Search PubMed⌕ Search

Biomedical subjects

Michiya Kobayashi

Publications and source records attributed to Michiya Kobayashi.

At least 55 records · Page 3Linked to original sources
PubMed2005

Survey of the levels of satisfaction with pharmacy practice among third-year students in the Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido--influence of experience in voluntary training at a community pharmacy and plans after graduation.

Pharmacy practice, which is executed in the taught of pharmaceutical sciences in Japan, has been assessed and improved student questionnaires. The levels of student satisfaction with the practice are expected to be influenced by their plans after graduation and their experience of training in pharmacies. However, there are few reports analyzing the information in the questionnaires from these viewpoints. In this report, we surveyed the levels of satisfaction of 148 third-year students in the Faculty of Pharmaceutical Sciences of the Health Sciences University of Hokkaido using questionnaires and analyzed the influence of the students' background on the levels of satisfaction with pharmacy practice. Almost half of the students had received voluntary training in hospital and/or community pharmacies. Concerning plans after graduation, 36.5%, 27.7%, and 21.6% wanted to become community pharmacists, hospital pharmacists, and graduate students, respectively. More than 70% of the students were well satisfied with all the programs of practice. The levels of satisfaction with the overall practice and prescription analysis were significantly higher among students who had experienced training in pharmacies than among those who had not. Students who planned to become hospital pharmacists were more satisfied with manners seminars, one-dose package practice, and practice in a simulated pharmacy than the students who planned to enter the other field. Such surveys are useful for finding points for improvement and the development of new curricula when the assessment of pharmacy practice takes student background into consideration.

Clinical Clerkship↗
PubMed2005

Characterization of secretory intestinal transport of phenolsulfonphthalein.

It is known that secretory transport limits the oral bioavailability of certain drugs. However, there is little information on the secretion of anionic compounds in the intestine. Phenolsulfonphthalein (PSP) and p-aminohippuric acid (PAH) have been used widely as substrates for organic anion transport systems. PAH is transported in the secretory direction in the intestine. It is possible that PSP and PAH share the same transport system at the mucosal membrane. The purpose of this study was to characterize the transport system for PSP in the intestine. In the jejunum, the serosal-to-mucosal permeation rate of PSP was significantly reduced in an ATP-depleted condition, whereas a significant difference was not observed in the ileum. Some multidrug resistance-associated protein 2 (Mrp2) inhibitors inhibited PSP permeation in the jejunum. However, pravastatin, a substrate of Mrp2, did not inhibit the PSP permeation. The jejunal secretory transport of pravastatin was significantly reduced in an ATP-depleted condition and by addition of probenecid, but PSP did not affect the jejunal permeation of pravastatin. These results suggest that PSP is secreted into the intestinal lumen by Mrp2-like transporter and that two Mrp2 substrates, PSP and pravastatin, are likely to be transported by different transport systems at the mucosal membrane.

Adenosine Triphosphate↗
PubMed2005

[A case of recurrent breast cancer causing malignant pericardial effusion successfully managed with instillations of cisplatin].

A 44-year-old female patient was admitted to our hospital because of dyspnea caused by malignant cardiac tamponade 2 years and 8 months after standard radical mastectomy for a stage III breast cancer. Malignant pericardial effusion was diagnosed by echocardiography and differentiated by cytology. Pericardiocentesis improved her hemodynamics and 9 consecutive pericardial instillations of cisplatin (10 mg) prevented reaccumulation of pericardial effusion, which had never reoccurred until she died of breast cancer one year and 6 months later. Therefore, it is suggested that instillation of cisplatin is one of the beneficial alternatives to surgical treatment.

Adult↗
PubMed2005

Usefulness of laparoscopic radiofrequency ablation of hepatocellular carcinoma.

Our intent was to evaluate whether laparoscopic radiofrequency ablation for patients with unresectable hepatocellular carcinoma and a high degree of liver damage has a role to play in the management of the disease. Laparoscopic and hand-assisted laparoscopic radiofrequency ablations were performed on five patients and the short-range outcome and complications of these patients were evaluated. The evaluation of the primary liver tumor by the radiofrequency ablation was carried out by computed tomography on the seventh day after surgery. Three patients underwent laparoscopic radiofrequency ablation, and the other two patients underwent hand-assisted laparoscopic radiofrequency ablation. The Child-Pugh status of all tumors was B status, and one patient had complications due to postoperative ascites. Laparoscopic and hand-assisted laparoscopic radiofrequency ablation with a cooled-tip electrode needle was found to be a safe and effective local treatment of hepatic focal lesions.

Aged↗
PubMed2004

Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs.

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in beta-cyclodextrin (beta-CD) and hydroxypropyl beta-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent beta-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4,000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% beta-CD had no significant impact on the integrity of the intestinal membrane. One percent beta-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% beta-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.

Animals↗
PubMed2004

Comparison of urinary excretion of phenolsulfonphthalein in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Wistar rats: involvement of primary active organic anion transporter.

PURPOSE: The aim of this study was to determine the cause of the decline in phenolsulfonphthalein (PSP) excretion in Long-Evans Cinnamon (LEC) rats. METHODS: The uptake of PSP into rat renal basolateral membrane vesicles (BLMV) was studied. Cyclosporin A (CYA) was used to modulate an ATP-dependent primary active transporter. PSP was intravenously injected into rats with or without CYA. The transcellular transport of PSP was examined by using primary cultured renal proximal tubule cells (PTC). RESULTS: No significant difference was found between the uptake of PSP into renal BLMV of Wistar rats and that into renal BLMV of LEC rats. In the presence of CYA, the urinary excretion and the plasma concentrations of PSP in Wistar rats were decreased and increased, respectively. In primary cultured renal PTC from Wistar rats, the basal-to-apical transport of PSP was greater than that in the opposite direction and the basal-to-apical transport of PSP was substantially reduced by the addition of CYA. However, CYA did not affect the basal-to-apical transport of PSP in PTC from LEC rats. CONCLUSIONS: The results suggest that PSP is transported by primary active organic anion transporter and that the activity level of this transporter is reduced in LEC rats.

Animals↗
PubMed2004

Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats.

The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.

Animals↗
PubMed2004

Localization of thymidine phosphorylase in advanced gastric and colorectal cancer.

Thymidine phosphorylase (TP) is known to be more concentrated in human cancer tissues than in adjacent normal tissue based on findings using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. However, the ultrastructural localization of TP in cancer tissues has not previously been demonstrated. We investigated the localization of TP in gastric cancer and colorectal cancer tissue by ELISA, immunohistochemistry, and immunoelectron microscopy. Between April 1997 and May 2000, we obtained surgically resected specimens from 42, 46, and 36 cases of advanced gastric, colon, and rectal cancer, respectively. ELISA demonstrated that the TP level was higher in cancer tissues than in adjacent normal tissue. Immunohistochemically, cancer cells were positive for the enzyme in some cases. However, in a number of cases immunopositive inflammatory cells were also present in cancerous tissues. At the electron microscope level, TP was diffusely distributed in the cytoplasm of cancer cells and in the mitochondria of the neutrophil in gastric cancer tissue. In rectal cancer tissues, cytoplasmic granules in macrophages in cancer tissues were immunoreactive for the TP. These findings suggest that TP is produced by macrophages and exists in neutrophils and cancer cells.

Colorectal Neoplasms↗
PubMed2004

Apocynum venetum extract does not induce CYP3A and P-glycoprotein in rats.

We investigated the effect of Apocynum venetum L. extract (AV) on the activity of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp). The plasma concentration of nifedipine (NF), which is a substrate for CYP3A, did not change after oral administration with AV (3.3 mg/kg). Also, AV (3.3 and 33 mg/kg) did not affect the intestinal absorption of NF. In the rats treated with multiple administrations (15 mg/kg/d) of St. John's wort extract (SJW) for 2 weeks, the plasma concentration of NF after oral administration was significantly decreased. On the other hand, there was no significant differences in the pharmacokinetic parameters of NF between AV-treated (3.3 mg/kg/d) and none-treated rats. Furthermore, the intestinal absorption of methylprednisolone, which is a substrate for P-gp, was not affected by AV treatment for 2 weeks. These results suggest that, unlike SJW, the recommended dose of AV (3.3 mg/kg/d) would not influence hepatic CYP3A and intestinal P-gp in rats.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Comparison of the disposition behavior of organic anions in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Long-Evans Agouti rats.

Long-Evans Cinnamon (LEC) rats have an abnormality similar to that observed in Wilson's disease in humans and are therefore a good animal model for the study of Wilson's disease. LEC rats develop hereditary hepatitis and severe jaundice. Mutant animals with hyperbilirubinemia have been widely used as animal models for human diseases. Among these mutant animals, Eisai hyperbilirubinemic rats (EHBR) have defective biliary excretion of organic anions. Thus, biliary excretion of sulfobromophthalein (BSP) and urinary excretion of phenolsulfonphthalein (PSP) in LEC rats were compared with those in Long-Evans Agouti (LEA) rats. In LEC rats, the excretion of BSP, a multidrug resistance-associated protein 2 (Mrp2/Abcc2) substrate, was significantly decreased compared to that in LEA rats. It has been reported that the transport function for organic anions on the kidney is maintained in EHBR. However, the urinary excretion of PSP is impaired in LEC rats. It is possible that organic anion transporters responsible for the urinary excretion of PSP in LEA rats and EHBR are impaired in LEC rats. It is important to elucidate the relationship between organic anion secretion and Wilson's disease.

Animals↗
PubMed2003

An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs.

We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.

Administration, Oral↗
PubMed2003

Major role of organic anion transporters in the uptake of phenolsulfonphthalein in the kidney.

Phenolsulfonphthalein is used for testing renal function. However, its excretion mechanism has not been elucidated. The purpose of this study was therefore to elucidate the transporter-mediated excretion system for phenolsulfonphthalein. p-Aminohippuric acid, a substrate of rat organic anion transporter1 (rOat1), and cimetidine, a substrate of rOat3, reduced the urinary excretion of phenolsulfonphthalein. The uptake of phenolsulfonphthalein by kidney slices was found to consist of two components. The IC50 values of rOat1 substrates were higher than those of rOat3 substrates. In the presence of cimetidine, the Eadie-Hofstee plot gave a single straight line. The profile of the phenolsulfonphthalein uptake component in the presence of cimetidine was similar to that of the low-affinity component in the absence of cimetidine. We conclude that rOat1 and rOat3 are involved in the renal uptake of phenolsulfonphthalein and that phenolsulfonphthalein is a high-affinity substrate for rOat3 but is a relatively low-affinity substrate for rOat1.

Animals↗
PubMed2003

Uptake of dipeptide and beta-lactam antibiotics by the basolateral membrane vesicles prepared from rat kidney.

The transport of dipeptides and beta-lactam antibiotics across the rat renal basolateral membrane was examined. The initial uptake of glycylsarcosine and cefadroxil by rat renal basolateral membrane vesicles was inhibited by the presence of all the di- and tripeptides and beta-lactam antibiotics that were tested in this study. However, the uptake of both substrates was not inhibited by glycine, an amino acid. The initial uptake of zwitterionic beta-lactam antibiotics, cefadroxil, cephradine, and cephalexin, was stimulated by preloaded glycylsarcosine (countertransport effect). On the other hand, the uptake of dianionic beta-lactam antibiotics, ceftibuten and cefixime, was not affected. A concentration-dependent initial uptake of glycylsarcosine and cefadroxil suggested the existence of a carrier-mediated mechanism, whereas the transport of ceftibuten did not show any saturated uptake. The transporter that participates in the permeation of dipeptides and beta-lactam antibiotics across basolateral membranes showed lower affinity than did PEPT1 and PEPT2. This is the first study that showed an evidence for a peptide transporter, expressed in the rat renal basolateral membrane, that recognizes zwitterionic beta-lactam antibiotics using basolateral membrane vesicles isolated from normal rat kidney.

Animals↗
PubMed2003

Arbekacin is actively secreted in the rat intestine via a different efflux system from P-glycoprotein.

This study was undertaken to examine the secretory transport of arbekacin, an aminoglycoside antibiotic, in the rat small intestine and to compare it with those in Caco-2 and LLC-PK1 cells. In vitro permeation of arbekacin was examined using an Ussing chamber technique. Serosal-to-mucosal (secretory)/mucosal-to-serosal (absorptive) permeation ratios of 0.5 mM arbekacin were 2.8 in the jejunum and 7.0 in the ileum, respectively, indicating that arbekacin permeation was highly secretory-oriented. In the ileum, the ratios became smaller with increase in arbekacin concentration applied. When D-glucose was replaced with 3-o-methyl-D-glucose in the experimental medium, the directionality of the arbekacin permeation disappeared almost completely. Absorptive permeation of arbekacin was not significantly influenced by verapamil, cyclosporin A, or probenecid. On the other hand, when gentamicin sulfate was added to the serosal medium, secretory transport of arbekacin was significantly inhibited. The results of this study strongly suggest that a specialized efflux system other than P-glycoprotein and multidrug resistance proteins was involved in the secretory transport of arbekacin in the rat intestine. There was no directionality in arbekacin permeation across Caco-2 cell monolayers, suggesting the absence or very slight expression of the secretory system for arbekacin in this cell line.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

[An approach to complete the manual for determination of serum pirmenol levels].

In order to complete TDM manual for pirmenol in Sapporo Medical Center NTT East, we developed HPLC method and pretreatment procedure for pirmenol samples obtained from patients. Serum (250 microliters) was alkalinized and pirmenol was extracted into n-hexane, and then the drug was again extracted into an acidic solvent, 0.044 M KH2PO4 (pH 2.6) including 0.5% triethylamine. The aqueous extract was used for quantitative determination of the drug by HPLC. The mobile phase consisted of the above acidic solvent-acetonitrile (5:1, v/v) was delivered at 45 degrees C with a flow rate of 1 ml/min through a 4.6 mm x 25 cm ODS-3, a reversed-phase column. Detection of pirmenol and the internal standard (disopyramide) was achieved at 263 nm. Pirmenol and disopyramide was eluted at 5 and 11 min, respectively. Assay limit (25 ng/ml) and accuracy of the analytical method were satisfactory for TDM of pirmenol. During the HPLC analysis of patient samples, no substances that interfered with pirmenol detection were found. It was shown that 1) hemolysis did not affect pirmenol assay at all, 2) pirmenol was stable in the blood samples for at least 24 h even if they were stood at room temperature, and 3) pirmenol was stable for at least 3 days in frozen serum but there significant decrease was observed in pirmenol concentration after 7 days.

Anti-Asthmatic Agents↗
PubMed2003

Mechanism of active secretion of phenolsulfonphthalein in the liver via Mrp2 (abcc2), an organic anion transporter.

Phenolsulfonphthalein (PSP) has been selected as a model drug that is eliminated from both the kidney and liver in rats. Although the renal PSP transport system has been studied, few details of the biliary excretion of PSP have been reported. We investigated the biliary excretion system for PSP in rats. It has been reported that the biliary excretion of many organic anions from hepatocytes into bile is mediated by a primary active transporter, referred to as multidrug resistance-associated protein 2 (Mrp2/abcc2). The biliary excretion of PSP in SD rats was significantly decreased in the presence of Mrp2 inhibitors. The biliary excretion of PSP in Eisai hyperbilirubinemic rats (EHBR), hereditarily Mrp2-defective rats, was significantly lower than that in SD rats. Moreover, an efflux experiment using Caco-2 cells was carried out to confirm Mrp2-mediated PSP transport. Mrp2 inhibitors significantly decreased PSP efflux from Caco-2 cells. These results suggest that Mrp2 contributes to the biliary excretion of PSP in SD rats.

Journal Article↗
PubMed2002

Ionic strength has a greater effect than does transmembrane electric potential difference on permeation of tryptamine and indoleacetic acid across Caco-2 cells.

The effects of transmembrane electric potential difference and ionic strength on the permeation of tryptamine and indoleacetic acid across a Caco-2 cell monolayer were examined. A decrease in the transmembrane electric potential difference caused by the addition of potassium ion to the transport buffer had no effect on the permeation rate of either compound. On the other hand, an increase in ionic strength resulted in a decrease in the permeation rate of tryptamine and an increase in the permeation rate of indoleacetic acid. The changes in the permeation rate with changes in the ionic strength were correlated with the membrane surface potential monitored by 1-anilino-8-naphthalenesulfonic acid (ANS), a fluorescent probe. We tested these effects using several other cationic and anionic compounds. These effects of ionic strength were found to be common to all drugs tested. The compound that showed a relatively lower permeation rate was given relatively stronger effect. The possibility of overestimation or underestimation caused by these effects should be considered when the permeation of an ionic compound is evaluated using a cell monolayer system.

Anilino Naphthalenesulfonates↗