Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
18 巻 , 2 号
選択された号の論文の35件中1~35を表示しています
  • 中島 孝則, 桑江 豊保, 三浦 洋四郎, 倉田 宗司
    1995 年 18 巻 2 号 p. 199-202
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    On rabbit alveolar macrophages prelabeled with double tracers of [3H] arachidonic acid (20 : 4) for 30 min (short-term labeling) and of [14C] 20 : 4 for 12 h (long-term labeling), the relationship between phospholipid subclasses and the release of 20 : 4 on stimulation with opsonized-zymosan (OZ) was investigated. Stimulation with 500μg of OZ/ml for 1h caused a significant decrease in the radioactivity of incorporated [3H] 20 : 4 in all phosphatidylcholine (PC) subclasses of the cells : by 48% in 1-O-alkyl-2-acyl-sn-glycerol-3-phosphocholine (alkylacyl-GPC), and by 24% in 1, 2-diacyl-GPC (diacyl-GPC), and slightly in 1-O-alk-1'-enyl-2-acyl-GPC (alkenylacyl-GPC). In phosphatidylethanolamine (PE), a significant decrease in the incorporated [3H] 20 : 4 was also observed in the 1, 2-diacyl-sn-glycerol-3-phosphoethanolamine (diacyl-GPE, 45%). On the other hand, the radio activity of [14C] 20 : 4 incorporated by long-term labeling into PC decreased significantly, by approximately 40%, in the alkylacyl-GPC and slightly in the alkenylacyl-GPC. In PE, a significant decrease (approximately 32%) in radioactivity of [14C] 20 : 4 was observed only in the alkenylacyl-GPE which incorporated the largest amount of [14C] 20 : 4 among the cellular phospholipids in its labeling and which showed the biggest decrease in [14C] 20 : 4 in the PC and PE subclasses on stimulation with OZ. These results suggest that on OZ stimulation of rabbit alveolar macrophages, PC and PE subclasses involved in the mobilization of 20 : 4 depend on each 20 : 4 pool which is extracted in the cells.
  • 奥出 政義, 山中 愛子, 秋浜 澄行
    1995 年 18 巻 2 号 p. 203-207
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    In fibrinogen-fibrin conversion by thrombin, the polymerization of a fibrin monomer is accompanied by gelation and an increase turbidity. Since sialic acids at the terminal of the carbohydrate chains bound to fibrinogen are part of the low affinity calcium binding site necessary for polymerization, they are closely involved in the network structure of fibrin clots. Fibrin clots derived from asialofibrinogen exhibited definite differences in turbidity and elasticity compared with those derived from intact fibrinogen, and were markedly dependent on the pH during the reaction. The turbidity during polymerization of fibrin, evaluated according to the absorbance at 350 nm, was maximum at pH 6.5-7.0, but it decreased in the other pH ranges, with the changes being unremarkable at higher pH levels but remarkable at lower pH ranges. The turbidity of fibrin derived from asialofibrinogen was far higher than that from intact fibrinogen near neutrality, but decreased rapidly and was lower than in intact fibrinogen at higher and lower pH ranges. Concerning the elasticity evaluated by thromboelastography, the coagulation time (k) and the maximum amplitude (ma) were lower in asialofibrinogen, indicating a deterioration of the clotting function of fibrinogen with the loss of sialic acid. These results suggest that sialic acid bound to fibrinogen is closely related to the fibrin network formation in blood coagulation, which is the most important function of fibrinogen, and plays a functional role in the stabilization of fibrin clot formation against environmental changes, including pH.
  • 朴 鐘伯, 今村 理佐, 小橋 恭一, 伊藤 久富, 宮崎 寿次, 堀崎 寿雄
    1995 年 18 巻 2 号 p. 208-213
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Three glucosyl-phenolic hydroxamates, 4-O-(β-D-glucopyranosyl) benzohydroxamic acid, 4-O-(β-D-glucopyranosyl) hippuric hydroxamic acid, and 3-[4-O-(β-D-glucopyranosyl) phenyl] propionohydroxamic acid (Glc-PPHA), were hydrolyzed to their corresponding aglycones by β-glucosidase of intestinal flora of rat without any major adverse hydrolysis in vitro. Inhibitory potency of these glucosyl-hydroxamates on urease was recovered to the same extent as that of the corresponding aglycone hydroxamates by preincubation for 2h with rat intestinal flora. p-Hydroxyphenylpropionohydroxamic acid inhibited noncompetitively jack-bean urease activity and its glucose-ligated form, Glc-PPHA inhibited it competitively. A single oral dose of Glc-PPHA tended to inhibit urease activity in proximal colon contents of rat at 6h after administration (p=0.06). After14C-urea was orally administered to rat, 14CO2 was collected for to measure the ureolysis in vivo. Expired 14CO2 was limited to 40% by a single oral dose of Glc-PPHA during 6h, and 75% of intestinal ureolysis was repressed during the first 1h in the breath test.
  • 植木 寛, 山崎 康晴, 肥後 克彦, 木屋敷 敏雄, 川畑 尚代, 森田 哲生
    1995 年 18 巻 2 号 p. 214-218
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Sodium orthovanadate (vanadate) stimulated cAMP phosphodiesterase (PDE) and protein tyrosine kinase (PTK) activities and inhibited the phosphotyrosine phosphatase (PTPase) activity in the particulate of isolated rat fat pads. Okadaic acid never showed any increase in the PDE activity up to 1μM. Amiloride inhibited in part both stimulations of PDE and PTK activities by vanadate. The particulate PTK activity had an optimal divalent ion requirement of 15 mM Mg+2+2 mM Mn+2 in the assay medium and was not inhibited by 1 mM N-ethylmaleimide, suggesting it to be a different type from the insulin receptor and cytosolic PTK activities. The PDE, PTK, and PTPase active fractions were separated from the solubilized particulate fraction on a DEAE-Sephacel column. PDE activity was increased by the addition of the PTK active fraction. A further increase was observed by using the PTK active fraction pretreated with 1mM vanadate. In contrast, the addition of PTPase active fraction decreased the PDE activity. This decrease disappeared by using the PTPase active fraction pretreated with 1mM vanadate. These results suggest that the PDE activity is in part regulated through a process involving the particulate PTK and PTPase activities sensitive to vanadate.
  • 八木 弘光, 小林 弘子, 井口 法男, 小山 隆, 入江 昌親
    1995 年 18 巻 2 号 p. 219-222
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    An acid ribonuclease (RNase RCL2) was purified to nomogeneity on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) from a homogenate of bullfrog liver (Rana catesbeiana). The apparent molecular weight estimated from SDS-PAGE was ca. 25kDa. The pH optimum of the RNase was 5.0. The RNase released mononucleotides from RNA in the order of 3'-UMP, 3'-GMP and 3'-AMP. The N-terminal amino acid sequence of RNase RCL2 was determined up to the 20th residue, and it was found to have a 5 residue sequence homology with that of oyster acid RNase [H. Watanabe et al. J. Biochem. (Tokyo), 114, 800 (1993)]. Thus, RNase RCL2 seems to be a member of the RNase T2 family RNase. This is the first evidence of the RNase T2 family RNase in amphibians.
  • 木下 美弥, 能登 恒寿, 玉木 元
    1995 年 18 巻 2 号 p. 223-226
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    We studied the effect of single oral administration of ecabet sodium (ecabet), a gastroprotective agent, in combination with the histamine H2-receptor antagonist cimetidine on gastric acid secretion, mucosal prostaglandin E2 (PGE2) production and experimentally induced acute hemorrhagic gastric lesions in rats. The effect of repeated administration of ecabet in combination with cimetidine on the vulnerability of gastric mucosa to the ulcerogenic agents 0.6N HCl and aspirin was also studied. In pylorus-ligated rats, oral administration of cimetidine reduced gastric acid secretion, whereas ecabet did not affect the cimetidine-induced reduction in acid secretion. On the other hand, ecabet increased the capacity of gastric mucosa to synthesize PGE2, while cimetidine showed no effect on this parameter either in the presence or absence of ecabet. Both ecabet and cimetidine inhibited the formation of aspirin-induced gastric mucosal lesions, and the combination of ecabet and cimetidine showed a more potent inhibition than either drug alone. After cessation of repeated administration of cimetidine, but not ecabet, the 0.6N HCl-and aspirin-induced gastric lesions were significantly aggravated. The co-administration of ecabet improved the cimetidine-induced aggravation of these gastric lesions. These results suggest that ecabet in combination with cimetidine augments the antiulcer effect of cimetidine and improves the cimetidine-induced increase in gastric mucosal vulnerability to the ulcerogenic agents.
  • 津島 己幸, 真岡 孝至, 勝山 政明, 小塚 睦夫, 松野 隆男, 徳田 春邦, 西野 輔翼, 岩島 昭夫
    1995 年 18 巻 2 号 p. 227-233
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    As a screening study for anti-tumor promoters, 51 carotenoids with diverse structures were examined for their inhibitory effects on the Epstein-Barr virus activation activity of 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The results showed that most of the carotenoids exhibited inhibitory activity, and in general, no cytotoxicity on Raji cells was observed in the assay. Among the carotenoids, β-cryptoxanthin, lutein, and lactucaxanthin showed the strongest inhibitory activity, superior to the well known anti-tumor promoter, β-carotene. Heteroxanthin, peridinin, and halocynthiaxanthin showed cytotoxicity at the high concentration (1000 molar ratio per TPA), but indicated a strong inhibitory effect at the lower concentrations, which were only weakly toxic (500 and 100 molar ratios). Based on these results, the essential moiety for the activity of carotenoids was considered to be the 3-hydroxy-ε-end group.
  • 北村 佳久, 有馬 隆, 佐藤 太二, 中村 順司, 野村 靖幸
    1995 年 18 巻 2 号 p. 234-238
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of pentamidine, a therapeutic drug for Pneumocystis carinii pneumonia (PCP) in acquired immunodeficiency syndrome (AIDS), on specific bindings of [3H] (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 11-imine maleate (MK-801) and [3H] nitrendipine were investigated in crude synaptic membranes (CSM) of rat brain. Pentamidine inhibited [3H] MK-801 binding but did not change [3H] nitrendipine binding, althouth neither binding was inhibited by 3'-azido-2', 3'-dideoxycytidine (inhibitors for reverse transcriptase of HIV-1), or FK-506 or cyclosporin A (immunosuppressants). In Triton X-100-treated CSM (post-synaptic density-rich fractions), the inhibitory effect of pentamidine on [3H] MK-801 binding was partially prevented by addition of spermine and NMDA plus glycine (Gly). Electrophysiological experiments showed that pentamidine also inhibited Ca2+-current evoked by NMDA plus Gly in Xenopus oocytes injected with rat brain mRNA. These results suggest that pentamidine is a potent inhibitor for NMDA receptor/channels.
  • 永井 博弌, 櫻井 利実, 稲垣 直樹, 森 裕志
    1995 年 18 巻 2 号 p. 239-245
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Biphasic skin reactions, with peaks at 1 and 24h after epicutaneous challenge with antigen (immediate phase response : IPR and late phase response : LPR, respectively), were induced in ddY, ICR, Balb/c and Balb/c-nu/nu mice passively sensitized with monoclonal IgE antibody 24h before. In WBB6F1-W/Wv mice, which lack mast cells, only the LPR was observed. The IPR was characterized by a rapid increase in capillary permeability and the LPR by skin thickening with significant infiltration of eosinophils and other inflammatory cells in Balb/c mice. Histamine H1 receptor antagonists, including diphenhydramine and homochlorcyclizine, and the allergic histamine release inhibitors, tranilast and amlexanox, clearly inhibited the IPR, but not the LPR. Prednisolone and dexamethasone, however, inhibited both. Prednisolone also inhibited the LPR in WBB6F1-W/Wv mice. These results indicate that IgE antibody-dependent biphasic skin reactions consist of a mast cell-and histamine-dependent IPR and a mast cell-independent LPR.
  • 牛島 ひろみ, 五味 保男
    1995 年 18 巻 2 号 p. 246-250
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    In the isolated vas deferens of the guinea pig, the inhibitory effect of manganese (Mn2+) on contractions induced by norepinephrine decreased when the contractions were induced repeatedly in the presence of Mn2+. This phenomenon, "tachyphylaxis" to the inhibitory effect of Mn2+, was minimally observed when contractions were induced by acetylcholine. Contractions induced by acetylcholine as well as by norepinephrine in a Mn2+-free medium were augmented in preparations in which manganese had accumulated intracellularly by repetitive applications of high potassium in the presence of Mn2+. The magnitudes of their augmentation were dependent on the manganese contents of the preparations. The augmented contractions were remarkably resistant to the inhibitory effect of Mn2+ applied to the medium. These results suggest that intracellular manganese augments the contractions and this augmentation results in an apparent decrease in the inhibitory effect of Mn2+ in the medium.
  • 福山 隆子, 山岡 清, 田端 健司, 中川 照眞
    1995 年 18 巻 2 号 p. 251-255
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of the acute hepatic failure induced by CCl4 on the pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation (EHC) in normal rats, was evaluated. This hepatic failure extinguished the secondary peak on the plasma time course which is usually observed in normal rats due to EHC. In the group without EHC by means of bile cannulation, the total clearance (CL) markedly decreased by CCl4-intoxication from 0.7l/h/kg down to 0.1l/h/kg, and mean residence time (MRT) increased from 0.29 h up to 2.8 h. The plasma time curves of the rats with laparotomy and with bile duct-cannulation were almost the same in the CCl4-intoxicated group. The bile excretion ratio of diclofenac markedly decreased by CCl4-intoxication from 43% down to 13%. In both groups, 92% of the total diclofenac excreted into the bile was glucuronide. While EHC made area under the curve (AUC) and MRT obviously increase in the CCl4-free rats, the effect of EHC on these moments was negligible in the CCl4-intoxicated rats. In the CCl4-intoxicated condition, the elimination of diclofenac in the rats with laparotomy was considerably slower than that in the rats without laparotomy. The plasma time courses were obviously monoexponential in the former group, while those were almost biexponential in the latter group.
  • 手塚 雅勝, 定延 紳朗, 五味 謙之, 立川 眞理子, 澤村 良二
    1995 年 18 巻 2 号 p. 256-261
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Using primary cultured mouse hepatocytes, in vitro study was performed to discuss the effect of Cr (III) and several other trace metals, Cr (VI), Mn (II), Zn (II), Co (II), Cu (II), Ni (II), and Ga (III) on acute liver damage induced by CCl4 exposure. 1) The LDH activity 60 min after CCl4 exposure increased dose-dependently with CCl4 concentrations in all of the trace metal pretreatment groups, except for the Cr (VI) pretreatment group, which showed a significant protective effect even after 30 min of CCl4 exposure. 2) LDH leakage was not observed 10 min after CCl4 exposure at 3 or 5 mM, while lipid peroxidation was increased dose-dependently with CCl4 concentrations in all groups except the Cr (VI) pretreatment group, in which the production of peroxidated lipid was significantly inhibited. 3) Similarly to the pretreatment with Cr (VI), LDH leakage 30 min after exposure to 5 mM CCl4 was inhibited by pretreatment with such antioxidants as N, N'-diphenyl-p-phenylenediamine or DL-α-tocopherol. 4) The Cr (VI) uptake was about 50% of the added amount, whereas the Cr (III) uptake was only 5% of the added amount. 5) 90% or more of the intracellular chromium was reduced to Cr (III) 10 min after Cr (VI) treatment. The results suggested that the in vitro protective effect of pretreatment with Cr (VI) was due to a rapid reduction of Cr (VI) to Cr (III), and the radical scavenger-like effect of the produced Cr (III) was the same effect as in vivo Cr (III) ; it was therefore suggests that Cr (III) contributes to protective effect on CCl4-induced hepatotoxicity.
  • 桜井 光一, 小木曽 健人
    1995 年 18 巻 2 号 p. 262-266
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The incubation of λDNA in the reaction system of alloxan plus NADPH-cytochrome P450 reductase (fp2) in the presence of ferritin caused strand breaks after a lag time of about 5 min. Addition of ferritin to the reaction system at concentrations below 50 μg/ml caused the strand breaks of DNA in a concentration-dependent fashion. Catalase, scavengers of hydroxyl radicals (HO·) and iron-chelators almost completely inhibited the DNA strand breaks, but superoxide dismutase (SOD) did not, suggesting that the strand breaks are induced by the generation of HO·via the reaction of H2O2 and Fe (II), namely, the Fenton reaction. When the ferritin was incubated in the reaction system of alloxan plus fp2, the iron release from ferritin increased with incubation time depending on the amount of fp2. The addition of increasing concentrations of ferritin to the reaction system resulted in progressive increase in the iron release and a decrease in the electron spin resonance signal intensity of alloxan radical (HA·), the one electron reduced from of alloxan, suggesting that HA·generated in the reaction system is capable of releasing iron from ferritin. These results support the possibility that the iron released from ferritin may be involved in the diabetogenic action of alloxan.
  • 木倉 瑠理, 中原 雄二
    1995 年 18 巻 2 号 p. 267-272
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Deprenyl (DPN) and its metabolites, desmethyl deprenyl (desmethyl DPN), methamphetamine (MA) and amphetamine (AP), in the hair of rats and humans dosed with DPN were analyzed by selected ion monitoring of gas chromatograph-mass spectrometry (GC-MS-SIM). After intraperitoneal administration of DPN-HCl to rats (10mg/kg/d, 10d, n=3), the area under the concentration versus time curves (AUCs) of DPN and its metabolites in the rat plasma were compared with the concentrations of drugs in rat hair newly grown for 4 weeks. The concentrations of DPN, desmethyl DPN, MA and AP in the rat hair were 0.97±0.06, 0.68±0.02, 14.04±0.54 and 13.20±1.09ng/mg, and the ratios of the concentrations in the hair to AUCs in their plasma were 0.05 : 0.02 : 0.3 : 0.2, respectively. This fact suggested that the incorporation rates of DPN and desmethyl DPN into hair from blood were relatively lower than those of MA and AP. The method was applied to determination of the metabolites in scalp hair, beard and urine of humans who orally ingested DPN (15mg/d, 5d, n=3). DPN (trace level), desmethyl DPN (0.17-0.29ng/mg), MA (1.30-2.25ng/mg) and AP (0.42-0.99ng/mg) were detected in the scalp hair collected three weeks after the first intake, while in beard or urine these drugs were detected only for a few days. It was concluded that DPN use could be distinguished from MA abuse retrospectively by the detection of DPN and/or desmethyl DPN in scalp hair. It was also shown that the ratio of AP to MA in hair or enantiomeric compositions of MA in hair would allow distinction of DPN use from MA use.
  • 祐田 泰延, 鈴木 健二, 滝 寿伸, 伊藤 康子, 山口 勝, 櫻井 孝司, 谷下 由紀子
    1995 年 18 巻 2 号 p. 273-278
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    In this study, renal Na+/K+-ATPase activity was demonstrated to be strongly suppressed prior to the glucosuria caused by a fluoride dose (NaF 35mg/kg, i. p.), and the 50% suppression of the enzyme activity was almost at the same dose of NaF, about 30mg/kg, i.p. to rats. In the rats, renal Na+/glucose cotransporter activity in brush border membranes was not affected by in vivo NaF, whereas the renal Na+/K+-ATPase in basolateral membranes showed a dip in activity 3h after NaF treatment of the whole animal. Moreover, it was suggested from experiments with inhibitors of calphostin C and KT5720 that protein kinase C, but not protein kinase A, may play an important role in the suppression of Na+/K+-ATPase following the administration of fluoride to rats. Na+/glucose cotransporter was fairly insensitive to NaF, being competitively inhibited with a Ki of about 100 mM, whereas Na+/K+-ATPase was much more sensitive, with a Ki of about 2 mM. From these results, the elevation of urinary glucose excretion after a single dose of fluoride was deduced to be due to suppression of the renal Na+/K+-ATPase activity by a direct and/or secondary action of fluoride, rather than of the corresponding Na+/glucose cotransporter activity.
  • 小野 敦央, 堀越 勇, 上野 雅晴
    1995 年 18 巻 2 号 p. 279-283
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    As a novel method for the medical application of liposomes, we have tried hepatic artery chemoembolization using temperature-sensitive liposomes with hyperthermia for the treatment of hepatic tumors. In this study, the effect of temperature-sensitive liposomes was compared with that of Lipiodol emulsion, which has been used clinically. The temperature-sensitive liposomes, consisting of dipalmitoylphosphatidylcholine or Lipiodol emulsions entrapping doxorubicin, were administered into the hepatic artery of hepatic tumor-bearing rats via a cannula. Doxorubicin administered in a liposomal form showed a high accumulative property toward tumors, with heating, while that in the emulsion form showed a show release property toward tumors. Not noly was tumor growth inhibited, but also, an actual diminishing of the tumor was observed in each form. Side effects were also examined : an abnormal rise in GPT, or necrosis of the normal tissues in liver, which was often observed in hepatic artery chemoembolization using Lipiodol emulsion, was remarkably reduced in the liposomal chemoembolization.
  • 木島 孝夫, 高崎 みどり, 小塚 睦夫, 長尾 常敦, 岡部 光, 入野 信人, 中隅 哲郎, 徳田 春邦, 西野 輔翼
    1995 年 18 巻 2 号 p. 284-287
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    To search for possible anti-tumor-promoters, we carried out a primary screening of twenty-four 29-nor-cucurbitacin glucosides isolated from the roots of Cayaponia tayuya (Cucurbitaceae) using an in vitro synergistic assay system. Of these glucosides, cayaponosides B (5), B3 (7), D (8), D3b(22) and C2 (23) exhibited significant inhibitory effects on Epstein-Barr virus (EBV) activation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, 5 and 23 exhibited remarkable anti-tumor-promoting effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.
  • 高崎 みどり, 木島 孝夫, 小塚 睦夫, 米山 弘一, 吉田 茂男, 徳田 春邦, 西野 輔翼, 岩島 昭夫
    1995 年 18 巻 2 号 p. 288-294
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    One hundred and fifteen synthesized mono, di, and trihydroxybenzamide and thiobenzamide derivatives having structures related to euglobals were examined for their inhibitory effects on Epstein-Barr virus (EBV) activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) as a primary screening test for anti-tumor-promoters. In general, 3-acyl-2, 4, 6-trihydroxybenzamide and 3-acyl-2, 4, 6-trihydroxythiobenzamide derivatives exhibited strong or moderate activities, and the latter compounds were less cytotoxic than the former. Meanwhile, little or no activity was observed with mono and dihydroxybenzamide and dihydroxythiobenzamide derivatives. Structural requirements for the activities of these compounds have been discussed in detail. Among the above compounds, compounds 36 and 73, which were significantly active on the inhibition of EBV activation, were investigated using a two-stage mouse skin carcinogenesis test induced by 7, 12-dimethylbenz [a] anthracene (DMBA) and TPA. The results of the in vivo test showed that both compounds have a stronger inhibitory effect than that of the well-known anti-tumor-promoter, glycyrrhetic acid. These results suggested that the two compounds might be valuable as anti-tumor-promoters in chemical carcinogenesis.
  • 永井 隆之, 鈴木 雄次郎, 富森 毅, 山田 陽城
    1995 年 18 巻 2 号 p. 295-299
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    We investigated effects of isoscutellarein-8-methylether (5, 7, 4'-trihydroxy-8-methoxyflavone, F36) from the roots of Scutellaria baicalensis on the single-cycle replication of mouse-adapted influenza viruses A/Guizhou/54/89 (H3N2 subtype) and B/Ibaraki/2/85 in Madin-Darby canine kidney (MDCK) cells. The agent suppressed replication of these viruses from 6 to 12h after incubation in a dose-dependent manner by 50% at 20μM and 90% at 40μM, respectively. F36 (50μM) reduced the release of B/Ibaraki virus in the medium by 90-93% when it was added to the MDCK cells at 0 to 4 h after incubation. The cell-associated virus determined by sialidase activity was also reduced by the treatment at 0 to 4 h. F36 (120μM) inhibited the low pH-dependent membrane fusion of both the viruses with the liposome containing mixed gangliosides from bovine brain. However, the agent little affected the bemagglutination and RNA-dependent RNA polymerase activities of these viruses in vitro. These results suggest that F36 inhibits the replication of A/Guizhou and B/Ibaraki viruses at least partly by inhibiting the fusion of viral envelopes with the endosome/lysosome membrane which occurs at the early stage of the virus infection cycle. F36 (0.5mg/kg) showed no antiviral activity against A/Guizhou and B/Ibaraki viruses in mice when administered intranasally 5 min prior to virus inoculation, whereas it significantly inhibited their proliferation in the mouse lung when administered intranasally 7 times (total 3.5mg/kg) from 18h before to 54h after virus infection.
  • 安田 高明, 鹿野 美宏, 斉藤 謙一, 大澤 啓助
    1995 年 18 巻 2 号 p. 300-303
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Examination was made of the urinary and biliary excretion of the metabolites of puerarin, the major component of the roots of Pueraria lobata OHWI (Leguminosae) in rats. The urine of rats administered puerarin orally contained puerarin and four major metabolites, daidzein 4', 7-di-O-sulfate (M-I), daidzein 7-O-β-D-glucuronide (M-II), daidzein 4'-O-sulfate (M-III), daidzein (M-IV), as determined from spectroscopic and chemical data. Total cumulative amounts of the puerarin and four metabolites excreted in the urine at 48 h following the oral administration of puerarin were approximately 3.6% the doses administered. The bile of rats administered puerarin orally contained puerarin and two major metabolites, which were identified as puerarin 4'-O-sulfate (PB1) and puerarin 7-O-β-D-glucuronide (PB2) on the basis of chemical and spectroscopic data. These experimental data suggest that C-glycoside puerarin is partially hydrolyzed to aglycone in the body, but mainly excreted in the urine as unchanged puerarin.
  • 竹内 由和, 安川 秀仁, 山岡 由美子, 田口 賢二, 福島 昭二, 下仲 康弘, 西永 浩子, 森本 泰子
    1995 年 18 巻 2 号 p. 304-309
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Rat abdominal intact skin was treated with fatty acids, fatty amines, or Azone which were dissolved in propylene glycol (PG) and PG appearing in the rat dermis was studied. Analysis was done by Fourier transform infrared/attenuated total reflection (FT-IR/ATR) spectroscopy. The appearance of PG with time seemed to be in three phases when the skin sample was treated with a skin penetration enhancer such as oleic acid : (1) in the first stage, PG penetrated the skin barrier which was not substantially altered, and gradually appeared in the dermis ; (2) in the second stage, it rapidly distributed in/throughout the dermis, and this rapid distribution was probably due to the alteration of the dermal structure : the penetration enhancing effect of the enhancer was thought to reach maximal ; and (3) in the third stage, PG was saturated in the dermis. The value of Tmax alteration, at which the alteration of the dermal structures is completed, showed that the action of both oleic acid and oleylamine were more rapid than other enhancers. Both the value of PG peak areamax at the third stage which reflects the distribution volume of PG in the dermis and the value of Tsat at which PG is saturated in the dermis were calculated, and the results suggested that both the distribution volume of PG in the dermis and the time of the saturation varied depending on the enhancer. In conclusion, our present work indicated the importance and necessity of evaluating the rate and extent of appearance of a drug in the dermis to characterize an enhancer. The dermis was also suggested to act as the skin barrier to drug penetration.
  • 大迫 雅彦, 岡 靖博, 都築 脩三, 松本 康裕
    1995 年 18 巻 2 号 p. 310-314
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The transport of aspirin (ASP) and its derivatives (m-or p-acetoxybenzoic acid (m-or p-AcOHBA), o-propionyloxybenzoic acid (PrOHBA), o-butyryloxybenzoic acid (BuOHBA), o-acetoxyhippuric acid (AcOHPA), and o-acetoxy-N-benzoyl-β-alanine (AcONBA)) through human erythrocyte membrane was investigated. ASP derivatives were transported into the erythrocytes where they were hydrolyzed and then released, although the derivatives varied in the rate of transport. In different binding positions, the hydrolyzed derivatives were released rapidly in the order of p->m->o-AcOHBA (ASP). The rates of derivatives were accelerated by lengthening of the side chain of the acetoxyl group (BuOHBA>PrOHBA>ASP). The rate of release of o-, m-or p-AcOHBA, BuOHBA and PrOHBA was related to hydrolysis rate in erythrocytes but not to partition coefficient (log P). In different amino acids in a carboxyl group of ASP, the release of AcONBA was slower and about 2h was required to attain equilibrium. The release of AcOHPA was also slower and increased gradually during an incubation of 3h. The rate of release of AcOHPA and AcONBA was not related to hydrolysis rate in the erythrocytes. The rates were equivalent values with the predicted values calculated by log P of tested drugs. It was suggested from these results that ASP derivatives were able to control the release from human erythrocytes.
  • 谷川原 祐介, 野村 寿, 鍵本 紀子, 奥村 勝彦 /, Ryohei HORI
    1995 年 18 巻 2 号 p. 315-320
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The population pharmacokinetics of levofloxacin (LVFX), the l-enantiomer of ofloxacin, were studied in 522 subjects, including normal subjects and patients with infectious diseases. Altogether, 1572 LVFX serum concentrations were obtained following a single oral administration during clinical trials. The influences of renal function, age, meals and concurrent durg administration on the pharmacokineti■ parameters of LVFX were examined by the likelihood ratio test using a nonlinear mixed-effect model (NONMEM). In patients with renal insufficiency, the total body clearance (CL) of LVFX was related to creatinine clearance (Ccr) and body weight (WT), as expressed by CL=0.0836 Ccr+0.013 WT. The CL with normal renal function was 0.178 (l/h/kg). The apparent volume of distribution (Vd) was calculated to be 1.46 (l/kg). The elderly subjects, aged 65 years old or over, exhibited, on average, a 32% reduction in CL and 6% greater Vd. LVFX was rapidly absorbed in the gastrointestinal tract, but the concurrent administration of antacids (magnesium, aluminum, etc.) decreased the bioavailability of LVFX by 15-52%. The recommended dose of LVFX was decided on the basis of current pharmacokinetic information and the minimum inhibitory concentrations. Population pharmacokinetic parameters are also useful for the individualization of a dosage regimen by means of the Bayesian forecasting method.
  • 齋藤 泉, 池田 かおり, 高岸 靖
    1995 年 18 巻 2 号 p. 321-325
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The action of benzyl alcohol (BA) as a major solvent of a liquid droplet dispersion ointment (LDDS), a preparation enabling excellent percutaneous absorption of drugs, was evaluated and compared with Azone and dimethyl sulfoxide (DMSO), which are known percutaneous absorption enhancers. Using a water sorption-desorption test, BA was found to increase hygroscopicity and decrease water-holding capacity to the same extent as Azone and DMSO. Differential scanning calorimetry (DSC) determination of the whole stratum corneum, and its lipids and proteins confirmed that BA and Azone act on the stratum corneum lipids while DMSO acts on its lipids and proteins. Furthermore, DSC and X-ray diffraction spectrum determinations of lipids in the stratum corneum suggest that the action of BA is moderate and reversible. The effect of BA may be one of the factors underlying the high percutaneous absorption found with LDDS.
  • 齋藤 泉, 高岸 靖
    1995 年 18 巻 2 号 p. 326-329
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    A liquid droplet dispersion ointment, LDDS, a formulation containing a drug solution as droplets in an oily vehicle, is excellent for percutaneous drug absorption. Bleeding of LDDS and in vitro drug release from LDDS were found to be enhanced by temperature increase. The influence of temperature on the physical properties of LDDS was studied using differential scanning calorimetry and X-ray diffraction spectroscopy. The liquid component content, possibly a hydrocarbon in the vehicle, increased with temperature ; this may have been due to melting of the vehicle. In this liquid component, the drug concentration measured by HPLC increased with temperature. This change in the drug concentration may cause an increase in drug release, leading to the conclusion that, compared with conventional ointments, temperature has much greater effect on drug release from LDDS.
  • 近藤 孝浩, 倉田 百合子, 吉田 清志, 吉村 義信
    1995 年 18 巻 2 号 p. 330-336
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The disposition of DN-2327 after oral dosing of 14C-labeled DN-2327 ([14C]DN-2327) to rats, dogs and monkeys was studied. DN-2327 was absorbed from the small intestine after oral administration. In the plasma of these animals, a small amount of unchanged compound and M-I were detected, with M-II (a pharmacologically active metabolite) as a major component. The concentration of the unchanged compound in rat plasma attained a peak (Cmax0.002μg/ml), then declined, with a half-life (t1/2) of 3 h. Ttax, Cmax and t1/2 of DN-2327 in dogs and monkeys were 0.6 h, 0.332μg/ml and 1.5h, and 2.3h, 0.036μg/ml and 6.2h, respectively. About 60, 75 and 48% of the radioactivity dosed was absorbed in rats, dogs and monkeys, respectively, whereas the bioavailability in rats, dogs and monkeys was less than 1, 34 and 10%, respectively, indicating that DN-2327 had been subjected to the first pass effect. In rats given [14C] DN-2327 orally, the radioactivity was distributed widely in various tissues, including the brain. In the brain regions, DN-2327 and M-II were distributed and M-II was major component, indicating that the pharmacological effects of DN-2327 may depend largely on M-II. In these animals, [14C] DN-2327 was excreted in feces via bile mostly as metabolites. During repeated oral administration, DN-2327 and its metabolites did not accumulate in rat tissues, except in the kidney.
  • 山村 喜一, 三田 智文, 小滝 一, 内野 克喜, 澤田 康文 /, Tatsuji IGA
    1995 年 18 巻 2 号 p. 337-341
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The pharmacokinetic behavior of glycyrrhizin after intravenous (i. v.), oral and intraperitoneal (i. p.) administration was compared in rats. The elimination half-life, total body clearance and volume of distribution at steady-state of glycyrrhizin were not significantly different among doses (2, 10 and 50mg/kg i. v.). Glycyrrhizin was only detected in the plasma (maximum level : 1.3μg/ml) after oral administration of 50mg/kg. From comparison of the area under the plasma concentration-time curves after i. v. and oral administration of 50mg/kg, the bioavailability of glycyrrhizin was estimated to be approximately 1%. Glycyrrhizin was stable for at least 3h in gastric juice. The plasma concentration of glycyrrhizin after oral administration to neomycin-treated rats was not significantly different from that after administration to untreated rats. Furthermore, in in situ absorption study the cumulative ratio of glycyrrhizin in the mesenteric venous plasma after injection was only 1-2% of the dose. From these results, it appeared that the extremely low bioavailability by the oral route may be due to poor absorption of glycyrrhizin from the intestinal tract. On the other hand, the plasma concentration of glycyrrhizin rapidly increased after i. p. administration of doses of 2, 10 and 50mg/kg, and reached a maximum level (4.7, 33.0 and 238.9μg/ml, respectively) within 30 min. The bioavailabilitity (65-90%) of glycyrrhizin after i. p. administration was enhanced dramatically. The i. p. route of administration may thus improve the bioavailability of glycyrrhizin.
  • 平野 剛, 井関 健, 菅原 満, 宮崎 正三, 高田 昌彦, 宮崎 勝巳
    1995 年 18 巻 2 号 p. 342-346
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The mechanism of the renal transport of enoxacin (ENX) has been investigated using brush-border membrane vesicles (BBMVs) isolated from the rat renal cortex. The initial rate and time-course of ENX uptake were quite dependent upon the medium pH (pH 5.5>pH 7.5). The pH dependence was in accordance with the degree of cationic form. Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) affected the transient uphill transport of ENX across the renal brush-border membrane in the presence of an outward-directed H+-gradient. The initial uptake was saturable, and transport kinetic parameters were given for a Km and Vmax of 0.59mM and 1.37 nmol/ (mg protein)/30s, respectively. On the other hand, an outward H+-gradient (pHin=5.5, out=7.5) dependent uptake of ENX was partially decreased by the voltage-clamped BBMVs. Furthermore, a valinomycin-induced K+-diffusion potential (interior negative) was found to increase the uptake of ENX at pH5.5, which is cationic from-rich. These results suggest that ENX uptake participates in not only the H+/organic cation antiport system for organic cation secretion but also the ionic diffusion potential (interior negative) dependent permeation through the membrane.
  • 森田 哲生, 今川 尊雄, 金川 麻子, 植木 寛
    1995 年 18 巻 2 号 p. 347-349
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Phospholipase (PL) A2 activity prepared from isolated rat fat pads incubated with sodium orthovanadate (vanadate) was increased in a time-and dose-dependent manner. The increasing effect of vanadate was reduced in the presence of tyrosine kinase inhibitors. Under the inhibition of protein synthesis by cycloheximide, vanadate still showed a full effect on the increase in PL A2 activity. Various PL A2 inhibitors, such as manoalide, quinacrine and p-bromophenacyl bromide, suppressed the stimulatory release of lipoprotein lipase (LPL) activity from the fat pads by vanadate. Moreover, the vanadate-stimulated release of LPL activity was decreased by the cyclooxygenase and thromboxane synthetase inhibitors, and a thromboxane A2 receptor antagonist, but was never suppressed by a lipooxygenase inhibitor. The stimulatory release of LPL activity by vanadate was also decreased in the presence of tyrosine kinase inhibitors. These results suggest that vanadate increases PL A2 activity, and the increase in PL A2 activity is partly involved in the vanadate-stimulated release of LPL activity with an association to the membrane tyrosine kinase.
  • 縄(旧姓小林) 香, 田村 由佳, 佐藤(旧姓古田) 久美子, 服部 順一, 下遠野 久美子, 遠藤 豊成
    1995 年 18 巻 2 号 p. 350-354
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Blasticidin S (BS) deaminase (BSR) from a BS-resistant strain, Bacillus cereus K55-S1, was purified to homogeneity. Molecular weights determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by gel filtration on HPLC are about 15500 and 35000, respectively, indicating the enzyme is a homodimer. The amino acid composition and N-terminal sequence of BSR are the same as those deduced from the nucleotide sequence of the BS-resistant gene, bsr. The optimum temperature and pH for enzyme activity are 60-65°C and near 10.0, respectively. The activity of BSR is inhibited by Cu2+, Hg2+, and p-chloromercuric benzoate (PCMB). Inhibition by PCMB or HgCl2 is reversible by the addition of SH reagents. The enzyme catalyzes the deamination of BS and its derivatives, but not cytosine nucleosides.
  • 白幡 晶, 細田 晴美, 高橋 紀雄, 別府 隆信, 新津 勝, 鮫島 啓二郎
    1995 年 18 巻 2 号 p. 355-359
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    Two unusual aminopropyl acceptors found in a survey of putrescine binding sites of mammalian spermidine synthase, N-methylputrescine (I) and 4-aminomethylpiperidine (II), were examined for their aminopropyl derivatives. Studies under in vitro incubation conditions suggested that the aminopropyl derivatives of the secondary amine of I and II, N4-methylspermidine (Is) and 1-N-(3-aminopropyl)-4-aminomethylpiperidine (IIs), and of the primary amine of I and II, N8-methylspermidine (Ip) and 4-[N-(3-aminopropyl) aminomethyl] piperidine (IIp), respectively, were biosynthesized by rat spermidine synthase. Studies on the cell culture system of cultured rat hepatoma (HTC) cells treated with α-difluoromethylornithine, an ornithine decarboxylase inhibitor, clearly showed the presence of Is and Ip when I was administered, and IIs and IIp when II was administered, with no detection of putrescine or spermidine. These results suggested that mammalian spermidine synthase can transfer the aminopropyl moiety of decarboxylated S-adenosylmethionine to certain secondary amines in living cells.
  • 池上 文雄, 草間(江口) 國子, 杉山 栄美, 渡邊 和子, / 村越 勇, Isamu MURAKOSHI
    1995 年 18 巻 2 号 p. 360-362
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    The neuropharmacological actions of some plant heterocyclic β-substituted alanines on rat brain N-methyl-D-aspartate (NMDA) receptors were studied. Of the compounds tested, 3-N-oxalyl-L-2, 3-diaminopropanopic acid (β-ODAP), the causal agent of human neurolathyrism, exhibited an inhibitory activity on the NMDA receptor binding assay at a relatively high concentration (IC50 : 4.7×10-5M). The biochemical precursor of β-ODAP, β-(isoxazolin-5-on-2-yl)-L-alanine (BIA) was inactive in this assay. These results suggest that β-ODAP, the neurotoxin of Lathyrus sativus, in addition to its excitatory action on α-amino-3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA) receptors, also has neurotoxic potential through its action on NMDA receptors.
  • 森田 全, 内藤 博敬, 大石 悦男
    1995 年 18 巻 2 号 p. 363-367
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    A total of 24 compounds were prepared by introducing an N-oxide, a hydrazino group, a methoxy group or a chloro group into 3 kinds of condensed pyridazines : pyrido [3, 4-d] pyridazines, pyrido [2, 3-d] pyridazines and phthalazines. The mutagenicity of these 24 compounds was assessed by the Ames method using two tester strains (Salmonella typhimurium TA98 and TA100). No mutagenic activity was detected with any of the 3 condensed pyridazines without substituents or any of the 5 condensed pyridazines with a methoxy group. The compounds with N-oxide in the pyridazine ring showed no or only very weak mutagenicity. However, when an oxide was introduced into the nitrogen of the pyridine ring, the mutagenicity against strain TA98 was higher than that of any other test compound. All compounds with a hydrazino group were mutagenic against strains TA98 and TA100, irrespective of the presence or absence of S9 mix-induced metabolic activation. 1-Hydrazinophthalazine (hydralazine) which has been clinically used as an antihypertensive agent was weakly mutagenic. The introduction of a chloro group increased the bactericidal effects of the condensed pyridazines, thus hampering the assessment of mutagenicity. A majority of the compounds which were found to be mutagenic in this study required no metabolic activation with S9 mix.
  • 長澤 一樹, 津村 彰子, 北澤 文章, 野見山 聖子, 大西 憲明, 堀崎 寿雄
    1995 年 18 巻 2 号 p. 368-371
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    We previously revealed that pirarubicin (THP) was actively taken up by rat polymorphonuclear leukocytes via a carrier-mediated transport system. In the experiment on the effects of the metabolic inhibitors, rotenone, 2, 4-dinitrophenol and sodium cyanide significantly decreased the THP transport. However, sodium fluoride (NaF) significantly increased the uptake, and this result is different from that in some reports. Therefore, we examined the action of NaF on THP uptake by the leukocytes to clarify the discrepancy in the effect of NaF on drug transport. The accelerating effect of 30mM NaF on the THP uptake by the cells had an optimum period of action (15-20min), and was concentration-dependent (5-30mM). Thirty mM potassium fluoride, as well as NaF, increased the uptake amount. On the other hand, NaF (5-30mM) dose-dependently decreased th ATP content in these cells. Additionally, the viable cells in the reaction suspension decreased by about 40% after incubation with 30mM NaF for 15min. Observing these leukocytes treated with NaF by optical microscopy, swelling of the cell and an alteration of the nuclei form occurred. On the basis of these results, we speculated that the increased THP transport in polymorphonuclear leukocytes by NaF, probably F-, might be due, at least in part, to an alteration of the morphological form.
  • 森野 重信, 寺岡 佳夏, 土井 光暢, 石田 寿昌, 上田 仁司, 上杉 晴一
    1995 年 18 巻 2 号 p. 372-376
    発行日: 1995/02/15
    公開日: 2008/04/10
    ジャーナル フリー
    In order to obtain the active form of recombinant human initiation factor (eIF) 4E effectively, an artificial synthetic gene was cloned into an expression vector (pMAL-p2) and the soluble expression was attempted in Escherichia coli under the control of a tac promoter. Two expression systems were finally constructed as a fusion protein with maltose-binding protein, which contain a recognition sequence for the site specific protease α-thrombin and factor Xa, respectively. Most of the fusion protein was induced as a soluble form. The soluble human eIF-4E digested from the fusion protein showed binding specificity for the m7GTP affinity column.
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