Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
17 巻 , 9 号
選択された号の論文の33件中1~33を表示しています
  • 田中 満男, 安斎 忍, 武野 久美, 中川 満夫
    1994 年 17 巻 9 号 p. 1151-1154
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The antioxidant action of thiopalmitic acid (SH-Pal) was studied in a lipid peroxidation system using microsomes from rat liver. The Fe (II)/ascorbic acid (AsA)-induced lipid peroxidation, as measured by the amount of thiobarbituric acid-reactive substances (TBA-RS), was progressively inhibited by the addition of increasing amounts of SH-Pal. The inhibitory effect of SH-Pal in this experimental system was greater than that of α-tocopherol, glutathione (GSH) and palmitic acid. The antioxidative effect was abolished gradually by the addition of increasing amounts of N-ethylmaleimide to the system. Similarly, microsomal lipid peroxidation induced by Fe (III)-ADP/NADPH or CCl4/NADPH was inhibited in a dose-dependent fashion by the addition of SH-Pal. Moreover, SH-Pal was able to reduce 1, 1-diphenyl-2-picrylhydrazyl (DPPH). The α-tocopherol content of the microsomal lipid peroxidation system decreased rapidly when no SH-Pal was present. However, upon adding SH-Pal (90 μM), the decrease in the α-tocopherol content of the assay system was markedly reduced. These findings indicate that SH-Pal acts as an antioxidant and free radical scavenger in lipid peroxidation carried out by rat liver microsomes.
  • 中陳 静男, 石井 晶大, 篠田 雅人
    1994 年 17 巻 9 号 p. 1155-1160
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    NADPH-dependent 5α-dihydrotestosterone 3β-hydroxysteroid dehydrogenase (3β-HSD) was purified to apparent homogeneity from mature pig testicular cytosol. The purified enzyme catalyzed the conversion of 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3β, 17β-diol. The molecular weight was estimated to be 31 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 28 kDa by gel filtration chromatography, indicating that the native 3β-HSD is a monomer. The isoelectric point of the purified enzyme was 5.8 as determined by chromatofocusing. The purified enzyme reduced not only 5α-DHT but also 5β-DHT, 5α (or 5β)-androstanedione, 5α (or 5β)-dihydroprogesterone, prostaglandin E1, 13, 14-dihydro-15-keto-prostaglandin F, glycelaldehyde, xylose and glucuronic acid. Moreover, the enzyme reduced other carbonyl compounds including aromatic aldehydes, aromatic ketones and quinones such as 4-nitrobenzaldehyde, 4-benzoylpyridine, phenylglyoxal, cyclohexanone and 9, 10-phenanthrenequinone at high rates when compared with steroids, prostaglandins and sugars. The purified enzyme was inhibited by AgNO3, SH-reagent, disulfiram, hexesterol, stilbestrol, disulfiram and divalent cations such as Cu2+, Hg2+, Cd2+ and Co2+. Furthermore, the enzymatic properties of the purified enzyme, including catalytic activity, inhibitory effects by various agents and immunological properties, were compared with those of 3α/β-HSD enzymes from pig testicular cytosol.
  • 友田 正司, 松本 慶子, 清水 訓子, 権田 良子, 大原 直子, 平林 啓子
    1994 年 17 巻 9 号 p. 1161-1164
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    An acidic polysaccharide, called peonan PA, was isolated from the root of Paeonia lactiflora PALLAS. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was estimated to be 6.0×104. Peonan PA is composed of L-arabinose : D-galactose : D-galacturonic acid in the molar ratio of 2 : 1 : 10, in addition to small amounts of O-acetyl groups and peptide moieties. About forty percent of the hexuronic acid residues in peonan PA exist as methyl esters. Reduction of carboxyl groups, methylation analysis, lithium degradation and nuclear magnetic resonance studies indicated that its main structural features involve both α-1, 5-linked L-arabino-β-3, 6-branched D-galactan type and α-1, 4-linked D-galacturonan type structural units. The polysaccharide exhibited remarkable reticuloendothelial system-potentiating activity in a carbon clearance test and considerable anti-complementary activity.
  • 臼井 茂之, 村嶋 康平, 酒井 美穂, 木方 正, 鵜飼 茂夫
    1994 年 17 巻 9 号 p. 1165-1170
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The conjugate of mitomycin C (MMC) with carboxymethylated schizophyllan (CMSPG) which was prepared from monochloroacetic acid and schizophyllan (SPG), a β-(1→6)-branched (1→3)-β-D-glucan from Schizophyllum commune FRIES, was synthesized by using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The degree of the substitution of carboxymethyl groups in CMSPG was estimated as approximately 0.87, and locations of carboxymethyl groups in CMSPG were predominantly determined at O-4, O-6, and O-4, 6 positions in glucose residues. The contents of MMC in the conjugate were estimated to be between 8 and 12% (w/w). The conjugate showed successive monoexponential liberation, with a half-life of 7.2 h. Although the in vitro cytotoxicity of the conjugate against L1210 leukemia cells was similar to that of MMC when the cells were exposed for 24 and 48 h, the 50% growth-inhibitory concentration of the conjugate for L1210 was two times higher than that of MMC with exposure for 12 h. The antitumor activity of the conjugate against subcutaneously implanted sarcoma 180 solid tumor in mice by intraperitoneal (i.p.) administration was similar to that of MMC at a dose of 1.5mg eq MMC per kg per d for both 7 times of continuous administration and 4 times of intermittent administration. However, the reduction in the number of leukocytes in the peripheral blood, which was the side effect of MMC, was suppressed by the intermittent administration of the conjugate. The conjugate maintained the ability to induce the tumor regressing factor and the neutrophil chemotactic factor in the serum.
  • 小濱 靖弘, 仙波 太郎, 田中 啓詞, 刀根 秀樹, 田中 忍, 伊東 進, 三村 務
    1994 年 17 巻 9 号 p. 1171-1175
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    A new enhancer of the induction of concanavalin A (Con A)-activated suppressor T (Ts) cells has been demonstrated in the ethanolysate of Bacillus stearothermophilus UBT8038. It was purified by successive silica gel column chromatographies and identified as phosphatidylglycerol with C14 : 0-C18 : 0 isofatty acids (Fr. 7-C). Mouse splenocytes activated with Con A and Fr. 7-C (0.01-1μg/ml) in vitro significantly suppressed the proliferative response of syngenic splenocytes by mitogen stimulation in a dose-dependent manner, compared to those stimulated by Con A alone. The immunosuppressive response enhanced by Fr. 7-C disappeared when the cell populations of Thy-1.2 or CD8 positive lymphocytes were depleted. The result strongly suggests that Fr. 7-C is an immunosuppressive substance which enhances the induction of Con A-activated CD8 positive Ts cells.
  • 長浦 健, 岡部 素典, 古林 伸二郎, 木村 郁子, 木村 正康
    1994 年 17 巻 9 号 p. 1176-1181
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The proliferative effects of basic fibroblast growth factor (bFGF) on the cell cycle were compared in subcultured endothelial cells (EC) and primary cultured smooth muscle cells (SMC) from rat aorta by monitoring the starting time (an index of the competence phase) and rate (an index of the progression phase) of [3H] thymidine incorporation. Persistent treatment with bFGF (1, 10 and 30 ng/ml) reduced the starting time of EC proliferation in the presence of 1% fetal bovine serum (FBS) in a concentration-dependent manner. The starting time of [3H] thymidine incorporation into EC was reduced by a maximum of 4 h by pretreatment with bFGF for 12 h but not for 3 h. DNA synthesis in EC was inhibited by pretreatment with bFGF for 24 h. The rate of [3H] thymidine incorporation into SMC was accelerated both by persistent treatment with bFGF and pretreatment for 3h in the presence of 3% FBS. In serum-free medium, bFGF (30 ng/ml) stimulated [3H] thymidine incorporation into SMC but not into EC after incubation for 36h. Together, bFGF (10 ng/ml) and insulin (10 μg/ml) synergistically stimulated [3H] thymidine incorporation into EC, but insulin alone did not. These findings indicate that bFGF is a competence factor in EC and a progression factor in SMC from rat aorta.
  • 広川 信一, 能勢 充彦, 石毛 敦, 雨谷 栄, 荻原 幸夫
    1994 年 17 巻 9 号 p. 1182-1186
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of Hachimijiogan on cognitive disturbance was investigated using step-through passive avoidance failure techniques : scopolamine-, cycloheximide- and cerebral ischemia-induced amnesia. Pre-acquisition trial administration of Hachimijiogan (0.5 g/kg, p.o.) prolonged the step-through latency reduced by scopolamine and cycloheximide. Hachimijiogan (0.5 and 1.0 g/kg, p.o.) also ameliorated the cerebral ischemia-induced amnesia. Physostigmine (0.1 mg/kg, i.p.) ameliorated all three amnesia models. The ameliorating effects of Hachimijiogan and physostigmine on cycloheximide-induced amnesia were diminished by the combination with scopolamine. These results suggest that Hachimijiogan possesses a wide-ranging pharmacological profile in anti-amnesic actions and that its anti-amnesic activities may be related to the cholinergic neuronal system.
  • 木村 博, 寺戸 勅雄, 青山 喬
    1994 年 17 巻 9 号 p. 1187-1192
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Sensitization by 1-methyl-3-isobutylxanthine (MIX), a potent inhibitor of cAMP phosphodiesterase, of cellular sensitivity to mitomycin C (MC) was tested using various cell lines. Sensitization was seen with CHO cells and Balb/c 3T3 cells, but a decrease in sensitivity was seen with HeLa, K-balb and other cell lines. To measure the extent of crosslinks produced by MC, we used an alkaline elution assay. The extent of crosslinks was increased by MIX in CHO cells and decreased in K-balb cells. These changes in extent are well reflected by changes in sensitivity to MC in both cell lines. In CHO cells, an intracellular dose of MC was increased by MIX with no change in the rate of uptake or efflux of MC. There was a slight decrease in the dose in HeLa or K-balb cells. Among the enzymes which engage in the reductive activation of MC, we tested DT-diaphorase and NADPH-cytochrome P450 reductase using CHO, HeLa and K-balb cells. MIX had almost no effect on the activity of NADPH-cytochrome P450 in each cell line, whereas it suppressed the activity of DT-diaphorase, significantly in HeLa and K-balb cells, and slightly in CHO cells. All these facts indicate that MIX caused an increase in the extent of crosslinks via an increase in the intracellular dose of MC in CHO cells, and that these increases may lead to the sensitization. On the other hand, the decrease in the sensitivity shown in HeLa and K-balb cells may be due to the suppression of DT-diaphorase activity and/or to a decrease in MC dose. The effect of forskolin, another cAMP raising agent, on the sensitivity to MC was examined in CHO cells to test whether the sensitization by MIX involves the intracellular cAMP level. The treatment with forskolin had little effect, indicating that there was no such involvement.
  • 棟近 公司, 十亀 祥久, 貴志 徳秀, 川畑 好之康, 上田 泰生, 山内 紘一, 横山 和正
    1994 年 17 巻 9 号 p. 1193-1198
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Tissue distribution of the radioactivities after intravenous administration of [14C] adriamycin ([14C] ADM) or [14C] ADM linked to oxidized dextran ([14C] ADM-OXD) in mouse bearing Lewis lung carcinoma (LLC) and rat bearing Walker 256 carcinosarcoma was studied. ADM conjugated with OXD increased plasma half-life and gave high area under the plasma concentration-time curve (AUC). The AUC values were 13.0 and 5.8 times higher than those of the [14C] ADM group in mice and rats, respectively. In the tumor tissues, AUC values of the [14C] ADM-OXD group were also respectively 1.6 and 1.9 times higher than those of the [14C] ADM group. However, the AUC values in the heart of the [14C] ADM-OXD group were about half those of [14C] ADM group in both animals. Thus the distribution of ADM was changed by the conjugation with OXD. The excretion profile of ADM was also changed by the conjugation. During 6h after administration, [14C] ADM-OXD was mainly excreted into rat urine at 45.2% of the original dose, but in the [14C] ADM group recovery in urinary excretion was 4.2%. Using [14C] ADM-OXD and ADM-[14C] OXD, the respective tissue distribution of ADM and OXD portions in the ADM-OXD was studied in rats bearing Walker 256. The radioactivities of both [14C] ADM-OXD and ADM-[14C] OXD groups increased in tumor and liver within 1h after administration. In the liver, both radioactivities were retained for 24h, which suggested that ADM and OXD were retained as conjugated form, however, different behavior was observed between the two groups in tumor tissues. Peak [14C] ADM-OXD radioactivity was reached 6h after administration and then decreased, while, ADM-[14C] OXD was quickly cleared from the tumor after 1h administration. The results suggested that ADM was released from ADM-OXD and the remaining ADM-OXD, which was low in ADM content, was then cleared from the tumor tissues.
  • 張 永祥, 斉藤 洋, 西山 信好
    1994 年 17 巻 9 号 p. 1199-1205
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The subject mice were thymectomized 4 weeks after birth. Ten months after the thymectomy, learning behaviors in passive and active avoidance performances and a spatial memory task, the contents of brain monoamines and brain choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated. DX-9386, a traditional Chinese medicinal prescription consisting of ginseng, polygala, acorus and hoelen, was prepared in CE-2 mouse food (1%, w/w) and given to the thymectomized mice after the operation until all the experiments were finished. DX-9386 treatment significantly ameliorated the learning and memory ability impaired by thymectomy in passive avoidance performances and in a spatial memory task, and the mice tended to improve in the active avoidance performance of a lever press test. However, DX-9386 treatment did not improve the thymectomy-reduced immune response. The contents of hypothalamic norepinephrine, 3, 4-dihydroxyphenylacetic acid and homovanillic acid, and hypothalamic ChAT activity were significantly increased in thymectomized mice, and DX-9386 restored them to the control levels. These results suggested that DX-9386 mainly affected the cognitive process of the central nervous system to ameliorate the learning and memory deficit induced by thymectomy.
  • / 松本 欣三, / 渡辺 裕司, Arunporn ITHARAT, Hiroshi WATANABE
    1994 年 17 巻 9 号 p. 1206-1209
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Analgesic activities of Randia siamensis CRAIB (R. siamensis) extract and pseudoginsenoside-RP1, a constituent of the extract, were examined in the writhing test, hot plate test and Randall-Selitto test. Oral administration of R. siamensis extract dose-dependently decreased the number of writhings and stretchings induced by 0.6% acetic acid in the writhing test in mice. Moreover, in the Randall-Selitto test in rats, the extract raised the nociceptive threshold of the carrageenan-inflamed but not of non-inflamed paw. It did not affect the nociceptive response in the hot plate test in mice. The R. siamensis extract did not affect hexobarbital-induced sleep or spontaneous motor activity in mice, suggesting that it has no sedative effect. Pseudoginsenoside-RP1 produced similar effects to the R. siamensis extract, but its effective doses in the analgesic tests were lower than those with the extract. These results suggest that R. siamensis extract produces anti-nociceptive actions similar to those of a peripherally acting analgesic drug aspirin, and that pseudoginsenoside-RP1 may partly contribute, but is not the main contributor, to the antinociceptive action of the extract.
  • 木村 康浩, 三宅 勝志, 北浦 照明, 木平 健治, 福地 坦
    1994 年 17 巻 9 号 p. 1210-1214
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Cholecystokinin octapeptide sulfated (CCK8) tissue levels in several regions of the rat brain were measured by amino terminal specific radioimmunoassay following the intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) to investigate the interaction between CCK8 and dopamine (DA). Pargyline and desmethylimipramine were administered 2 h before 6-OHDA injection. The levels of CCK8-like immunoreactivity in the frontal cortex, striatum, hippocampus, substantia nigra, and nucleus accumbens increased transiently on day 1 after 6-OHDA treatment. The levels in the frontal cortex, striatum and substantia nigra fell gradually to reach a subnormal level on day 7. In the nucleus accumbens, where the coexisting CCK8 and DA neurons lie, the tissue levels fell to a subnormal level on day 3. These decreased levels were unchanged until day 28. The irreversible destruction of DA neurons induced by 6-OHDA might cause drastic changes in regional CCK8-like immunoreactivity. The changes would depend on the neuromorphological differences in each structure. These results suggest that the CCK8 systems are closely related to the DA systems in several brain regions and that DA plays an important role in CCK8 release.
  • 長谷川 達也, 三原 眞, 中室 克彦, 佐谷戸 安好
    1994 年 17 巻 9 号 p. 1215-1219
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    To elucidate the relationship between chemical forms of selenium in tissues and subacute liver damage induced by selenocystine (T. Hasegawa et al., Arch. Toxicol., 68, 91 (1994)), the distribution and chemical form of selenium were investigated in ICR male mice treated with the chemical orally (50 mg/kg) and intravenously (5 mg/kg). The time-distribution of selenium in plasma, erythrocytes and liver after separate administration varied. However, Sephadex G-150 chromatograms of plasma, and stroma-free hemolysate from mice treated orally or intravenously with selenocystine, revealed that selenium exists mainly in the albumin and hemoglobin fractions, respectively, and is neither route- or time-dependent. Sephadex G-150 chromatograms of liver cytosol of the animals 1 h after oral administration or 1 and 6 h after intravenous administration showed two selenium-containing fractions, void volume and a low-molecular fraction (Kav=0.85) ; 6 h after oral treatment, however, animals had an additional high-molecular fraction (Kav=0.45). Levels of acid-volatile selenium and dialyzable selenium in the fraction with a Kav value of 0.45 were similar, being 31.2% and 30.3%, respectively. No acid-volatile selenium was recognized in the non-dialyzable high-molecular fraction. The present study demonstrated that when selenocystine is administered orally to mice, the selenium which produces acid-volatile selenium by acidification may bind to protein sulfhydryl groups in the liver cytosol ; this was not seen in the case of intravenous administration.
  • 三浦 俊明, 村岡 早苗, 小木曽 健人
    1994 年 17 巻 9 号 p. 1220-1223
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Adriamycin (ADM)-Fe3+ caused inactivation of rat heart mitochondrial creatine kinase (CK) with lipid peroxidation. Superoxide dismutase, catalase and hydroxyl radical scavengers were without effect on the CK inactivation and the lipid peroxidation induced by ADM-Fe3+, indicating the lack of involvement of superoxide, hydrogen peroxide or hydroxyl radicals in these reactions. The antioxidant butylated hydroxytoluene strongly inhibited not only lipid peroxidation but also CK inactivation, indicating that mitochondrial CK was inactivated with lipid peroxidation. Reduced glutathione and dithiothreitol (DTT) prevented CK inactivation without inhibiting lipid peroxidation. The CK activity of 5, 5'-dithiobis-(nitorobenzoic acid)-treated mitochondria exposed to ADM-Fe3+ was partially reversed by addition of DTT, indicating that CK inactivation was due to oxidative damage of sulfhydryl groups. In contrast, mitochondrial protein SH groups were not attacked via ADM-Fe3+-induced lipid peroxidation. Thus, the SH groups in mitochondrial CK are very susceptible to ADM-Fe3+-induced lipid peroxidation.
  • 木村 正康, 木村 郁子, 室井 正志, 田中 克尚, 野島 浩史, 上野 照子, 小泉 徹
    1994 年 17 巻 9 号 p. 1224-1231
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The structure-activity relationship of phenylene-polymethylene bis-ammonium (PMBA) derivatives, C6H4 [X (CH2)nR]2, on isolated mouse phrenic nerve-diaphragm muscle was investigated to obtain more potent and stable compounds for use as pharmacological tools to clarify the mechanism of succinylcholine (SuCh)-induced neuromuscular blockade. The neuromuscular blocking effect of all the PMBA derivatives was not reversed by neostigmine, a cholinesterase inhibitor. The potency of the neuromuscular blockade was in the order p-> o-> m- with respect to the side-chain substituents. A PMBA composed of X=CH2, n=5 and R=N+Et3 was 5.9- and 23-fold more potent than SuCh and decamethonium, respectively. The derivatives of R=N+Et3 were observed to be more potent than those of R=N+Me3, N-Me-piperidinio and pyridinio derivatives. Replacement of X=CH2 with O, CHOH and CHOAc decreased the neuromuscular activity while replacement with S, SO and SO2 increased it. Introduction of NO2 into the phenylene ring increased the activity, while the introduction of an alcohol, aldehyde and ketone group decreased it. Removal of a carbonyl or ether group from SuCh decreased its activity, whereas the introduction of these into PMBA failed to increase it. We managed to synthesize unhydrolyzable neuromuscular blocking agents which are more potent than SuCh.
  • 木村 正康, 田中 克尚, 高村 雄策, 野島 浩史, 木村 郁子, 矢野 伸吾, 田中 基明
    1994 年 17 巻 9 号 p. 1232-1240
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    β-Eudesmol, a sesquiterpenoid alcohol isolated from Atractylodes lancea rhizoma, potentiates the neuromuscular blocking effect of succinylcholine (SuCh). The potentiating effect is greater in diabetic muscles than in normal ones. To identify the structural components of β-eudesmol contributing to this action, we examined the potentiating effect of newly synthesized tertiary alcohols related to β-eudesmol in phrenic nerve-diaphragm muscle preparations of normal and alloxan-diabetic mice. Potentiating effects were exhibited by cyclohexylidene derivatives but not by cyclohexanone or cyclohexanol derivatives. The compound 2-(3-hydroxy-3-methylbutyl) cyclohexylidene exhibited a potentiating effect, but 3-(3-hydroxy-3-methylbutyl) cyclohexylidene did not. These results indicate that both the presence of an exo-methylene attached to a cyclohexane ring and the distance between the exo-methylene and the hydroxy group in β-eudesmol are involved in the potentiating effect on SuCh-induced neuromuscular blockade.
  • 原 文子, 中里 享美, 芝 紀代子, 下田 順子, 小島 登美枝, 福村 幸仁, 小林 功
    1994 年 17 巻 9 号 p. 1241-1245
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of storage time and temperature on the immunological turbidimetric measurement of a low concentration of albumin in urine was investigated. In storage at -20°C, the albumin level decreased, but the rate of this decrease differed considerably among specimens. However, under storage at room temperature for 2 weeks, or at 4°C for 5 weeks albumin levels did not show significant changes. At -40°C and -80°C there were only slight decreases. At -40°C decreases were slightly greater than at -80°C. Therefore, -80°C was found to be the optimal temperature for long-term storage of urinary albumin. Some of the specimens showed a 50% decrease in albumin level after storage for 9 weeks at -20°C, but remained unchanged after storage for the same period at -80°C. A pair of specimens preserved at -20°C and -80°C were isolated by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). After electrophoresis, urinary proteins were stained by silver staining to observe bands, and albumin content was determined by immunoblotting. A decrease in albumin concentration was also observed by densitometric detection.
  • 野田 倫, 小笠原 富夫, 飯田 貴史, 山川 秀史, 道下 久, 三谷 隆彦, 黒野 昌庸, 八木 國夫
    1994 年 17 巻 9 号 p. 1246-1250
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Ceramide sulfate (N-acylsphingosine-1-O-sulfate), which lacks the galactose residue of sulfatide, was examined as a possibly preferable constituent of liposomes for drug delivery. Multilamellar vesicles prepared from phosphatidylcholine, cholesterol, and N-lignoceroylsphingosine-1-O-sulfate in a molar ratio of 5 : 4 : 1 efficiently entrapped adriamycin, and the retention of the drug in the liposomes in saline at 4°C for 8d was nearly 100%. In terms of entrapment efficiency and retention of the drug in liposomes, N-lignoceroylsphingosine-1-O-sulfate was superior to N-stearoylsphingosine-1-O-sulfate. A pharmacodynamic study revealed that the blood level of adriamycin was far higher with the drug encapsulated in N-lignoceroylsphingosine-1-O-sulfate-containing liposomes than with the free drug. The drug level in the heart was remarkably reduced with the liposome-entrapped drug, which is advantageous in reducing the cardiotoxicity of this drug. The effect of N-lignoceroylsphingosine-1-O-sulfate-containing liposomes on the blood level of adriamycin was superior to that of sulfatide-containing liposomes, though the effect of the former on the heart level was comparable to that of the latter. The tumoricidal effect on ascitic P388 leukemia and Lewis lung carcinoma was higher with adriamycin entrapped in N-lignoceroylsphingosine-1-O-sulfate-containing liposomes than with the free drug.
  • 西岡 豊, 京谷 庄二郎, 岡村 政志, 大西 三朗, 山本 泰猛, 川島 嘉明, 棚田 成紀, 中村 武夫
    1994 年 17 巻 9 号 p. 1251-1255
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    We prepared chitin-containing cis-diamminedichloroplatinum (II) (CDDP) albumin microspheres with various particle sizes, and investigated in vitro CDDP release ; the antitumor effect towards VX2 tumor introduced into rabbits was then examined. It was found that the rate of release of CDDP from chitin-containing CDDP albumin microspheres in vitro was increased with reduced particle size. Administration of microspheres to VX2 tumor-bearing rabbits via the hepatic artery resulted in different profiles of plasma platinum concentration depending on the particle size, and a higher concentration of platinum was released from the beginning of administration as particle size was reduced. The platinum content in hepatic tissue following the administration of CDDP microspheres was increased as the particle size decreased, although the rate of increase was not uniform. The antitumor effect of CDDP assessed by the suppression of tumor growth tended to be higher when microspheres of smaller sizes were used. However, no significant difference was observed in tumor growth rate between rabbits injected with microspheres smaller than 20 μm and those injected with sizes between 20 and 37μm (p>0.05). We also examined the relationship between the CDDP dose and antitumor effect using microspheres of less than 20 μm and observed a dose-dependent antitumor effect. No significant difference was observed, however, between 2 and 4 mg eq CDDP/kg dose levels (p>0.05). From these results, we concluded that microsphere size and CDDP dose were strongly correlated with the augmentation of antitumor effect of chitin-containing CDDP albumin microspheres used in chemo-embolization therapy via the hepatic artery.
  • 佐々木 功, 藤田 卓也, 村上 正裕, 山本 昌, 中村 英次, 今崎 一, 村西 昌三
    1994 年 17 巻 9 号 p. 1256-1261
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, from the gastrointestinal (GI) tract was evaluated. The bioavailability of this compound after oral administration was considerably poor in rats. Studies were undertaken to elucidate the mechanisms for this low oral bioavailability of azetirelin. The plasma azetirelin levels following intravenous and hepatoportal vein injection were virtually identical over the dose range of 0.02-0.1 mg/kg, indicating a minor contribution of the hepatic first-pass metabolism of this drug. Azetirelin was stable against peptide hydrolases both in luminal fluid and intestinal mucosal homogenates, whereas its degradation occurred when incubated with cecal contents under an anaerobic condition. In addition, complete degradation of azetirelin during the GI transit was disclosed by analyzing the fecal sample collected after oral administration of [14C] azetirelin. These results suggested that gut bacteria may be responsible for the hydrolysis of azetirelin in the GI tract. The low intestinal permeability of azetirelin was revealed by a modified everted gut experiment in various segments of the rat intestine. The poor membrane transport characteristics of azetirelin may be due to its high hydrophilicity. From these results, it was suggested that the insufficient oral bioavailability of azetirelin may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity, and also to the degradation of the peptide by intestinal microflora.
  • 湯浅 博昭, 関谷 充恵, 尾関 昭二, 渡辺 淳
    1994 年 17 巻 9 号 p. 1262-1266
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    As a study to assess the potential application of milk fat-globule membrane (MFGM), which is of natural origin and expected to be a safer alternative to synthetic emulsifiers, to pharmaceutical dosage forms, the oral absorption of α-linolenic acid was evaluated by the analysis of gastrointestinal disposition after oral administration as an MFGM emulsion to rats. A linear model incorporated with first-order gastric emptying followed by first-order intestinal absorption was fitted to the data of the remaining fraction of α-linolenic acid versus time profiles for the stomach and small intestine to estimate the rate constants of gastric emptying (kg) and intestinal absorption (ka). The ka (0.045 min-1) was about 4 times larger than the kg (0.011 min-1). The kg was comparable to the apparent oral absorption rate constant estimated by the pharmacokinetic analysis of plasma concentration data. These results suggest that the oral absorption of α-linolenic acid administered as MFGM emulsion is gastric emptying-limited and, hence, any change in the intestinal absorption process would only modestly affect its oral absorption.
  • 西方 真弓, 中井 亜紀, 伏田 仁美, 三宅 [ケイ]司郎, 有田 隆一, 井関 健, 宮崎 勝巳
    1994 年 17 巻 9 号 p. 1267-1271
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)-and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)-and (+)-HCZ and between (-)-and racemic HCZ after oral administration (50 mg/kg) of these three forms. The Cmax and AUC0-∝ of (-)-HCZ were lower than those of (+)-isomer and racemate, and its CL0 was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)-and racemic HCZ in vitro using rat liver 9000×g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The Vmax in vitro showed a good correlation with the CL0 in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a Ki of 6.96 μM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a Ki of 20.4 μM. This is consistent with the observation that the (+)/(-) ratio of AUC0-∝ after dosing with a racemic mixture was clearly lower than after dosing with the individual enantiomers. Moreover, the blood concentrations of racemic HCZ were similar to those of (+)-HCZ rather than intermediate between those of (+)-and (-)-HCZ, probably because of the stronger inhibitory effect of (+)-HCZ on (-)-HCZ than vice versa. These results suggest that the enantiomeric differences in the pharmacokinetics of HCZ after oral administration were caused by enantioselective first-pass metabolism in the liver, and that the pharmacokinetics of HCZ after the administration of its racemate was affected by the enantiomeric inhibitory interactions in the hepatic metabolism.
  • 内田 享弘, 後藤 茂
    1994 年 17 巻 9 号 p. 1272-1276
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The objective of the present study was to produce ovalbumin (OVA) loaded poly (lactide-co-glycolide) (PLGA) microspheres with different diameters and to evaluate their possibilities as vaccine formulation in mice following oral inoculation. Four kinds of OVA loaded PLGA microspheres with different mean average volume diameters (1.3, 4.0, 7.5, and 14.0 μm) were manufactured using a w/o/w emulsion/solvent evaporation method. Low loading efficiencies (8-20% w/w) were observed in all batches although smooth spherical particles were obtained. Single oral administrations of OVA loaded PLGA microspheres with different diameters to mice produced immune responses (serum IgG levels by ELISA) which were statistically higher than OVA solution as negative control (Fisher's paired t-test). A dose-response was observed, and single and double inoculation orally produced similar serum antibody levels. The rank of immune response was as follows : 4.0 μm->1.3 μm-=7.5 μm->14.0 μm-microspheres. The oral inoculation with 0.13% OVA loaded PLGA microspheres having a mean volume diameter of 4.0 μm exhibited the best immune responses with values greater than those obtained after subcutaneous inoculation with complete Freund's adjuvant (CFA) as positive control, and not significantly different from those obtained after subcutaneous inoculation with the same microspheres.
  • 山田 直樹, 村上 啓寿, 河村 典久, 榊原 仁作
    1994 年 17 巻 9 号 p. 1277-1281
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    We have previously demonstrated that bacteria-containing Phormidium tenue, a cyanobacterium which produces musty odor 2-methylisoborneol, grew beyond 8 weeks, whereas axenic alga perished suddenly between the 3rd week and the 4th week while being cultured in the laboratory. This mechanism was investigated. It is assumed that when algal cells grow beyond a certain level, the supply of CO2 becomes inadequate and results in the rapid lysis of axenic alga. At that time, inhibitory substances liberated from algal cells kill the surviving alga. Since the process occurs continuously, this alga is finally annihilated. On the other hand, since inhibitory substances are metabolized or degraded by bacteria coexistent with alga, bacteria-containing P. tenue maintains growth for a long time. The growth-inhibitory substance was found to be unsaturated free fatty acids.
  • 久保 道徳, 浅野 年紀, 塩本 秀己, 松田 秀秋
    1994 年 17 巻 9 号 p. 1282-1286
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of 50% ethanolic extract (JR-ext) from Chinese Rehmanniae Radix (the steamed and dried root of Rehmannia glutinosa, "Jyuku-Jio"in Japanese) on the hemorheology of inflammatory, thrombosic and intact animals were examined in the in vivo models. JR-ext (200 mg/kg, p.o.) inhibited the reduction of fibrinolytic activity and erythrocyte deformability, the decrease in erythrocyte counts and the increase in connective tissue of the thoracic artery in a chronic inflammatory model, adjuvant-induced arthritis. However, JR-ext was ineffective on the development of edema in the arthritic rats and on acute and chronic inflammation. JR-ext inhibited the reduction of erythrocyte deformability, but not the decrease of coagulative factors in a thrombosic model, endotoxin-induced disseminated intravascular coagulation (DIC). JR-ext also showed a promoting effect on erythrocyte deformability and fibrinolytic activity in intact rats. These results suggest that orally administered JR-ext can prevent an inducement of impediment in the peripheral microcirculation of various chronic diseases through the improvement of hemorheology.
  • 友田 正司, 平林 啓子, 清水 訓子, 権田 良子, 大原 直子
    1994 年 17 巻 9 号 p. 1287-1291
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Controlled Smith degradation and limited hydrolysis of ginsenan PA, the main phagocytosis-activating polysaccharide isolated from the root of Panax ginseng C. A. MEYER, were performed. The reticuloendothelial system-potentiating and anti-complementary activities of the degradation products were investigated. Methylation analysis of the primary and secondary Smith degradation products indicated that the core structural features of ginsenan PA include a backbone chain mainly composed of β-1, 3-linked D-galactose. Almost half of the galactose units in the backbone carry side-chains composed of β-1, 6-linked D-galactosyl residues at position 6. Further 3, 6-branching of D-galactose units was observed in a part of the side-chains. α-L-Arabinose units are connected mainly to the core galactose moieties via position 6. Removal of most of the arabinose units had a considerable effect on immunological activity.
  • 松島 曜子, 深澤 弘志, 遠藤 泰之, 橋本 祐一, 首藤 紘一
    1994 年 17 巻 9 号 p. 1292-1295
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Human papillomavirus type 18 (HPV18) is involved in the genesis of cervical cancer through expression of its viral oncoprotein in infected cells. A tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), was found to increase the level of HPV18 transcripts in an HPV18-harboring cervical cancer cell line, HeLa. A similar increase in HPV18 expression was also observed on treatment of the cells with an oxygenated cholesterol, 3β, 5α-dihydroxycholestan-6-one (yakkasterone). The effects on HPV18 expression elicited by TPA and yakkasterone were repressed by a protein kinase inhibitor, staurosporine. Treatment of the cells with cholesterol under serum-free conditions also resulted in an apparent increase of HPV18 expression.
  • 細機 好章, 鈴木 政彦, 唐木澤 裕子, 丸山 恵子, 長友 孝文
    1994 年 17 巻 9 号 p. 1296-1298
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Bopindolol and its two metabolites (18-502 and 20-785) were examined for their affinity to a β2-adrenoceptor in the bovine mesenteric artery using the radioligand binding assay method with [3H]CGP12177 as a radioligand. The Scatchard analysis of the data demonstrated a uniphasic plot with Kd and Bmax values of 0.86±0.16 nM, and 13.34±1.11 fmol/mg protein, respectively. The pKi values of bopindolol and its two metabolites for β2-adrenoceptors in the bovine mesenteric artery were 7.70±0.13, 8.07±0.13, 8.20±0.24, respectively, with 20-785 showing the highest values among these drugs. The present findings indicate that the bovine mesenteric artery membrane is predominantly β2-adrenoceptor tissue, and that bopindolol and its two metabolites were potent for β2-adrenoceptors in the bovine mesenteric artery.
  • 松本 陽子, 山田 栄一, 亀井 昇司, 岩原 正宜, 上岡 龍一
    1994 年 17 巻 9 号 p. 1299-1300
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    A high affinity of hybrid liposomes towards normal human epidermal keratinocytes was observed. The fluorescence micrograph showed that hybrid liposomes may be incorporated into the keratinocytes by fusion.
  • 西村 益浩, 山岡 清, 安井 裕之, 内藤 真策, 中川 照眞
    1994 年 17 巻 9 号 p. 1301-1304
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The local hepatic disposition of BOF-4272, a newly developed xanthine oxidase (XO)/xanthine dehydrogenase (XDH) inhibitor, was evaluated in the rat perfusion system following pulse input of the drug into the portal vein. The elution time profiles from the liver into the hepatic vein were analyzed by dispersion models. The disposition of BOF-4272 through the rat liver was represented by a two-compartment dispersion model based on the Akaike's Information Criterion (AIC). The area under the concentration time curve (aucH) of BOF-4272 was proportional to the dosing amount, and the mean transit time was constant from 62.5 up to 500 μg/liver, which demonstrates that the local hepatic disposition of BOF-4272 is linear in this dosing range. The local disposition parameters were precisely estimated at the dosing amount of 250 μg/liver using several rats. These parameters in the dispersion model were correlated to the local moment characteristics. The hepatic recovery ratio (FH) was 22.8±3.2% and the mean transit time (tH) was 0.112±0.008 min, which show that the influx of BOF-4272 into the liver is efficiently large.
  • 長澤 一樹, 野見山 聖子, 大西 憲明, 横山 照由, 岩川 精吾, 奥村 勝彦
    1994 年 17 巻 9 号 p. 1305-1308
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    We performed experiments on the cis-inhibition and trans-stimulation effect on pirarubicin uptake in order to clarify the involvement of a carrier in the pirarubicin, daunorubicin and/or doxorubicin transport systems in rat polymorphonuclear leukocytes. The uptake of daunorubicin and doxorubicin was a saturable concentration-dependent process. Since the apparent kinetic constants, Michaelis constant (Km) and inhibition constant (Ki), were almost comparable, these drugs presented mutually competitive inhibition. Furthermore, the pirarubicin uptake by polymorphonuclear leukocytes was significantly elevated by increasing the preloaded amount of doxorubicin, indicating that there was a trans-stimulation effect on the pirarubicin transport in the leukocytes. These results suggest that carrier-mediated transport might be involved in the uptake of anthracycline derivatives, pirarubicin, daunorubicin and doxorubicin, by rat polymorphonuclear leukocytes.
  • 湯浅 博昭, 渡辺 淳
    1994 年 17 巻 9 号 p. 1309-1312
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    The influence of various experimental treatments on propulsive gastrointestinal motility was examined in rats, using inulin as a marker. In unanesthetized rats without any surgery, the distribution center of inulin, which was expressed as a dimensionless distance normalized by the length of the small intestine, reached 0.587 down the intestinal tract from the pylorus 60 min after the intragastric adiministration of inulin. However, the distribution center of inulin moved only 0.061 in 60 min in unanesthetized rats with minimial abdominal surgery for intraduodenal administration of inulin, and did not move in unanesthetized rats with cannulas for perfusion or in the rats anesthetized with urethane and treated with abdominal surgery. In urethane-anesthetized rats without surgery, almost 100% of the inulin was recovered from the stomach 60 min after intragastric administration. These results suggest that gastrointestinal motility is extensively suppressed by minimal abdominal surgery as well as by anesthesia.
  • 佐崎 敬三, 柴田 芳宏, 西村 幸治, 橋本 祐一, 岩崎 成夫
    1994 年 17 巻 9 号 p. 1313-1315
    発行日: 1994/09/15
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of phenyl-, benzyl-, phenethyl-, and phenylpropylphthalimides on 12-O-tetra-decanoylphorbol-13-acetate (TPA)-induced tumor necrosis factor (TNF)-α production by human leukemia cell line HL-60 were examined. Among the four phthalimide derivatives, only phenethylphthalimide showed potent enhancing effect on TNF-α production.
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