Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
18 巻 , 12 号
選択された号の論文の39件中1~39を表示しています
  • 木方 正, 森元 穂高, 佐久嶋 美穂, 臼井 茂之, 鵜飼 茂夫
    1995 年 18 巻 12 号 p. 1627-1629
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    An acidic polysaccharide (TAP) was isolated from a hot-water extract of the fruiting bodies of Tremella aurantia. It showed remarkable hypoglycemic activity in normal mice and two diabetic mouse models, streptozotocininduced diabetes and genetic diabetes, following intraperitoneal administration. Continuous oral administration of TAP solution (0.5 g/l) for a long period was found to be also effective in hyperglycemia in glucose-loaded mice and no harmful physical effects were found. TAP had an [α]D-7° in water, and its molecular weight was estimated to be about 1500000. TAP is composed of mannose, xylose, glucuronic acid and glucose (molar ratio, 4 : 2 : 1 : 0.3), and it contains 2.2% of O-acetyl groups.
  • 臼井 茂之, 伴野 泰伯, 酒井 美穂, 木方 正, 鵜飼 茂夫
    1995 年 18 巻 12 号 p. 1630-1636
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The formylmethylated and aminoethylated derivatives of schizophyllan (SPG), a β-(1→6)-branched (1→3)-β-D-glucan from Schizophyllum commune FRIES, were prepared through dimethoxyethylated SPG which was synthesized by the reaction of SPG with dimethylchloracetal under an alkaline condition. The degree of the substitution of formylmethyl groups in the formylmethylated derivative of SPG was estimated as approximately 0.19, and the locations of formylmethyl groups in the derivative were predominantly located at O-6 and/or O-4 positions in glucose residues. The molecular weights of these derivatives were similar to that of SPG, and the helical structure of the derivatives did not seem to be different. The antitumor activities of the formylmethylated and aminoethylated derivatives of SPG against subcutaneously implanted sarcoma 180 solid tumor in mice by intraperitoneal (i.p.) administration were increased more effectively than that of SPG at a dose of 10 mg/kg/d for 7 d starting from 7 d after transplantation of sarcoma 180. The activities inducing tumor regressing factor of the formylmethylated and aminoethylated derivatives were 1.5 to 2 times stronger than that of SPG at a dose of 100 mg/kg. Formylmethylated and aminoethylated derivatives of SPG as well as SPG itself retained the potentiating activity for the reticuloendothelial system. The productions of soluble cytotoxic factors secreted from murine macrophages by the administration of the formylmethylated and aminoethylated derivatives of SPG, which were probably superoxide anion and tumor necrosis factor as measured by the potency of the nitro blue tetrazolium reduction and the cytotoxic activity against L929 cells, respectively, appeared to be more efficient than that of SPG.
  • 下條 正仁, 榊原 隆三, 石黒 正恒
    1995 年 18 巻 12 号 p. 1637-1642
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Human chorionic gonadotropin (hCG) in first trimester placental cells is composed of immature α- and β-subunits containing only N-linked high-mannose sugar chains. Intracellular immature intermediates are accumulated in rough endoplasmic reticulum in much greater quantity than mature hCG composed of mature subunits. We have previously shown that this immature hCG might be bound to other protein (s), including an ATP-binding protein, forming high molecular weight-hCG (HMW-hCG), which is not aggregate of immature hCG alone. To identify the ATP-binding protein forming the HMW-hCG in detail, proteins in HMW-hCG preparation were photoaffinity-labeled with 8-azido-[α-32P] ATP. Autoradiography followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that the labeled protein with Mr=78000 was immunoprecipitated with any antibody against α-subunit, β-subunit and hCG, indicating that this protein is bound to immature hCG. Furthermore, to determine whether some other proteins associate to form HMW-hCG, we purified HMW-hCG without breakdown to its components using columns of DE52, Heparin-Sepharose and Sephacryl S-300. As the final step of the purification, HMW-hCG was allowed to adsorb on a column of ATP-agarose and anti-hCG IgG-agarose, respectively. SDS-PAGE analysis of eluted proteins from the columns bound to the respective column via the constituent of HMW-hCG, such as ATP-binding protein or immature hCG, showed four common protein bands with molecular weights of 78000, 43000, 28000 and 20000. The protein with Mr=43000 was stained with any antibody against α-subunit, β-subunit and hCG, indicating it to be immature hCG. The protein band with Mr=78000, which might correspond to the ATP-binding protein described above, was stained with anti-heat shock protein 70 (HSP70) monoclonal antibody. To confirm the association of immature hCG and HSP70-like protein, immature hCG preparation was incubated with HSP70-like protein purified from placental extracts. The molecular weight change of immature hCG appeared to increase by this incubation and was close to HMW-hCG, but not exactly the same. These results suggest that immature hCG intermediate exists as HMW-hCG containing HSP70-like protein, which has ATP-binding capacity, and two other proteins in first trimester placental cells.
  • 渡部 俊彦, 岡田 章利, 三上 健, 松本 達二, 鈴木 益子
    1995 年 18 巻 12 号 p. 1643-1646
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The number of spleen Mac-1-positive cells was markedly increased in methylcholanthrene-induced Meth-A fibrosarcoma (Meth-A)-implanted mice. When the sera of Meth-A-implanted mice were added to normal bone marrow cells, granulocyte and macrophage colony stimulating factor (GM-CSF)-dependent growth of bone marrow cells was significantly enhanced. Analysis of the Meth-A-implanted mice sera showed that the levels of serum transferrin were markedly elevated. When the sera of Meth-A-implanted mice were pretreated with anti-mouse transferrin antibody, the enhancement of GM-CSF-dependent cell growth was almost abolished. Cell growth was also stimulated by the addition of transferrin which also caused an increase in the number of Mac-1-positive cells. Analysis of the effect of transferrin on bone marrow cells showed that the response of the cells to GM-CSF was significantly increased by preincubation with transferrin.
  • 今村 光雄, 上森 隆司, 加藤 郁之進, 石野 良純
    1995 年 18 巻 12 号 p. 1647-1652
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We identified a DNA polymerase with properties that differed from those of α-like DNA polymerase (Pol I), in Pyrococcus furiosus, a hyperthermophilic archaeon. The novel DNA polymerase (Pol II) was partially purified and characterized. The DNA polymerizing activity of Pol II was relatively sensitive to dideoxythymidine-triphosphate (ddTTP) and it was inhibited by N-ethylmaleimide, but not by aphidicolin. Activity staining gel electrophoresis showed that the DNA polymerizing activity was derived from a polypeptide with a molecular weight of 130000 on sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The DNA elongation ability of Pol II using a natural DNA template was much lower than that of Pol I from this organism and DNA synthesis of Pol II seems to be non-processive.
  • 赤尾 光昭, 小橋 恭一
    1995 年 18 巻 12 号 p. 1653-1656
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The oral administration of glycine remarkably decreased the blood ethanol level in mice which had ingested ethanol, and a large amount of ethanol was retained in their stomachs. These effects were observed by the oral administration of glycine previous to the ethanol ingestion, and depended on the dose of glycine. An intravenous injection of glycine did not affect the ethanol absorption at all. These findings indicate that glycine suppresses the rate of ethanol absorption from the gastrointestinal tract. Glycylglycine, glycylglycylglycine and alanine showed the same effects, but glucose did not. However, ethanol absorption from the ligated stomach of mouse was inhibited not only by glycine but also by glucose. On the other hand, the rate of ejecting a pigment from the stomach to the small intestine was lowered by glycine, but not by glucose. Thus, glycine lowers the gastric emptying rate, resulting in the suppression of ethanol absorption from the gastrointestinal tract.
  • 川地 晶子, 三木 卓一, 高畠 英伍
    1995 年 18 巻 12 号 p. 1657-1659
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Flavin-containing monooxygenase (FMO) was partially purified from rat brain microsomes through two successive chromatographies on columns of DEAE Sepharose and 2', 5'-ADP Sepharose. The specific activity, benzydamine N-oxidation of partially purified brain FMO, was 122-fold higher than that of microsomes. A single band of 60 kDa was recognized by Western blotting analysis with anti-rat liver FMO. The Km value of brain FMO for thiourea was 4-fold lower, but that for cysteamine was 10-fold higher than that of liver FMO. The enzymatic activity for n-octylamine was detected in neither brain nor liver FMO. Kinetic analysis for neurotoxins also revealed that Km values of brain FMO for 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), 1, 2, 3, 4-tetrahydroisoquinoline (TIQ) and N-methyl TIQ (NMTIQ) were lower than those of liver FMO. These results indicate that rat brain FMO catalyzes several substrates of liver FMO involving neurotoxins, but it seems likely that the kinetic properties of brain FMO are somewhat different from those of liver FMO.
  • 三村 泰彦, 古林 伸二郎, 岡部 素典, 木村 郁子, 堀越 勇, 木村 正康
    1995 年 18 巻 12 号 p. 1660-1664
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The inhibitory effect of 3-butylidene-4, 5-dihydroxyphthalide (BP-42) on platelet derived growth factor (PDGF)-BB-induced DNA synthesis was investigated in synchronized smooth muscle cells (SMC) in primary culture of rat aorta. BP-42 (0.3-3μg/ml) inhibited the PDGF-BB (30 ng/ml)-stimulated [3H]thymidine incorporation of the SMC in a concentration-dependent manner. BP-42 inhibited both the competence and progression phases of [3H] thymidine incorporation induced by PDGF-BB. Using the competence assay, BP-42 (0.3-10 μg/ml) delayed PDGF-BB (30 ng/ml)-accelerated starting time of [3H] thymidine incorporation in a concentration-dependent manner, confirming that BP-42 inhibited PDGF-BB-induced competence phase of DNA synthesis of SMC. BP-42 (1-10 μg/ml) also delayed basic fibroblast growth factor (bFGF : 30 ng/ml)-accelerated starting time of [3H] thymidine incorporation. The inhibitory potency of BP-42 for the competence action of PDGF-BB was similar to that for the action of bFGF. BP-421 (3-heptylidene-4, 5-dihydroxyphthalide) and BP-422 (3-benzylidene-4, 5-dihydroxyphthalide) had 3-fold greater inhibitory potencies than BP-42 for the PDGF-BB-induced competence activity. These results demonstrated that BP-42 inhibited PDGF-BB-induced competence activity of DNA synthesis in primary cultured SMC of rat aorta via a common signal transduction mechanism with bFGF. BP-421 and BP-422 were more potent inhibitors for the competence activity, suggesting that they may become a prototype of new anti-atherosclerotic drugs.
  • 岡部 素典, 木村 郁子, 木村 正康
    1995 年 18 巻 12 号 p. 1665-1670
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We investigated with flow cytometry the platelet-derived growth factor (PDGF)-induced competence in primary cultured smooth muscle cells (SMC) of rat thoracic aorta. A cytogram was obtained by a double staining technique with fluorescein isothiocyanate-conjugated mouse monoclonal antibody against the proliferation-associated nucleus antigen Ki-67, and propidium iodide for total DNA content. (1) The nearly confluent SMC after 6d-culture with 5% fetal bovine serum (FBS) were further cultured under serum starvation for 2d. (2) SMC was cultured with 5% FBS for 4d, and then with 5% FBS+trichostatin-A (TS-A) (1 μg/ml) for 2d. The cytogram showed the broadening of Ki-67 antigen signal for G0/G1 phase by TS-A compared with that of SMC under serum starvation, suggesting the existence of early and late phases of G1.(3) After serum starvation, the preculture with PDGF (100 ng/ml) for 3h which was followed by a further 15 h-culture with 3% FBS caused significant more entry into S phase than control culture. The extent was greater than that with 15 h-culture with 10% FBS. (4) 15 h-culture with 1% FBS after PDGF (30 ng/ml) pretreatment stimulated entry into S phase cells, which was inhibited by TS-A (1 μg/ml) and by a butylydene phthalide derivative BP-421 (3 μg/ml). Flow cytometric analysis demonstrate that PDGF pretreatment stimulates the entry into S phase by 20% of total SMC having early and late phases of G1, and that the PDGF-competence is inhibited by TS-A and BP-421.
  • 岸林 伸行, 唐沢 啓
    1995 年 18 巻 12 号 p. 1671-1675
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    KW-5092 ({1-[2-[[[5-(piperidinomethyl)-2-furanyl] methyl] amino] ethyl]-2-imidazolidinylidene} propanedinitrile fumarate) enhances acetylcholine release from enteric neurons and inhibits acetylcholinesterase (AChE), resulting in the enhancement of a wide range of gastrointestinal motilities. The present study examined the effects of KW-5092 on intestinal water and electrolyte transport in rats. In the jejunum, oral or intrajejunal administration of the laxative bisacodyl (30 mg/kg) significantly inhibited absorption of water, Na+ and Cl-, and significantly enhanced K+ secretion. In contrast, neither KW-5092 (1-30 mg/kg) nor the AChE inhibitor neostigmine (0.3-10 mg/kg), orally or intrajejunally administered, affected water or electrolyte transport in the jejunum. Similar results were obtained in the colon when the drugs were applied orally or intracolonically. Moreover, neither KW-5092 (1-30 mg/kg, p.o.) nor neostigmine (0.3-10 mg/kg, p.o.) induced diarrhea, while bisacodyl (30 mg/kg, p.o.) induced diarrhea in all the rats examined. These results demonstrate that KW-5092 or neostigmine at the gastroprokinetic doses does not affect intestinal water or electrolyte transport in rats, suggesting that cholinergic activation enhances gastrointestinal motility rather than intestinal secretion of water and electrolytes.
  • 陳 福君, 中島 登, 木村 郁子, 木村 正康, 浅野 直樹, 小屋 佐久次
    1995 年 18 巻 12 号 p. 1676-1680
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of hot water extracts and six compounds of N-containing sugars, 1-deoxynojirimycin (DNJ), N-methyl-DNJ (N-Me-DNJ), 2-O-α-D-galactopyranosyl-DNJ (GAL-DNJ), fagomine, 1, 4-dideoxy-1, 4-imino-D-arabinitol (DAB), and 1, 2α, 3β, 4α-tetrahydroxynortropane (calystegin B2), derived from mulberry leaves (Morus alba L.), were investigated on pilocarpine-induced saliva secretion in streptozocin (STZ)-induced diabetic mice. The extracts (100 and 200 mg/kg, i.p.) significantly potentiated the pilocarpine-induced salivary flow but not the protein content. The component compounds (37.5-300 μmol/kg) potentiated the saliva secretion, and the potency order was DAB>fagomine>GAL-DNJ. Only fagomine significantly increased the protein content in the saliva. The potentiation of pilocarpine-induced salivary flow was correlated with anti-hyperglycemic effects by the extract and GAL-DNJ from mulberry leaves in the same dose ranges.
  • 藤猪 英樹, 駒澤 宏幸, 森 秀登, 小島 政芳, 伊藤 勇, 村田 純, 東 市郎, 済木 育夫
    1995 年 18 巻 12 号 p. 1681-1688
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We have investigated the inhibitory effect of the N-terminal modified Arg-Gly-Asp-Ser (RGDS) analogues, AcDRGDS and AcDRLDS, on tumor cell adhesion to the components of extracellular matrix and basement membrane, and also tested the antimetastatic effect of their conjugates with trimesic acid, Ar (DRGDS)3 and Ar (DRLDS)3. AcDRGDS significantly inhibited tumor cell adhesion to fibronectin, vitronectin and RGDS substrates, but not to CS1 substrate which is a ligand for the α4β1 tumor surface integrin receptor. In contrast, AcDRLDS variant peptide significantly inhibited tumor cell adhesion to laminin, in addition to RGDS-mediated adhesion to fibronectin and vitronectin. AcDRLDS also inhibited tumor cell adhesion to CS1 as well as the RGDS sequence within the fibronectin molecule in a concentration-dependent manner, although the inhibitory effect was less than that of the CS1 (EILDV) peptide. Ar (DRLDS)3 inhibited the laminin- and fibronectin-mediated invasion and migration of tumor cells, whereas Ar (DRGDS)3 selectively inhibited fibronectin-mediated invasion and migration. Ar (DRGDS)3 and Ar (DRLDS)3 were much more effective in inhibiting experimental lung or liver metastases of various types of murine and human tumors than the original RGDS-containing peptides or Ar (COONa)3. Multiple administrations of Ar (DRGDS)3 or Ar (DRLDS)3 potently inhibited spontaneous lung metastasis produced by intra-footpad injection of B16-BL6 cells without affecting the primary tumor size at the time of surgical excision, as compared with RGDS peptide or untreated control. Thus, Ar (DRGDS)3 and Ar (DRLDS)3 substantially increased the exhibiting any antimetastatic effect of the peptides without direct cytotoxicity.
  • 遠藤 哲也, 木村 治, 笹谷 政史, 高田 昌彦, 阪田 正勝
    1995 年 18 巻 12 号 p. 1689-1693
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of sodium ions (Na+) and metabolic inhibitors on cadmium (Cd) uptake were investigated in LLC-PK1 cells derived from pig kidney under the nontoxic conditions of Cd. The inoculated cells became confluent on day 7 after the logarithmic growth phase. The initial uptake of Cd (1-60 μM) by the confluent cells (day 7) was assayed. The relationship between the Cd uptake at 37°C and Cd concentration was nonlinear, but the relationship at 4°C was linear. Subtraction of the Cd uptake at 4°C from that at 37°C showed a saturable uptake against the Cd concentration. By the Eadie-Hofstee analysis of saturable uptake, Km and Vmax were 24.6 μM and 164 pmol Cd/mg protein/min, respectively. The uptake of Cd by the cells was significantly decreased by ouabain and the metabolic inhibitors, and by the replacement of Na+ with potassium or choline ion in the incubation medium. These results suggest that Cd is incorporated into the confluent LLC-PK1 cells not only by simple diffusion but also by the carriermediated transport involved in Na+-and energy-dependent process (es).
  • 木倉 瑠理, 中原 雄二
    1995 年 18 巻 12 号 p. 1694-1699
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    In order to study the disposition of benzphetamine (BZP) and its metabolites, desmethyl benzphetamine (norBZP), p-hydroxy desmethyl benzphetamine (OHnorBZP), methamphetamine (MA) and amphetamine (AP), from plasma to hair in rats, an analytical method for identifying these drugs in plasma, urine and hair was developed with selected ion monitoring of gas chromatograph/mass spectrometry (GC/MS-SIM) results. After the intraperitoneal administration of BZP to rats (10 mg/kg/d, 10d, n=3), concentrations of BZP and its metabolites in rat hair newly grown for 4 weeks were compared to the areas under the concentration versus time curve (AUCs) of these drugs in the rat plasma. The concentrations of BZP, norBZP, OHnorBZP, MA and AP in the rat hair were 14.8±1.4, 6.1±0.3, 2.6±0.5, 2.3±0.1 and 9.2±0.3 ng/mg, and the ratio of the concentrations in the hair to AUCs in the rat plasma was 3.0 : 0.1 : 0.1 : 0.6 : 0.2, respectively. This fact suggested that BZP tends to be readily incorporated into hair from blood. The method was applied to the determination of the metabolites in scalp hair and pubic hair of humans who orally ingested BZP (30 mg/d, 5d, n=2). BZP, norBZP, MA and AP were detected at 0.14-0.56, 0.29-0.63, 0.10 and 1.06-1.66 ng/mg in the scalp hair and at 0.10-0.20, 0.13-0.18, trace-0.15 and 0.23 ng/mg in the pubic hair, respectively. It was shown that BZP use could be retrospectively distinguished from MA use by the detection of BZP and/or norBZP in hair.
  • 土屋 照雄, 今枝 厚宗, 木方 正, 鵜飼 茂夫
    1995 年 18 巻 12 号 p. 1700-1704
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The potency of carbohydrate sulfate (dextran sulfate, DS ; glucose sulfate, GS), alkyldisulfonate (butanedisulfonate, BDS ; propanedisulfonate, TDS) and polyvinyl sulfate (PVP) as the quencher of active oxygen species was studied. Co-incubation of GS, BDS or TDS and tert-butylhydroperoxide together with human erythrocytes resulted in a marked decrease in hemolysis relative to the hemolysis induced by peroxide alone. DS and PVP exhibited no suppressive effect. When hemolysis was induced by a singlet oxygen derived from a photosensitizercoupled reaction, PVP, BDS and TDS lowered its extent by 30-40%. DS and GS did not exhibit any effect on singlet oxygen-induced hemolysis. The quenching effect towards hydroxyl radical was assessed by investigating the protective effect on DNA strand breakage which was introduced by the Fenton reaction and enzymatic reduction of paraquat (PQ). The result showed that BDS and TDS are potent hydroxyl radical scavengers. All compounds examined here failed to reduce PQ toxicity assessed by the inhibition of E. coli cell growth. In addition, all compounds had no effect on the magnitude of PQ-induced induction of superoxide dismutase in E. coli. These results strongly suggest that low-molecular weight alkyldisulfonates, BDS and TDS, are potent scavengers of peroxyl, alkoxyl and hydroxyl radicals, and singlet oxygen although these reagents cannot interact with superoxide anion radicals.
  • 西垣 淳子, 鈴木 聡, 由井 譲二, 重松 昭世
    1995 年 18 巻 12 号 p. 1705-1709
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    With the aim of making direct investigational studies of various liver functions of sustained healthy animals, we devised operative procedures which are not only simple and reproducible but also adaptable to experiments even over the course of one-week without anesthesia. Using rats which have been operated upon, three kinds of tracers, 99mTc-pool scinti, 99mTc-pertechnetate and 99mTc-phytate, were recorded by a scintillation camera with a single-photon system immediately after intraportal administration. The results revealed that the discharge of these radioactive components from the hepatic vein began 0.2 s after the administration, that the maximum intrahepatic concentration was reached between 2 and 5 s thereafter, and that 10 s later, these radioactive components were returned to the liver after their systemic circulation. Intrahepatic uptake of these three tracers was about 20% for all radioactivities administered.
  • 岩田 進, 西野 剛史, 永田 信幸, 里見 佳子, 西野 輔翼, 柴田 承二
    1995 年 18 巻 12 号 p. 1710-1713
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    More than forty chalcone derivatives were synthesized to examine their structure-activity relationship against tumorigenesis. As a primary screening test, the inhibitory activities of the chalcones for the 32Pi-incorporation into phospholipids of HeLa cells enhanced by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) were examined. 3-Hydroxy-chalcone derivatives possessing methyl group in 3'-, 4'-, or 2'-position and isoliquiritigenin homologs showed potent inhibitory activities in the phosphorylation test, which suggests their antitumorigenic effects.
  • 川崎 紘一, 並川 眞知子, 水田 豊彦, 井上 幸恵, 前田 光子, 柿内 雅, 伊豆野 康広, 山本 晋, 堤 康史, 中川 晋作, 真 ...
    1995 年 18 巻 12 号 p. 1714-1717
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Laminin-related peptide poly (ethylene glycol) hybrid, Tyr-Ile-Gly-Ser-Arg-aminopoly (ethylene glycol) was prepared by the solution method and carboxylated poly (ethylene glycol)-Tyr-Ile-Gly-Ser-Arg was prepared by the solid phase method. Their inhibitory effects on experimental tumor metastasis were examined in mice. The inhibitory effect of Tyr-Ile-Gly-Ser-Arg was significantly potentiated by hybrid formation with poly (ethylene glycol) either at amino- or carboxyl terminals of the peptide. Of the hybrids, Tyr-Ile-Gly-Ser-Arg-amino (polyethylene glycol) #6000 hybrid exhibited about 10 times more potent anti-metastatic effect than the peptide itself. The inhibitory effect of a mixture of the carboxylated poly (ethylene glycol) hybrid and Arg-Gly-Asp-aminopoly (ethylene glycol) hybrid also exhibited an inhibitory effect.
  • 松澤 綾子, 森下 真莉子, 高山 幸三, 永井 恒司
    1995 年 18 巻 12 号 p. 1718-1723
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The present work was undertaken to prepare water-in-oil-in-water (W/O/W) emulsions as a carrier for insulin via the enteral route. The emulsions were prepared by a two-step procedure using a homogenizer. To avoid insulin escape from the inner aqueous phase, 3, 5 or 10% gelatin was added in the inner phase. The oily phase was composed of 5% lecithin, 20% Span 80 and 75% soybean oil. The purified water containing 3% Tween 80 was used for the outer aqueous phase. In addition, these emulsions were filtered with a membrane filter (0.45 μm) to obtain smaller emulsion particles. The stability of the emulsions was evaluated by a turbidity measurement method and photomicrographic observation. By the addition of gelatin to the inner aqueous phase and storage at 4°C, the stability of the emulsions could be improved. The hypoglycemic effects of insulin after administration of emulsion to the stomach, the duodenum, the jejunum, the ileum and the colon were examined using an in situ loop method in rats. A significant hypoglycemic effect was observed at the ileum and colon loops after administration of the filtered emulsions containing 5% gelatin in the inner phase. These findings suggest that the W/O/W multiple emulsions stabilized by gelatin can improve ileal and colonic absorption of insulin.
  • 田中 哲郎, 金尾 義治, 宮下 正日出, 白元 正一
    1995 年 18 巻 12 号 p. 1724-1728
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    In order to improve the deposition of mitomycin C (MMC) in the administered site, water-insoluble mitomycin C-albumin conjugate (MMC-G-BSA) was prepared. MMC was covalently attached to the glutarylated bovine serum albumin (G-BSA) in the presence of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC) to give MMC-G-BSA. The MMC content of the conjugate (16.3% (w/w)) was higher than that of water-soluble mitomycin C-albumin conjugates. MMC was liberated from MMC-G-BSA suspended in a phosphate buffer (pH 7.4, 37°C) with a half-life of 155.3 h. In the same buffer system containing α-chymotrypsin, MMC-G-BSA was dissolved perfectly within 24h due to enzymatic degradation, and the liberation of MMC from the conjugate was significantly accelerated (t1/2=24.5 h). After intraperitoneal injection in mice, most of the MMC-G-BSA was retained in the abdominal cavity. Furthermore, the survival time of mice inoculated with Sarcoma 180 was significantly increased by the intraperitoneal injection of MMC-G-BSA. These findings suggest that MMC-G-BSA is a biodegradable macromolecular hybrid which acts as a sustained release delivery system of MMC.
  • 水谷 義勝, 岡田 良樹, 小川 道子, 長谷川 高明, 鍋島 俊隆
    1995 年 18 巻 12 号 p. 1729-1737
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A pharmacokinetic model of oral levodopa is proposed to elucidate the effects of carbidopa on the pharmacokinetics of levodopa. The propriety of the model was evaluated by simultaneous computer Multi-Line fitting for the plasma concentration-time data of levodopa and dopamine-3-O-sulfate (DA-S), a major metabolite of levodopa, after oral administration of three different levodopa doses to parkinsonian patients. Plasma profiles of levodopa and DA-S were also determined in 12 parkinsonian patients during daily oral administration of Neodopaston[○!R], a levodopa preparation containing carbidopa in tablet form. We investigated the role of carbidopa by comparing the populational mean parameters calculated in the levodopa alone model with those obtained in patients coadministered levodopa and carbidopa. The results indicated that the pharmacokinetics of levodopa coadministered with carbidopa were dose-independent and that carbidopa reduces the first-pass metabolism of levodopa in the gut wall to less than 10% of the dose absorbed, and decreases the systemic clearance of levodopa by 35-39%. The proposed pharmacokinetic model and the evaluation of carbidopa in this study will provide useful information for the development of drug delivery systems for levodopa or catechol-O-methyltransferase inhibitors, for further stabilization of plasma concentrations of levodopa in parkinsonian patients.
  • 鄭 年新, 佐藤 均, 足立 伊佐雄, 金本 郁男, 堀越 勇
    1995 年 18 巻 12 号 p. 1738-1743
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The pharmacokinetic and pharmacodynamic (PK/PD) characteristics of ozagrel, a new potent and selective thromboxane synthetase inhibitor, were investigated in rabbits after its intravenous, oral, and rectal administration. Serum level of TXB2 (the stable metabolite of TXA2), a direct pharmacological marker, was measured after each dosing. A marked reduction of serum TXB2 within 30 min was shown after the three routes of administration, reflecting rapid onset of action. Due to rapid and complete absorption (i.e., Tmax ; 20 min, bioavailability ; 100%) and longer duration of pharmacological action after rectal dosing, the rectum offers a practical delivery route for ozagrel. An Emax model was employed to fit the pharmacological data, and IC50 and Emax for thromboxane synthetase inhibition were estimated to be 56.0 ng/ml and 94%, respectively. These pharmacodynamic parameters were incorporated into an integrated mathematical model to simulate the PK/PD profiles of ozagrel after i.v., oral, and rectal administration at lower (50 mg) and higher (200 mg) doses, and good agreement between the experimental and calculated values was achieved. The present PK/PD model may be useful for optimizing the therapeutic regimens of ozagrel.
  • 松本 宜明, 山本 郁生, 渡辺 善照, 松本 光雄
    1995 年 18 巻 12 号 p. 1744-1749
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of the viscosity of sodium hyaluronate solution on the rectal absorption of morphine was determined in rabbits. Hollow-type suppositories containing 10 mg morphine in viscous sodium hyaluronate solution of various mean molecular weights (MWs) were prepared. Rectal absorption of morphine in the sodium hyaluronate solution (MW 2.1×106 daltons) was dependent on sodium hyaluronate concentrations in the range of 0.1 to 3% (w/v). Bioavailability after rectal administration of morphine in 0.1% sodium hyaluronate solution is consistent with that of morphine solution in the absence of sodium hyaluronate and the sustained-release plasma profile was observed for morphine in 3% sodium hyaluronate solution. Administration of hollow-type suppositories containing 10 mg morphine in 1% sodium hyaluronate solution resulted in the highest bioavailability of approximately 2-fold that after administration of morphine in physiological saline solution. Five kinds of sodium hyaluronate solution with MWs of 2.4×105, 1.0×106, 1.2×106, 1.8×106 and 2.1×106 daltons and respective viscosities of 70, 3.3×103, 3.2×103, 5.1×103 and 5.7×103 cP (20°C) were examined. Optimal viscosity of the sodium hyaluronate solution was found to enhance rectal morphine absorption. These results indicate that the selection of relevant viscosity of the sodium hyaluronate solution may contribute to the improvement of bioavailability of morphine on rectal administration.
  • 長谷川 靖, 杉本 恵美佳, 遠藤 智子, 小川 行平, 荒武 尚, 森川 安理, 北口 暢哉
    1995 年 18 巻 12 号 p. 1750-1754
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Alzheimer's β-amyloid protein (Aβ) is the main component of senile plaques, which are characteristic hallmarks of the Alzheimer's disease brain. Recently, there have been several reports that Aβ has toxic effects on both cultured neurons and in the brain. We confirmed the neurotoxicity of Aβ in vitro and found a new compound, called AZ36041 (4-chloro-N-(5-nitro-2-tiazoyl) benzenesulfone amide), which dramatically reduced Aβ neurotoxicity. This compound was also found to have a neuroprotective effect against toxicity of glutamate and enhanced neuronal survival in the absence of neurotoxic compounds. AZ36041 may be a useful tool for investigating the mechanism of Aβ neurotoxicity in vitro and in vivo.
  • 坂井 利彰, 高舘 明, 小田切 優樹
    1995 年 18 巻 12 号 p. 1755-1761
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The interaction of uremic toxins including indole-3-acetic acid (IA), indoxyl sulfate (IS), hippuric acid (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) with human serum albumin (HSA) has been investigated by three methods of fluorescent probe displacement, ultrafiltration and equilibrium dialysis. The binding parameter of CMPF was found to have the strongest affinity (107M-1) among all the uremic toxins studied. Competitive experiment based on the method of Kragh-Hansen suggested that IA, IS and HA bind to site II, whereas CMPF binds to site I. The present limited data indicated that the four uremic toxins caused inhibition to any endo- or exogenous substances on HSA.
  • 中島 正晴, 大和 進, 若林 広行, 嶋田 健次
    1995 年 18 巻 12 号 p. 1762-1764
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The precolumn derivatization reagent, 2-[2-(isocyanate)ethyl]-3-methyl-1, 4-naphthoquinone (IMQ) was applied to the simultaneous determination of cholesterol and cholestanol in human serum by HPLC with electrochemical detection. The compounds extracted with hexane from human serum, to which was added 1-eicosanol as an internal standard, were reacted with IMQ in acetone and converted into the corresponding carbamic acid esters. After chromatographic separation of the derivatives, they were reduced once in a platinum catalyst reduction column connected on-line, then quantified with an electrochemical detector in the oxidation mode. The detection limits at a signal-to-noise ratio of 3 were 6.6 pg (17 fmol) and 7.4 pg (19 fmol) for cholesterol and cholestanol, respectively in a 10 μl injection volume. This method was successfully applied to the determination of free and total cholesterol and total cholestanol in normal human serum, and the concentrations of free and total cholesterol were compared with those obtained by an enzymatic method.
  • 松浦 一也, 佐藤 久美子, 出屋敷 喜宏, 中西 雅之, 原 明
    1995 年 18 巻 12 号 p. 1765-1767
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    3-Deoxyglucosone is one of the major cytotoxic intermediates in the Maillard reaction. Adrenal glands showed the highest NADPH-linked 3-deoxyglucosone reductase activity of dog tissues. The enzyme was purified to homogeneity from the adrenal glands, and demonstrated to be structurally, functionally and immunologically identical with aldose reductase, which comprises about 6% of the soluble adrenal proteins.
  • 佐藤 豊光, 村山 典恵, 山添 康, 加藤 隆一
    1995 年 18 巻 12 号 p. 1768-1769
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A clear chain-length dependent effect was observed for peroxisomal fatty acid β-oxidation and carnitine acetyltransferase and also for mitochondrial carnitine palmitoyltransferase in primary cultures of rat hepatocytes. The extent of modulation of peroxisomal β-oxidation was higher with even-carbon numbered dicarboxylic acids than with odd-carbon numbered ones, although such a tendency was not detected in the mitochondrial reactions. These results indicate difference in the effect of fatty acid-derived dicarboxylates on peroxisomal and mitochondrial functions.
  • 森野 博文, 榊原 隆三, 石黒 正恒
    1995 年 18 巻 12 号 p. 1770-1772
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Ricin toxin is a toxic glycoprotein comprising two polypeptide chains, A and B, joined by a disulfide bond. The binding of its B-chain to the cell surface glycoconjugate having non-reducing terminal galactose (ricin receptors) has been assumed to allow the internalization of ricin into the cell, followed by the release of the free A-chain into cytosol, which then inhibits cellular protein synthesis in eukaryotic cells (cytotoxic effect). In order to investigate whether the binding of ricin to its receptors is essential to the expression of its toxicity, ricin was allowed to be incorporated into the cells using liposome encapsulated ricin (ricin-encapsulated liposomes). Protein synthesis in cultured Hela cells was inhibited by incubation not only with intact ricin but also with ricin-encapsulated liposomes, indicating that the binding of ricin to its receptor is not required for the expression of its toxicity.
  • 中田 彩, 齋藤 洋, 西山 信好
    1995 年 18 巻 12 号 p. 1773-1775
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Cysteamine has been reported to disturb learning performance in rats. Our study was made to determine if this is also true in mice. Adult male ddY mice were subjected to a battery of learning tests following our standard experimental protocols. Cysteamine injected 30 min prior to the learning trial dose-dependently increased the number of errors in the testing trial of step-down test, and its effect was statistically significant at a dose of 200 mg/kg. In the lever press test, 200 mg/kg injection of cysteamine also suppressed the conditioned avoidance rate. However, no significant changes were observed in other tests. These results suggest that the learning disorder induced by cysteamine in mice is restricted to a specific type of behavioral performance. In conclusion, the mechanism by which cysteamine generates learning deficiency in mice may differ from that in rats.
  • / , / 馬場 明道, HackSeang KIM, Akemichi BABA
    1995 年 18 巻 12 号 p. 1776-1778
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of ginseng total saponins (GTS) on L-glutamate-induced swelling of cultured astrocytes from rat brain were studied. Following exposure to 0.5 mM glutamate for 1 h, the intracellular water space (as measured by [3H] O-methyl-D-glucose uptake) of astrocytes increased three-fold with a morphological change : the disappearance of cellular processes. Simultaneous addition of GTS with glutamate reduced the astrocytic swelling in a dose-dependent manner. GTS at 0.5 mg/ml did not affect the viability of astrocytes for up to 18 h, which was determined by a colorimetric assay for cellular growth and survival. These data suggest that GTS prevents the cell swelling of astrocytes induced by glutamate.
  • 小野 哲, 山藤 哲夫, 茶木 久晃, 藤堂 洋三, 前川 睦子, 北村 和則, 木村 龍生, 中田 恭史, 最住 邦子, 成田 弘和
    1995 年 18 巻 12 号 p. 1779-1783
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The title compound (T-588) has been evaluated for its ameliorating effect on memory impairment generated by cerebral embolization and by a basal forebrain (BF) lesion in male Wistar rats. The memory and learning deficits induced by injection of carbon-microspheres into the internal carotid artery were significantly improved by T-588 at oral dose of 3-10 mg/kg, as determined by an active avoidance response assay, whereas the reference drugs (tacrine, idebenone and indeloxazine) proved almost inactive in the same assay procedure. As far as the embolization was concerned, a significant decrease in cerebral acetylcholine and monoamines was observed. The effect on the memory impairment caused by an electrolytic lesion of the BF was assessed by a passive avoidance task. T-588 exhibited a bell-shaped dose-response curve and was most active at 1 mg/kg (oral dose), while tacrine showed equal activity at 10 mg/kg.
  • Alejandra O. MARIA, Graciela H. WENDEL, Teresita GUARDIA, Jorge A. GUZ ...
    1995 年 18 巻 12 号 p. 1784-1786
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The cytoprotective activity of the isolated functional groups of several sesquiterpene lactones is reported. Among them the highest activity is shown by α-methylen-γ-butyrolactone and 2-cyclopenten-1-one. The activity shown by those Michael acceptors with a β carbon hindered by an alkyl substituent was always lower or almost null. A three-way mechanism of action is proposed : a) reduced glutathione synthesis, b) prostaglandin synthesis and c) mucosal glycoprotein synthesis.
  • 山下 富義, 坂東 博人, 高倉 喜信, 橋田 充
    1995 年 18 巻 12 号 p. 1787-1789
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A deconvolution method for estimating the first-pass metabolism of orally administered drugs is proposed. This analysis can be carried out without assuming any pharmacokinetic models. The applicability of the deconvolution method was evaluated by application to the plasma concentration-time courses of aspirin and its metabolite, salicylic acid, reconstructed from pharmacokinetic parameters for orally administered drugs. The estimated absorption profiles for aspirin and salicylic acid were in fairly good agreement with the theoretical ones, although a series of numerical calculations is involved in the procedures. The potential of the present method was also confirmed by applying it to pharmacokinetic data with random errors.
  • Pao-Chu WU, Jia-You FANG, Yaw-Bin HUANG, Yi-Hung TSAI
    1995 年 18 巻 12 号 p. 1790-1792
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Sodium nonivamide acetate (SNA) is a newly synthetic analogue of capsaicin which produces no overt pungent sensation or irritation. In this present study, the effects and roles of penetration enhancers for SNA through rat skin were investigated by in vitro skin penetration experiment and differential scanning calorimeter (DSC) determination. The penetration fluxes of SNA after the incorporation of enhancers increased in the order of Polysorbate 20<sodium laurylsulfate&gne ; benzalkonium chloride. This result was consistent with that of DSC profiles which indicated the disruptive effects of surfactants on the rat stratum corneum increased in the order of Polysorbate 20<sodium laurylsulfate<benzalkonium chloride. The information gained is particularly helpful in the development of SNA transdermal drug delivery system.
  • 川重 誠, 千堂 年昭, 大坪 健司, 青山 敏信, 大石 了三
    1995 年 18 巻 12 号 p. 1793-1796
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The quality of three commercial injections (Genotropin, Humatrope and Norditropin) of lyophilized recombinant human growth hormone (r-hGH) was evaluated in tests by visual inspection, high-performance gel permeation chromatography, polyacrylamide gel electrophoresis, scanning electron microscopy and energy dispersion X-ray microanalysis. The influence of the reconstitution method on gel formation was examined as follows : rapid injection of the diluting solution into a vial against the wall, slow injection onto the surface of the content, and rapid injection onto the surface of the content. The degree of gel formation differed among reconstitution methods. Moreover, fibrous particulate matter in addition to degradation products of r-hGH were evident in all preparations. The quality of r-hGH injection differed among commercial products. Norditropin included the least particulate matter when examined immediately after reconstitution, but it was easily denatured after storage in solution. We advise medical specialists to reconstitute a preparation by the optimal method.
  • 三浦 敏秀, 大野 尚仁, 須田 昌宏, 三浦 典子, 島田 慈彦, 宿前 利郎
    1995 年 18 巻 12 号 p. 1797-1801
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Intraperitoneally or intravenously administered (1→3)-β-D-glucan remained in the liver and spleen, for a long time without major structural changes, but the priming activity to lipopolysaccharide (LPS)-triggered tumor necrosis factor-α (TNF-α) production was reduced more quickly. The relationship between the deposited glucan contents and the antitumor activity was examined by comparing kinetics of the activity using solid form Sarcoma 180 tumor in ICR mice. We used three kinds of soluble glucans, sonifilan (SPG), grifolan (GRN), and SSG, and a particulate glucan, zymosan (ZYM). These were administered 5 weeks before (-5W) the tumor inoculation and the tumor weight was compared 5 weeks after the inoculation. Compared with the activity of those administered at the optimum timing, all of the glucans reduced the activity about 5 fold, although significant activity still remained, especially in the case of SPG. Five weeks after intraperitoneal (SPG, GRN, SSG) or intravenous (ZYM) administration of the glucans, all were found in the liver and spleen in significant quantities. These facts strongly suggested that the activity of the glucan was reduced not only because of chemical/physical degradation but also a certain physiological inactivation mechanism.
  • 増子 洋, 田澤 賢次, / 竹森 繁, 清水 哲朗, 藤巻 雅夫, 長江 英夫, 佐藤 均, 堀越 勇, Isamu HORIKOSHI
    1995 年 18 巻 12 号 p. 1802-1804
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    This study examined a possibility of dextran magnetite (DM)-incorporated thermosensitive liposomes, namely thermosensitive magnetoliposomes (TMs), as a new hyperthermic agent. The temperatures of TM suspensions and cancer tumors injected with TM suspensions were efficiently elevated up to 42°C by electromagnetic induced heating at a frequency of 500 kHz under both in vitro and in vivo conditions. Thus, a possibility of TMs for selective hyperthermia was demonstrated. The temperature rises obtained at various concentrations of TMs suggest that approximately 15 mg Fe/cm3 tumor volume is adequate as a therapeutic dose of TMs for efficient selective hyperthermia.
  • 松村 康史, 塩沢 竜志, 松下 秀鶴, 寺尾 良保
    1995 年 18 巻 12 号 p. 1805-1807
    発行日: 1995/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Alkyl azides showed mutagenicity for S. typhimurium TA100 strain with S9 mix. However, no significant activity was observed for TA98 either with or without S9 mix or for TA100 without S9 mix. On the other hand, 3-azido-1, 2-propanediol showed the enantioselective activity regardless of S9 mix. Two aryl azides tested were not mutagenic, and trimethylsilyl azide exhibited potent activity for TA100. Their structure-activity relationships are discussed.
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