Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
18 巻 , 11 号
選択された号の論文の37件中1~37を表示しています
  • 佐治 英郎, 渡邊 章, 清野 泰, 間賀田 泰寛, 飯田 靖彦, 高石 勇希, 横山 陽
    1995 年 18 巻 11 号 p. 1463-1466
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    [125I] (S)-5-Iodonicotine was prepared and its application in the assay of nicotinic acetylcholine receptor binding in the brain was studied. [125I] (S)-5-Iodonicotine bound to the rat cortical membrane with high affinity (Kd, 15.0nM). Various nicotinic cholinergic compounds showed competition with [125I] (S)-5-iodonicotine for the binding sites in the rat cortical membrane, and the specificity of its binding was correlated well with that of [3H] cytisine (r=0.98). These findings suggest that [125I] (S)-5-iodonicotine binds to the same sites as [3H] cytisine and indicate that [125I] (S)-5-iodonicotine can be applied as a brain nicotine receptor binding assay.
  • 奥山 光伸, 角皆 政信, 渡辺 紀子, 朝倉 康予, 重松 昭世
    1995 年 18 巻 11 号 p. 1467-1471
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    A possible evaluation technique was devised for examing timely cholesterol synthetic activity in the rat liver. The principle of the technique is to measure the incorporation rate of 14C atoms into a few target metabolites excreted in bile with time after an intraportal injection of [1, 2-14C] acetate to the conscious rats. The measuring technique, TLC-autoradioluminography (TLC-ARLG), was devised for much more accurate, quantitative, simple and quick ultramicroanalysis of radioactive metabolites than ever before. Practically, a few μI of the bile samples were analyzed by TLC before recording of a 2-dimensional radioactive image on the TLC plate. The incorporation ratio of 14C into cholesterol to succinic acid (C/S ratio) varied such that the value found in a 24-h fasting group was less than one-tenth of that in a sufficiently fed control group. For use as an antihyperglycemic drug, the bile C/S ratio in the nicotinic-acid-dosed group was approximately one-fifth of that in the control group.
  • 寺田 衣子, 本田 千恵, 竹山 志朱代, 諏訪 紀代子, 上硲 和輔
    1995 年 18 巻 11 号 p. 1472-1475
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The biosynthetic pathway of phenolics with an acetylenic group, 4-[5-(4-methoxyphenoxy)-3-penten-1-ynyl] phenol (1) and its related compounds, isolated from suspension-cultured cells of Asparagus officinalis L. (Liliaceae), was studied in feeding experiments using [1-13C]-and [U-13C] glucose. Analyses of the 13C-NMR spectra of the methyl ether and acetate of the 13C-labelled species of 1 indicated that the aromatic rings at both ends of the molecule are formed from shikimic acid. It was also assumed that the acetylenic carbons in the C5 chain could be incorporated together with its adjacent aromatic ring through any phenethyl class compound derived from phenylpropanoids, and the propenylene carbon through glycolysis metabolites with C3 carbon units.
  • 柏倉 幾郎, 村上 美穂, 早瀬 幸俊, 高木 良成
    1995 年 18 巻 11 号 p. 1476-1481
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    We have partially purified a factor from porcine kidney, hematopoietic-promoting factor (HPF), which enhances granulocyte-macrophage colony-forming units (CFU-GM) and erythropoietic burst-forming unit (BFU-E) colony formation in the presence of various exogenous colony-stimulating factors (CSF) or erythropoietin (Epo) from mouse bone marrow cells. In this paper we examine the combined effects of HPF and/or stem cell factor (SCF) with interleukin-3 (IL-3) and interleukin-6 (IL-6) on the proliferation of primitive hemopoietic progenitor cells in liquid cultures for 7 or 14d. The combination of IL-3+IL-6+HPF could not increase the number of CFU-GM, BFU-E, and day-8 colony forming units in spleen (CFU-S) in the cultures of unfractionated bone marrow cells, while this combination resulted in a marked increase of progenitors in cultures of c-kit+ enriched cells. In contrast, expansion of progenitors was observed by IL-3+IL-6+SCF or IL-3+IL-6+SCF+HPF in the culture of both unfractionated bone marrow cells and c-kit+-enriched cells after 7 d. The number of CFU-GM and BFU-E in the combination of IL-3+IL-6+SCF+HPF for c-kit+ cells showed the largest increase, 109-fold and 38-fold respectively after 14 d. These results show that HPF has promoting activity on hematopoietic stem cells and acts synergistically with SCF in the early stages of hematopoiesis.
  • 松岡 真由美, 遠藤 菊太郎, 斉藤 志織, 加藤 三佳, 中島 良徳
    1995 年 18 巻 11 号 p. 1482-1486
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    A plasmid pEP2104 originated from Staphylococcus aureus was clinically isolated in Hungary during 1977. The plasmid mediates inducible resistance to PMS-antibiotics ; partial macrolide [the 14-membered macrolides, erythromycin (EM) and oleandomycin and the 16-membered macrolides mycinamicin I (MCM I) and mycinamicin II (MCM II)] and type B streptogramin (MKM-B) antibiotics. The sequence of 31 amino acid residues obtained by N-terminal analysis of the 63 kDa protein (MsrSA) present in the membrane from 8325 (pEP2104) cells, whose PMS-resistance was induced by a concentration of 1.35 μg EM/ml [EM-induced 8325 (pEP2104)], was identical to the corresponding sequence in a membrane protein MsrA related to promoting efflux of [14C] EM [Ross J.I., et al., Mol. Microbiol., 4, 1207 (1990)]. A constitutive PMS-resistant strain 8325 (pMC38) was obtained from the 8325 (pEP2104) strain in the presence of 1μg MCMI/ml. No inactivation of EM in EM-induced 8325 (pEP2104) was observed. Moreover, poly (A)-directed polylysine synthesis by a cell-free system containing ribosomes from EM-induced 8325 (pEP2104) cells and S100 from Escherichia coli was inhibited by not only EM but spiramycin and MKM-B [Matsuoka M., et al., Biol. Pharm. Bull., 16, 1288 (1993)]. In addition, ribosomes from both EM-induced 8325 (pEP2104) and 8325 (pMC38) strains showed about the same affinity as those from the host strain, NCTC8325. These results suggest that, like MsrA protein, active drug-efflux due to MsrSA protein may be responsible for PMS-resistance. How can the 8325 (pMC38) strain discriminate PMS-antibiotics from most of 16-membered macrolides and lincosamides? A possible explanation is discussed in terms of the pKa-value related to the physicochemical nature of the antibiotics.
  • 元木 一宏, 森田 真弘, 小林 栄一, 内田 丈士, 秋元 功司, 福島 英明, 肥塚 靖彦
    1995 年 18 巻 11 号 p. 1487-1491
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Ten kinds of monoglycosylceramides (MonoCers), having the same ceramide portion and different sugar moieties, were synthesized and their immunostimulatory and antitumor activities were examined. The manner of combination between sugar and ceramide has been demonstrated to affect the manifestation of immunostimulatory and resultant antitumor activities of MonoCers, and in the case of D-MonoCers having the D-sugar, α-D-MonoCers (sugar combined to ceramide in an α-configuration) show stronger activities than β-D-MonoCers. Furthermore, the form of sugar, not the furanose-form but the pyranose-form, and the 2''-and 4''-hydroxyl groups of the pyranose-form of sugar, seemed to play an important role in the manifestation of the activities of α-D-MonoCers.
  • 樫田 龍雄, 奈良崎 直子, 酒井 敦子, 辻原 健二, 黒葛原 啓, 竹山 茂之
    1995 年 18 巻 11 号 p. 1492-1497
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    We investigated the antitumor effect of 6-mercaptopurine (6-MP) and its analogs using the double grafted tumor technique. BALB/c mice were inoculated intradermally with MethA fibrosarcoma cells at the right inguinal region on day 0 (the primary tumor) and at the left on day 10 (the secondary tumor). Intraperitoneal or intra-lesional administration of 6-MP, 6-mercaptopurine riboside (6-MP-r) and 6-mercaptopurine riboside triacetate (6-MPRTA) from day 3 to 7 dose-dependently inhibited growth of the secondary tumor. Without the primary inoculation, 6-MP showed no effect on growth of the tumor inoculated on day 10, indicating that the antitumor effect of 6-MP could not be attributable to its direct antimetabolic or tumoricidal action only, and that the primary tumor inoculation is necessary for these compounds to inhibit growth of the challenging tumor. 6-MP did not inhibit the secondary MethA growth in the BALB/c (nu/nu) mouse. Both CD4+ and CD8+ T cells increased in the spleen of mice treated with 6-MP. Meanwhile, delayed-type hypersensitivity (DTH) reaction to the methylated bovine serum albumin (MBSA) antigen at the footpad was not augmented but inhibited by 6-MP, 6-MP-r and 6-MPRTA in both normal and tumor-bearing mice. Thus, the immunomodulatory activity of 6-MP could be observed in two opposite directions, augmentation of tumor immunity and inhibition of DTH to MBSA. This indicates that the immune mechanism and/or the type of effector cells induced in these two cell-mediated immune systems are different from each other.
  • 西山 信好, 王 元〓, 齋藤 洋
    1995 年 18 巻 11 号 p. 1498-1503
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of S-113m, a novel herbal prescription consisting of Biota orientalis, Panax ginseng and Schisandra chinensis, were studied regarding learning and memory performance in the step-down and lever-press tests in normal, as well as in learning-impaired, mice. The prescription had no effect on memory registration, consolidation and retrieval processes or on motor activity in normal mice. However, a single oral administration of S-113m at doses of 250 and 500 mg/kg reduced the ethanol-induced and scopolamine-induced impairment of memory registration in the step-down test. The preparation also improved the electroconvulsive shock-induced impairment of memory consolidation in the same test. S-113m did not, however, attenuate the ethanol-induced impairment of memory retrieval. These results suggest that S-113m has a preferential beneficial effect on the impairment of memory registration and memory consolidation rather than on memory retrieval in mice, through direct action on the learning and memory processes.
  • 木村 郁子, 牧野 充弘, 本多 立, 馬 健, 木村 正康
    1995 年 18 巻 11 号 p. 1504-1508
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Influence of aconite extract and a main component of aconite, aconitine were investigated on the plasma corticosterone level for the expression of major histocompatibility complex class II (Ia antigen) of macrophage. In peritoneal macrophage exposed to corticosterone (2.9-87 μM) in vitro the interferon (IFN)-γ (0.1 unit/ml)-induced Ia antigen expression was inhibited in a dose-dependent manner. Ia antigen expression in macrophages harvested from the corticosterone (1.25 mg/mouse/d, i.m., 4d)-excessive mice and aconitine (3 μg/kg, i.p., 7d)-treated mice was significantly stimulated, whereas that of adrenalectomized (7d) mice was inhibited. In macrophage exposed to aconitine up to 46.5 μM in culture Ia antigen expression was not affected. Administration of aconite extract (3mg/kg, i.p., 7d) and aconitine (3 μg/kg, i.p., 7d) increased plasma corticosterone levels. These results demonstrate that high levels of corticosterone increase the macrophage response to IFN-γ on Ia antigen expression and that low levels of corticosterone decrease it. Aconite extract and aconitine stimulate the response to IFN-γ-activated expression of Ia antigen by macrophages which is caused by increasing the plasma corticosterone level.
  • 木村 郁子, / 木村 正康, Masayasu KIMURA
    1995 年 18 巻 11 号 p. 1509-1512
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    (±)-Higenamine (demethylcoclaurine), a cardiotonic principle from aconite root, has positive chronotropic and inotropic actions mediated through β1-adrenergic receptors. We have investigated the influence of cholera toxin (CTX), a Gs-protein activator, and pertussis toxin (PTX), a Gi-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice. CTX (100 nM, 1h) pretreatment accentuated the inhibitory responses to cumulative applications of ACh (30 nM-30 μM) for the positive chronotropic effects induced by higenamine (100 nM), isoproterenol (3 and 10 nM) or dobutamine (100 nM). In normal atria (CTX-untreated), ACh physiologically antagonized the positive chronotropic effects of these β-adrenergic agonists. Pretreatment with PTX (150μg/kg, i.p., 3d) abolished the CTX (100 nM, 1h)-induced accentuation in the inhibitory effect of ACh against higenamine. PTX pretreatment also attenuated the physiological antagonism by ACh against higenamine in normal atria. The negative chronotropic effect of ACh was not affected by a submaximal concentration of forskolin (1μM). These results suggest an accentuated antagonism between higenamine and ACh in CTX-treated, but not in untreated, isolated right atria of mice, which may occur through a functional interaction between the β1-adrenergic-Gs and muscarinic-Gi systems.
  • 西山 信好, [Chu] 鵬江, 齋藤 洋
    1995 年 18 巻 11 号 p. 1513-1517
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of biota (Biota orientalis ENDL.) on learning impairment produced by bilateral lesion of basal forebrain in mice were studied using step-through and step-down type passive avoidance tasks. Basal forebrain-lesion was generated by applying radiofrequency current. Behavioral experiment, started 15d after the surgery, revealed prominent delay in the memory acquisition process in the lesioned mice. The operation also induced memory retention deficit in both learning tests. Chronic oral administration of ethanol extract of biota seeds at doses of 250 and 500 mg/kg/d, from the day of surgery until the end of the behavioral test, dose-dependently improved memory acquisition impairment in the step-down test and memory retention disturbance in both behavioral tasks. The preparation also had a tendency to alleviate memory acquisition impairment in the step-through test. Although precise action mechanisms of biota extract remains speculative, such as what component works on which target, the present results clearly suggest that the preparation affects the learning and memory processes in the central nervous system and improves the impairment of memory acquisition and retention disturbances produced by basal forebrain-lesion.
  • 亀井 千晃, 出石 啓治, 中村 哲
    1995 年 18 巻 11 号 p. 1518-1521
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of certain antiallergic drugs on experimental conjunctivitis were studied with guinea pigs. Chlorpheniramine, ketotifen and levocabastine were effective in inhibiting histamine-and antigen-induced conjunctivitis in guinea pigs. By contrast, amlexanox was only effective in inhibiting antigen-induced conjunctivitis. Topical application of antigen released 46.5±3.8% of histamine from the conjunctiva in sensitized guinea pigs. Both levocabastine and amlexanox were effective in inhibiting conjunctival histamine release induced by antigen application. Lacrimal histamine contents were also increased after antigen challenge. The increase in the histamine content of tears was inhibited by pretreatment with levocabastine and amlexanox, but no significant effect was observed with chlorpheniramine and ketotifen. From these findings, it is concluded that certain antiallergic drugs, but not amlexanox, exhibited potent inhibition on experimental conjunctivitis in guinea pigs. In addition, it has been established that measurement of histamine in the conjunctiva and tears as well as observation of conjunctivitis syndromes are useful for evaluating the effectiveness of antiallergic drugs on various kinds of allergic conjunctivitis in clinical situations.
  • 青木 隆, 高崎 智子, 古川 智子, 森川 惇二, 矢野 喬史, 渡部 博之
    1995 年 18 巻 11 号 p. 1522-1525
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    A new acid proteinase in human gastric cancer, named medium moving proteinase (Med. P), was found also in a gastric cancer transplanted into nude mouse. However, Med. P disappeared when the samples prepared from gastric cancer tissues were left for over 4 weeks at -80°C, whereas the activity of cathepsin E (CE) increased. When these samples were reduced by dithiothreitol (DTT), Med. P appeared again and the CE activity decreased. These phenomena, revealed by electrophoretic analyses, indicated that Med. P is a monomeric form of CE (mono-CE). At weakly alkaline pH and after heating, mono-CE appeared to be more unstable than CE. These results indicated that CE assume an enzymatically unstable monomeric form in cancer cells.
  • 井上 誠, 鈴木 理恵, 坂口 菜朋子, 李 宗, 竹田 忠紘, 荻原 幸夫, 姜 宝源, 陳 英傑
    1995 年 18 巻 11 号 p. 1526-1530
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Gallic acid (3, 4, 5-trihydroxybenzoic acid) is a naturally occurring plant phenol obtained by the hydrolysis of tannins and is known to show some pharmacological activities. In screening anti-cancer agents in traditional Chinese medicines, gallic acid was found to show cytotoxicity against all cancer cells that we examined in this study (IC50s : 4.8-13.2 μg/ml). Gallic acid, however, showed no cytotoxicity against primary cultured rat hepatocytes and macrophages, and lesser cytotoxicity against fibroblasts and endothelial cells. Cell death in dRLh-84 cells occurred within 6h after gallic acid treatment at a concentration of more than 20μg/ml. A study of structurally related compounds suggested that the cytotoxicity shown by gallic acid was not a common feature in phenolic compounds, but was a fairly specific characteristic of gallic acid. That is, three adjacent phenolic hydroxyl groups of gallic acid were responsible for the cytotoxicity, and the carboxyl group was not responsible, but seemed to be implicated in distinguishing between normal cells and cancer cells.
  • 池上 文雄, 松苗 薫, 久光 正文, 栗原 孝, 山本 武司, 村越 勇
    1995 年 18 巻 11 号 p. 1531-1534
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    β-D-Glucuronidase (baicalinase, GUS [EC 3.2.1.31]) activity in the crude drug, Scutellaria root, was assayed in line with the quality control standards of Kampo (Japanese herbal) medicines. GUS was purified to homogeneity in the purification steps including DEAE-Sepharose Fast Flow and chromatofocusing used PBETM94 and Polybuffer 74. These results suggest that the Scutellaria GUS is composed of 55 kDa active subunits and that the isoelectric point of this enzyme is pH 5.4. Optimal catalytic activity was found at pH 4.7 in the pH range 3.6-6.2 in 50 mM Na-citrate buffer. The purified enzyme hydrolyzed baicalin and wogonin glucuronide, but did not hydrolyze glycyrrhizin or some β-glucosides found in other crude drugs. GUS activity in several crude drugs is also described.
  • 森本 泰子, 油谷 雄一郎, 賀戸 昌子, 飯田 環, 塩田 めぐみ, 竹内 由和
    1995 年 18 巻 11 号 p. 1535-1538
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Some neutral amino acids were compared for their anti-hemolytic effects with sugars which are well-known colloid-osmotic protectants. The kinetic studies in isotonic suspensions of erythrocytes indicated that the hemolysis induced by the amphipathic drug chlorpromazine (CPZ) or flufenamic acid (FA) was retarded by addition of sugars, and the degree of the anti-hemolytic effect increased with increases in molecular size. Phenylalanine (Phe), the largest among the amino acids tested, showed the greatest inhibitory effect on CPZ-induced hemolysis, but not on FA-induced hemolysis. This demonstrated that the anti-hemolytic effects of amino acids were not the result of colloid-osmotic protection. Hemolytic actions of amino acids were also examined to determine their interaction with the erythrocyte membrane, and the mechanism of their inhibitory effects against amphipathic drug-induced hemolysis was discussed.
  • 真船 英一, 高橋 雅行, 高杉 紀雄
    1995 年 18 巻 11 号 p. 1539-1543
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Bucladesine, sodium N6, 2'-O-dibutyryl cyclic 3', 5' adenosine monophosphate (DBcAMP), which is effective for the treatment of chronic skin ulcers including decubitus ulcer, was evaluated for percutaneous absorption in rats with normal skin, stripped skin and full-thickness abrasion models. Percutaneous absorption from aqueous solution or ointment was very low in intact skin. When the aqueous solution was applied to the site where the skin had been excised, DBcAMP was absorbed very rapidly and almost completely. In the case of stripped skin, DBcAMP was absorbed rapidly but slower than in the full-thickness abrasion model. In both damaged skin models, a better absorption profile was obtained with the polyethylene glycol (PEG) than the petrolatum ointment and DBcAMP was released continuously from the PEG ointment, indicating that this ointment is suitable for the treatment of ulcers of the skin. The percutaneous absorption from stripped skin was considerably influenced by the powder formulation. It is appropriate to evaluate the bioavailability in damaged skin models for a drug, such as DBcAMP, which is used in the treatment of skin ulcer.
  • 金尾 義治, 上村 智哉, 田中 哲郎, 加納 聰, 松岡 綾
    1995 年 18 巻 11 号 p. 1544-1547
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    A fluorescein-labeled dextran-glutathione conjugate (FD-GSH) was synthesized in order to examine its disposition in the body. GSH was covalently attached to the FITC-labeled dextran by the cyanogen bromide activation method. Mice were injected with FD-GSH through the tail vein, and the levels of FD-GSH in the blood and various organs were measured fluorometrically. A substantial level of FD-GSH was found in the liver and this reached a maximum at 6-8h after the injection. The hepatic uptake clearance was estimated to be 0.541±0.014 ml/h/g tissue or 42.4±9.8 ml/h/kg body weight. FD-GSH accumulated in the liver for a long period, while the half-life of the conjugate in the blood circulation was 1.45h. The cumulative urinary and fecal excretions of FD-GSH were 14% and 4% of dose at 72h after the injection, respectively. A molecular design of the conjugate was discussed on the basis of the results.
  • 西田 孝洋, 佐藤 準人, 佐々木 均, 中村 純三
    1995 年 18 巻 11 号 p. 1548-1550
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of bovine serum albumin (BSA) on drug absorption from the liver surface in rats was examined by using three organic anions (phenol red, bromphenol blue and bromosulphonphthalein) as model drugs which have a high affinity for albumin. The binding ratio of the model drugs (3 mg/ml in phosphate buffer) to BSA varied widely at a BSA concentration of 0.1-10% (w/v). The model drugs (3 mg/ml×0.1ml) with or without BSA were applied to the rat liver surface in vivo employing a cylindrical glass cell (i.d. 9 mm, area 0.64 cm2). The absorption ratios of the model drugs from the rat liver surface at 6h, calculated from the amount recovered from the glass cell, decreased with an increase in BSA concentration. A similar trend was observed with biliary recovery of the model drugs. A marked reduction in the absorption ratio was seen with bromosulphonphthalein, which has the highest binding activity to BSA among the three organic anions. Accordingly, protein binding appears to be a significant factor with respect to drug absorption from the liver surface.
  • 米谷 芳枝, 玻座真 めぐみ, 東條 寿子, 斉 憲栄, 永井 恒司
    1995 年 18 巻 11 号 p. 1551-1555
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects on Wistar rat body weight were examined after a single subcutaneous (s.c.) or oral (p.o.) administration of dipalmitoylphosphatidylcholine (DPPC) liposomes composed of soybean-derived sterols (SS) and their glucosides (SG) with or without entrapping recombinant human erythropoietin (Epo) for 1 week. Body weight increased significantly after both types of administration compared with the control groups irrespective of the existence of Epo. The neutral lipid concentration in plasma increased with the increase in body weight whereas the total contents of cholesterol and high density lipoprotein cholesterol in the plasma did not change significantly. The SS and SG suspensions following p.o. administration, however, did not alter the body weight. These findings suggest that liposomal SS and SG may be absorbed through the intestinal membrane and induce a change in the uptake of lipid, in contrast to the suspension state. SS in liposomes significantly increased body weight more than SG after p.o. administration.
  • 木村 聰城郎, 畑野 徳久, 和田 昌子, 岩田 建, 黒崎 勇二, 中山 太二, 山浦 哲明, 中島 宏
    1995 年 18 巻 11 号 p. 1556-1559
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The disposition of diadenosine 5', 5'''-P1, P4-tetraphosphate (Ap4A), an endogenous dinucleotide, was investigated in rats. The degradation of Ap4A in rat plasma was very rapid and could be explained by a Michaelis-Menten equation : Km and Vmax values were 1.69 μg/ml and 4.32 μg/min/ml, respectively. Ap4A was degraded in rat plasma to ATP and AMP, but not to 2 ADP molecules, and these nucleotides were further degraded through adenosine. The degradation kinetics were examined. After intravenous bolus injection, Ap4A in plasma declined rapidly and the rate of elimination was dose-dependent : the biological half-life was about 3s at the dose of 1 mg/kg and was longer at 3mg/kg. When Ap4A was administered by intravenous infusion (0.5 or 1.0 mg/kg/min), the plasma level rapidly reached a steady-state, which then rapidly declined after stopping the infusion.
  • HungHong LIN, LiRen HSU, PaoChu WU, YiHung TSAI
    1995 年 18 巻 11 号 p. 1560-1565
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Preparation of the fatty alcohol propylene glycol (FAPG) ointment base plays an important role in controlling the physicochemical properties of ointments. This essay investigates the effects of preparative conditions such as cooling rate and stirring rate on the percutaneous absorption of norfloxacin from FAPG ointment. The influence of process-induced variation in enhancing effect of stearic acid which was incorporated into FAPG base was evaluated in vitro on rat skin. In the permeation experiment, norfloxacin penetration significantly increased with faster cooling rate. This result directly related to the increasing norfloxacin skin-vehicle partition coefficient. Histological analysis results showed no appreciable exfoliation of the stratum corneum. The differential scanning calorimetry (DSC) results show that stearic acid enriched lipid in the stratum corneum resulting from treatment with supercooling products may result in more crystalline structure and, hence, preferential partitioning of the norfloxacin into the more crystalline regions of the membrane can be observed. A much greater enhancing effect can be achieved when we use stearic acid together with norfloxacin in propylene glycol (PG) ; but such effect cannot be found if 5wt% stearic acid/PG suspension is used to pretreat skin before the application of norfloxacin PG solution.
  • 小木曽 太郎, 朴 剛, 岩城 正宏, 谷野 公俊
    1995 年 18 巻 11 号 p. 1566-1571
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    To identify the mechanism involved in the enhancement effect of enhancers on the intercellular penetration of large polar molecules, the skin penetration of fluorescein isothiocyanate (FITC)-dextrans (average molecular weight ; 4400, 9400 and 69000 Da) and the lipid removal from the intercellular spaces by enhancers were studied using hairless rat skin. Pretreatment of hairless rat skin with enhancers such as n-octanol (20%), laurocapram (2%), isopropylmyristate (IPM, 20%), oleic acid (5%) and cineol (2%), which are water-immiscible, significantly enhanced the flux of FITC-dextrans, while pretreatment with water-miscible enhancers, i.e. dimethyl sulfoxide (DMSO, 5%) and N-methyl-2-pyrrolidone (NMP) did not increase the flux compared with the control. The penetration of FITC-dextrans was approximately size dependent. n-Octanol, laurocapram, IPM and oleic acid dramatically removed ceramides which are the intercellular lipids, whereas NMP and DMSO partly extracted the sphingolipids. A linear relationship was observed between the flux and removal of ceramides (p<0.01), indicating that the removal of intercellular lipids would cause dramatic dilatations between adherent cornified cells and enhance the penetration through the intercellular pathways. When the penetration of FITC-dextrans through Wistar rat skin was compared with that via hairless rat skin, the steady state flux of FITC-dextrans through Wistar rat skin pretreated with water-immiscible enhancers was 1.2- to 4.9-fold higher, suggesting that the penetration of large polar molecules through follicles may play at least some role in the percutaneous absorption.
  • 吉岡 寿, 谷澤 久之, 尾形 健明, 風間 舜介
    1995 年 18 巻 11 号 p. 1572-1575
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    A dextran-bonded nitroxide radical (TEMPO-DX) was synthesized to obtain a radical with long life in vivo for ESR imaging. TEMPO-DX was injected intravenously into a rat tail vein and the decrease in ESR intensity in the collected, circulating blood was followed. The result showed that the half life of TEMPO-DX in vivo was 30 min, the longest value reported so far and more than 30 times longer than the corresponding radicals of the six-membered piperidine ring, which means that the bonding of a radical to the polymer greatly prolonged life. The stabilities of TEMPO-DX against the reduction with L-ascorbic acid and the rat liver homogenate were also examined and compared with those of the 3-carbamoyl-2, 2, 5, 5-tetramethylpyrolidin-1-yloxy (CPROXYL) known as a radical stable in vivo. TEMPO-DX was shown not to be as stable as CPROXYL, thus in vivo stability of TEMPO-DX arises from the fact that it is slowly absorbed into the tissues where the radicals are quenched. An ESR image of the mouse head domain was obtained only by an intravenous injection of TEMPO-DX solution into the tail vein.
  • 武藤 徳男, 堂田 敦義, 田中 徹也, 伊藤 徳夫, 岡部 勝, 稲田 昭, 中西 勤, 田中 慶一
    1995 年 18 巻 11 号 p. 1576-1579
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Hinokitiol, a constituent of the wood of Chamaecyparis taiwanensis, was found to induce differentiation of teratocarcinoma F9 cells. When examined by the agar-overlay method, in which expression of plasminogen activator as a differentiation marker protein was detected, this compound exhibited a dose-and time-dependent induction. Induction of differentiation by hinokitiol occurred irreversibly and required its addition for more than 12h. Among its structure-related compounds tested, tropolone and two colchicine-related compounds exerted potent activities comparable to that of hinokitiol. These findings indicate that free tropolone structure in the molecules plays an essential role in inducing differentiation of F9 cells. Hinokitiol showed a strong inhibitory effect on DNA synthesis in very early stages of culture, suggesting that this effect may be responsible for triggering differentiation of F9 cells.
  • 山田 潤, 杉本 由美, 堀坂 和敬
    1995 年 18 巻 11 号 p. 1580-1583
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Chlorpromazine-and haloperidol-induced hypothermia were examined in mice. The α1 receptor agonist phenylephrine partially antagonized the hypothermia, while the dopamine D2 receptor agonist apomorphine did not inhibit it. The central serotonin2 (5-HT2) receptor agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) strongly inhibited the chlorpromazine-and haloperidol-induced hypothermia. Both drugs at doses which can elicit hypothermia antagonized head twitch responses mediated by the central 5-HT2 receptor. These results suggest that the chlorpromazine-and haloperidol-induced hypothermia may be mediated by the blockade of the central 5-HT2 receptor.
  • 浅見 正人, 高崎 渉, 岩渕 晴男, 春山 英幸, 和智 一之, 寺田 敦祐, 田中 頼久
    1995 年 18 巻 11 号 p. 1584-1589
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    CS-670, (±)-2-[4-(2-oxocyclohexylidenemethyl) phenyl] propionic acid, is a novel derivative of 2-arylpropionic acid non-steroidal anti-inflammatory drugs (profen NSAIDs). The major urinary metabolite of this drug from dogs was isolated and its chemical structure was determined by MS and NMR spectroscopy. The metabolite was identified as a taurine conjugate of the trans-OH form (trans-OH-taurine) which was first generated by stereoselective reduction of the double bond and the carbonyl function of the CS-670 molecule. The taurine conjugate was excreted in urine as the main metabolite, regardless of the optical configuration of CS-670 administered [(2R)-enantiomer : 47.2% of the dose, (2S)-enantiomer : 70.9% of the dose]. The trans-OH-taurine was hydrolyzed by refluxing it in 6N HCl without racemization. The released trans-OH was derivatized to diastereoamides with (+)-(R)-1-(1-naphthyl) ethylamine to examine the stereochemical properties of the 2-arylpropionic acid side chain. It was found that the configuration of the 2-carbon of the trans-OH-taurine was almost entirely (S). As the CoA thioesters are obligate intermediates for amino acid conjugation, the results suggest that the (2S)-enantiomer of the trans-OH metabolite serves as a substrate for canine acyl CoA ligase (EC 6.2.1.3) as well as the (2R)-enantiomer, but only the CoA thioester with a (2S)-configuration is a substrate for taurine N-acyl transferase. It is interesting to note that these results are not consistent with the chiral inversion mechanism by which the (2R)-enantiomers of profen NSAIDs are stereospecifically converted to CoA thioester intermediates.
  • 谷川原 祐介, 駒田 富佐夫, 清水 孝子, 岩川 精吾, 岩井 鉄司, 前川 広海, 堀 了平, 奥村 勝彦
    1995 年 18 巻 11 号 p. 1590-1598
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparation. Food ingestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption. The 400-mg tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not older than 15 years showed 58% longer absorption lag time. The inter-individual variability in Ka was 19%, suggesting small variability in the in vivo release process. The total body clearance was related to hepatic function, smoking habits, and age. Furthermore, clearance decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for dose individualization based on serum concentration monitoring with or without the Bayesian feedback method.
  • 幸 義和, 中川 智世, 加藤 和夫
    1995 年 18 巻 11 号 p. 1599-1601
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    Our previous study has shown that urinary bikunin has four major isomers, which differ with respect to the sulfation ratio in a glycosaminoglycan chain but which do not exhibit any differences in amino acid composition, N-terminal amino acid sequence, C-terminal amino acid, sialic acid and uronic acid content. In this study, the amino acid sequences of the four isomers were examined. Sequence analysis showed that the amino acid sequence of the four isomers was completely identical and was also the same as the amino acid sequence deduced from cDNA encoding bikunin. We conclude that the charge heterogeneity of urinary bikunin is due to only a difference in the sulfation ratio of a glycosaminoglycan chain.
  • 岡野 一彦, 倉石 泰, 佐藤 公道
    1995 年 18 巻 11 号 p. 1602-1604
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    We previously demonstrated the involvement of spinal glutamatergic system in repeated cold stress (RCS)-induced hyperalgesia. In the present experiments, to estimate the involvement of an enhancement of responsiveness to endogenously released glutamate in RCS-induced hyperalgesia, we examined the effects of RCS on behavioral nociceptive responses (biting or licking the hind paws and the tail) produced by intrathecal injections of selective agonists at subtypes of glutamate receptor, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate, in rats. The exposure of rats to RCS significantly intensified the behavioral responses produced by intrathecal NMDA (1 nmol/rat) in comparison to the control rats. The increase in the behavioral response of the RCS rats to AMPA was significant at a dose of 1 nmol/rat of AMPA as compared to the control rats. A significant increase in aversive response over control rats was not seen when kainate (0.3-3 nmol/rat) was injected into the spinal subarachnoid space of the RCS rats. These results suggest that RCS induces an enhancement of transmission mediated by endogenously released glutamate through NMDA and non-NMDA (especially AMPA) receptors in the spinal dorsal horn.
  • 三浦 俊宏, 加藤 篤
    1995 年 18 巻 11 号 p. 1605-1606
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The hypoglycemic effect of the rhizomes of Polygonatum sibricum and Polygonatum officinale (Liliaceae) was investigated in KK-Ay mice, one of the animal models of non-insulin dependent diabetes mellitus (NIDDM). The methanol extract of the rhizomes of both Polygonatum sibricum (OM) and Polygonatum officinale (IM) (800mg/kg) reduced the blood glucose levels in KK-Ay mice 4h after intraperitoneal administration. In terms of hypoglycemic effect, the blood glucose of IM was lower than that of OM. IM-treated mice significantly decreased the blood glucose level in an insulin tolerance test, but OM-treated mice did not change. We estimated that the hypoglycemic effect of IM raised insulin sensitivity.
  • 荒牧 すが子, 鈴木 悦子, 石高 治, 百瀬 篤
    1995 年 18 巻 11 号 p. 1607-1609
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of exercise on the metabolism of caffeine (CA) were studied 3 h after administration of the drug to race horses which then underwent exercise sets (1000-m gallop). Analysis was made of pharmacokinetics of CA, changes in its plasma concentrations, its metabolites, i.e., theophylline (TP), theobromine (TB) and paraxanthine (PX), and the molar concentration ratios of CA to these metabolites. After exercise, AUC and t1/2 tended to decrease, and the concentration of CA decreased, while the concentrations of TP and TB significantly increased. The TP/CA ratio and TB/CA ratio significantly increased from 6 to 74h and from 25 to 50h after drug administration, respectively. This indicated promotion of metabolism of CA into TP and TB. The effects on PX were minimal.
  • 永井 尚美, 古旗 美和, 緒方 宏泰
    1995 年 18 巻 11 号 p. 1610-1613
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of roxatidine acetate hydrochloride (Rox) on the pharmacokinetics of theophylline were compared to those of cimetidine in rats in vivo. Cimetidine or Rox was maintained at a steady state level using continuous infusion, then theophylline was injected into the rats as a bolus (7.5 mg/kg). Cimetidine showed competitive inhibition of theophylline elimination in vivo, with an inhibition constant (Ki) of 28.5 μM. Cimetidine significantly decreased the total body clearance and extended the plasma half-life of theophylline, but did not change its volume of distribution. In contrast, Rox did not significantly influence the pharmacokinetics of theophylline in rats. The in vivo animal model used in the present study for investigating the mechanism of the drug interaction showed good agreement with the results obtained in clinical and in vitro studies.
  • 小林 吉晴, 松井 淳, 渡邊 富久子
    1995 年 18 巻 11 号 p. 1614-1616
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    We studied the effects of acetonitrile and sodium dodecyl sulfate (SDS) in the running buffer of micellar electrokinetic chromatography (MEKC) on the separation of free and conjugated steroids. When the acetonitrile concentration was increased, the migration time of the conjugated steroids decreased. On the other hand, the migration time of free steroids decreased up to 5-15% acetonitrile, then increased. This behavior of the free steroids was due to the changes of the partition between SDS micelles and the aqueous phase in the running buffer. Increasing the concentration of SDS in the running buffer decreased the migration time of nonpolar free steroids whereas that of polar conjugated steroids was not affected. A practical method for the simultaneous separation of free and conjugated steroids by MEKC was established. The application of this procedure to the analysis of steroids in serum from a patient with Cushing's syndrome and a premature infant is also described.
  • 木村 由美子, 安川 憲, 滝戸 道夫, 秋久 俊博, 田村 利武
    1995 年 18 巻 11 号 p. 1617-1619
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The oxygenated stigmastane-type sterols stigmastane-3β, 6α-diol, stigmastane-3β, 6β-diol, 7α-hydroxysitosterol and its diacetyl derivative, 7β-hydroxysitosterol and its diacetyl derivative, 7-oxositosterol, 4β-hydroxysitosterol, and stigmast-4-ene-3β, 6β-diol were evaluated with respect to their anti-inflammatory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. All of the sterols, with the exception of 7α-hydroxysitosterol and its diacetyl derivative, were found to possess marked inhibitory activity. The 50% inhibitory dose of these compounds for TPA-inflammation (1 μg) was 0.5-1.0 mg/ear.
  • 二改 俊章, 鈴木 淳子, 小森 由美子, 大倉 正道, 大泉 康, 杉原 久義
    1995 年 18 巻 11 号 p. 1620-1622
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The complete amino acid sequence of lectin from Bitis arietans venom was determined by using clostripain, lysyl endopeptidase, and V8 protease.
  • 三浦 俊宏, 宇佐美 勝, 津浦 佳之, 石田 均, 清野 裕
    1995 年 18 巻 11 号 p. 1623-1625
    発行日: 1995/11/15
    公開日: 2008/04/10
    ジャーナル フリー
    The hypoglycemic and hypolipidemic effect of chitosan was investigated in normal and neonatal streptozotocin-induced diabetic (NSZ) mice, one of the animal models of lean type non-insulin-dependent diabetes mellitus (NIDDM) with hypoinsulinaemia. Chitosan (5% food admixture) reduced the blood glucose (P<0.01), cholesterol (P<0.01) and triglyceride (P<0.01) of normal mice after 4 weeks, and also significantly lowered the blood glucose (P<0.05) and cholesterol (P<0.05) of NSZ mice under the same conditions. But these parameters of KK-Ay mice, which exhibit obese type NIDDM with hyperinsulinaemia, were not affected by chitosan administration. It is concluded that chitosan would be useful for the treatment of lean type NIDDM with hypoinsulinaemia.
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