The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
最新号
選択された号の論文の10件中1~10を表示しています
Full Papers
  • Yoshiji Ohta, Takashi Kobayashi, Kazuo Inui, Junji Yoshino, Saburo Nak ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 295-303
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    The protective effect of ebselen, which possesses glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, against the progression of acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Ebselen (50, 100 or 200 mg/kg) was orally administered 0.5 h after compound 48/80 treatment, at which time gastric mucosal lesions appeared. Post-administered ebselen suppressed gastric mucosal lesion progression at 3 h after compound 48/80 treatment dose-dependently, although no dose of ebselen affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. A decrease in Se-glutathione peroxidase activity and increases in myeloperoxidase and xanthine oxidase activities and the concentration of thiobarbituric acid reactive substances were found in gastric mucosal tissues at 0.5 h after compound 48/80 treatment, and these changes were further enhanced at 3 h. Post-administered ebselen attenuated all these changes found at 3 h after compound 48/80 treatment dose-dependently. The present results indicate that ebselen exerts a protective effect against the progression of compound 48/80-induced acute gastric mucosal lesions in rats, and they suggest that this protective effect of ebselen could be due to its glutathione peroxidase-like activity and its antioxidative and anti-inflammatory properties.
  • Hiroshi Takane, Shigehiro Ohdo, Reiji Baba, Satoru Koyanagi, Eiji Yuka ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 304-312
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    The influence of interferon-β (IFN-β) dosing time on antiviral activity was investigated in ICR male mice under light-dark cycle conditions (lights on at 07:00, off at 19:00) with food and water available ad libitum. There was a significant dosing time-dependent change in 2',5'-oligoadenylate synthetase (2',5'-OAS) activities, as an index of antiviral activity, in liver at 12 h after IFN-β (15 MIU/kg, i.v.) injection. IFN-β-induced 2',5'-OAS activity was more potent after the drug injection during the late dark phase. The higher antiviral effect of IFN-β was observed when the interferon-α/β receptor (IFNAR) expression in the liver increased, and the lower effect was observed when its expression decreased. IFN-β-induced fever was more serious after IFN-β injection from the late dark phase to the early light phase. A significant dosing time-dependent change was demonstrated for plasma IFN-β concentrations, which showed a higher level during the light phase and a lower level during the dark phase. The dosing time-dependent change of plasma IFN-β concentrations was not associated with that of the antiviral effect or fever induced by IFN-β. These results suggest that selecting the most suitable dosing time of IFN-β, associated with the 24-h rhythm of IFNAR expression in the liver, may be important to increase effectively the antiviral activity of the drug in experimental and clinical situations.
  • Atsuko Inui, Takashi Yoshikawa, Ryuji Nagai, Naoyuki Yoshida, Tsugutak ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 313-320
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    It is known that 5-HT4 receptors in the colon of guinea pigs show a distribution similar to that in humans. Thus, we examined the effects of mosapride citrate (mosapride) and cisapride, two 5-HT4-receptor agonists, on colonic motility in conscious guinea pigs implanted with force transducers. Mosapride and cisapride administered intragastrically at doses of 3 – 30 mg/kg significantly enhanced the colonic motility. The enhancing effect of mosapride was antagonized by atropine or GR113808, a 5-HT4-receptor antagonist, but not by methysergide, a 5-HT1- and 5-HT2-receptor antagonist; ondansetron, a 5-HT3-receptor antagonist; or CP-99994, a tachykinin NK1-receptor antagonist. In vitro receptor autoradiography showed that mosapride and cisapride inhibit the specific binding of [125I]-SB207710, a selective radioligand of 5-HT4 receptors, in the colon of guinea pigs. These results suggest that mosapride enhances colonic motility through the 5-HT4-receptor activation in guinea pigs and may be useful for treating constipation in patients with colonic motility dysfunction.
  • Nobuaki Egashira, Katsunori Iwasaki, Motoki Ishibashi, Izzetin Hatip-A ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 321-327
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    We investigated the effect of hypoxia on β-amyloid (Aβ)-induced apoptosis in rat cultured hippocampal neurons. Aβ (25 μM for 48 h) decreased the number of neuronal cells and increased the number of TUNEL-positive cells. Hypoxia (6 h) also decreased the number of neuronal cells, but did not increase the number of TUNEL-positive cells. Moreover, combined treatment with both Aβ and hypoxia (Aβ/hypoxia) significantly enhanced the decrease in the number of neuronal cells and the increase in the number of TUNEL-positive cells. Z-Asp-CH2-DCB, an inhibitor of interleukin-1β-converting enzyme (ICE), or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-N-methyl-D-aspartate (non-NMDA) receptor antagonist, decreased the number of TUNEL-positive cells with Aβ/hypoxia. These findings suggest that ischemia or hypoxia is an important factor that facilitates the symptoms of Alzheimer’s disease and that non-NMDA receptors are involved in the induction of apoptosis in patients suffering from both cerebrovascular disease and Alzheimer’s disease.
  • Yoshiki Ikeda, Atsushi Kaneko, Masahiro Yamamoto, Atsushi Ishige, Hiro ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 328-336
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    The clinical effectiveness of the Kampo medicine Sho-seiryu-to (SST) has recently been demonstrated in a double-blind randomized study of allergic asthma and rhinitis. We investigated the effect of SST on a type 1 allergic model in mice. Ovalbumin (OVA)-induced sneezing and the total and OVA-specific IgE levels were significantly suppressed with SST at 1.0 g/kg, but that of OVA-specific IgG2a was not. In the splenocytes isolated from SST-administered mice, OVA-induced interleukin (IL)-4 production decreased while interferon (IFN)-γ production was not. The co-culture experiments using purified CD4+T cells and antigen-presenting cells (APCs) suggested that SST influenced both cell types. Flow-cytometric analysis showed that SST suppressed the number of IL-4 producing CD4+T cells but not the number of IFN-γ producing CD4+T cells. The CD86+ major histocompatibility complex class II+ (MHC II)+ cells and CD28+CD4+T cells were decreased by SST treatment, while CD80+MHC II+ cells, CD40+MHC II+ cells and CD154+CD4+T cells showed no change. These data suggested that SST may suppress IL-4 production in CD4+T cells via influencing CD28-CD86 interaction. In addition to the previously reported inhibitory activity on histamine release, suppression of Th2 differentiation at the stage of APC-CD4+T cell interaction may be involved in the anti-allergic effects of SST.
  • Maria Swiatkowska, Zofia Pawlowska, Janusz Szemraj, Józef Drzew ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 337-344
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-α. The inhibitory effect of CRV could be detected at the level of PAI-1 promoter in EA.hy 926 cells transfected with plasmid p800 LUC containing PAI-1 promoter fragment (+71 to −800), as well as at the level of PAI-1 mRNA. The PAI-1 promoter activity was markedly suppressed in the nonstimulated cells and almost completely inhibited in TNF-α-stimulated cells. In addition, CRV at low doses (IC50 of 4 – 6 μM) significantly inhibited mitogen-activated protein kinases (MAPKs) phosphorylation. The majority of inhibitory effects occurred at significantly lower concentrations for CRV compared to LOV. The mechanism by which CRV inhibits PAI-1 expression appears to be directly associated with geranylgeranylation of some cell proteins, since the inhibitory effect on PAI-1 expression can be reversed by geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.
  • Keizo Umegaki, Keiko Saito, Yoko Kubota, Hiroo Sanada, Kazuhiko Yamada ...
    専門分野: Infomation Science
    2002 年 90 巻 4 号 p. 345-351
    発行日: 2002年
    公開日: 2002/12/20
    ジャーナル フリー
    We examined the effect of Ginkgo biloba extract (GBE) on hepatic drug-metabolizing enzymes, particularly cytochrome P450 (CYP), in rats. Rats were fed a GBE-containing diet or received GBE by intragastric gavage. The concentration of CYP and activity of various CYP enzymes in the liver were increased in a dose- and time-dependent manner. Significant increases in the concentration and activities of CYP enzymes were detected on day 1 of feeding of a 0.5% GBE diet and after administration of 10 mg GBE/kg body weight for 5 days by intragastric gavage. Among the CYP enzymes, the activity of pentoxyresorufin O-dealkylase (PROD), a CYP2B enzyme, was especially markedly increased. The induction of CYP2B enzyme by GBE was confirmed by Western blot analysis. Addition of GBE to a CYP assay system in vitro caused concentration-dependent inhibition of various CYP enzyme activities. The inhibition was more marked for the microsomal enzymes from GBE-treated rats than for those from control rats and more marked against PROD activity among the CYP enzymes tested. When the inhibition of various CYP enzymes activities by GBE in vitro was compared, no marked difference was observed between rat and human hepatic microsomal enzymes. These results indicate that excess intake of GBE induces CYP enzymes, particularly PROD, and may modify the efficacy of drugs taken simultaneously.
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