROUND: Fetal and newborn intestine often are revascularized after subcutaneous transplantation without surgical vascular anastomosis. However, the mechanism of this ability remains unclear. METHODS: First, the ability of natural revascularization in newborn organs was tested. Newborn organs in whole (liver, kidney, heart, intestine, spleen, and pancreas) were grafted i nto the subcuta neous tissue of the adult rat and evaluated histopathologically 2 weeks after transplantation. Second, expression of vascular endothelial growth factor (VEGF) mRNA in the intestinal graft was determined before and after transplantation. Finally, we tested whether the free graft survival of newborn intestine was interrupted by TNP-470, an antiangiogenic agent. RESULTS: Spleen and intestine were revascularized at a higher rate (91.6%, 75%, respectively), and kidney and heart grafts survived at a lower rate (41.7%, 25%, respectively). But all of liver and pancreas grafts failed to be revascularized. VEGF mRNA was not induced in the course of revascularizing. Furthermore, TNP-470 did not interfere with neovascularization of the newborn intestinal graft in vivo. CONCLUSIONS: Each organ had an organ-specific angiogenic activity. Neovascularization of intestinal graft was not dependent on VEGF expression.

Angiogenesis Inhibitors↗

PubMed1999

Experimental small bowel transplantation using newborn intestine in rats: I. Lipid absorption restored after transplantation of nonvascularized graft.

BACKGROUND/PURPOSE: Utilizing the characters of neovascularized activity of newborn organs, the authors developed a rat model of small bowel transplantation with a free graft of newborn intestine into the recipient's omentum. METHODS: Segmental intestine from newborn rats were grafted into the omentum without vascular anastomosis in a syngeneic combination (n = 19). The transplanted intestine was examined morphologically and electrophysiologically 4 weeks after grafting. Then, recipients' small intestine was totally substituted by the transplanted newborn intestine, and recipients' survival was recorded after orthotopical reconstruction. During the experimental periods, feces of these rats were collected, and total lipid excretion was measured. The short-gut rats, whose small bowel was totally resected, served as a control (n = 12). RESULTS: Thirteen of 19 grafts (68.4%) were judged as a histologically mature intestine. They showed typical slow waves that were identical to those of native small intestine. After all of the mature grafts were interposed, six recipients (46.2%) survived longer than 15 weeks. Control short gut animals severely lost weight and died except for one. CONCLUSION: Newborn intestinal transplantation could restore severe weight loss in the short-gut rats and save them.

Animals↗

PubMed1999

Immunotherapy for experimental rat autoimmune thyroiditis using a novel immunosuppressant, FTY720.

While autoimmune disease needs to be continuously treated via long term, administration of immunosuppressants conventional immunotherapy using drugs such as cyclosporin and tacrolimus may cause adverse effects. Recently, a novel agent, FTY720, which was structurally modified from a natural product, has been shown to have a moderate and different immunosuppressive effect from conventional drugs. In this study, we examined the effect of FTY720 on experimental autoimmune thyroiditis (EAT), which was induced in rats by neonatal thymectomy, followed by subsequent sublethal irradiation. Thyroid stimulating hormone (TSH) was measured before and at the end of drug therapy. Histological and hematological examinations were performed using the samples from sacrificed animals. High TSH levels in the animals returned to the normal range following treatment with FTY720. The severity of the thyroiditis was lower in the FTY720 group than in the control group. FTY720 markedly decreased the number of circulatory lymphocytes, and no infections episodes were observed under this treatment. Thus, FTY720 treatment might be preferred for continuous immunotherapy for autoimmune disease without adverse effects.

Animals↗

PubMed1999