YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
130 巻, 2 号
選択された号の論文の19件中1~19を表示しています
誌上シンポジウム
  • 八木 清仁, 林 利光
    2010 年 130 巻 2 号 p. 141-142
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
  • 竹原 徹郎
    2010 年 130 巻 2 号 p. 143-156
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Antiviral therapy for chronic hepatitis C has advanced dramatically since the discovery of the hepatitis C virus and the introduction of interferon in early 1990s. An initial treatment regimen, 24 weeks of interferon monotherapy, achieved sustained virologic response, which is formally defined at 24 weeks after completion of the treatment, only for 5% of patients with genotype 1 high-viral load belonging to a difficult-to-treat group. Current standard therapy is a combination of pegylated interferon and ribavirin. Forty eight weeks of the combination therapy achieves successful viral eradication for 40-50% of genotype 1 patients while 24 weeks of that do so for 80% of genotype 2 patients. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response for genotype 1 patients, serving as recommendation criteria for extended duration, 72 weeks, of combination therapy. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for patients that do not respond to combination therapy. Hepatitis C is not just an infectious disease, but a potentially serious liver disease progressing to end-stage liver cirrhosis and hepatocellular carcinoma. Antiviral therapy should be considered from the view point of suppressing liver-related death in hepatitis C virus-infected patients.
  • 平田 雄一, 須藤 正幸, 小原 道法
    2010 年 130 巻 2 号 p. 157-161
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Hepatitis C virus (HCV) persists chronically in most infected patients, eventually causing chronic hepatitis, liver cirrhosis, and in some cases hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves efficacy in many patients, although it does not lead to sufficient achievements in genotype 1b patients. To aid in invention of new anti-HCV reagents, we focused on host factors that contributed to HCV lifecycle. We identified serine palmitoyltransferase inhibitor as an anti-HCV reagent through high-throughput screening using HCV replicon cells. We investigated the mechanism of anti-HCV effect of SPT inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft where replication of HCV occurs. We investigated the influence of SPT inhibitor to lipid rafts by analyzing the detergent-resistant membrane (DRM). The analysis showed that SPT inhibitor moved HCV RNA-dependent RNA polymerase (NS5B) to detergent-soluble fraction from DRM, and Biacore analysis indicated binding of sphingomyelin to NS5B. These results suggest that SPT inhibitor disrupts the interaction between NS5B and sphingomyelin. Moreover, we evaluated the anti-HCV effect of SPT inhibitor in vivo with humanized chimeric mice. SPT inhibitor led to rapid decline in serum HCV-RNA of about 1-2 log within 8 days. Furthermore, combination therapy of SPT inhibitor and PEG-IFN achieved about 3 log reduction in serum HCV-RNA.
  • 内田 恵理子, 山口 照英
    2010 年 130 巻 2 号 p. 163-169
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      The most important issue for the safety of biological products and blood products derived from human sources is how to prevent transmission of infectious agents. The hepatitis C virus (HCV) is a major public health problem due to its high prevalence. HCV is mainly transmitted by exposure to blood and highly infectious during the early window period with extremely low viral loads. Therefore it is important to develop more sensitive detection methods for HCV. In the case of blood products, both serological test and nucleic acid amplification test (NAT) are required to detect HCV. Since NAT is highly sensitive, establishment of a new standard is required for validation of NAT assay. NAT guideline and establishment of the standard for HCV RNA and HCV genotype panel is introduced in this review. On the other hand, to enhance the sensitivity of virus detection by NAT, a novel viral concentration method using polyethyleneimine (PEI)-conjugated magnetic beads (PEI beads) was developed. PEI beads concentration method is applicable to a wide range of viruses including HCV. Studies using the national standard for HCV RNA, HCV genotype panel and seroconversion panel, suggest that virus concentration method using PEI-beads is useful for improvement of the sensitivity of HCV detection by NAT and applicable to donor screening for HCV.
  • 林 京子, 林 利光, 李 貞範
    2010 年 130 巻 2 号 p. 171-176
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      The limited efficacy and significant clinical toxicity of combination interferone and ribavirin therapy have generated strong interest in developing novel inhibitors of hepatitis C virus (HCV) replication. Recently, a growing understanding of the structure and function of critical viral enzymes and the development of HCV replicons have accelerated the development of highly specific candidate antiviral agents. In the life cycle of HCV, enveloped virions bind and penetrate into host cell using viral envelope glycoproteins. In the cytoplasm, the viral RNA genome serves as mRNA, and produces viral protein as a long polyprotein that is cleaved by both host and viral proteases. Progeny virions assemble by budding into ER/Golgi apparatus, where the glycoproteins maturate, and are released at the cell surface. All stages of replication cycle from the attachment of virus to the release of progeny should be antiviral targets. We have searched for antiviral candidates from natural resources for about 20 years. So far, we have found several classes of compounds with unique antiviral action. Among them, anionic substances interfere with virus attachment and/or entry, several substances inhibit the maturation of virus-specific glycoproteins, low molecules can inhibit the virus release from infected cells, glycerol derivatives reduce the pathogenicity of virus, and some compounds exert virucidal action that impairs the ability of virus to infect host cells. These substances might be worthy to be evaluated as novel anti-HCV agents by using HCV replication systems in cultured cell lines.
  • 森井 孫俊, 酒井 秀紀
    2010 年 130 巻 2 号 p. 177
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
  • 鈴木 裕, 山崎 和生, 大保 貴嗣, Stefania DANKO
    2010 年 130 巻 2 号 p. 179-189
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Sarco(endo)plasmic reticulum Ca2+-ATPase is a representative member of P-type cation transporting ATPases and catalyzes Ca2+ transport coupled with ATP hydrolysis. The ATPase possesses three cytoplasmic domains (N, P, and A) and ten transmembrane helices (M1-M10). Ca2+ binding at the transport sites in the transmembrane domain activates the ATPase and then the catalytic aspartate is auto-phosphorylated to form the phosphorylated intermediate (EP). Structural and functional studies have shown that, during the isomerization of EP in the Ca2+ transport cycle, large motions of the three cytoplasmic domains take place, which then rearranges the transmembrane helices thereby destroying the Ca2+ binding sites, opening the lumenal gate, and thus releasing the Ca2+ into lumen. Stable structural analogues for the Ca2+-occluded and -released states of phosphorylated intermediates and for the transition and product states of the phosphorylation and dephosphorylation reactions were developed for biochemical and atomic-level structural studies to reveal the coupled changes in the catalytic and transport sites. Mutation studies identified the residues and structural regions essential for the structural changes and Ca2+ transport function. Genetic dysfunction of Ca2+-ATPase causes various isoform-specific diseases. In this manuscript, recent understanding of the Ca-ATPase will be reviewed.
  • 前田 正知
    2010 年 130 巻 2 号 p. 191-197
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      ATP synthases, widely distributed in bacteria, eukaryotic mitochondria and chloroplasts, are highly conserved multi-subunit complexes. Although the conserved acidic residue in the transmembrane helix of the c subunit functions in proton transport, the surrounding residues differ among species. Such divergence could lead to different regulatory modes since pH-dependent proton transport has been demonstrated in Escherichia coli with a c subunit carrying an additional acidic residue in the helix. There is further divergence in the number of c subunits that form the ring structure in F0. Recently, it was also suggested that certain chemicals recognize the a and c subunits of pathogenic bacterial F0. Since there may be structural divergence even in well-conserved ATP synthases, the c subunit-ring as well as the a subunit in F0 could be targets for drugs for specific bacterial species.
  • 篠原 康雄, 橋本 満, 木平 孝高, 大倉 一人, 真島 英司, 寺田 弘
    2010 年 130 巻 2 号 p. 199-204
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Mitochondrial ADP/ATP carrier (AAC) is a protein catalyzing the transport of adenine nucleotides across inner mitochondrial membrane. In this review article, we first briefly introduce structural and functional properties of this protein. Next, we describe the results of our recent studies on the difference in the C-terminal region between yeast type 2 AAC isoform and bovine type 1 AAC isoform. Furthermore, based on the reactivities of cysteine residues that replaced amino acids in the sixth transmembrane segment, the probable structural features of the C-terminal region of this carrier are discussed.
  • 阿部 一啓, 谷 一寿, 西澤 知宏, 藤吉 好則
    2010 年 130 巻 2 号 p. 205-210
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Acid secretion by the stomach results in a pH of about 1. This highly acidic environment is essential for digestion and also acts as a first barrier against bacterial and viral infections. Conversely, too much acid secretion causes gastric ulcer. The mechanism by which this massive proton gradient is generated is of considerable biomedical interest. In this review, we introduce the first molecular model for this remarkable biological phenomenon. The structure of H+,K+-ATPase at 6.5 Å resolution was determined by electron crystallography of two-dimensional crystals. The structure shows the catalytic α-subunit and the non-catalytic β-subunit in a pseudo-E2P conformation. Different from Na+,K+-ATPase, the N-terminal tail of the β-subunit is in direct contact with the phosphorylation domain of the α-subunit. This interaction may hold the phosphorylation domain in place, thus stabilizing the enzyme conformation and preventing the reverse reaction of the transport cycle. Indeed, truncation of the β-subunit N-terminus allowed the reverse reaction to occur. These results suggest that the N-terminal tail of the β-subunit functions as a “ratchet”, preventing inefficient transport and reverse-flow of protons. We can thus provide a mechanistic explanation for how the H+,K+-ATPase can generate a million-fold proton gradient across the gastric parietal cell membrane, the highest cation gradient known in any mammalian tissue.
総説
一般論文
  • Rajneet KAUR, Amteshwar Singh JAGGI, Nirmal SINGH
    原稿種別: Regular Article
    2010 年 130 巻 2 号 p. 215-221
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Stress preconditioning has been documented to confer on gastroprotective effects on stress-induced gastric ulcerations. However, the effects of prior exposure of stress preconditioning episodes on stress-induced behavioral changes have not been explored yet. Therefore the present study was designed to investigate the ameliorative effects of stress preconditioning in immobilization stress-induced behavioral alterations in rats. The rats were subjected to restrain stress by placing in restrainer (5.5 cm in diameter and 18 cm in length) for 3.5 h. Stress preconditioning was induced by subjecting the rats to two cycles of restraint and restrain-free periods of 15 min each. Furthermore, a similar type of stress preconditioning was induced using different time cycles of 30 and 45 min. The extent and severity of the stress-induced behavioral alterations were assessed using different behavioral tests such as hole-board test, social interaction test, open field test, and actophotometer. Restrain stress resulted in decrease in locomotor activity, frequency of head dips and rearing in hole board, line crossing and rearing in open field, and decreased following and increased avoidance in social interaction test. Stress preconditioning with two cycles of 15, 30 or 45 min respectively, did not attenuate stress-induced behavioral changes to any extent. It may be concluded that stress preconditioning does not seem to confer any protective effect in modulating restrain stress-induced behavioral alterations.
  • 河上 強志, 伊佐間 和郎, 中島 晴信, 大嶋 智子, 土屋 利江, 松岡 厚子
    2010 年 130 巻 2 号 p. 223-235
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      The use of tributyltin (TBT) and triphenyltin (TPT) in some household products are prohibited by “Act on the Control of Household Products Containing Harmful Substances” in Japan. In this study, methods for determination of TBT and TPT in water soluble paints and adhesives were developed by GC-MS. These compounds in paints and adhesives, which were mainly composed of vinyl acetate, urethane and acryl resins, and chloroprene rubber, were firstly extracted with HCl-acetone, and then extracted with hexane. On the other hand, the adhesive composed of natural rubber was firstly dispersed in water before acidification. The organotins were extracted with hexane from this solution and then these compounds were extracted with acetonitrile from hexane extract. These extracts were purified by a florisil cartridge column after ethyl-derivation with sodium tetraethylborate, and analyzed by GC-MS. The quantifications using deuterated compound of both organotins as surrogate standard were conducted, and good results were obtained. The recoveries were 81 to 118% and the coefficients of variation were 0.83 to 4.3% (TBT and TPT added; 5 μg/g). The method quantification limits were 0.0090 to 0.025 μg/g, which were lower than those of an official method. These methods were applied to monobutyltin (MBT), dibutyltin (DBT), monophenyltin (MPT), and diphenyltin (DPT). DBT and DPT in paints and adhesives were quantified, except for DPT in natural rubber. These methods were applied to commercial products. DBT was detected at low concentrations (t.r.-0.19 μg/g) in some paint samples, while TBT and TPT were not detected in all samples.
  • 吉松 嘉代, 北澤 尚, 河野 徳昭, 飯田 修, 川原 信夫
    2010 年 130 巻 2 号 p. 237-246
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Illegal cannabis (Cannabis sativa L.) cultivation is still a social problem worldwide. Fifty inquiries on cannabis that Research Center for Medicinal Plant Resources (Tsukuba Division) received between January 1, 2000 and March 31, 2009 were itemized in to 8 categories; 1: seed identification, 2: plant identification, 3: indoor cultivation, 4: outdoor cultivation, 5: germination and growth characteristics, 6: expected amount of cannabis products derived from illegal cannabis plant, 7: non-narcotic cannabis and 8: usage of medicinal cannabis. Top three inquiries were 1: seed identification (16 cases), 3: indoor cultivation (10 cases) and 4: outdoor cultivation (6 cases). Characteristics of cannabis, namely seed morphology, germination and growth characteristics, and distinction from kenaf (Hibiscus cannabinus L.) that is frequently misjudged as cannabis, were studied to contribute for prevention of illegal cannabis cultivation.
ノート
  • 皆川 信子, 上原 麻理子, 関 志織, 新田 あゆみ, 古河原 健人
    2010 年 130 巻 2 号 p. 247-251
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Atovaquone, an analog of ubiquinone, binds tightly to the ubiquinol oxidation site (Qo site) of parasite cytochrome bc1 complex to inhibit electron transport at concentrations far lower than those at which the mammalian system is affected. The mode of action is thought similar to that of myxothiazol. To treat Pneumocystis jirovecii and Plasmodium falciparum infections, atovaquone has been used worldwide whereas it is unapproved in Japan. Since the pathogenic Candida species fungi seem resistant to atovaquone, this drug is not clinically available for candidosis, particularly deep mycosis. We examined the effects of atovaquone on cellular respiration and in vitro growth of C. albicans to explore a new therapeutic possibility for fungal infections. Atovaquone strongly inhibited glucose-dependent cellular respiration similarly to antimycin A, stigmatellin, and myxothiazol, specific bc1 complex inhibitors. However, atovaquone suppressed glucose-dependent cell growth to a much lesser extent versus the comparator agents. When added alone, lithium exerted slight growth inhibition. The combined addition of lithium with atovaquone showed a significant increase in inhibition of growth. Although the way lithium acts synergistically with atovaquone remains to be elucidated, our results suggest a new therapeutic possibility of this combination for the treatment of candidosis.
資料
  • 濃沼 政美, 宮崎 美子, 湯本 哲郎, 佐藤 透, 鈴木 慎一郎, 中島 博史, 荒川 基記, 小池 勝也, 佐藤 秀昭, 中村 均
    2010 年 130 巻 2 号 p. 253-261
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      The purpose of this study was to clarify the subconsciousness of hospital pharmacists regarding them practicing drip infusion or blood drawing for therapeutic drug monitoring (TDM), etc. We conducted a mail-in survey targeting 476 randomly-selected hospital pharmacists. In our survey sheet we presented our “hypothetical condition” i.e., “that medical practices such as drip infusion or blood drawing for TDM by hospital pharmacists be legally allowed” and we asked them 23 items about the pros and cons of this hypothetical condition and its influence on medical practice. Then, using factor analysis, we searched for the subconsciousness of hospital pharmacists from their answers to the 23 items. We then analyzed the causal association between the factors extracted from the survey and the pros and cons of the “hypothetical condition” using logistic regression analysis. 47.7% of respondents agreed to the “hypothetical condition”. The results of this research provided 5 factors, consisting of “expectation of medical care and society”, “temperament of pharmacists”, “pharmacotherapy”, “employment”, and “medical team”. We understood from the result of logistic regression analysis that hospital pharmacists subconsciously had two kinds of expectation, i.e., expectation about medical care and society, and about qualitative improvement of pharmacotherapy, as their background when they decided to agree to themselves practicing drip infusion or blood drawing for TDM, etc.
  • 内山 奈穂子, 宮澤 法政, 河村 麻衣子, 花尻(木倉) 瑠理, 合田 幸広
    2010 年 130 巻 2 号 p. 263-270
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Thirty-two psychotropic substances were listed as designated substances (Shitei-Yakubutsu, 31 compounds and 1 plant) in Japan by the Pharmaceutical Affairs Law in April 2007 for preventing the abuse of these substances. Subsequently, other psychoactive compounds were also added to this category, 40 substances (classified as 12 tryptamines, 17 phenethylamines, 3 piperazines, 6 alkyl nitrites, 1 diterpene and 1 plant) are controlled as designated substances as of July 2009. However, new designer drugs are still distributed in illegal drug market according to the results of our annual survey. This study presents the analysis of four newly distributed designer drugs detected from two products, which were purchased from October 2008 to February 2009 in Japan. As the results of NMR, GC-MS and LC-MS analyses, three phenethylamine derivertives, 1-(2-fluorophenyl)-N-methylpropan-2-amine (N-Me-2-FMP), 1-(2,5-dimethoxy-4-isopropylsulfanylphenyl)propan-2-amine (ALEPH-4) and 1-(2,5-dimethoxy-4-nitrophenyl)propan-2-amine (DON) and a tryptamine derivative, N-ethyl-5-methoxy-N-propyltryptamine (5-MeO-EPT), were detected. N-Me-2-FMP and 5-MeO-EPT were newly identified in this study. Additionally, ALEPH-4 and DON were found as novel illegal drugs distributed in Japan.
  • 朝比奈 泰子, 堀 里子, 澤田 康文
    2010 年 130 巻 2 号 p. 271-275
    発行日: 2010/02/01
    公開日: 2010/02/01
    ジャーナル フリー
      Hyperkalemia is common in patients with renal disease, and is sometimes caused by dietary potassium intake. We aimed to determine and compare the content of potassium in nine brands of glucosamine supplements sold in the Japanese market and via the Internet. The potassium content was 0.165-3 mg per daily dose in Japanese products, which contained glucosamine hydrochloride or N-acetylglucosamine, while the content in foreign products, in which glucosamine was sulfated, was 197-280 mg. Our results show that the potassium content in glucosamine sulfate supplements can correspond to 20% of the maximum daily intake of potassium by patients on hemodialysis, because the products sometimes contain glucosamine as glucosamine sulfate potassium chloride for stabilization. Although it is not permitted to sell glucosamine sulfate as food in Japan, consumers can easily buy foreign products that contain glucosamine sulfate via the Internet, and those products rarely indicate the potassium content. Health professionals should pay attention to patients' use of glucosamine supplements, especially when patients' dietary potassium intake needs to be restricted.
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