Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
17 巻 , 12 号
選択された号の論文の31件中1~31を表示しています
  • 小笠原 裕樹, 磯田 伸二, 田辺 信三
    1994 年 17 巻 12 号 p. 1535-1542
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The tissue and subcellular distribution in liver and kidney of bound and acid-labile sulfur as well as the enzyme capacity for sulfide production related to the desulfuration pathway were determined in rats. Bound sulfur was widely distributed in tissues and highest in kidney, whereas acid-labile sulfur was highest in heart. Bound sulfur was found primarily in the cytosolic fraction in the form of high molecular weight material in liver, and as both high and low molecular weight material in kidney. Acid-labile sulfur was located in the mitochondrical fraction. Sulfide production capacity from cysteine was greatest in liver cytosol. This capacity was well correlated with the distribution of γ-cystathionase in tissues and subcellular fractions.
  • 小濱 靖弘, 伊藤 雅彦, 田中 啓詞, 飯田 健太郎, 陳 丹〓, 田中 忍, 森山 一樹, 石井 強, 三村 務
    1994 年 17 巻 12 号 p. 1543-1548
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A new fraction, Fr. 8-A, which consists of a phosphatidylethanolamine with C14 : 0-C18 : 0 isofatty acids was obtained from Bacillus stearothermophilus UBT8038. The fraction inhibited major histocompatibility complex class II (Ia) antigen expression and antigen presentation on mouse macrophages. The effect of Fr. 8-A on macrophage functions related to antigen presentation was investigated. Fr. 8-A increased arachidonate release, prostaglandin (PG) E2 release and nitrite production from peritoneal macrophages. It increased further the levels of PGE2, nitrite and tumor necrosis factor in the culture supernatant of the macrophages induced by the supernatant from concanavalin A-stimulated spleen cell cultures. Fr. 8-A augmented the activity of peritoneal macrophages to suppress Con A-stimulated T cell proliferation. Addition of either indomethacin or NG-methyl-L-arginine had no effect on the augmentation of suppressor macrophage activity or the inhibition of antigen presentation by Fr. 8-A, while simultaneous addition of both inhibitors abrogated the effect of the fraction. These results indicate that Fr. 8-A inhibits Ia expression and antigen presentation, and augments suppressor macrophage activity at least partly via the activation of both cyclooxygenase and nitric oxide synthase pathways.
  • 権田 良子, 友田 正司, 清水 訓子, 大原 直子, 高木 浩子, 星野 しのぶ
    1994 年 17 巻 12 号 p. 1549-1553
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    An acidic polysaccharide, called pinellian PA, was isolated from the tuber of Pinellia ternata BRETT. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was estimated to be 11.8×104. Pinellian PA is composed of L-arabinose : D-galactose : L-rhamnose : D-galacturonic acid : D-glucuronic acid in the molar ratio of 5 : 15 : 1 : 3 : 3, in addition to small amounts of O-acetyl groups and peptide moieties. Reduction of carboxyl groups, methylation analysis and nuclear magnetic resonance studies show that the core structural features include a backbone chain composed of β-1, 3-linked D-galactose units. Some of the galactose units in the backbone carry β-1, 6-linked D-galactosyl side-chains at position 6. Pinellian PA produces significant potentiation of the reticuloendothelial system, as shown by a carbon clearance test, and also exhibits potent anti-complementary activity.
  • 安達 禎之, 岡崎 光洋, 大野 尚仁, 宿前 利郎
    1994 年 17 巻 12 号 p. 1554-1560
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The ability of grifolan (GRN), a purified fungal (1→3)-β-D-glucan, to induce various cytokines from macrophages was examined in vitro. Interleukin-6 (IL-6) activity in supernatants from the culture of macrophage cell line, RAW264.7 was dependent on increasing doses of GRN. The level of IL-6 induced with 500μg/ml of GRN was comparable to that induced with lipopolysaccharide (LPS) 10μg/ml. Enhancement of the mRNA level of IL-6 by treatment with GRN was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The effect of GRN on production of IL-6 was also observed using peritoneal macrophages from C3H/HeJ mice which did not respond to endotoxins. This data suggested that the ability of GRN to activate IL-6 production of macrophages is not due to contamination of endotoxins in the preparation. Enhanced production of cytokine by GRN was observed not only with IL-6, but also with interleukin-1 (IL-1) and tumor necrosis factor α (TNFα). In the production of TNFα, GRN was more effective than LPS used in this study. Other soluble or gel-forming (1→3)-β-D-glucans from various sources did not enhance the production of such cytokines although they are structurally similar to GRN. The above results indicated that GRN is a novel macrophage activator which augments cytokine production without dependence on endotoxins.
  • 陳 丹〓, 太田 直子, 鵜飼 真理, 益田 美穂子, 権田 良子
    1994 年 17 巻 12 号 p. 1561-1566
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The incubation of γ-globulin with cis-diamminedichloroplatinum (II) (cis-DDP) resulted in gradual formation of insoluble aggregates. Since the precipitate, composed of polymerized γ-globulin and cis-DDP, were completely solubilized with urea, the reaction mixture containing precipitate was examined in terms of the binding of cis-DDP and the effect on disulfide (S-S) bonds in the γ-globulin. When γ-globulin was incubated with 30 molar excess cis-DDP at pH 7.4 and 37°C, cis-DDP gradually bound to as much as 12mol per mol of γ-globulin in 14d. Concurrently, about four disulfide bonds were cleaved without reaching a certain plateau. An sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the aggregated γ-globulin induced by cis-DDP was significantly different from that of the heat-denaturated aggregate form or the reduced form by sulfitolysis. The aquated complexes of cis-DDP also produced an insoluble precipitate and affected the S-S bond to a greater extent than the parent drug.
  • 三浦 進司, 渡辺 順一, 油田 正樹, 佐野 満昭, 富田 勲
    1994 年 17 巻 12 号 p. 1567-1572
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Tea polyphenols (flavan-3-ol derivatives) suppressed the oxidative modification of low density lipoprotein (LDL) which is assumed to be an important step in the pathogenesis of atherosclerosis lesions. Inhibitory experiments on the oxidative impairment of porcine serum LDL by flavan-3-ols were carried out by incubating them at 37°C in the presence of 5 μM Cu2+. The oxidation of LDL was monitored either by an absorption increase at 234nm due to the conjugated diene formation, or the formation of hydroperoxides and thiobarbituric acid reactive substances (TBARS). It was found that the oxidation was strongly inhibited by various flavan-3-ols, and a lag time over 100 min appeared, depending on the types of flavan-3-ols used. The activities based on the prolongation of the lag time were in the order of (-)-epigallocatechin (EGC)<(+)-catechin (C)<(-)-epicatechin (EC)<(-)-epicatechingallate (ECG)<(-)-epigallocatechingallate (EGCG). IC50 of flavan-3-ols on Cu2+ mediated hydroperoxides and TBARS formation of LDL were 0.90, 0.95μM for ECG and 2.38, 2.74μM for EGC, respectively. It was found that the Cu2+ mediated cholesterol ester degradation in LDL was almost completely inhibited by 5.0μM C or EGCG. Cu2+ mediated apolipoprotein B-100 fragmentation was also inhibited (up to 60%) in the presence of C or EGCG.
  • 赤尾 光昭, 小橋 恭一, 油田 正樹
    1994 年 17 巻 12 号 p. 1573-1576
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Geniposide, a main iridoid glucoside of Gardenia fruit, is transformed to genipin, a genuine choleretic, in vivo in rats (Aburada et al., J. Pharmacobio-Dyn., 1, 81 (1978)). As geniposide was not hydrolyzed to any metabolite by rat liver homogenate, which has β-D-glucosidase and esterase activities, β-D-glucosidases in intestinal bacteria seem to be required for an exhibition of its choleretic action. The crude extract of Eubacterium sp. A-44, a human intestinal anaerobe, hydrolyzed geniposide, but that of Ruminococcus sp. PO1-3, another human anaerobe, did not, though both extracts had β-D-glucosidase activities for p-nitrophenyl β-D-glucopyranoside. Only one of three β-D-glucosidases from E. sp. A-44 and none of two from R. sp. PO1-3 hydrolyzed geniposide to genipin. However, carboxylesterases from E. sp. A-44 and pig liver were unable to hydrolyze geniposide to geniposidic acid, but hydrolyzed genipin to an aglycone of geniposidic acid, indicating that geniposide is first hydrolyzed to genipin by β-D-glucosidases and subsequently to the aglycone of geniposidic acid by esterases. Thus, when geniposide is orally administered, genipin seems to be effectively produced in the intestine and then absorbed to act as a genuine choleretic.
  • 井上 吉郎, 藤沢 広, 本永 朝彦, 井上 淑恵, 興井 隆, 上田 房雄, 木村 喜代史
    1994 年 17 巻 12 号 p. 1577-1583
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The anti-inflammatory effects of etodolac (Eto) were compared with those of 6 other anti-inflammatory drugs : indomethacin (Ind), diclofenac Na (Dic), piroxicam (Pir), naproxen (Nap), ketoprofen (Ket) and aspirin (Asp). Eto inhibited carrageenin-induced edema in rats, adjuvant-induced arthritis in rats, acetic acid-induced writhing in mice and brewer's yeast-induced hyperalgesia and fever in rats. In the adjuvant arthritis test, the ED30 value (1.88mg/kg) on day 3 and ED50 values (adjuvant-injected paw : 1.18mg/kg and non-injected paw : 0.96mg/kg) on day 18 for Eto were comparable to those for Dic (2.16, 1.72 and 1.28) when given prophylactically and the ED50 values for Eto (adjuvant-injected paw : 1.61 and non-injected paw : 1.20mg/kg) were comparable to those for Ket (1.24 and 1.22) when used therapeutically. The analgesic activity of Eto (ED50 value : 3.67mg/kg) in the acetic acid-induced writhing test was greater than that of Nap (9.83) or Asp (31.6) and less than that of Ind (0.71), Dic (1.54), Pir (0.92) or Ket (1.34). In the antipyretic test, the minimum effective dose (MED : 1mg/kg) for Eto was comparable to that for Ind (1.0), Nap (1.0) or Ket (1.0). Eto was less potent in inhibiting carrageenin-induced edema (ED30 value : 6.99mg/kg) and inflammatory pain (ED50 value : 9.24mg/kg) than the other drugs (Ind : 2.32 and 3.47, Dic : 0.69 and 3.80, Pir : 1.31 and 1.94, Nap : 1.83 and 2.78, Ket : 1.12 and 0.63), except for Asp (167 and 51.8). Eto was the least ulcerogenic (UD50 value : the dose which caused ulcer action in 50% rats : 84.2mg/kg) compound among the drugs tested (Ind : 4.24, Dic : 12.7, Pir : 3.14, Nap : 42.3, Ket : 2.69, Asp : 20.8), so its safety margin (the ratio of the UD50 value to the ED30, ED50 or MED value) was greater than those of the other drugs. Thus, Eto is considered to be an effective anti-inflammatory drug with weak ulcerogenic activity.
  • 大森 栄, 工藤 早苗, 仲佐 啓詳, 堀江 透, 北田 光一
    1994 年 17 巻 12 号 p. 1584-1588
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We isolated a form of cytochrome P450 (P450) from hepatic microsomes of untreated doguera baboons. The final preparation (referred to as P450 BLa) was apparently homogenous, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The estimated minimum molecular weight of P450 BLa was 50kDa. The N-terminal amino acid sequence of P450 BLa (identified 10 residues) was identical with that of P450 3A8 purified from cynomolgus monkeys. This protein was cross-reactive with antibodies raised against P450 3A4 and P450 CMLc which were P450 3A enzymes purified from hepatic microsomes of humans and cynomolgus monkeys, respectively. P450 BLa was capable of catalyzing testosterone 6β-hydroxylation and zonisamide reduction. P450 BLa antibody inhibited the activity of testosterone 6β-hydroxylase, but not the activities of testosterone 16α-and 16β-hydroxylases in liver microsomes of doguera baboons. From these lines of evidence we conclude that P450 BLa can be classified as part of the P450 3A subfamily and acts as a constitutive testosterone 6β-hydroxylase in hepatic microsomes of doguera baboons.
  • 守口 徹, 高科 謙, 〓 鵬江, 齋藤 洋, 西山 信好
    1994 年 17 巻 12 号 p. 1589-1594
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of aged garlic extract (AGE) on longevity and learning and memory performances were studied in the senescence accelerated mouse (SAM). A solid diet containing 2% (w/w) AGE was given to SAM from 2 months of age. The survival ratio of SAM P8, senescence accelerated animals, treated with AGE was significantly higher than that of untreated controls. AGE, however, did not affect the life span of SAM R1, a senescence-resistant strain. AGE had no effect on body weight and motor activity. In the passive and conditioned avoidance tests, AGE markably improved a memory acquisition process in the step-down and shuttle-box tests, and also a retention process in the step-through and step-down tests in SAM P8. The beneficial effects of AGE were observed in a memory retention process in the step-down test and in an acquisition stage in lever-press test in SAM R1. These results suggest the possibility that AGE might be useful for treating physiological aging and age-related memory deficits in humans.
  • 宍戸 祐之, 酒井 正士, 兼田 憲昌, 三沢 宏, 志村 喜作, 橋本 秀介, 横倉 輝男
    1994 年 17 巻 12 号 p. 1595-1598
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We compared the fibrinolytic properties of recombinant staphylokinase (SAK), a fibrin-specific plasminogen activator, with those of streptokinase and tissue-type plasminogen activator (t-PA) by means of the amidolytic method. We also investigated the involvement of α2-macroglobulin, C1-inactivator and α1-antitrypsin in SAK-induced fibrin-specific fibrinolysis. Both SAK and t-PA activated plasminogen efficiently in the presence of fibrin in human plasma. Although t-PA activated plasminogen dependently on fibrin in the reconstituted plasma system, SAK activated plasminogen independently of fibrin without α2-plasmin inhibitor (α2-antiplasmin, α2-PI). These findings suggest that fibrin and α2-PI play important roles in plasminogen activation by SAK but not by t-PA. Furthermore, protease inhibitors such as α2-PI, α2-macroglobulin, C1-inactivator and α1-antitrypsin inhibited plasminogen activation by SAK and the inhibitory actions of these protease inhibitors disappeared in the presence of fibrin. This shows that α2-macroglobulin, C1-inactivator and α1-antitrypsin, other than α2-PI, contribute to the fibrin-specificity of SAK.
  • 山形 強, 小林 俊明, 日下 英昭, 唐沢 啓
    1994 年 17 巻 12 号 p. 1599-1603
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of intravenous infusion of KW-3902 (8-(noradamantan-3-yl)-1, 3-dipropylxanthine), a novel adenosine A1-receptor antagonist, on urine volume, urinary excretion of electrolytes and renal hemodynamics were examined in anesthetized dogs. KW-3902 at 10 and 30μg/kg/min for 20min inhibited the decline of renal blood flow induced by intrarenal arterial injection of adenosine (0.5-2.0μg). KW-3902 at these doses produced significant increases in urine volume and sodium excretion with little change in potassium excretion. The diuretic effect of KW-3902 at 30μg/kg/min for 20min continued for longer than 1h even after discontinuation of the KW-3902 infusion. KW-3902 did not affect creatinine clearance, renal blood flow, arterial blood pressure or heart rate. Furosemide at 10μg/kg/min for 20min brought about significant increases in urine volume and excretion of sodium and potassium. The diuresis and saliuresis induced by furosemide continued for only 40min after discontinuation of the drug infusion. Trichlormethiazide at 3μg/kg/min for 20min also provoked increases in urine volume and sodium excretion, but did not affect potassium excretion. The diuretic and natriuretic effect of trichlormethiazide gradually disappeared after discontinuation of the drug infusion. The present study in anesthetized dogs suggests that KW-3902, an adenosine A1-receptor antagonist, produces diuresis and natriuresis but not kaliuresis and that the diuresis and natriuresis are caused in large part by the inhibition of sodium reabsorption at tubular sites.
  • 山崎 眞津美, 広田 克則, 千葉 賢三, 毛利 哲郎
    1994 年 17 巻 12 号 p. 1604-1608
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We studied the effect of (+)- and (-)-syringaresinol, (+)-syringaresinol glucosides, syringin, aucubin and catalpol on neurite outgrowth of a cultured cell line of paraneuron, PC12h cells. Of these compounds, (+)-syringaresinol diglucoside and partly glucosidase-hydrolyzed aucubin were found to be the most potent in promotion of the neurite outgrowth and stimulated responses to a high concentration of KCl and to carbachol in the cells, as observed by increase of the concentration of cytosolic free calcium. It is suggested that some of these herb-derived compounds can induce neuronal differentiation in PC12h cells.
  • 福岡 正道, 小林 哲, 早川 堯夫
    1994 年 17 巻 12 号 p. 1609-1612
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    In previous studies we have described mechanisms of testicular atrophy whereby di-n-butyl phthalate (DBP) caused a sloughing of the germ cells, prior to the testicular atrophy ; this sloughing might be attributed to iron depletion in the blood and the testicular interstitial cells. To determine whether the iron depletion is mediated by iron-release from hemoglobin (Hb), the effects of DBP upon erythrocytes have been studied. In the in vivo studies, it was observed that DBP induced glutathione (GSH) depletion, a decrease in GSH reductase activity and Heinz body formation in the red blood cells, and iron release from Hb. In the in vitro studies, in which mono-n-butyl phthalate (MBP), a metabolite of DBP, was incubated with erythrocytes, Heinz bodies and iron release from Hb were observed. The present study proposes that a mechanism for the testicular atrophy induced by DBP might involve Heinz body formation, accompanied by iron release from Hb followed by depletion of iron in the blood and testes.
  • Brigitte VENNAT, MarieAndree BOS, Aimee POURRAT, Pierre BASTIDE
    1994 年 17 巻 12 号 p. 1613-1615
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A standardised water-soluble extract was prepared from rhizomes of Potentilla tormentilla. The procyanidins in the extract were fractionated according to their degree of polymerisation by chromatography on Sephadex LH20. The anti-radical activities of the different fractions towards superoxide anion were compared when pentamers and hexamers were found to be the most active.
  • 佐藤 眞治, 小板橋 敏信, 神代 昭
    1994 年 17 巻 12 号 p. 1616-1621
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The purpose of this investigation was to quantitatively describe the pharmacokinetics of exogenous and endogenous L-dopa in plasma and the striatum using a basic physiological model, and to determine the apparent metabolism clearance from L-dopa to dopamine in the striatum. Male Wistar rats were used in this study. The time courses of L-dopa concentrations in plasma and the striatum were determined before and after the rapid i. v. injection of 10, 50 and 100mg/kg. Plasma and striatum samples were obtained over 480min (17 time points) from different group of animals and the assayed by HPLC-ECD. The endogenous L-dopa concentration in plasma before drug administration was 2.1±0.6mg/I. The exogenous L-dopa concentration declined biexponentially with time after drug injection. The total clearance of exogenous L-dopa in plasma was 3.13 (I/h)/kg. The production rate constant of endogenous L-dopa in plasma was 6.59 (mg/h)/kg. The value of the production rate constant of endogenous L-dopa in plasma could be calculated by the multiplication of the total clearance of L-dopa and the endogenous L-dopa concentration in plasma before drug injection. The pharmacokinetics of endogenous and exogenous L-dopa in plasma could be described quantitatively by a two compartment model which included the production rate constant of endogenous L-dopa. The time course of L-dopa concentrations in the striatum was analyzed on a hybrid model in which the striatum compartment is independently connected with the plasma compartment by the apparent diffusion clearance. The striatum compartment has two apparent first-order clearance terms, one from the plasma to the striatum, the other from the striatum to the outside of the striatum, including the metabolism clearance from L-dopa to dopamine in the striatum. The time course of L-dopa concentration in the striatum could be described by the basic physiological model, and the apparent metabolism clearance from L-dopa to dopamine in the striatum could be determined by the basic physiological model.
  • 佐藤 眞治, 小板橋 敏信, 神代 昭
    1994 年 17 巻 12 号 p. 1622-1629
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The purpose of this investigation was to quantitatively describe the time courses of dopamine, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations in the striatum after L-dopa injection using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was determined before and after the rapid i. v. injection of 10, 50 and 100mg/kg using the same animals as in the previous report. The endogenous dopamine, DOPAC and HVA concentrations in the striatum before L-dopa administration were 5.9±0.7μg, 3.6±0.4μg and 1.0±0.2μg/g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9±0.5μg/g) occurring at 3 min ; then it returned to the pre-medication level until 2h at 100mg/kg dosing. The time course of dopamine concentration in the striatum was analyzed on a constructed dopamine metabolism model which has a zero-order production rate for the production of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which was estimated in the previous report, and the other from dopamine to dopamine metabolites (DOPAC and HVA). However, the time course of dopamine concentration in the striatum could not be described by this model. Since the effect of L-dopa on the enlargement of dopamine concentration is known to be attributable to the endogenously released dopamine from the dopamine neuronal terminals, the time course of dopamine concentration in the striatum after L-dopa injection was analyzed on the assumption that the effect of L-dopa on the increase of dopamine concentration is caused not only by the metabolism from L-dopa to dopamine but also by the endogenously released dopamine from dopamine neuronal terminals. The result indicated that the effect of L-dopa on the enlargement of dopamine concentration could be described quantitatively by these assumptions. The DOPAC and HVA concentrations in the striatum also increased gradually after L-dopa injection, with the peak concentration (15.6±2.0 and 6.6±0.3μg/g) occurring at 20 and 90 min, and they then returned to the control level until 4 and 6h, respectively, at 100mg/kg dosing. The time course of DOPAC and HVA concentration in the striatum could be reasonably well described by a constructed dopamine metabolism model which has an apparent first-order clearance from dopamine to DOPAC and HVA, and Michaelis-Menten type elimination kinetics of DOPAC and HVA. Thus, it was clarified that the time courses of dopamine, DOPAC and HVA concentration in rat striatum after the i.v. injection of L-dopa can be explained using the dopamine metabolism model. This dopamine metabolism model might be able to be used for the pharmacokinetic-pharmacodynamic analysis of dopaminergic acting drugs.
  • 中嶋 幹郎, 竹内 直子, 濱田 元子, 松山 賢治, 市川 正孝, 後藤 茂
    1994 年 17 巻 12 号 p. 1630-1634
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The use of microdialysis to study the binding of valproate (VPA) to plasma proteins was evaluated in rabbits. Prior to an in vivo microdialysis, in vitro relative recovery of VPA respectively from Ringer's solution, 5% (w/v) of albumin solution and plasma sample via a microdialysis probe was examined. The in vitro relative recovery was defined as a ratio of the VPA concentration determined in the dialysate to the free VPA concentration in the sample solution surounding the membrane of the microdialysis probe. When the sample solution was well stirred at 700rpm and maintained at 37°C, the in vitro relative recovery of VPA was significantly different among them. It increased in the order of Ringer's solution (34.3±2.6%)>5% (w/v) of albumin solution (25.7±4.6%)> rabbit plasma sample (15.8±1.2%). Thereafter, pharmacokinetics of VPA was determined using both microdialysis sampling via the rabbit femoral vein and collection of whole blood via the rabbit ear vein after intravenous administration of VPA at a dose of 43mg/kg. Free concentrations of VPA in plasma were determined by ultrafiltration method as opposed to microdialysis method. There was no difference in the elimination half-life of VPA determined by microdialysis, 1.09±0.22h, or ultrafiltration, 1.22±0.21h. The AUC of VPA in dialysate was 15±4μg·h/ml, which corresponded to 15% of that in ultrafiltrate (103±17μg·h/ml). The value was in good agreement with the in vitro relative recovery of VPA from plasma sample (15.8±1.2%). On the basis of the obtained recovery of 15.8±1.2%, free VPA in dialysate was corrected to calculated free VPA in plasma, followed by determination of the extent of plasma protein binding of VPA. The extent of plasma protein binding of VPA determined by microdialysis was found to be 69.2±6.9%, which was almost the same as that determined by ultrafiltration (66.6±2.7%). In vivo determination of plasma protein binding of VPA was successfully performed by microdialysis when the in vitro relative recovery of VPA was calculated using plasma sample of the tested animal.
  • 五郎丸 毅, 前田 晴美
    1994 年 17 巻 12 号 p. 1635-1639
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Isotopic fractionation of isopropylantipyrine (IPA) and its deuterated analogues was examined by gas chromatography (GC) using capillary column. The separation of IPA and seven kinds of deuterated IPAs were proportional to the number of labeled deuterium atoms and inversely to the temperature of the column oven. The resolution coefficient between IPA and IPA-3-C2H3-4-(C2H3)2 (IPA-2H-7) was 1.46 at 200°C for column temperature. The present isotopic fractionation procedure was applied to the isotope dilution analysis of IPA. Measurement of the samples prepared by the addition of a known amount of IPA and IPA-2H-7 to the control plasma of rabbit allowed observation of a linear relationship between peak area ratio and added amount ratio. The correlation coefficient obtained by regression analysis was 1.000. The present method was also applied to determine the plasma level of IPA in rabbit after oral administration.
  • 程 宇慧, 細谷 治, 杉林 堅次, 森本 雍憲
    1994 年 17 巻 12 号 p. 1640-1644
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Pressure sensitive adhesives (PSA) tapes containing different concentrations of lidocaine were prepared by a general casting method using styrene-isoprene-styrene block copolymer, and the in vitro skin permeation of lidocaine from each tape was evaluated using diffusion cell and excised hairless rat skin. The skin permeation was proportionally increased by up to 40% lidocaine in the PSA tape and did not change after this concentration. Although the bending point of the steady-state flux via skin concentration curve was found at 40%, saturated concentration or solubility of lidocaine in the tape was estimated to be about 20% by differential scanning calorimetry (DSC) measurement. In addition, the steady-state flux of lidocaine through skin from water or silicone fluid suspension (92 or 120μg/cm2·h, respectively) was very similar to those of 40, 50 and 60% tapes (105, 101 and 112μg/cm2·h, respectively). Decrease in the concentration in tapes during the permeation experiment explained only part of these phenomena. To analyze them further, the drug free PSA tape with or without (control) skin surface lipid was affixed to 50% lidocaine PSA tape for 48h, and the amount of lidocaine crystal in the layered tapes was measured by DSC. The amount was found to be lower in the lipid-containing tape than in the lipid-free tape, suggesting that skin surface lipid can dissolve lidocaine crystal or solid in PSA tape to decrease its thermodynamic activity. Thus it is important to follow the concentration and thermodynamic activity of lidocaine in PSA tape, skin and the interface between the two layers to exactly assess its skin permeation flux.
  • 小杉 弘子, 榎本 英子, 石塚 由美子, 菊川 清見
    1994 年 17 巻 12 号 p. 1645-1650
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The level of urinary thiobarbituric acid (TBA) reactants in healthy human subjects due to malonaldehyde derivatives was measured to assess the lipid peroxidation status of the whole body. For each subject the TBA reactant level over a day varied over a 2-3 fold range while the daily level varied over a 1.5-3 fold range under normal life-style conditions. One of the factors causing an increase in the reactant level within a single day may be the subjects's physical activity, because the reactant level of each subject was higher in the afternoon or in the evening than in the morning. Remaining awake all night or hard exercise caused a dramatic increase in the reactant level over a day and in the daily reactant level. The reactant level within a single day for a subject was increased 5.5 fold and the daily level 3 fold by remaining awake all night, and the level within a day was increased 22 fold by hard exercise while the corresponding daily level was increased 7 fold. It is unlikely that food, alcohol and smoking greatly affect the reactant level. The results suggest that increased physical activity enhances lipid peroxidation in the whole body and thus the increased urinary excretion of malonaldehyde derivatives.
  • 長谷川 高明, 灘井 雅行, 王 莉, / 鍋島 俊隆, 加藤 延夫, Nobuo KATO
    1994 年 17 巻 12 号 p. 1651-1655
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The contribution of lipid A, an active component of endotoxin (LPS), to changes in the pharmacokinetics, renal handling and intrarenal accumulation of gentamicin induced by Klebsiella pneumoniae LPS was investigated in rats. Either LPS (250μg/kg) or lipid A (equivalent to dose of LPS) was infused 2h before the administration of gentamicin (10mg/kg). The effects of LPS and lipid A on the intrarenal accumulation of gentamicin were also evaluated. Significant increases in the levels of plasma creatinine and blood urea nitrogen were observed in both the LPS and lipid A groups. Both LPS and lipid A induced significant decreases in the glomerular filtration rate (by approximately 30%) and systemic clearance of gentamicin (by approximately 25%). No changes in the fraction of urinary excretion (>0.9) or steady-state volume of distribution of gentamicin were observed between either the control, LPS or lipid A groups. There were no significant differences among the three groups in the tubular reabsorption or intrarenal accumulation of gentamicin. The degree of effect of lipid A on the pharmacokinetics of gentamicin observed in this study was nearly equal to that of LPS. These results suggest that lipid A plays a major role in changes in the pharmacokinetics and renal handling of gentamicin induced by LPS.
  • 山崎 啓之, 三好 稔美, 丸山 徹, 高館 明, 小田切 優樹
    1994 年 17 巻 12 号 p. 1656-1662
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Characteristics of region Ic among at least three overlapping binding regions (regions Ia, Ib and Ic) in site I on human serum albumin (HSA) were analysed using n-alkyl p-aminobenzoates (n-alkyl p-ABEs), all of which are specific fluorescent probes for region Ic. In the interaction processes between n-alkyl p-ABEs and HSA, hydrophobic interaction, van der Waals interaction and local structural changes in region Ic were found to be involved based on the results obtained by analyses of the fluorescence spectra, structure-activity relationships and thermodynamic parameters. In addition, comparison of the fluorescence spectra of n-alkyl p-ABEs in HSA and detergents indicated that the possibility of a hydrophobic region Ic around which an amino acid with cationic charge locates could not be denied because of the similarity of fluorescence spectra between n-alkyl p-ABEs in HSA and in neutral and cationic detergents. The deviation of n-alkyl p-ABEs with long alkyl chains (C9-C12) in the relationships between association constants and physicochemical properties of a series of n-alkyl p-ABEs (C1-C12) suggested that region Ic possess an optimal depth. A conformational change of HSA with increasing pH (pH 6-9) generated an increase in hydrophobicity and adaptability of the binding region and made interaction easy, with an increase in adaptability of the binding region Ic ; consequently, it enhanced the binding of n-alkyl p-ABEs to HSA.
  • 今成 登志男, 斉藤 實, 邱 国寧, 戸井田 敏彦, 穐山 浩
    1994 年 17 巻 12 号 p. 1663-1665
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Glycosaminoglycan (GAG) synthesis by cultured normal human dermal fibroblasts was examined. Hyaluronic acid (HA) synthesis reached a maximum on day 3 (0.3μg/ml medium) and then decreased to a low level (0.15μg/ml medium). The amounts of dermatan sulfate (DS) and chondroitin sulfate (ChS) synthesized by the cells increased with increasing cell numbers during the initial stage to attain constant levels (0.092μg DS/ml, 0.026μg ChS/ml medium) after the cells reached confluence. We also tested the effects of dibutyryl cyclic AMP (dbcAMP) and retinoic acid (RA) on GAG synthesis by the cells. The synthesis of HA and ChS by cells was stimulated, when the cells were cultured in medium containing dbcAMP (0.1mM), whereas DS synthesis was scarcely affected. However, addition of RA (5mM) suppressed GAG synthesis by the cells.
  • 清水 訓子, 大津 定記, / 権田 良子, 大原 直子, Naoko OHARA
    1994 年 17 巻 12 号 p. 1666-1668
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A glucan, called alisman SI, was isolated from the tuber of Alisma orientale JUZEPCZ. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was 1.1×104. It is composed solely of D-glucose. Methylation analysis, nuclear magnetic resonance and enzymic degradation studies indicated that it has a high-branched glucan type structure mainly composed of α-1, 4-linked D-glucopyranosyl residues with partially α-1, 6-linked units and both 3, 4- and 4, 6-branching points. The polysaccharide exhibited significant reticuloendothelial system-potentiating activity in a carbon clearance test, as well as a pronounced anti-complementary activity.
  • 大高 章, 玉村 啓和, 寺川良 司博, 増田 正雄, 小出 隆規, 村上 努, 中島 秀喜, 松崎 勝已, 宮嶋 孝一郎, 井深 俊郎, ...
    1994 年 17 巻 12 号 p. 1669-1672
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    T22 ([Tyr5, 12, Lys7]-polyphemusin II) was found to exhibit strong anti-human immunodeficiency virus (HIV) activity and exert its effects on a virus-cell fusion process. In the present study, the all-D enantiomer of T22 and its related compounds were synthesized to examine the molecular parameters required for the interaction of T22 with membrane components of cells or viruses in order to exert this anti-HIV activity. The anti-HIV activity of these analogs was investigated in comparison with their membrane permeability with aspect to large unilamellar vesicles (LUVs). The all-D enantiomer of T22 exhibited a 20-fold lower anti-HIV activity compared with T22, whereas they both showed the same membrane permeability. No positive correlation between anti-HIV activity and membrane permeability was observed. These results suggest that the anti-HIV activity of T22 is mediated through the interaction with chiral component (s) of the cell or virus.
  • 渡辺 明子, 黒川 智文, 佐藤 純, 岩佐 進, 小川 泰亮
    1994 年 17 巻 12 号 p. 1673-1675
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    An ex vivo antiviral assay was established which uses hepatocytes from mice given recombinant mouse interferon-β (rmIFN-β). Assay results were compared with results obtained with a 2', 5'-oligoadenylate synthetase (2-5AS) assay. rmIFN-β was intraperitoneally administered to C3H mice and the antiviral state of their liver parenchymal cells was evaluated in an in vitro cytopathic effect assay. In this assay, cells are infected with vesicular stomatitis virus (VSV) and surviving cells are determined colorimetrically. The antiviral state was measured as the resistance of hepatocytes to VSV infection with increasing doses of rmIFN-β. The antiviral state correlated well with the dose-dependent increase in hepatic 2-5AS activity. This good correlation suggests that induction of 2-5AS mediates the antiviral action of interferon in liver tissue. This ex vivo assay could be a useful tool for estimating the ability of hepatocytes to resist hepatitis virus infection.
  • 堀 均, 横山 英輝, 永沢 秀子, 村山 千恵子, 母里 知之, 米井 脩治, 佐藤 哲男, 稲山 誠一
    1994 年 17 巻 12 号 p. 1676-1678
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    A convenient in vitro screening test using E. coli B/r for evaluating a variety of hypoxic cell radiosensitizers/hypoxic cell cytotoxins has been developed for the initial selection of candidates in medicinal/organic chemistry laboratories. E. coli cells were used for convenience since : (1) the bacterium is grown using commercially available broths, where it multiplies repidly, and requires little specialized equipment for growth and handling. (2) More is known about the genetics and biochemistry of the radiation damage to these cells and their repair than any other organism.
  • 西山 信好, 周 躍平, 齋藤 洋
    1994 年 17 巻 12 号 p. 1679-1681
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    The amygdala is one of the key areas of the brain involved in learning and memory. Bilateral lesions of the amygdala in 9-week-old mice induced impairment of memory acquisition and retention. DX-9386, a traditional Chinese medicinal prescription consisting of ginseng, polygala, acorus and hoelen, was orally administered to the lesioned mice after the operation until all the experiments were completed. From 15d after surgery, learning behavior in the step-down test was observed daily for 10d. DX-9386 treatment ameliorated the memory acquisition deficit. The number of step-down events in the first testing trial was significantly decreased by administration of 250mg/kg of the prescription to the lesioned group of mice. Choline acetyltransferase activity in the cerebral cortex of the lesioned mice was significantly decreased, while repeated administration of the prescription did not affect this biochemical parameter. These results indicate that the memory acquisition enhancing effect of DX-9386 may not be achieved by direct activation of cholinergic transmission in the brain but by some other mechanism (s).
  • 佐藤 幸夫, 陳 戦松, 高橋 威夫, 鈴木 康男
    1994 年 17 巻 12 号 p. 1682-1685
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    We have observed the surface images of dimyristoylphosphatidylcholine (DMPC) monolayer and DMPC vesicles with an atomic force microscope (AFM). It was confirmed that the lattice structure of polar head groups of DMPC molecules in a Langmuir-Blodgett monolayer is similar to those of large unilamellar DMPC vesicles. AFM images of small unilamellar vesicles of DMPC showed larger lattice structures than those of the monolayer, reflecting differences of molecular packing in these membranes.
  • 及川 勉, 小野沢 千津子, 坂口 美里, 森田 育男, 室田 誠逸
    1994 年 17 巻 12 号 p. 1686-1688
    発行日: 1994/12/15
    公開日: 2008/04/10
    ジャーナル フリー
    Three isoforms of platelet-derived growth factors (PDGFs) composing of AA, AB and BB chains all exhibited angiogenic activity in a dose-dependent manner in an in vivo assay system involving the chorioallantoic membrane of chick embryo. The order of potency was BB>AB=AA. They, however, failed to stimulate proliferation of vascular endothelial cells, suggesting that their effects are indirect. These data suggest the possibility that three PDGF isoforms are indirect angiogenic factors.
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