YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
136 巻 , 11 号
選択された号の論文の14件中1~14を表示しています
総説
  • 平野 圭一
    2016 年 136 巻 11 号 p. 1455-1468
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     We have developed regio- and chemoselective heteroelement-introducing reactions based on ate complex formation. This review is focused on novelly designed reactive species for efficient access to perfluoroalkylated aliphatic and aromatic compounds as well as Csp2-borylated compounds.
  • 寺田 智祐
    2016 年 136 巻 11 号 p. 1469-1476
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     After the year 2000, the treatment of cancer remarkably changed, including the development of outpatient cancer chemotherapy. Meanwhile, we have encountered many clinical problems related to cancer patient pharmacy services. To resolve these problems, I have tried to establish the individualized and optimal cancer pharmacotherapy utilizing the findings of basic research. In this review, three topics of my research will be introduced. 1) In 2005, information regarding the genetic polymorphism of UGT1A1*28 was described in the package insert of the drug irinotecan in the United States. At that time, however, there was little similar information for Japanese patients. Through clinical research, we demonstrated that UGT1A1*6 was a significant factor for neutropenia, as induced by irinotecan. 2) Tyrosine kinase inhibitors are mainly used at a fixed dose, but wide interpatient variability has been observed relative to their pharmacokinetics and/or pharmacodynamics. To overcome these variations, clinical and basic pharmacological research on erlotinib, sorafenib and sunitinib was carried out. Especially, in sunitinib therapy, we demonstrated that the breast cancer resistant protein in the intestine functions as a limiting factor for oral absorption, and that therapeutic drug monitoring could be helpful for avoiding severe toxicities, resulting in prolonged progression-free survival. 3) We quantitatively assessed side effect management by pharmacist intervention for outpatient chemotherapy. We calculated the improvement ratio between before and after pharmacist intervention, and found that 135 suggestions (50.8%) led to significant improvements, indicating that pharmacist intervention could be useful for attenuating the side effects of cancer chemotherapies.
  • 中村 孝司
    2016 年 136 巻 11 号 p. 1477-1484
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     Delivery systems are a powerful technology for enhancing the effect of cancer immunotherapy. We have been in the process of developing lipid-based delivery systems for controlling the physical properties and dynamics of immunofunctional molecules such as antigens and adjuvants. The lipid nanoparticulation of these molecules improves their physical properties, resulting in a good water dispensability, greater stability, and small size. The cell wall skeleton of bacille Calmette-Guerin (BCG-CWS) could be used to replace live BCG as a drug for treating bladder cancer, but problems associated with the physical properties of BCG-CWS have prevented its use. To overcome such problems, we developed a novel packaging method that permits BCG-CWS to be encapsulated into lipid nanoparticles, which induce antitumor responses against bladder cancer. Lipid nanoparticulation also improves the intracellular trafficking and biodistribution of immunofunctional molecules. Cyclic di-GMP (c-di-GMP) is an adjuvant that is recognized by the cytosolic sensor. However, c-di-GMP cannot pass through the cell membrane. We encapsulated c-di-GMP into lipid nanoparticles containing a pH-responsive lipid that was developed in our laboratory and achieved efficient cytosolic delivery and the induction of antitumor immunity. Furthermore, we are attempting to control the functions of immune cells by RNA interference. We have recently succeeded in the efficient delivery of small interfering RNA into mouse dendritic cells (DCs), which led to the enhancement of antitumor activity of DCs. In this review, our recent efforts regarding cancer immunotherapy using lipid-based nanoparticles are reviewed.
  • 町田 拓自
    2016 年 136 巻 11 号 p. 1485-1490
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression is induced by interleukin-1β (IL-1β) stimulation in vascular smooth muscle cells (VSMCs), resulting in the production of nitric oxide and prostaglandins such as PGI2. The expression of iNOS and COX-2 in cultured VSMCs isolated from 6-7-week-old stroke-prone spontaneously hypertensive rats (SHRSP) is significantly lower than in cells of normotensive Wistar Kyoto rats (WKY). These reductions are also found in cells exposed to pulsatile atmospheric pressure between 80-160 mmHg at a rate of 4 cycles/min, which simulates systolic hypertension. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, potentiates IL-1β-induced iNOS and COX-2 expression in VSMCs isolated from WKY, but not those from SHRSP. In response to endothelial injury at a local site, iNOS and COX-2 induction in VSMCs may function primarily as a defensive and compensatory mechanism for endothelial dysfunction by preventing the development of pathological conditions. Thus, in certain pathological conditions associated with hypertension, vascular walls with reduced iNOS and COX-2 expression may aggravate or initiate further vascular injury. In this situation, DHA may contribute to maintaining homeostasis in VSMCs by potentiating iNOS and COX-2 expression. Using cells isolated from a genetic pathological animal model alongside cells exposed to experimental pathological conditions can be an effective tool for the analysis of cell response to hypertension and exploring pharmacological modes of action in vitro.
  • 喜多村 徳昭
    2016 年 136 巻 11 号 p. 1491-1499
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     Nucleic acid-based drugs (NABDs) have recently attracted considerable attention as next-generation medicines, following the development of low molecular-weight and antibody drugs, because it is likely that they will have fewer side effects and greater target specificity than conventional medicines. Short double-stranded RNAs contain a 2-nucleotide overhang at the 3′-end of each strand. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) inhibit gene expression by RNA interference (RNAi) and thus have great potential as NABDs. However, naked RNA strands have many problems that hinder their application as therapeutics, such as their rapid degradation in biological fluids, poor cellular uptake, and off-target effects. Therefore, artificially modified siRNAs and miRNAs have been studied extensively in an effort to overcome these problems. In this review, I summarize my recent studies on the synthesis of nucleic acid mimics and their application in RNAi-based medicine. The following two topics are specifically discussed: 1) the design and synthesis of chemically modified functional RNAs bearing nucleic acid mimics at their 3′-overhang region, which plays a key role in RNAi; and 2) the practical, reliable synthesis of nucleic acid mimics containing ethynyl groups.
  • 髙橋 達雄
    2016 年 136 巻 11 号 p. 1501-1508
    発行日: 2016年
    公開日: 2016/11/01
    ジャーナル フリー
     Site-specific drug delivery to bone is considered achievable using acidic amino acid (L-Asp or L-Glu) homopeptides known as acidic oligopeptides. We found that fluorescence-labeled acidic oligopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged enzymes (tissue-nonspecific alkaline phosphatase, β-glucuronidase, and N-acetylgalactosamine-6-sulfate sulfatase) and decoy receptors (endogenous secretory receptor for advanced glycation end products and etanercept) to assess whether these would improve therapeutic efficacy. The L-Asp hexapeptide-tagged drugs, including enzymes and decoy receptors, were efficiently delivered to bone in comparison with the untagged drugs. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged drugs on bone and joint disorders, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug from the acidic oligopeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs.
  • 町谷 充洋
    2016 年 136 巻 11 号 p. 1509-1515
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     The adenovirus (Ad) genome encodes two small noncoding RNAs, VA-RNA I and II, which support Ad replication by antagonizing the antiviral action associated with the Ad-induced activation of double-stranded RNA-dependent protein kinase (PKR). VA-RNAs are also processed in a manner similar to microRNAs (miRNAs), resulting in the production of VA-RNA-derived miRNAs (mivaRNAs). mivaRNAs are incorporated into the RNA-induced silencing complex (RISC) and exhibit posttranscriptional silencing in a manner similar to miRNAs. However, it remained to be clarified whether Dicer-mediated processing of VA-RNAs and the subsequent production of mivaRNAs were crucial for Ad replication. Recently, we have found that Dicer efficiently suppresses Ad replication via cleavage of VA-RNAs to mivaRNAs. Based on these findings, we have developed an oncolytic Ad that shows tumor cell-specific replication and carries an expression cassette of short-hairpin RNA (shRNA) against Dicer (shDicer). The oncolytic Ad expressing shDicer exhibited more efficient replication and oncolytic activity both in vitro and in vivo. In addition, we demonstrated that shRNA-mediated RNA interference is competitively inhibited by VA-RNAs. A replication-incompetent Ad vector lacking VA-RNA expression (AdΔVR vector) exhibited superior knockdown efficiencies compared with a conventional Ad vector, indicating that an shRNA-expressing AdΔVR vector is a powerful framework for shRNA-mediated knockdown. We believe that functional analyses of Ad-encoded genes, including VA-RNAs, could lead to the development of novel recombinant Ads.
  • 山岡 庸介
    2016 年 136 巻 11 号 p. 1517-1523
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     A potassium base-promoted formal [2+2] cycloaddition of 2-acyl-2′-vinyl-1,1′-biaryls was developed to afford benzo-fused polycyclic cyclobutanols in a highly stereoselective manner. We demonstrated synthesis of substituted polycyclic aromatic hydrocarbons and these heterocyclic derivatives via this cyclization, followed by an acid-promoted rearrangement. Furthermore, asymmetric total synthesis of phenanthroindolizidine alkaloid (−)-tylophorine was achieved using our methodology and late-stage asymmetric hydrogenation of a cyclic imine.
  • 田邊 知孝
    2016 年 136 巻 11 号 p. 1525-1532
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     The genus Vibrio includes >70 species, of which roughly a dozen cause vibriosis such as gastroenteritis, wound infections, and septicemia. Most bacteria, including Vibrio species, require iron for survival and growth. However, the bioavailability of iron is extremely low because it is usually present as an insoluble ferric complex in an aerobic environment or is bound to iron-binding proteins in mammalian hosts. Therefore many bacteria have developed iron acquisition systems, including biosynthesis and secretion of low-molecular-mass iron-chelating compounds called siderophores, and uptake of iron-bound siderophores into bacterial cells through specific active transport systems. Vibrio parahaemolyticus, a major pathogenic Vibrio species, contains multiple iron-acquisition systems mediated by its own siderophore vibrioferrin and several xenosiderophores produced by other microorganisms. In this review, I have focused on the transcriptional and posttranscriptional regulation of genes encoding iron acquisition systems in V. parahaemolyticus. All genes involved in its iron acquisition systems are repressed by Fur, which acts as a ferrous-dependent transcriptional repressor. Furthermore, the stability of polycistronic mRNA involved in vibrioferrin biosynthesis is positively regulated by a small RNA, RyhB, which is repressed by Fur. Expression of PeuA receptor required for utilization of a xenosiderophore, enterobactin, occurs under iron-limiting conditions at alkaline pH. PeuA expression is induced by a two-component regulatory system, PeuRS, which enhances expression of an alternative peuA transcript without an intrinsic translation-inhibitory structure in response to changes in alkaline pH.
  • 兒玉 幸修
    2016 年 136 巻 11 号 p. 1533-1539
    発行日: 2016年
    公開日: 2016/11/01
    ジャーナル フリー
     Nucleic acids are expected as novel effective medicines, although they require a drug delivery system (DDS). Complexes of nucleic acids with cationic liposomes and cationic polymers have been mainly used as DDS for clinical use. However, most cationic complexes have disadvantages such as strong cytotoxicity and low biocompatibility. We previously found that a plasmid DNA (pDNA) complex coated with biodegradable γ-polyglutamic acid (γ-PGA) provided adequate gene expression without cytotoxicity. Based on these results, we developed a new DDS (multi-functional Nano-device) of pDNA using biodegradable polyamino acids. A typical cationic polyamino acid, poly-L-lysine (PLL), was complexed with pDNA. The binary complexes, however, showed low gene expression and high cytotoxicity. Gene expression was enhanced by addition of poly-L-histidine (PLH) to the binary complexes. PLH can increase endosome escape of the complexes by inducing pH-buffering effects. The quaternary complexes (pDNA-PLL-PLH-γ-PGA complexes) exhibited high gene expression and low cytotoxicity. Furthermore, we used dendrigraft poly-L-lysine (DGL) instead of PLL and PLH to enhance gene expression. DGL had sterically congested cations and was biodegradable. The ternary complexes (pDNA-DGL-γ-PGA complexes) exhibited markedly high gene expression and low cytotoxicity. The pDNA-DGL-γ-PGA complexes also had high gene expression in the marginal zone (rich dendritic cells) of the spleen after intravenous injection into mice. These results indicate that pDNA-DGL-γ-PGA complexes may be useful as vaccine vectors. Therefore we prepared a novel malaria DNA vaccine using Plasmodium yoelii GPI8p-transamidase-related protein pDNA (PyTAM). The PyTAM-DGL-γ-PGA complexes markedly improved survival time of model mice infected with malaria.
一般論文
  • 石井 正和, 加藤 大貴, 石橋 正祥, 市川 瑞季, 黒川 信二, 塚田 節郎, 笠井 英世, 木内 祐二, 巖本 三壽
    2016 年 136 巻 11 号 p. 1541-1555
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     We herein analyzed the issues that pharmacists in a community pharmacy in peacetime need to prepare for regarding headache medical care in emergencies (the state that supply of medical supplies is difficult) using a questionnaire intended for doctors and pharmacists in a community pharmacy. Recovery rates were 48.0% (96/200) for doctors and 37.3% (112/300) for pharmacists. In order to distinguish between patients for whom pharmacists need to “recommend OTC drugs” and those who need to be encouraged “to consult a hospital or clinic”, doctors indicated that pharmacists need to use an “assistance tool to diagnosis headaches, such as a migraine screener” and “guidelines for chronic headaches”. However, few pharmacists used these tools. Approximately 66.7% of doctors indicated that it is “meaningful” for pharmacists to distinguish patients with headaches. Moreover, doctors indicated the need for guidance by pharmacists in peacetime regarding headache medical care in emergencies. Although 73.2% of pharmacists instructed the patients with headaches of the importance of medication notebooks in emergencies, guidance (“understanding the triggers of headaches”, “understanding the importance of removing the cause of the headache”, “standing OTC drugs” and “standing prescription drugs”) by pharmacists to prepare for an emergency was insufficient. These results provide useful information to improve the efforts by pharmacists in community pharmacies in peacetime for headache medical care in emergencies.
ノート
  • 小林 亮, 大友 慎也, 芝 祐輔, 海老沼 慶一, 須藤 俊明
    2016 年 136 巻 11 号 p. 1557-1562
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     According to a recent study and meta-analysis, trough levels of >10 μg/mL teicoplanin (TEIC) may be acceptable for the treatment of uncomplicated infection, but no method of TEIC personalized medicine has been established. Vancomycin (VCM) and TEIC are glycopeptide antibiotic agents effective against methicillin-resistance Staphyloccocus aureus. This study aimed to establish TEIC personalized medicine at a steady state calculated by VCM pharmacokinetic parameters. Bayesian forecasting and population mean methods were employed to estimate individual total VCM clearance (CL) using existing population pharmacokinetics (PPK) parameter, and the differences between the CL calculated by these two methods were defined as ΔCL. Serum drug concentration data for patients treated with TEIC were collected at a steady state concentration (>96 h post infusion). There was a significant relationship between the prediction error of TEIC trough level and ΔCL. The relation between ΔCL and TEIC trough concentration at steady state was used to develop the following equation to determine the maintenance dose: TEIC (μg/mL)=1.1119X−6.124ΔCL+3.9164 (X is defined as TEIC trough concentration calculated from the PPK parameter). The results of this study indicated that it is possible to improve the prediction error of TEIC trough concentration at a steady state for patients who have received VCM therapy.
  • 松村 美奈, 中山 拓人, 寒水 孝司
    2016 年 136 巻 11 号 p. 1563-1571
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     A survey of introductory statistics courses at Japanese medical schools was published as a report in 2014. To obtain a complete understanding of the way in which statistics is taught at the university level in Japan, it is important to extend this survey to related fields, including pharmacy, dentistry, and nursing. The current study investigates the introductory statistics courses offered by faculties of pharmaceutical sciences (six-year programs) at Japanese universities, comparing the features of these courses with those studied in the survey of medical schools. We collected relevant data from the online syllabi of statistics courses published on the websites of 71 universities. The survey items included basic course information (for example, the course names, the targeted student grades, the number of credits, and course classification), textbooks, handouts, the doctoral subject and employment status of each lecturer, and course contents. The period surveyed was July-September 2015. We found that these 71 universities offered a total of 128 statistics courses. There were 67 course names, the most common of which was “biostatistics (iryou toukeigaku).” About half of the courses were designed for first- or second-year students. Students earned fewer than two credits. There were 62 different types of textbooks. The lecturers held doctoral degrees in 18 different subjects, the most common being a doctorate in pharmacy or science. Some course content differed, reflecting the lecturers' academic specialties. The content of introductory statistics courses taught in pharmaceutical science programs also differed slightly from the equivalent content taught in medical schools.
  • 辻 敏和, 永田 健一郎, 川尻 雄大, 山田 孝明, 入佐 俊弘, 村上 裕子, 金谷 朗子, 江頭 伸昭, 増田 智先
    2016 年 136 巻 11 号 p. 1573-1584
    発行日: 2016/11/01
    公開日: 2016/11/01
    ジャーナル フリー
     There are many reports regarding various medical institutions' attempts at the prevention of dispensing errors. However, the relationship between occurrence timing of dispensing errors and subsequent danger to patients has not been studied under the situation according to the classification of drugs by efficacy. Therefore, we analyzed the relationship between position and time regarding the occurrence of dispensing errors. Furthermore, we investigated the relationship between occurrence timing of them and danger to patients. In this study, dispensing errors and incidents in three categories (drug name errors, drug strength errors, drug count errors) were classified into two groups in terms of its drug efficacy (efficacy similarity (−) group, efficacy similarity (+) group), into three classes in terms of the occurrence timing of dispensing errors (initial phase errors, middle phase errors, final phase errors). Then, the rates of damage shifting from “dispensing errors” to “damage to patients” were compared as an index of danger between two groups and among three classes. Consequently, the rate of damage in “efficacy similarity (−) group” was significantly higher than that in “efficacy similarity (+) group”. Furthermore, the rate of damage is the highest in “initial phase errors”, the lowest in “final phase errors” among three classes. From the results of this study, it became clear that the earlier the timing of dispensing errors occurs, the more severe the damage to patients becomes.
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