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Biomedical subjects

F Hirayama

Publications and source records attributed to F Hirayama.

At least 55 records · Page 3Linked to original sources
PubMed1999

Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils.

A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.

Adenocarcinoma↗
PubMed1999

A clonal culture assay for human cord blood lymphohematopoietic progenitors.

We describe a two-step clonal culture assay system for human lymphohematopoietic progenitors present in umbilical cord blood which are capable of differentiation along both myeloid and B-lymphoid lineages. Human cord blood CD34+ cells were plated in methylcellulose in the presence of stem cell factor (SCF), granulocyte-colony stimulating factor (G-CSF), interleukin (IL)-7, and the murine stroma cell line, MS-5. The growing primary colonies were individually examined for their potentials to differentiate along both myeloid and B-lymphoid lineages by reculturing aliquots of the primary colonies in methylcellulose culture containing IL-3, G-CSF and erythropoietin (Epo), and on a monolayer of MS-5 in the presence of SCF and G-CSF. Approximately 10-15% of the primary colonies generated various combinations of myeloid cells and CD19+ sIgM+ cells. Subsequent studies using micromanipulated single CD34+ cells unequivocally demonstrated the clonal origin of the lymphohematopoietic progenitors. This culture system should prove valuable for elucidation of the mechanisms regulating early stages of human lymphohematopoiesis.

Animals↗
PubMed1999

Determination of stability constant of beta-cyclodextrin complexes using the membrane permeation technique and the permeation behavior of drug-competing agent-beta-cyclodextrin ternary systems.

The stability constants (Kc) of beta-cyclodextrin (beta-CyD) complexes with phenacetin and various benzoic acids were determined using the membrane permeation technique using a cellophane membrane permeable for guest molecules which was impermeable for beta-CyD molecules. The permeation rate equations of guests in the presence of beta-CyD in the donor phase were derived and the permeation profiles were analyzed as a function of time to determine the Kc values. The Kc values determined using the membrane permeation technique were in close agreement with those determined by the conventional kinetic method and the solubility method. The membrane permeation technique is of greater advantage than the conventional methods, because in the former method the stability constant can be obtained from only one experimental run by analyzing the permeation data as a function of time. In the latter method, on the other hand, some property changes have to be measured at various CyD concentrations and in turn analyzed as a function of CyD concentration. The permeation profiles of phenacetin of the drug-competing agent-beta-CyD ternary system were estimated by using the stability constants and the experimental curves closely matched the theoretically derived ones.

Algorithms↗
PubMed1999

Solubility and mass and nuclear magnetic resonance spectroscopic studies on interaction of cyclosporin A with dimethyl-alpha- and -beta-cyclodextrins in aqueous solution.

The interaction of cyclosporin A (CsA) with dimethyl-alpha- and -beta-cyclodextrins (DM-alpha-CyD and DM-beta-CyD) was investigated by the solubility method, electrospray ionization mass spectrometry (ESI-MS) and 1H-nuclear magnetic resonance spectroscopy (1H NMR). The extremely low solubility (1.9 x 10(-5) M at 25 degreesC) of CsA in water was significantly improved by the complexation with DM-CyDs: for example, the solubility increased 87-fold in the presence of 5.0 x 10(-2) M DM-beta-CyD. The phase solubility diagram of CsA/DM-CyD systems showed an Ap type and the stability constants (1060 M-1 and 1050 M-1, respectively) of the 1:1 CsA/DM-alpha-CyD and CsA/DM-beta-CyD complexes were much higher than those of the 1:2 complexes (15 M-1 and 21 M-1, respectively). In ESI-MS spectra of the CsA/DM-beta-CyD system, a new signal emerged at 1268 which corresponds to the 1:1 adduct of the di-ionized guest molecule with the host molecule. This signal intensity was significantly decreased by the addition of chlorpromazine (CPZ) which has a large stability constant (8800 M-1) of the DM-beta-CyD complex, whereas the signal corresponding to the CPZ/DM-beta-CyD complex was little affected by the addition of CsA, indicating a competitive inclusion of CPZ and CsA within the host cavity. CsA gave many new peaks in the 1H NMR spectrum when the solvent was changed from chloroform to methanol/water, suggesting conformational diversity of CsA in polar solvents. Inspection of 1H-chemical shift changes and the two-dimensional rotating frame nuclear Overhauser effect (ROESY) spectra of the CsA/DM-CyD system suggested that the side chains of amino acids in CsA molecule take part in the inclusion within DM-CyDs, although there is seemingly no preference of particular amino acid residues. All the data obtained here suggested that CsA forms inclusion complexes with DM-alpha- and -beta-CyDs in an aqueous medium and side chains of CsA are mainly involved in the inclusion.

Cyclodextrins↗
PubMed1999

Characterization of tolbutamide polymorphs (Burger's forms II and IV) and polymorphic transition behavior.

Burger's two polymorphs of tolbutamide (TB), an oral hypoglycemic agent, were obtained by spray-drying the drug dissolved in a mixed solvent of ethanol/dichloromethane (Form IV) and allowing Form IV to stand at constant temperatures and humidities (Form II). These polymorphs were characterized by various physical methods [e.g., powder X-ray diffractometry, differential scanning calorimetry, infrared spectrometry, and solid-state carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy] and compared with two other TB polymorphs Forms I and III. The 13C NMR spectra showed that the chemical shift and the peak shape of resonance associated with the toluene and n-butyl moieties of TB were different for each of the four polymorphs, whereas the carbonyl carbon was unchanged, indicating different conformations and molecular motions of the toluene and n-butyl moieties in the solid states. Form IV converted itself to Form II within 3 h when it was stored at 45 degrees C and 75% relative humidity (RH) and, in turn, Form II transformed to Form I at higher temperatures. The conversion of Form IV to Form II proceeded according to a zero-order equation (Polany-Winger equation), and that of Form II to Form I according to a first-order equation. The increase in RH accelerated the polymorphic transition of Form IV. Both the apparent dissolution rate and the solubility of Form IV were nearly identical with those of Form II, because the former changed to the latter during the dissolution, but their dissolution rates and solubility were higher than those of Forms I and III. These dissolution characteristics of TB polymorphs were reflected in the oral absorption behavior in dogs; that is, the bioavailability increased in the order Form I < Form III < Form II approximately Form IV.

Animals↗
PubMed1999

Heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin: A water-soluble cyclodextrin derivative with low hemolytic activity.

Acetyl groups were introduced to the hydroxyl groups of heptakis(2, 6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and the resulting heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-CyD (DMA-beta-CyD) was evaluated for the inclusion property and hemolytic activity. It was confirmed by means of NMR and mass spectroscopies that in the DMA-beta-CyD molecule, all seven hydroxyl groups at the 3-position were substituted by acetyl groups. Thus, it has the degree of substitution (DS) of 7, whereas DMA4-beta-CyD with the lower substitution (DS 3.8) was a mixture of components with different DS. The aqueous solubility of DMA-beta-CyD was higher than those of beta-CyD, DM-beta-CyD, and heptakis(2,3,6-tri-O-methyl)-beta-CyD (TM-beta-CyD). The hydrophobicity of the whole molecule, assessed from measurements of surface tension, increased in the order of DM-beta-CyD < DMA-beta-CyD < TM-beta-CyD. The half-life of DMA-beta-CyD for hydrolysis in pH 9.5 and 60 degrees C was about 19 h, and there was only slight liberation of acetic acid in rabbit plasma and carboxylesterase (EC 3.1.1.1) at 37 degrees C. DMA-beta-CyD had an inclusion ability similar to that of TM-beta-CyD for p-hydroxybenzoic acid esters with different alkyl chain lengths and an antiinflammatory drug, flurbiprofen, although it was inferior to that of DM-beta-CyD. The hemolytic activity and rabbit muscular irritation of DMA-beta-CyDs were much weaker than those of DM-beta-CyD: no hemolysis was observed even in the presence of 0.1 M DMA-beta-CyD with DS 7. The results suggest that the water-soluble CyD derivative with superior bioadaptability and inclusion ability can be prepared by properly designing substituents at the 3-position and by optimally controlling their degree of substitution.

Animals↗
PubMed1999

Solid-state 13C nuclear magnetic resonance spectroscopic study on amorphous solid complexes of tolbutamide with 2-hydroxypropyl-alpha- and -beta-cyclodextrins.

PURPOSE: The objective of the study was to obtain structural information of inclusion complexes of tolbutamide with HP-alpha- and -beta-cyclodextrins in amorphous state. METHOD: The solid complexes of tolbutamide with HP-alpha- and -beta-CyDs in molar ratios of 1:1 and 1:2 (guest:host) were prepared by the spray-drying method, and their interactions were investigated by solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The solid 1:1 and 1:2 tolbutamide/HP-CyD complexes showed halo pattern on the powder X-ray diffractogram and no thermal change in DSC curves, indicating they are in an amorphous state. 13C NMR signals of the butyl moiety were broader than those of the phenyl moiety in the HP-alpha-CyD solid complex, whereas the phenyl moiety showed significantly broader signals than the butyl moiety in the HP-beta-CyD solid complex. As temperature increased, signals of the phenyl carbons became markedly sharper, whereas the butyl carbons only sharpen slightly in the HP-d-CyD complex. In contrast, signals of the butyl carbons became significantly sharper whereas those of phenyl carbons only slightly changed in the HP-beta-CyD complex. CONCLUSIONS: Solid state 13C NMR spectroscopic studies indicated that the butyl moiety of tolbutamide is predominantly included in the HP-alpha-CyD cavity, whereas the phenyl moiety in the HP-beta-CyD cavity in amorphous complexes.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Enhanced absorption of cyclosporin A by complexation with dimethyl-beta-cyclodextrin in bile duct-cannulated and -noncannulated rats.

The enhancing effects of dimethyl-beta-cyclodextrin (DM-beta-CyD) on the absorption of cyclosporin A (CsA) after oral administration to rats under bile duct-cannulated and -noncannulated conditions were investigated. The dissolution rate of CsA was markedly augmented by complexation with DM-beta-CyD. In a closed loop in situ study, DM-beta-CyD considerably increased the cumulative amounts of CsA in the mesenteric venous blood after injection of the aqueous CsA suspension into the small intestinal sac of rats. In addition, the cumulative amount ratio of M1, the dominant metabolite of CsA in rats, to CsA in the mesenteric venous blood for up to 40 min after the injection of the CsA-DM-beta-CyD suspension into the sac was lower than that of the CsA suspension alone. DM-beta-CyD inhibited the bioconversion of CsA in the small intestinal microsomes of rats. These results indicate that the bioconversion of CsA was abated by complexation with DM-beta-CyD. An in vivo study revealed that DM-beta-CyD increased the transfer of CsA to blood, not lymph, with low variability in the absorption after oral administration of the CsA suspension to rats. The variability of bioavailability of DM-beta-CyD complex was lower than that of Sandimmune, although the extent of bioavailability of DM-beta-CyD was only a little higher than that of Sandimmune. The bioavailability of CsA or its DM-beta-CyD complex was appreciably decreased by the cannulation of the bile duct of rats, and the extent of the lowering in the bioavailability in the presence of DM-beta-CyD was much less serious than that of CsA alone. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of CsA with an enhanced bioavailability and a reduced variability in absorption.

Administration, Oral↗
PubMed1999

[Cell cycle-dependent change of the adhesive character of CD34+ progenitor cells and their VLA-4 expression].

We identified the cell cycle status of CD34+ cells of steady-state bone marrow (BM) and peripheral blood (PB) obtained from healthy volunteers, and those of BM and apheresis PB samples collected from donors who had been administered granulocyte colony-stimulating factor (G-CSF). Regardless of whether G-CSF treatment was undergone, more than 10% of CD34+ cells in the BM was in the S + G2/M phase. In contrast, less than 2% of CD34+ cells in the PB was cycling. After co-culturing BM CD34+ cells with a monolayer of the stromal cell line MS-5 for 1 hour, some cells adhered to the stroma. The percentage of cells in the S + G2/M phase among these adherent cells was higher than that among the non-adherent cells. Flow cytometric analysis revealed that CD34+ cells in mobilized PB expressed less VLA-4 than those in BM and that in in vitro-cultured non-adherent cells exhibited a lower level of VLA-4 expression than adherent cells. In addition, CD34+ cells in the G0/G1 phase expressed lower levels of VLA-4 than those in the S + G2/M phase. These findings suggested that the reduced expression of adhesion molecules such as VLA-4 by the progenitor cells in the G0/G1 phase of the cell cycle result in the release of progenitor cells from the hematopoietic microenvironment to peripheral blood.

Antigens, CD34↗
PubMed1999

Virulence factors of Helicobacter pylori affecting its gastric colonization in Mongolian gerbils.

Helicobacter pylori is recognized to possess a number of virulence factors. We investigated the role of motility, vacuolating cytotoxin, and urease in gastric colonization by H. pylori. Mongolian gerbils (SPF, 7 weeks old) were challenged orally with a single administration of a 24-h culture broth of H. pylori and then were killed 6 and 26 weeks after challenge. Gastric colonization, severe gastritis, ulceration, and high levels of serum anti-H. pylori immunoglobulin G were observed in the gerbils challenged with strains motile in the semisolid medium (ATCC43504, HPY-127, HPY-204), but not in gerbils challenged with strains nonmotile in the medium (ATCC49503, HPY-205, HPY-206). Only strains ATCC43504, ATCC49503, HPY-204, and HPY-206 had vacuolating cytotoxin activity against HeLa and Vero cells. Thus, motile strains were able to colonize regardless of their vacuolating cytotoxin activities, and vacuolating cytotoxin was not associated with epithelial damage in the gastric mucosa. Furthermore, the phenotypic variants of strains with the ability to colonize that lacked either motility or urease activity lost their ability to colonize. In conclusion, motility and urease activity, but not vacuolating cytotoxin activity, are essential for gastric colonization by H. pylori in Mongolian gerbils.

Animals↗
PubMed1998

Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents.

A series of the titled compounds was synthesized and tested for anti-Helicobacter pylori activities. We discovered Y-34867 having the most potent activity against Helicobacter pylori among the quinolones tested along with high photostability. Furthermore, Y-34867 showed an excellent therapeutic effect in the experimental Helicobacter pylori infected Mongolian gerbil model.

4-Quinolones↗
PubMed1998

Different adhesive characteristics and VLA-4 expression of CD34(+) progenitors in G0/G1 versus S+G2/M phases of the cell cycle.

We identified the cell cycle status of CD34(+) cells of steady-state bone marrow (BM) and peripheral blood (PB) obtained from healthy volunteers, and those of apherasis PB samples collected from healthy donors who had been administered granulocyte colony-stimulating factor (G-CSF). More than 10% of CD34(+) cells in BM were in S+G2/M phase. In contrast, regardless of whether G-CSF treatment was performed, less than 2% of CD34(+) cells in PB were cycling. BM CD34(+) cells showed greater VLA-4 expression and adherence to stromal cells than PB CD34(+) cells. In addition, when cycling and dormant BM CD34(+) cells were analyzed separately, the cells in S+G2/M phase expressed more VLA-4 and adhered to the stromal cell monolayer more efficiently than the cells in G0/G1 phase. Furthermore, this adhesion of CD34(+) cells to the stromal cell layer was almost completely inhibited by anti-VLA-4 antibody. Taken together, these results suggest that CD34(+) progenitors in G0/G1 phase of the cell cycle differ from those in S+G2/M phase in adhesiveness mediated by VLA-4 in the hematopoietic microenvironment.

Adult↗
PubMed1998

Negative regulation by interleukin-3 (IL-3) of mouse early B-cell progenitors and stem cells in culture: transduction of the negative signals by betac and betaIL-3 proteins of IL-3 receptor and absence of negative regulation by granulocyte-macrophage colony-stimulating factor.

The receptors for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 share a common signaling subunit betac. However, in the mouse, there is an additional IL-3 signaling protein, betaIL-3, which is specific for IL-3. We have previously reported that IL-3 abrogates the lymphoid potentials of murine lymphohematopoietic progenitors and the reconstituting ability of hematopoietic stem cells. We used bone marrow cells from betac- and betaIL-3-knock-out mice to examine the relative contributions of the receptor proteins to the negative regulation by IL-3. First, we tested the effects of IL-3 on lymphohematopoietic progenitors by using lineage-negative (Lin-) marrow cells of 5-fluorouracil (5-FU)-treated mice in the two-step methylcellulose culture we reported previously. Addition of IL-3 to the combination of steel factor (SF, c-kit ligand) and IL-11 abrogated the B-lymphoid potential of the marrow cells of both types of knock-out mice as well as wild-type mice. Next, we investigated the effects of IL-3 on in vitro expansion of the hematopoietic stem cells. We cultured Lin-Sca-1-positive, c-kit-positive marrow cells from 5-FU-treated mice in suspension in the presence of SF and IL-11 with or without IL-3 for 7 days and tested the reconstituting ability of the cultured cells by transplanting the cells into lethally irradiated Ly-5 congenic mice together with "compromised" marrow cells. Presence of IL-3 in culture abrogated the reconstituting ability of the cells from both types of knock-out mice and the wild-type mice. In contrast, addition of GM-CSF to the suspension culture abrogated neither B-cell potential nor reconstituting abilities of the cultured cells of wild-type mice. These observations may have implications in the choice of cytokines for use in in vitro expansion of human hematopoietic stem cells and progenitors.

Animals↗
PubMed1998

Antithrombotic effect of YM-75466 is separated from its effect on bleeding time and coagulation time.

The antithrombotic effects of YM-75466 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid monomethane sulfonate), a novel orally-active factor Xa inhibitor, and its effects on bleeding time and coagulation time were studied in rats and compared with those of warfarin. Both agents were orally administered. In the venous thrombosis model, YM-75466 and warfarin inhibited thrombus formation dose-dependently, with ID50 values of 3.3 and 0.56 mg/kg, respectively. Ex vivo study showed that both YM-75466 and warfarin prolonged prothrombin time dose-dependently, with doses, causing a two-fold prolongation of prothrombin time in the control group, of 89 and 0.38 mg/kg, respectively. In bleeding time studies, YM-75466 and warfarin prolonged bleeding time dose-dependently, with doses, causing a two-fold prolongation of bleeding time in the control group, of > 100 and 0.43 mg/kg, respectively. These results show that the antithrombotic effects of YM-75466 are markedly separate from its effects on bleeding time and coagulation time compared with warfarin.

Animals↗
PubMed1998

Antithrombotic effects of YM-60828 in three thrombosis models in guinea pigs.

The antithrombotic effects of a novel factor Xa inhibitor, YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid dihydrochloride), in three thrombosis models in guinea pigs were studied in comparison with its effect on bleeding time. The antithrombotic effects of YM-60828 were most pronounced in the venous thrombosis and the arterio-venous shunt models but YM-60828 showed 10-fold weaker effects in the carotid thrombosis model. However, YM-60828 prolonged bleeding time at a much higher dose than that required in all thrombosis models. In conclusion, YM-60828 exerted its antithrombotic effects without prolonging bleeding time in all thrombosis models and may be of clinical value not only in venous thrombosis but also in arterial thrombosis.

Animals↗
PubMed1998

Relationship between the antithrombotic effect of YM-75466, a novel factor Xa inhibitor, and coagulation parameters in rats.

The relationship between the antithrombotic effects of intravenous infusions of YM-75466 [N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)methyl] sulfamoyl]acetic acid monomethanesulfonate), a novel factor Xa (FXa) inhibitor, and various coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin-antithrombin III complex (TAT), anti-FXa activity and anti-thrombin activity) in rats was studied and compared with results for heparin. In the arterio-venous shunt model, both agents exerted antithrombotic effects in a dose-dependent manner. Coagulation parameters were studied simultaneously with antithrombotic effects. YM-75466 did not prolong coagulation time even at the dose which exerted significant antithrombotic effects, while it decreased TAT level in plasma in a dose-dependent manner. YM-75466 exerted anti-FXa activity but not anti-thrombin activity. In contrast, heparin prolonged activated partial thromboplastin time in a dose-dependent manner and decreased TAT level in plasma with increasing inhibition of thrombus formation. Heparin exerted both anti-FXa and anti-thrombin activity in a dose-dependent manner. These results suggest that TAT is a suitable parameter for monitoring the antithrombotic effect of YM-75466 in the arterio-venous shunt model in rats and that YM-75466, unlike heparin, exerts its antithrombotic effect through specific inhibition of FXa without any effect on thrombin.

Animals↗
PubMed1998

Evaluation of combined antibiotic-omeprazole therapies in Helicobacter pylori-infected Mongolian gerbils.

Mongolian gerbils are a laboratory host for gastric colonization with Helicobacter pylori, showing gastritis followed by typical gastric ulcer after infection with H. pylori. In such gerbils, we evaluated combined therapies of amoxicillin (AMPC) and clarithromycin (CAM) as antibiotics, and omeprazole (OPZ) as a H+/K+ adenosine triphosphatase (ATPase) inhibitor. The gerbils were orally inoculated with 2 x 10(8) bacilli of H. pylori ATCC 43504. Four weeks after inoculation, the infected gerbils were orally treated singly with OPZ, AMPC, and CAM, and their insufficient efficacy on bacterial clearance was confirmed by a polymerase chain reaction technique, and by a culture method. In contrast, combined therapy of OPZ plus either AMPC or CAM showed significant bacterial clearance, demonstrating the efficacy of this combined therapy in the gerbil model. Mongolian gerbils are suggested to be useful for the pharmacological evaluation of anti-H. pylori compounds.

Amoxicillin↗