YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
129 巻, 1 号
選択された号の論文の18件中1~18を表示しています
誌上シンポジウム
  • 森 秀治, 西堀 正洋
    2009 年 129 巻 1 号 p. 1-2
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
  • 設楽 研也
    2009 年 129 巻 1 号 p. 3-9
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Antibody-dependent cellular cytotoxicity (ADCC), a lytic attack on antibody-targeted cells, is triggered upon binding of lymphocyte receptors (FcγRs) to the antibody constant region. ADCC is considered to be a major therapeutic function of antibodies. ADCC requires the presence of oligosaccharides in the Fc region and is sensitive to change in the oligosaccharide structure. We have demonstrated that fucose is the most critical IgG1 oligosaccharide component, and the removal of fucose from IgG1 oligosaccharides results in a very significant enhancement of ADCC and anti-tumor activity in vivo. Many therapeutic antibodies approved or clinical development are produced using Chinese hamster ovary (CHO) cells that express high level of α1,6-fucosyltransferase and consequently produce highly fucosylated antibodies. We have established the fucosyltransferase knockout CHO cells which could stably produce non-fucosylated antibodies, designated as Potelligent antibodies. Potelligent antibodies show potent ADCC upon target cells through the effective and antigen-specific activation of NK cells due to augmented binding to FcγRIIIa. Moreover, Potelligent antibodies can evade the inhibitory effect of plasma IgG on ADCC through its high FcγRIIIa binding. Thus, the application of Potelligent antibodies is expected to be a promising approach as next-generation therapeutic antibodies with improved efficacy, even when administered at low doses in humans in vivo.
  • 金山 直樹, 藤堂 景史, 曲 正樹, 大森 齊
    2009 年 129 巻 1 号 p. 11-17
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Monoclonal antibodies (mAb) have recently proven to be excellent biopharmaceutical agents. The generation of hybridomas from antigen-stimulated B cells has been a key technology for obtaining mAbs; however, it is a laborious and time-consuming process, and sometimes mAbs for molecules conserved between species are difficult to obtain because of immunological tolerance. Thus, it is of great importance to develop in vitro technologies for generating useful Abs as drug candidates. We have been attempting to develop a novel in vitro antibody generation system using a chicken B cell line DT40, which displays Abs and mutates Ig genes during culture, thereby generating a useful Ab library for screening mAbs. First, we generated an engineered cell line DT40-SW whose mutation machinery can be reversibly switched on and off. The Ab generation system using DT40-SW is useful in the following ways: (1) mAbs for various model antigens including antoantigens can be obtained from the DT40-SW Ab library that is free from immunological tolerance; (2) the switching device of the mutation machinery enables fixing desirable Ig mutants by stopping mutation; (3) by repeated culture and sorting of clones bearing higher affinity for target antigens, affinity maturation can be mimicked in vitro. We have also genetically improved DT40-SW cells for mutation efficiency and Ab production. The Ab generation system will be applicable for obtaining valuable Abs such as antitumor Abs.
  • 杉田 尚久
    2009 年 129 巻 1 号 p. 19-24
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      TNFα (tumor necrosis factor-alpha) plays a critical role in the pathogenesis of inflammatory diseases including rheumatoid arthritis and Crohn's disease. Infliximab is a monoclonal antibody that recognizes human TNFα. Clinical trials have been persuasive that infliximab is effective and far superior to the conventional drug therapy in various inflammatory diseases. Combination of infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying anti-rheumatic drugs, and has produced significant improvement in clinical, radiographic, and functional outcomes. Infliximab is also an important treatment option in patients with active Crohn's disease who have not responded to conventional therapy and in those with this disease who have fistulae. Moreover, infliximab treatment has resulted in effective suppression of ankylosing spondylitis, psoriasis and ocular inflammation in patients with refractory uveoretinitis due to Behçet's disease. Thus, biologics targeting TNFα have revolutionized the therapy of inflammatory diseases. Here, the current status of clinical application of anti-TNFα biologics is reviewed by describing the clinical outcome of infliximab and future prospects of biologics are discussed.
  • 森 秀治, 劉 克約, 高橋 英夫, 西堀 正洋
    2009 年 129 巻 1 号 p. 25-31
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Ischemic brain infarction is high among th causes of death in Japan, and the medical and social burden by severe sequela is also extremely serious. In this symposium, we show that treatment with anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by 2-hour occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Whereas HMGB1 is usually localized in nucleus, after stimulation it is secreted into extracellular space by an unknown non-classical pathway, and exhibits an inflammatory cytokine-like activity. Treatment with mAb reduced infarct size, and the accompanying neurological deficits in locomotor function were significantly improved. In addition, some biochemical markers such as permeability of the blood-brain barrier, the expression of tumor necrosis factor-alfa, inducible nitric oxide synthase and matrix metalloproteinase-9 were altered by mAb injection. These findings indicate the usefulness of HMGB1 as a novel therapeutic to target ischemic stroke.
  • 瀬戸 康雄
    2009 年 129 巻 1 号 p. 33
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
  • 早川 和一
    2009 年 129 巻 1 号 p. 35-43
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      The wastes, which have explosiveness, toxicity, infectious, and possibility to cause damage to other people's health and environments, are provided the special management municipal wastes or the special management industry wastes. All the treatment processes from collection to disposal is done under strict management. In this report, we focus on the inorganic and organic experimental waste fluid and the infectious waste among the special management municipal waste or industry waste, because of the similar toxic and chemical characteristics to that of biological and chemical weapons. Understanding how the decomposition and treatment of these wastes are actually done, we clarify the issues of the hazardous waste management and discuss on the possibility to develop the new degradation and treatment method for biological and chemical weapons.
  • 貝瀬 利一, 木下 健司
    2009 年 129 巻 1 号 p. 45-51
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      The old Japanese army developed several chemical warfare agents on Ohkuno Island in Seto inland sea, Hiroshima Japan, during the period between 1919 and 1944. These chemical agents including yperite (mustard; irritating agent), lewisite (irritating agent), diphenylchloroarsine (DA; vomiting agent), diphenylcyanoarsine (DC; vomiting agent) and other poisonous gases were manufactured to be used in China. After World War II, the old Japanese army abandoned or dumped these agents into seas inside or outside of Japan and interior of China. Rather than being used for terrorism, these chemical warfare agents containing arsenicals may cause injury to some workers at the digging site of abandoned chemical weapons. Moreover, the leakage of chemical agents or an explosion of the bomb may result in environmental pollution, as a result, it is highly possible to cause serious health damage to the residents. There are still many abandoned or dumped warfare agents in Japan and China, therefore chemical agents containing arsenic are needed to be treated with alkaline for decomposition or to decompose with oxidizing agent. Presently, a large quantity of chemical agents and the contaminated soil are processed by combustion, and industrial waste is treated with sulfur compounds as the insoluble sulfur arsenic complex. This report describes the methods for the disposal of these organic arsenic agents that have been implemented until present and examines the future prospects.
  • 瀬戸 康雄
    2009 年 129 巻 1 号 p. 53-69
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Chemical and biological warfare agents (CBWA's) are diverse in nature; volatile acute low-molecular-weight toxic compounds, chemical warfare agents (CWA's, gaseous choking and blood agents, volatile nerve gases and blister agents, nonvolatile vomit agents and lacrymators), biological toxins (nonvolatile low-molecular-weight toxins, proteinous toxins) and microbes (bacteria, viruses, rickettsiae). In the consequence management against chemical and biological terrorism, speedy decontamination of victims, facilities and equipment is required for the minimization of the damage. In the present situation, washing victims and contaminated materials with large volumes of water is the basic way, and additionally hypochlorite salt solution is used for decomposition of CWA's. However, it still remains unsolved how to dispose large volumes of waste water, and the decontamination reagents have serious limitation of high toxicity, despoiling nature against the environments, long finishing time and non-durability in effective decontamination. Namely, the existing decontamination system is not effective, nonspecifically affecting the surrounding non-target materials. Therefore, it is the urgent matter to build up the usable decontamination system surpassing the present technologies. The symposiast presents the on-going joint project of research and development of the novel decontamination system against CBWA's, in the purpose of realizing nontoxic, fast, specific, effective and economical terrorism on-site decontamination. The projects consists of (1) establishment of the decontamination evaluation methods and verification of the existing technologies and adaptation of bacterial organophosphorus hydrolase, (2) development of adsorptive elimination technologies using molecular recognition tools, and (4) development of deactivation technologies using photocatalysis.
  • 平川 力, 米良 信昭, 佐野 泰三, 根岸 信彰, 竹内 浩士
    2009 年 129 巻 1 号 p. 71-92
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Photocatalysis has been widely applied to solar-energy conversion and environmental purification. Photocatalyst, typically titanium dioxide (TiO2), produces active oxygen species under irradiation of ultraviolet light, and can decompose not only conventional pollutants but also different types of hazardous substances at mild conditions. We have recently started the study of photocatalytic decontamination of chemical warfare agents (CWAs) under collaboration with the National Research Institute of Police Science. This article reviews environmental applications of semiconductor photocatalysis, decontamination methods for CWAs, and previous photocatalytic studies applied to CWA degradation, together with some of our results obtained with CWAs and their simulant compounds. The data indicate that photocatalysis, which may not always give a striking power, certainly helps detoxification of such hazardous compounds. Unfortunately, there are not enough data obtained with real CWAs due to the difficulty in handling. We will add more scientific data using CWAs in the near future to develop useful decontamination systems that can reduce the damage caused by possible terrorism.
  • 鵜沢 浩隆
    2009 年 129 巻 1 号 p. 93-106
    発行日: 2009年
    公開日: 2009/01/01
    ジャーナル フリー
      The Shiga toxin is a highly poisonous protein produced by enterohemorrhagic Escherichia coli O157. This bacterial toxin causes the hemolytic uremic syndrome. Another plant toxin from castor beans, ricin, is also highly toxic. The toxin was used for assassination in London. Recently, there were several cases of postal matter containing ricin. Both toxins are categorized as biological warfare agents by the Centers of Disease Control and Prevention. Conventional detection methods based on the antigen-antibody reaction, PCR and other cell-free assays have been proposed. However, those approaches have drawbacks in terms of sensitivity, analytical time, or stability of the detection reagents. Therefore, development of a facile and sensitive detection method is essential. Here we describe new detection methods applying carbohydrate epitopes as the toxin ligands, which is based on the fact that the toxins bind cell-surface oligosaccharides. Namely, the Shiga toxin has an affinity for globobiosyl (Gb2) disaccharide, and ricin binds the β-D-galactose residue. For Shiga toxin detection, surface plasmon resonance (SPR) was applied. A polyanionic Gb2-glycopolymer was designed for this purpose, and it was used for the assembly of Gb2-chips using alternating layer-by-layer technology. The method allowed us to detect the toxin at a low concentration of LD50. A synthetic carbohydrate ligand for ricin was designed and immobilized on the chips. SPR analysis with the chips allows us to detect ricin in a highly sensitive and facile manner (10 pg/ml, 5 min). Our present approaches provide a highly effective way to counter bioterrorism.
総説
  • 今西 武
    2009 年 129 巻 1 号 p. 107-134
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      1,6-Dihydro-3(2H)-pyridinone, designed as a common synthon for synthesis of various natural products, was found to be easily prepared in large scale and successfully used to synthesize a variety of alkaloids such as ibogamine, quinine and tecomanine. A tricyclo[3.3.0.02.8]octane was also served as a common synthon for several sesquiterpenes such as pentalenene and quadrone. Synthetic studies by using sulfinyl chirality via an intramolecular Michael addition gave the novel route to construct spiro-ketal moiety in enantiomerically pure form. By applying this method, many natural spiro-ketal compounds were asymmetrically synthesized effectively. 3-Sulfinylated 1,4-dihydropyridine, a chiral NADH model compound, reduced activated ketones such as methyl benzoylformate to give the corresponding alcohols in excellent optical yields. A kind of 3-O-substituted pyridoxal chiral model compound was useful for preparation of α,α-dialkylated α-amino acids by asymmetric α-alkylation of α-amino acids. 2′-O,4′-C-Bridged nucleic acid analogs, BNAs, developed as novel type of artificial nucleic acids, showed an extraordinarily high binding affinity toward single stranded RNA and double stranded DNA complements along with excellent nuclease-resistant ability. Oligonucleotides containing BNA monomer units were proved to be very useful for various biotechnologies, such as antisense and antigene methodologies.
  • 玉起 美恵子
    2009 年 129 巻 1 号 p. 135-145
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Pharmacogenomics is expected to become one of the ways by which serious drug development problems can be broken down and solved. In fact, the field of pharmaceutical development seems to be using pharmacogenomics increasingly as a means of both drug selection (via genotyping) and proper dosage determination. Before pharmacogenomics can be put to practical use, however, scientific and technical issues must first be resolved, after which social and ethical issues must be addressed. In Japan, drug developers are preparing for the introduction of pharmacogenomics into clinical trials. As they anticipate the necessary revisions, they must keep in mind not only the differences between current practice and that including pharmacogenomics, but also international standards. Therefore, developers are discussing strategies for communicating the necessary changes to academic and regulatory parties in an attempt to obtain a consensus and smoothly implement these changes. A survey of the academic and regulatory parties revealed that there were concerns about what pharmacogenomic information should be obtained, who would have access to it, and how it should be transmitted. Since industry, academia, and the regulatory body all agree that pharmacogenomics need to be implemented in Japan, deeper discussion of the science, technology, regulation, and ethics relevant to this topic should be continued both domestically and internationally.
一般論文
  • 立浪 良介, 高橋 恭兵, 大場 達也, 丹保 好子
    2009 年 129 巻 1 号 p. 147-153
    発行日: 2009年
    公開日: 2009/01/01
    ジャーナル フリー
      Methylglyoxal (MG), a highly reactive dicarbonyl compound, is a metabolic by-product of glycolysis. MG is often detected at high levels in the blood of diabetic patients. We examined whether MG was capable of inducing reactive oxygen species (ROS) production in bovine aortic endothelial cells (BAECs). The viability of BAECs decreased with time on treatment with 5 mM MG, and was almost completely lost at 24 h. In contrast, MG at 1 mM had little influence on BAEC viability up to 24 h, but induced the elevation of intracellular glutathione content at 24 h. Exposure of BAECs to MG caused a dose-dependent increase in oxidized-hydroethidine fluorescence intensity, indicating ROS production. In addition, aconitase inactivation, which is an indicator of intracellular superoxide, was observed in MG-treated cells. Finally, we found that MG at 5 mM increased the fluorescence intensity of BES-So, a specific probe for superoxide. Together, the results suggest that MG induces superoxide production in endothelial cells, and that the accumulation of ROS may be linked to cytotoxic effects.
  • 加納 誠一朗, 田口 睦, 早勢 伸正, 金田 繁, 高栗 郷, 市原 和夫, 佐藤 久美
    2009 年 129 巻 1 号 p. 155-161
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      Mevalotin® containing pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is the brand medicine and well known to be effective for patients with dyslipidemia. Now, more than 20 generic pravastatins are available for clinical therapy. We compared pharmaceutical property of Mevan®, a generic pravastatin, with that of Mevalotin®. According to the definition of the Japanese Pharmacopoeia, Mevalotin® 10 mg tablets were uniform in pravastatin content, whereas 5 mg tablets were rather variable. Variation in pravastatin content of Mevan 5 mg tablets was the same as Mevalotin® 5 mg, whereas that of 10 mg tablets was very variable. The plasma concentration of pravastatin in the normal rabbits continuously increased until 180 min after oral administration of 30 mg Mevan®, whereas it increased in a biphasic pattern after 30 mg Mevalotin®. All rabbits were fed 0.2% cholesterol diet throughout the experiment. After 8 weeks, oral administration of either Mevalotin® or Mevan® was started at the dose of 30 mg pravastatin/day for 16 weeks. After a transient increase for a few weeks, the plasma levels of total- and LDL-cholesterol gradually decreased in Mevalotin® group, whereas these levels did not significantly changed in Mevan® group within 16 weeks. The level of HDL-cholesterol in Mevan® group tended to increase but not in Mevalotin® group. The triglyceride level in Mevan® group changed as well as that in Mevalotin® group until 10 weeks after administration, and then gradually increased. The present results suggest that pharmaceutical properties of Mevan® are not always identical with those of Mevalotin®.
ノート
  • 伊達 英代, 寺内 正裕, 杉村 光永, 豊田 安基江, 松尾 健
    2009 年 129 巻 1 号 p. 163-172
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      A systematic analysis for 11 ingredients of oral hypoglycemic agent in health foods was established using three different analytical methods; i.e. thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and comparison of MS/MS spectra analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). In Normal-phase and reversed-phase TLC, each condition to separate and detect 10 ingredients except nateglinide was developed. On the other hand, 11 ingredients were detected qualitatively and quantitatively by HPLC. The recovery rates were 92-101% and each coefficient of variation was less than 5.4%. Then UV spectra were monitored using this HPLC method and furthermore MS/MS spectra of 11 ingredients were obtained by LC/MS/MS. Identification of each ingredient became precise and rapid by comparing UV and MS/MS spectra of standard solutions with that of extract solutions from health foods. Using this systematic analysis, glibenclamide was accurately determined and identified from health foods.
  • 田上 貴臣, 梶村 計志, 野村 千枝, 田口 修三, 岩上 正蔵
    原稿種別: Note
    2009 年 129 巻 1 号 p. 173-176
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      In Japan, maximum residue levels (MRL) have been set for eight pesticides (α-BHC, β-BHC, γ-BHC, δ-BHC (BHCs), p,p′-DDE, o,p′-DDT, p,p′-DDD, p,p′-DDT (DDTs)) in 14 crude drugs (below 0.2 ppm as total of BHCs, below 0.2 ppm as total of DDTs). There are fears that pesticides present in crude drugs for which MRL are set will be changed from BHCs and DDTs to other pesticides with MRL setting as the turning point. There are few surveys of pyrethroid pesticide in crude drugs distributed in Japan. The actual situation of pyrethroid pesticides in crude drugs distributed in Japan after setting MRL is not unclear and should be clarified. Although a method to analyze permethrin, cypermethrin and fenvalerate in 11 crude drugs was reported, it is not adequate because the recovery rates of permethrin, cypermethrin and fenvalerate from Cinnamomi cortex were very low and the method, including liquid-liquid partition is difficult. In this study, we developed a method using solid-phase extraction to analyze permethrin, cypermethrin and fenvalerate in Cinnamomi cortex with acceptable recovery rates. The sample solution was determined by gas chromatography/mass spectrometry with negative chemical ionization. The recovery rates of permethrin, cypermethrin and fenvalerate from Cinnamomi cortex were between 87.9 and 90.7%. Five samples of Cinnamomi cortex were analyzed according to the proposed method. No samples contained permethrin, cypermethrin and fenvalerate over detection limits. The proposed method could analyze permethrin, cypermethrin and fenvalerate in all crude drugs for which MRL are set.
資料
  • 足立 哲夫, 酒々井 真澄, 直井 国子, 神谷 哲朗, 原 宏和
    2009 年 129 巻 1 号 p. 177-182
    発行日: 2009/01/01
    公開日: 2009/01/01
    ジャーナル フリー
      To prepare for the introduction of the advanced problem-based learning (PBL) tutorial for higher-grade students under the six-year pharmacy curriculum, a trial of the tutorial was performed in a fourth-grade class under the former four-year curriculum in 2007. A questionnaire survey conducted to identify any problems in performing the tutorial revealed: 1) the number of students in each group was too large; 2) the contents of presentations seemed to overlap due to the limited number of task cases, which forced more than one group to address a particular case; and 3) the time-line from the day of product presentation to that of periodic examination was too short to hold a sufficient group discussion. In 2008, to resolve these problems: 1) the number of groups was increased to reduce the number of students in each group; 2) new task cases were added to decrease the number of groups addressing a particular case; and 3) an adequate time period was arranged between the days of product presentation and periodic examination. The survey conducted this year demonstrated that students' learning environment had been improved by these changes in the method of performing the tutorial, but also revealed new problems such as prolongation of the time required for product presentation and the difficulty levels of task cases. In addition, the usefulness of customer satisfaction (CS) analysis was demonstrated as a result of applying it to the data analysis of evaluation performed on group presentations.
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