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K Someya

Publications and source records attributed to K Someya.

At least 37 records · Page 2Linked to original sources
PubMed1996

A lipid A analog inhibits LPS-induced cytokine expression and improves survival in endotoxemic mice.

It has recently been shown that inactive disaccharidic analogs of lipid A, an essential structure of lipopolysaccharide (LPS), may act as LPS antagonists which would be effective against septic shock induced by gram-negative bacteria endotoxin. In the present study we examined the inhibitory effect of DY-9973, a synthetic monosaccharidic lipid A analog, on LPS-induced cytokine expression in macrophages and lethal toxicity in mice. DY-9973 inhibited TNF-alpha production induced by LPS in human monocytes and monoblastic U937 cells. Expression of cytokine mRNAs such as TNF-alpha and IL-1 beta induced by LPS was inhibited by treatment with DY-9973 in U937 cells. Meanwhile, DY-9973 did not inhibit IL-1 beta-induced TNF-alpha production in U937 cells. TNF-alpha production induced by LPS or IL-1 beta was similarly inhibited by treatment with herbimycin, a tyrosine kinase inhibitor. Pretreatment with DY-9973 inhibited the elevation of serum TNF-alpha activity induced by the injection of LPS and reduced the lethal toxicity of LPS in BCG-primed mice. These results suggest that monosaccharidic lipid A analog such as DY-9973 can inhibit LPS-induced activation of macrophages and that it reduces lethal toxicity of LPS.

Animals↗
PubMed1995

Production of tumor necrosis factor induced by synthetic low-toxicity lipid A analog, DT-5461a, is mediated by LPS receptor sites and tyrosine kinase-MAP kinase signaling pathway in murine macrophages.

The synthetic low-toxicity lipid A analog DT-5461a induces endogenous TNF production in mice. The activity of TNF so induced is probably the main contributor to the antitumor effect of this compound. In the present study, we investigated the mechanism by which DT-5461a induces TNF production in murine macrophage RAW 264 cells. DT-5461a mimicked the ability of LPS to induce TNF production in a dose-dependent manner. DT-5461a at higher concentrations inhibited specific binding of [3H]LPS to the cells and reduced LPS-induced TNF production to the level induced by DT-5461a alone. In addition, DT-5461a, as well as LPS, induced tyrosine phosphorylation of MAP kinases, the early signal transduction pathway of this production. Herbimycin A, an inhibitor of tyrosine kinase, inhibited the LPS- and DT-5461a-induced tyrosine phosphorylation, expression of TNF mRNA, and subsequent TNF secretion. These results suggest that DT-5461a and LPS induce TNF production in murine macrophages through the common receptor sites and the similar early signaling pathway.

Animals↗
PubMed1995

Yersinia pseudotuberculosis in China.

Thirty strains of Yersinia pseudotuberculosis were isolated from rabbits (17 strains), wild rats (9 strains) and house rats (4 strains) in China between 1990 and 1993. The biochemical properties of these isolates were identical with those of Y. pseudotuberculosis and no special characteristics were found in these strains. Serologically, serogroups 4b and 5b were identical to isolates found in Japan, and a new serogroup 1c and unclassified strains have also been detected. The existence of virulence-associated properties were different among strains. The pYV plasmid was detected from 6 strains of 30 isolates. This report documents the presence of Y. pseudotuberculosis in China, providing important epidemiological information.

Animals↗
PubMed1995

Leukocyte subpopulation changes in rats with autotransplanted endometrium and the effect of danazol.

PROBLEM: This study examines immune cell populations in rats with autotransplanted endometrium and determines the effect of danazol on leukocyte subsets. METHODS: As an experimental model of endometriosis, an autologous endometrial segment was implanted in the rat peritoneum. We used flow cytometry to analyze lymphocyte subsets in the peripheral blood (PB) and peritoneal fluid (PF) of the following groups of rats: no treatment, sham operation, endometrial implantation, endometrial implantation treated with danazol, and normal rats treated with danazol. RESULTS: The natural killer (NK) cell population was decreased in both the PB and PF of rats with autotransplanted endometrium. Moreover, NK cells increased in a dose-dependent manner following danazol administration. Surgery itself increased the number of peritoneal macrophages as compared with the untreated group. This elevation was suppressed partially by endometrium-implantation and was attenuated by subsequent administration of danazol in a dose-dependent fashion. CONCLUSIONS: These data suggest that ectopic endometrial cells may release immunosuppressive factors. This is the first documentation that rats with autotransplanted endometrium show the same immunologic changes as humans with endometriosis, and establishes the utility of this model for the study of endometriosis.

Animals↗
PubMed1995

In vitro and in vivo antifungal activities of DU-6859a, a fluoroquinolone, in combination with amphotericin B and fluconazole against pathogenic fungi.

DU-6859a is an investigational fluoroquinolone agent with potent bactericidal activity, but by itself it has no antifungal activity. When combined with amphotericin B (AmB), however, DU-6859a clearly enhanced the in vitro antifungal activity of AmB against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, and Cryptococcus neoformans in microdilution checkerboard studies. Positive interactions of DU-6859a with AmB against Aspergillus fumigatus were dependent on the medium used; yeast nitrogen base supplemented with amino acids, ammonium sulfate, and 1% glucose was better for demonstrating synergism, while in RPMI 1640 medium, unexpected antagonism between the drugs occurred against three of the strains tested. In combination with fluconazole (Flu), DU-6859a increased the activity of Flu against C. albicans both in synthetic amino acid medium fungal and in supplemented yeast nitrogen base. An in vitro time-kill study revealed that DU-6859a combined with AmB significantly suppressed the regrowth of C. albicans compared with the suppression brought about by AmB used alone in a concentration-dependent fashion. Furthermore, in a model of C. albicans infection in mice, the fungal load in infected kidneys was significantly less in mice given the combination treatment of DU-6859a plus either AmB or Flu, and thus, the combination treatment resulted in prolonged survival of infected mice compared with treatment with either antifungal alone. The prolonged survival in mice given the combined treatment was also observed in mice with A. fumigatus infection, indicating that DU-6859a potentiated the actions of the antifungal agents in vivo as well as in vitro.

Amphotericin B↗
PubMed1995

[Induction of protective immune responses by a chimeric soluble protein from a recombinant BCG vector candidate vaccine to HIV-1].

We have been isolated HIV strains from blood specimens of HIV infected individuals in Japan for these 6 years. The number of specimens tested reached approximately 1,700 that ninety percent of them were from hemophiliacs repeatedly injected blood products from the United States. More than 300 of field HIV were successfully isolated from the samples. The isolation rates has decreased to 30 percent in 1993 from 40 percent in 1992, suggesting that treatment with anti-HIV drugs such as AZT and/or ddI may be effective to HIV-infected individuals. Further, both of the viral and genomic sequences of HIV were classified to be clade B virus. The clinical isolates that expressed IHIGPGRAFY sequence at the center of the HIV-V3 domain were found to be neutralized by an anti-clade B-V3 monoclonal antibody, mu 5.5. By individual levels, when asymptomatic seropositives have progressed to disease-states, neutralization core motif of GPGR in approximately 6% of the viruses has changed to GPGG and hydrophilic amino acid changed to hydrophobic amino acid, correlating the loss of binding activity to PND-peptide of Japanese Consensus virus. Further, rapid progressors to HIV-induced diseases showed decreased activity of the binding antibody. By using the Japanese consensus sequence of HIV-1, we successfully constructed chimeric protein secretion vectors by selecting an appropriate insertion site of a carrier protein, and established the PND-peptide secretion system in BCG. The recombinant BCG inoculated guinea pigs were initially screened by delayed-type hypersensitivity (DTH) skin reactions to the PND peptide followed by passive transfer of the DTH by the systemic route.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Vaccines↗
PubMed1995

Relationship between the therapeutic effects or side-effects and the serum disopyramide or mono-N-dealkylated disopyramide concentration after repeated oral administration of disopyramide to arrhythmic patients.

After we had developed a method to determine simultaneously the blood concentrations of disopyramide (DP) and its metabolite mono-N-dealkylated disopyramide (MND) by high-performance liquid chromatography, DP was administered repeatedly to arrhythmic patients in order to examine the relationship between the serum DP or MND concentration and the therapeutic effects or side-effects. To 79 arrhythmic patients (57 patients with ventricular premature contraction, 13 with supraventricular arrhythmia and 9 with atrial fibrillation), DP was administered repeatedly at an initial oral dose of 200 to 400 mg/day. Of the 61 patients which were possible to evaluate after reaching a steady state, 32 were evaluated as effective and 29 as non-effective, the effective rate being 52.5%; the mean blood DP concentration (+/- S.D.) was 2.14 +/- 0.65 and 1.74 +/- 0.62 micrograms/ml, respectively, with a significant difference between the two groups (p +/- 0.05). At the final dose, 40 patients were evaluated as effective and 18 as non-effective, the effective rate being 69.0%; the mean blood DP concentration was 2.03 +/- 0.67 and 2.09 +/- 0.68 micrograms/ml, respectively, with no significant difference between the two groups. Among 42 patients with premature contraction, 26 were evaluated as effective and 16 as non-effective, the effective rate being 62%; the mean blood DP concentration was 2.01 +/- 0.62 and 2.20 +/- 0.70 micrograms/ml respectively, with no significant difference between the two groups. The incidence of side-effects was 17.7%, and there were no significant differences in blood DP or MND concentrations between the groups with and without side-effects. A blood DP concentration more than 2 micrograms/ml may be required to achieve the therapeutic effect of DP administered repeatedly.

Adult↗
PubMed1994

Antitumor synthetic lipid A analog DT-5461a upregulates cytokine expression in a murine macrophage cell line through LPS pathway.

We previously showed that DT-5461a, a lipid A analog, has antitumor activity and relatively low toxicity in animals. To clarify its immunostimulatory effect we have studied the cytokine inducibility of DT-5461a and the mechanism involved in the cytokine expression in macrophages. While the activity is lower than that of LPS, DT-5461a enhanced production of TNF-alpha and GM-CSF in the murine macrophage cell line J774.1 in a dose-dependent fashion. Simultaneous addition of IL-4 inhibited DT-5461a and LPS-induced TNF-alpha production in a similar manner. Expression of cytokine mRNAs including TNF-alpha, IL-1 beta, IL-6, and GM-CSF was also enhanced by the treatment with DT-5461a. Treatment with cycloheximide indicated that the expression of TNF-alpha mRNA does not require new protein synthesis. Actinomycin D chase experiments revealed that cytokine mRNAs have rather long half-lives and we could not find significant changes in mRNA stability of cytokines in the J774.1 cells. The binding activity of a nuclear transcription factor NF-kappa B was enhanced by treatment with DT-5461a, suggesting enhanced transcription of cytokine genes. Specific binding of [3H]LPS to the cells was significantly inhibited by the addition of DT-5461a. These results indicate that DT-5461a enhances production of a variety of cytokines in macrophages through the LPS receptor sites and that this cytokine induction may occur primarily via transcriptional enhancement. These immunostimulatory effects may provide evidence for the mechanisms of the antitumor effect of this lipid A analog.

Animals↗
PubMed1994

beta 2-GPI-dependent and independent binding of anticardiolipin antibodies in patients with recurrent spontaneous abortions.

We measured anticardiolipin antibodies (aCL) in plasma samples from 214 women with a history of recurrent spontaneous abortions by an enzyme-linked immunosorbent assay (ELISA) utilizing solid phase cardiolipin (CL) and beta 2-glycoprotein I (beta 2-GPI). Sixteen patients (7.5%) were positive for beta 2-GPI-dependent aCL. Though beta 2-GPI appeared to enhance the binding of aCL, beta 2-GPI-independent aCL were also observed in these patients (4.7%). The patients were classified into three groups on the basis of their medical history, and analysis of data of individual groups revealed that the incidence of beta 2-GPI-dependent aCL was significantly higher in patients who had experienced at least one fetal loss in the second or third trimester.

Abortion, Habitual↗
PubMed1994

The effect of natural carotenoid (palm fruit carotene) intake on skin lipid peroxidation in hairless mice.

To study the effect of palm fruit carotene intake on skin lipid peroxidation, hairless mice were given ad libitum palm fruit carotene, beta-carotene, or vehicle emulsions for 15 weeks in which the carotene (0.005%, w/w) was suspended in drinking water, and then their dorsal skin was exposed to ultraviolet ray (UV). The carotene content of the skin was increased by the oral intake of palm fruit carotene or beta-carotene. In carotene-drinking mice, before the UV irradiation, the amount of thiobarbituric acid-reacting substances (TBARS) in the skin was lower than that of control (carotene untreated) mice. The skin TBARS immediately after the UV irradiation was lower in carotene-treated mice than in control mice. At 24 h after irradiation, the skin TBARS of mice that orally received palm fruit carotene was lower than that of beta-carotene mice. Immediately after the UV irradiation, the skin carotene content transiently decreased but gradual recovery was observed at 48 h. In palm fruit carotene-treated mice, the rate of carotene recovery after UV irradiation was higher than in beta-carotene-treated mice. Retinol found in the skin had also decreased after UV irradiation, and recovered gradually in both carotene-drinking groups within 48 h. These results suggested that the carotene intake, especially palm fruit carotene, prevented skin lipid peroxidation in hairless mice.

Animals↗
PubMed1994

The antioxidant effect of palm fruit carotene on skin lipid peroxidation in guinea pigs as estimated by chemiluminescence-HPLC method.

To study the antioxidant effect of palm fruit carotene on skin lipid peroxidation, the guinea pigs were orally fed ad libitum palm fruit carotene, beta-carotene, or vehicle emulsions, in which carotene (0.05%, w/w) was suspended in drinking water. After treatment of carotene for 12 weeks, animals were exposed to ultraviolet ray (UV), and squalene monohydroperoxide (SqOOH)/squalene (Sq) ratios in the skin lipid were analyzed using the chemiluminescence-HPLC method. Carotene accumulation was found in the skin of guinea pigs that were orally administered palm fruit carotene or beta-carotene. After UV irradiation, especially immediately after, the rise in the SqOOH/Sq ratio was effectively suppressed in both carotene-drinking groups in contrast with the control (carotene-untreated) group. An inverse correlation between the carotene content and the SqOOH/Sq ratio in the skin was also observed. The results suggested that palm fruit carotene intake prevents skin lipid peroxidation caused by UV irradiation.

Animals↗
PubMed1994

[Hematologic abnormalities in a patient with chronic myelogenous leukemia with advanced myelofibrosis were improved by G-CSF].

A 56-year-old woman was admitted with pyrexia, cough, and dyspnea on August 21, 1991. Physical examination revealed anemia in the palpebral conjunctivas and moist rales at the right lower lung field. Neither the Liver nor spleen was enlarged. Examination of the peripheral blood showed a hemoglobin level of 8.1 g/dl, a platelet count of 14.8 x 10(4)/microliters, and a white blood cell count of 2,800/microliters, with 7% blasts and 8% megakaryocytes. Tear drop-like erythrocytes, agranular neutrophils, and erythroblasts were also seen in the peripheral blood. Examination of the bone marrow showed 15% peroxidase positive blasts, and many micromegakaryocytes. Cytogenetic studies for bone marrow cells revealed the existence of the Philadelphia (Ph1) chromosome. Bone marrow biopsy showed normal cellularity with increase of megakaryocytes and advanced myelofibrosis. Breakpoint cluster region (bcr) rearrangement analysis using the peripheral blood mononuclear cells revealed M-bcr rearrangement. According to the Hannover classification for myeloproliferative disease, she was diagnosed as having CML with advanced myelofibrosis followed by CML with megakaryocytic increase. Since she had neutrocytopenia and severe infectious disease, she received a subcutaneous injection of 125 micrograms of G-CSF. Not only increase of the white blood cell count, but also disappearance of blasts, improvement of anemia, increase of the platelet count, and improvement of myelofibrosis were observed.

Blood Cell Count↗
PubMed1993

Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations.

The relative bioavailability of two 100-mg disopyramide formulations which showed almost an 8- to 10-fold difference in their dissolution rates at pH 1.2 and 6.8 was determined in eight healthy subjects using a randomized block design. Although no significant differences in relative bioavailability were observed between the two formulations when based on the total disopyramide concentration, an almost 30 per cent difference in the extent of bioavailability was observed when assessed in terms of the unbound (+/-)- and (-)-disopyramide concentration, due probably to stereoselective nonlinear plasma protein binding. This suggests that unbound enantiomer parameters would be more sensitive to differences in bioavailability between two disopyramide formulations. Therefore, the type of concentration used would be an important factor for precise evaluation of the relative bioavailability of racemic drugs.

Adult↗
PubMed1993

Characterization of Yersinia pseudotuberculosis serogroups O9, O10 and O11; subdivision of O1 serogroup into O1a, O1b, and O1c subgroups.

In this study, three new antigens (O9, O10 and O11) of Yersinia pseudotuberculosis are described. The O1 antigen is further subdivided into O1a, O1b and O1c. The methods used to prepare specific antisera for O-antigen identification are also described. Furthermore, the H antigens of these new serogroups are determined and their biochemical characteristics analysed. The antigenic formulae of the known serogroups within the basic antigenic scheme introduced by the authors' laboratories are presented.

Antigenic Variation↗
PubMed1993

Dosing rate-dependent relationship between propranolol plasma concentration and beta-blockade.

The effect of propranolol dosing rate on beta-blockade was studied in human volunteers after administration of a conventional tablet and a sustained release capsule. The slope of the plot of the percentage of reduction in the heart rate against log plasma propranolol concentration was significantly greater after administration of a sustained release capsule than after administration of a conventional tablet. A marked leftward shift of the plasma concentration-response curve was also observed in rabbits as the infusion rate was decreased over the same infusion period. This shift was not altered by pretreatment with 6-hydroxydopamine and plasma catecholamine levels were not affected by the rate of infusion, indicating that the contribution of sympathetic activation to the effect was minimal. By contrast to the anticlockwise hysteresis of the temporal response after propranolol, no such hysteresis was found with the more hydrophilic beta-adrenoceptor antagonist atenolol, or was there any leftward shift in the plasma concentration- response relationship. Data from the isolated guinea pig atrial preparation also showed anticlockwise hysteresis and a leftward shift of the concentration-response curve at a low propranolol input rate, whereas no shift was observed with more hydrophilic beta-blockers such as atenolol, pindolol and metoprolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[A case of significant, non-neoplastic, ovarian hypertestosteronism].

A 24-year-old female with significant ovarian hypertestosteronism, who responded well both to gonadotropin releasing hormone (GnRH) agonist and cyclic administration of estrogen and gestagens in terms of suppressing circulating testosterone levels is reported. The patient's menstrual periods had been regular since menarche at the age of 12 until she became amenorrheic at the age of 20. She visited our facility in November 1988 after receiving three cycles of estrogen and gestagen replacement therapy from a previous physician which caused withdrawal bleeding. Clomiphen citrate reportedly failed to induce apparent ovulation. On her first visit with us, she was 160 cm tall weighing 47 kg with apparent hoarseness but not with hirsutism. Pelvic examination revealed significant clitoromegaly but otherwise normal external and internal genitalia. Laparoscopic examination disclosed that her uterus appeared to be normal with bilateral ovaries relatively small (4 x 4 x 3 cm) without tumorous or polycystic appearance. Histological examination of her ovaries obtained at laparoscopy showed several primary follicles with mild infiltration of the stromal cells. No thickened tunica albuginea or cystic formation were observed. These findings did not support either polycystic ovary or hyperthecosis. Serum testosterone (T) levels were extremely high (7.1 ng/ml), while serum androstenedione levels were only slightly above normal range (3.1 ng/ml). Urine 17-KS excretion was slightly increased (6.1 mg/day), while 17-OHCS output was within normal range (4.0 mg/day). Basal serum LH and FSH levels were within normal range and LH pulse frequency was reduced to 1 in 4 hours. Administration of dexamethasone 1 mg/day for 2 days did not suppress circulating T and free T levels but lowered serum cortisol concentration and urine excretion of 17-OHCS. Blood glucose and insulin levels were within normal limits and their responses to oral glucose administration were normal. Abdominal and pelvic ultrasonography and computed tomography as well as adrenal scintigraphy did not reveal any tumorous lesions in bilateral adrenals and ovaries. Administration of GnRH agonist, Buserelin 900 micrograms/day, suppressed circulating T concentrations to 0.7 ng/ml in 8 days, while it had no significant effects on DHEA and DHEA-S levels. After 16 weeks of Buserelin administration, ovulation was successfully induced by hMG administration. Cyclic estrogen and gestagen replacement therapy by Kaufmann's schedule for 2 cycles also suppressed serum T levels to normal, female range. Thus, the present case represents non-neoplastic, non-PCO, ovarian hypertestosteronism which responded well both to GnRH agonist and estrogen and gestagen replacement therapy in terms of lowering circulating T levels.

Adult↗