YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
122 巻, 10 号
選択された号の論文の13件中1~13を表示しています
Reviews
  • 毛利 哲郎
    2002 年 122 巻 10 号 p. 707-726
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    Na+-dependent and -independent transport sites were elucidated for glycine and L-leucine, respectively, in Chang liver cells, a human culture cell line. Findings of acceleration of the L-leucine uptake by the cells in the acidic medium and synchronized acidification within the cell membrane vesicles with the uptake by them all suggested cotransport of L-leucine and proton and the uptake of L-leucine dependent on the inward proton gradient in Chang liver cells. Cotransport of L-leucine and proton was also demonstrated in human peripheral lymphocytes and accelerated by the addition of concanavalin A, probably accompanied by membrane hyperpolarization. It was shown that the Na+-gradient-depend-ent uptake of glycine can be regulated by insulin and 17β-estradiol in the rat uterus and by Ca2+-calmodulin and membrane potential in Chang liver cells. D-Aspartate uptake as a model of glutamate transport was characterized in rat hippocampal slices and found to consist of Na+-dependent (higher-affinity) and -independent (lower-affinity) components. The vulnerability of hippocampal neurons to the Alzheimer β-amyloid protein was confirmed in vitro with primary cultured rat hippocampal neurons in the presence of the amyloid protein β1-42 or its core fragments. The toxicity of the amyloid protein could be blocked by the addition of insulin and several other growth factors to the medium. The addition of genipin, a plant-derived iridoid, was demonstrated to prevent the toxicity of a synthetic fragment of β1-42, β25-35. Genipin had a neuritogenic activity in PC12h cells, a rat pheochromocytoma cell line, an activity extremely sensitive to inhibitors of the nitrogen oxide (NO) synthase and soluble guanylate cyclase and an NO scavenger. It was also demonstrated in PC12h cells that the activation of the MAP kinase cascade was essential for the neuritogenesis of genipin. These properties of genipin are very comparable to those of nerve growth factor in the cells. It is considered likely that various useful, neurotrophic substances and their extracts will be found in plants in future.
  • 山田 泰司
    2002 年 122 巻 10 号 p. 727-743
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    This paper describes the discovery and total synthesis of bioactive marine natural products conducted in our laboratory. Clavulone, chlorovulone, bromovulone, and iodovulone are antitumor marine prostanoids isolated from the Okinawan soft coral Clavularia viridis. The synthesis of clavulone and chlorovulone was achieved from chiral 4-hydroxy-2-cyclopentenone. Marine prostanoid punaglandins 3 and 4 were synthesized via similar methodology. The chemical structures of punaglandins 3 and 4 were revised by these syntheses. Dollaberane-type diterpenoid stolonidiol and claenone were isolated from Okinawan soft coral Clavularia sp. Stolonidiol showed potent choline acetyltransferase-inducible activity in cultured basal forebrain cells. The synthesis of stolondiol and claenone was conducted via sequential Michael reaction and retro-aldol reaction. Aragusterols, isolated from the Okinawan marine sponge Xestospongia sp., are structurally unique steroids possessing a rare 26,27-cyclo structure in the side chain. Aragusterols express potent in vivo antitumor activity against L1210 leukemia in mice. The synthesis of aragusterols was carried out via stereoselective construction of the side chain and stereocontrolled coupling reaction with the steroid skeleton. Kalihinane-type diterpen-oid kalihinol A, isolated by Scheuer, has remarkable in vitro antimalarial activity. The absolute configuration of kalihinol A was determined by applying the CD exciton chiral method. Synthesis of kalihinene X, a kalihinane-type diterpenoid, was achieved. This synthesis involves the regioselective coupling reaction of carbanion of alkyl sulfone with epoxyalcohol and construction of cis-decalin by an intramolecular Diels-Alder reaction.
  • 板部 洋之
    2002 年 122 巻 10 号 p. 745-753
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    Oxidized low-density lipoprotein (OxLDL) is thought to be involved in atherosclerotic lesion formation. We established a monoclonal antibody, DLH3, that recognizes oxidized phosphatidylcholine (OxPC) formed in OxLDL. A sensitive method for detecting OxLDL was enabled by a sandwich ELISA procedure utilizing DLH3 together with an anti-apoB antibody. Using the method, we demonstrated the presence of OxLDL in human circulating plasma for the first time, and the plasma OxLDL level in healthy subjects was estimated to be about 0.1ng/μg LDL protein. OxLDL levels in patients with acute myocardial infarction are more than 3 times higher than in controls. Thus the plasma OxLDL level could be a good marker for cardiovascular disease. There are multiple metabolic enzymes for OxPC in plasma. We demonstrated that lecithin: cholesterol acyltransferase (LCAT) is capable of metabolizing OxPC molecules in OxLDL, and that the plasma OxLDL level in patients with familial LCAT deficiency was about 3.5 times higher than in controls. OxLDL in vivo is likely to be metabolized by enzymatic activities in plasma, the reticuloendothelial system including Kupffer cells, and immunological responses. The OxLDL levels determined by this analytical procedure would reflect the physiologic balance between oxidative modification of LDL and metabolic clearance of OxLDL.
  • 高橋 秀依
    2002 年 122 巻 10 号 p. 755-771
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    The development of two novel ring conversions of sugar derivatives is described. The first is an efficient conversion of 5-enopyranosides and 6-O-acetyl-5-enopyranosides to the corresponding substituted cyclohexanones mediated by a catalytic amount of palladium dichloride. After a survey of various substrates, the reaction was confirmed to be general and useful. Syntheses of bioactive compounds utilizing this method were therefore investigated. Cyclophellitol, which is a potent β-glucoidase inhibitor, and its diastereoisomer were efficiently synthesized. Furthermore, novel synthesis of all enantiomerically pure diastereoisomers of inositol starting with 6-O-acetyl-5-enopyranosides was investigated. Good accessibility of these enantiomerically pure inositol diastereoisomers results in the efficient syntheses of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate. The second investigation involved novel and efficient conversion of D-glycono-1,5-lactones into the corresponding L-sugars. The important intermediate, δ-hydroxyalkoxamate, was provided by a practical alkoxyamination of D-glycono-1,5-lactones mediated by Me3Al. In contrast to the preparation of β-lactam skeletons from β-hydroxyalkoxamates, the cyclization of δ-hydroxyalkoxamates under Mitsunobu conditions resulted in O-alkylation rather than N-alkylation. It is noteworthy that δ-hydroxyalkoxamates derived from D-mannono-1,5-lactones afforded the O-alkylation product in 91% yield. No N-alkylation product was detected in this case. These O-cyclized oximes, in which the inversion of the configuration at C5 was secured, were efficiently converted into L-sugars.
  • 野瀬 清
    2002 年 122 巻 10 号 p. 773-780
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    Reactive oxygen species (ROS) are generated from cells stimulated by various cytokines, hormones, and stresses, and regulate celluar functions such as gene expression and cell growth. They affect activities of many types of molecular targets, including signaling molecules and transcription factors. Early-respons genes (c-fos, egr-1 and JE) that encode transcription factors are induced by ROS, and activities of their products are modulated by ROS through redox-based mechanisms. We isolated a novel gene, hic-5, that was induced by hydrogen peroxide and encodes a focal adhesion protein. hic-5 was found to translocate to the nucleus in cells treated with ROS and regulates several cellular genes. We propose that hic-5 is a key element in the transduction of signals from the cell surface to the nucleus under oxidative stress.
  • 中川 公恵
    2002 年 122 巻 10 号 p. 781-791
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] has antiproliferative, differentiation and apoptosis-inducing effects on many malignant cells. These properties have raised the possibility of its use as a therapeutic agent in cancer. Our recent studies using stereoisomers of the A-ring of monohydroxylated 19-nor or 2-methyl substituted 1α,25(OH)2D3 have clearly demonstrated that the A-ring analogs that contain 1α-hydroxy or 3β-hydroxy group are potent inducers of HL-60 cell differentiation. In contrast, the A-ring analogs that contain 1β-hydroxy or 3α-hydroxy group are potent stimulators of HL-60 cell apoptosis. It was interesting to note that the analogs could induce differentiation or apoptosis of HL-60 cells on the basis of the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring. To further elucidate the possible roles of both the hydroxy groups in regulating cell differentiation and apoptosis, we have synthesized all possible diastereomers of the A-ring of 1α,25(OH)2D3 and examined their molecular mechanism of differentiation and apoptosis-inducing actions of HL-60 cells in vitro. This study shows that differentiation and apoptosis of HL-60 cells are strictly controlled by the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring of 1α,25(OH)2D3, and the proteins responsible for the regulation of cell cycle and mitochondrial membrane potential are the major targets of 1α,25(OH)2D3 analogs. These findings provide useful information not only for structure-function studies of 1α,25(OH)2D3 analogs but also for the development of therapeutic agents for the treatment of cancer.
  • 青木 伸
    2002 年 122 巻 10 号 p. 793-804
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    Novel supramolecular chemistry of multinuclear zinc(II) complexes in aqueous solution has been created by utilizing multiple interactions with polyanions. We have established reliable and convenient synthetic methods of multidentate macrocyclic polyamines and their zinc(II) complexes and thereby undertook a focused investigation of four topics: 1) efficient inhibition of photo[2+2]cycloaddition of thymidine dimer by dimeric zinc(II) complexes; 2) selective extraction and transport of thymidine nucleotide derivatives from the aqueous phase to the organic phase by lipophilic zinc(II) complexes and selective recognition of thymidine nucleotides by ditopic zinc(II) complexes in aqueous solution; 3) supramolecular polyhedrons formed by self-assembly of a trimeric zinc(II) complex with cyanuric acid or trithiocyanuric acid; and 4) a selective fluorescent probe for lanthanide ions such as Y3+ and La3+ based on a double-functionalized ligand with carbamoyl and dansyl groups. This knowledge should afford new methodology for supramolecular chemistry in aqueous solution.
  • 伊藤 潔
    2002 年 122 巻 10 号 p. 805-811
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    Formaldehyde dehydrogenase (PFDH) was isolated from the creatinine-decomposing bacterium Pseudomonas putida, and its gene has been cloned. PFDH is unique because it was the only enzyme that catalyzed the dehydrogenation of formaldehyde without glutathione. PFDH belongs to a zinc-containing alcohol dehydrogenase family. Quantitative analysis of the reaction products using NMR revealed that the enzyme is not simply a dehydrogenase but is an aldehyde dismutase catalyzing a simultaneous conversion of both aldehyde to carboxylate and aldehyde to alcohol. The enzyme contains a tightly bound cofactor of NAD+/NADH per subunit and is classified as a nicotinoprotein. The enzyme reaction can proceed without external addition of the nucleotide cofactor. The formaldehyde was crystallized using the hanging-drop vapor diffusion method with ammonium sulfate as a precipitant. The crystal structure was determined using the multiwavelength anomalous diffraction method with intrinsic zinc ions. The overall structure of PFDH is similar to that of a classic horse liver alcohol dehydrogenase. However, a comparison of these structures indicated that the insertion loop specifically found in PFDH may be responsible for the tight binding of the cofactor, thereby making PFDH a dismutase.
Regular Articles
  • Hiroki KONISHI, Kashie KANEMOTO, Yoshihiro IKUNO, Tokuzo MINOUCHI, Tet ...
    原稿種別: Regular Article
    2002 年 122 巻 10 号 p. 813-817
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    A 47-year-old woman received combination therapy with prednisolone (PSL), danazol, cepharanthin, ascorbic acid, and cimetidine for the treatment of idiopathic thrombocytopenic purpura. The platelet count was well controlled for over 1 year. Then the PSL tablet formulation was altered from Tablet A to Tablet B with the same treatment regimen, but the platelet counts fell drastically thereafter. However, the platelet counts recovered by changing the PSL tablet formulation back from Tablet B to Tablet A. In vitro dissolution testing was undertaken to assess bioequivalence between Tablet A and Tablet B. PSL in Tablet B was released more slowly compared with that in Tablet A regardless of the medium pH conditions, and the difference in the release rate between the two tablet formulations increased with increasing medium pH value. The difference exceeded the allowance limit (15%) for judgement of bioequivalence under conditions above pH 4, indicating that Tablet A and Tablet B might be nonbioequivalent. The intragastric pH of the patient was probably raised due to coadministration of cimetidine. Therefore the present results suggest that the disparity in the immunosuppressive effects between the two PSL tablet formulations was attributable to the difference in their dissolution behavior in the gastrointestinal tract. We consider that it is better to avoid interchanging PSL tablet formulations in clinical practice.
  • 川上 純一, 三村 泰彦, 足立 伊佐雄, 竹口 紀晃
    2002 年 122 巻 10 号 p. 819-829
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    The P-drug seminar, a novel method of teaching the process of rational pharmacotherapy, was introduced in 2000 into the practice program of the clinical pharmacy course in the Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University (TMPU). The P-drug concept is evidence-based drug selection according to criteria (i.e., efficacy, safety, suitability and cost) deter mined in advance and rational prescribing by each physician. The P-drug seminar originated from educational courses for medical students at the University of Groningen and has been propagated by the WHO Action Programme on Essential Drugs world wide. In the TMPU, the seminar consists of 5 half-days before the start of bedside teaching during clinical pharmacy practice. Each term, 8 graduate students licensed as pharmacists form one seminar group, and 32 students have completed it successfully in the past 2 years. Problem-based learning and self-awareness methods are applied through discussion among students. The same teaching materials as those used in the WHO P-drug workshop and the English textbook Guide to Good Prescribing were adopted. A short lecture on the pharmacist's role in the rational use of drugs was added to modify the original P-drug workshop for medical students since this was considered suitable for graduate students in clinical pharmacy. Our graduate students were able to learn the process of pharmacotherapy by following the steps of P-drug selection and rational treatment under the P-drug concept and also understand the viewpoint of prescribers and pharmacists' roles as medical staff. In conclusion, this is the first report on application of the P-drug method to clinical pharmacy education.
  • 加藤 三佳, 桜井 光一, 藤本 幸男
    2002 年 122 巻 10 号 p. 831-839
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    The diabetogenic action of alloxan is thought to be initiated by generation of reactive oxygen species (ROS). Ascorbate can be an antioxidant in a predominantly aqueous environment, such as plasma and extracellular fluids. We have investigated the generation of ROS in the interaction of alloxan with ascorbate. Rapid oxygen consumption was observed in the reaction system of alloxan with ascorbate. The oxygen consumption was suppressed by superoxide dismutase and catalase, suggesting that superoxide and hydrogen peroxide could be generated in the reaction system. In addition, the generation of alloxan radical, an electron reductance of alloxan, and ascorbate free radical (AFR), an electron oxidant of ascorbate, was observed using electron spin resonance (ESR). Under anaerobic conditions, the ESR signal intensity of alloxan radical was significantly increased in comparison with that under aerobic conditions, whereas the intensity of AFR was significantly decreased. These results suggest that alloxan radical and AFR were generated in the reaction system of alloxan with ascorbate, and that the alloxan radical but not AFR reacted with molecular oxygen, resulting in the generation of ROS.
  • ―3文字入力及び警告画面表示システムの有用性―
    渡部 恵, 杉浦 宗敏, 清野 敏一, 光永 義治, 中村 均, 山田 安彦, 土屋 文人, 大江 和彦, 伊賀 立二
    2002 年 122 巻 10 号 p. 841-847
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    In the computerized prescription order entry system, it has been pointed out that a physician's input mischoice for medicine is one of the causes of medication errors. We therefore investigated the input mischoices by physicians at the time of writing prescriptions. Subsequently, the number of input characters in a prescription order was changed to three characters from two characters. Furthermore, 105 items of high-alert medications, which are likely to result in injury if errors occur, were established. A warning screen display system that requests reconfirmation of the effect, name, usage, and dosage of those medicines was also built. It was found that 70% of input mistakes were caused by choosing the medicine displayed immediately above or below the desired drug. By changing the number of input characters of a prescription order to three characters from two characters, the rate of specification of a trademark improved sharply from 36% to 85%. Consequently, the rate of choice of a drug with another trademark decreased significantly from 0.028% to 0.0047%. In 5% of cases when the warning screen was displayed for a high-alert medicine, the prescription was stopped, and 25% were changed to other medicines. The above results show that the system that requires the input of three or more characters for the physician order entry and displays a warning screen for high-alert medicines is useful in preventing mischoices at the time of prescription input.
  • 岩上  猛, 植田 泰輔, 木村 良夫, 森本 副吉, 松田 りえ子, 林   譲, 今井 一洋
    2002 年 122 巻 10 号 p. 849-854
    発行日: 2002/10/01
    公開日: 2003/02/18
    ジャーナル フリー
    In system suitability tests, the daily conditions of an analytical instrument are checked with the standard deviation (SD) of measurements as a criterion. This paper examines how exactly the SD values obtained from the measurements can indicate instrumental conditions. The HPLC measurement for acetaminophen is repeated six times daily to obtain an SD estimate, and these procedures are repeated for seven days. The degree of scattering of the seven SD values corresponds well to the 95% confidence intervals calculated from the chi-square distribution (n=6). Therefore it is concluded that the variability of the daily conditions of the HPLC system used in this study is too small to detect by referring to the SD estimates (n=6) and the daily change in the SD estimates only represents the error of the SD estimation itself. However, if the repetition number is 40 (n=40), the SD estimates will be a good indicator. Forty measurements are practically impossible for a slow analysis like HPLC, and this paper recommends the function of mutual information theory as a substitute for repetitive measurement.
feedback
Top