巻号一覧
135 巻, 7 号
選択された号の論文の9件中1～9を表示しています
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誌上シンポジウム
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角田 慎一, 石井 明子2015 年 135 巻 7 号 p. 841-842
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーPDF形式でダウンロード (156K) -
鎌田 春彦2015 年 135 巻 7 号 p. 843-849
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーThe clinical use of cytokines is fairly limited because of their characteristics of having significant bioactivity and low stability, although some are useful biopharmaceuticals, such as interferon. Cytokines, which are secreted from various immune cells, show many kinds of bioactivities including unexpected activities; thus it would be desirable to regulate cytokine activity. Recently, we have developed a new drug delivery system (DDS) to create structural mutant cytokines using a phage display system. This system can produce functional mutant proteins that can bind their objective targets specifically. In this study, tumor necrosis factor (TNF) was used as a model cytokine to create agonist and antagonist activities against two TNF receptors TNFR1 and TNFR2, respectively. We created a phage library expressing mutant TNF, where the amino acids in the binding interface between TNF and TNF receptors were alternately exchanged. Affinity panning was performed at the optimum condition and the bioactivities of these mutant TNFs were analyzed to obtain the objective agonists or antagonists. The pharmacological activity and toxicity of these engineered TNF mutants could indicate their potential use as novel biopharmaceutical agents.
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浅野 竜太郎, 熊谷 泉2015 年 135 巻 7 号 p. 851-856
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーAlthough antibodies have been used as molecularly targeted agents for difficult-to-treat diseases such as cancers, the high production costs associated with mammalian expression systems continue to be a drawback. In addition, the clinical efficacy of conventional IgG antibodies is limited. Several types of recombinant antibody (e.g. fused with anticancer drugs, multivalent, or multispecific) have been designed in efforts to develop next-generation antibodies with higher functionality. We used protein engineering to construct several anticancer recombinant antibodies by developing bispecific antibodies that induced specific antitumor effects against cancer cells through the recruitment of lymphocytes. We found that a humanized small bispecific antibody (Ex3) that targets epidermal growth factor receptor on tumor cells and CD3 on T lymphocytes had marked anticancer activity. Furthermore, the function of Ex3 was enhanced by fusion with the human Fc region, domain rearrangement, multimerization, and affinity maturation; a combination of these modifications showed at least additive cytotoxic effects. Interestingly, merely rearranging the domain order of Ex3 induced substantial cytotoxic enhancements, even though the structural format remained the same. Here, we describe our efforts to develop highly functional bispecific antibodies as next-generation therapeutic antibodies using protein engineering.
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石井 明子, 多田 稔, 鈴木 琢雄, 川崎 ナナ2015 年 135 巻 7 号 p. 857-866
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーTherapeutic monoclonal antibodies (mAbs) exert their effects via binding to specific target molecules, which is expected to show rare off-target adverse reactions. However, nonclinical evaluation of mAbs is difficult because they often lack reactivity toward orthologous targets in animals. During the nonclinical evaluation of mAbs, not only the target molecules but fragment crystallizable (Fc) receptors, which regulate the immune effector functions and pharmacokinetic properties of mAbs, should be considered. In this review, factors for extrapolating nonclinical study results to clinical settings are discussed by focusing on Fc receptors. The human Fcγ receptor family consists of FcγRI, IIa, IIb, IIIa, and IIIb; Fcγ receptors in laboratory animals are structurally and functionally different from those in humans. In addition, interactions between human IgG-Fc, a component of therapeutic mAbs, and animal Fcγ receptors are still not fully understood. With regard to neonatal Fc receptor (FcRn), related molecules comprising the FcRn family are not known; however, critical amino acid residues involved in IgG binding are different between human and mouse. In case of next-generation mAbs with a novel structure or mode of action, knowledge from related drugs is limited. To ensure safety of next-generation mAbs, a thorough understanding of the differences in Fc receptors among species and the interactions between mAbs and Fc receptors is required, and the appropriateness of the nonclinical study design should be carefully examined prior to conducting clinical studies.
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総説
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水上 元2015 年 135 巻 7 号 p. 867-882
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーPlant secondary product glycosyltransferases belong to family 1 of the glycosyltransferase superfamily and mediate the transfer of a glycosyl residue from activated nucleotide sugars to lipophilic small molecules, thus affecting the solubility, stability and pharmacological activities of the sugar-accepting compounds. The biotechnological application of plant glycosyltransferases in glycoside synthesis has attracted attention because enzymatic glycosylation offers several advantages over chemical methods, including (1) avoiding the use of harsh conditions and toxic catalysts, (2) providing strict control of regio-and stereo-selectivity and (3) high efficiency. This review describes the in vivo and in vitro glycosylation of natural organic compounds using glycosyltransferases, focusing on our investigation of enzymatic synthesis of curcumin glycosides. Our current efforts toward functional characterization of some glycosyltransferases involved in the biosynthesis of iridoids and crocin, as well as in the sugar chain elongation of quercetin glucosides, are described. Finally, I describe the relationship of the structure of sugar chains and the intestinal absorption which was investigated using chemoenzymatically synthesized quercetin glycosides.
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森山 芳則2015 年 135 巻 7 号 p. 883-894
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーEukaryotic cells possess acidic compartments with pH ranging from 0.1-6.5. Studies in the last couple of decades indicated that the acid pool is established by vacuolar proton ATPase, and is essential for various physiological and pathological processes. I have identified the vacuolar ATPase as well as several secondary transporters which are energetically coupled with vacuolar ATPase. I have also established the protocol for analysis of the structure and function of transporter proteins applicable to essentially all known transporters. In this article, I am going to summarize this study and describe some topics.
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一般論文
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鈴木 亮平, 大津 史子, 後藤 伸之2015 年 135 巻 7 号 p. 895-916
発行日: 2015/07/01
公開日: 2015/07/01
ジャーナル フリーThe purpose of this study was to develop and validate estimate equations for preventing adverse drug reactions (ADRs). We conducted five case-control studies to identify individual risk factors and subjective symptoms associated with the following five ADRs: drug-induced ischemic heart disease; renal damage; muscle disorder; interstitial pneumonia; and leucopenia. We performed logistic regression analysis and obtained eight regression equations for each ADR. We converted these to ADR estimate equations for predicting the likelihood of ADRs. We randomly selected 50 cases with non-individual ADRs from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 65000 case reports of ADRs, and assigned these cases to a validation case group. We then calculated the predictive probability for 50 cases using the eight estimate equations for each ADR. The highest probability for each ADR was set as the probability of each ADR. If the probability was over 50%, the case was interpreted as ADR-positive. We calculated and evaluated the sensitivity, specificity, and positive likelihood ratio of this system. Sensitivity of the estimate equations for muscle disorder and interstitial pneumonia were ≥90%. Specificity and positive likelihood ratios of estimate equations for renal damage, interstitial pneumonia and leucopenia were ≥80% and ≥5, respectively. Our estimate equations thus showed high validity, and are therefore helpful for the prevention or early detection of ADRs.
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村井 ユリ子, 鈴木 裕之, 森 大, 田坂 英久, 鈴木 直人, 島田 美樹, 佐藤 博, 平澤 典保, 眞野 成康, 富岡 佳久2015 年 135 巻 7 号 p. 917-923
発行日: 2015/07/01
公開日: 2015/07/01
[早期公開] 公開日: 2015/04/28ジャーナル フリーThis study sought to determine whether a long-term case review (LTCR) program helped pharmacy students develop their abilities as pharmacists, and how their level of satisfaction changed. LTCRs were comprised of four elements: self-learning, one-on-one bedside training with advising pharmacists, daily group sessions including three members, and weekly plenary sessions (case conferences). This program conducted on-site training in a hospital for 21 fifth-year students. The students were divided into 7 groups. One member of each group was assigned to a ward for bedside training for three weeks, while other member(s) of the central pharmacy provided support through daily group sessions. Each week, students training in the wards delivered case presentations in the case conference. All students, advising pharmacists, and teachers participated in these weekly case conferences. Upon conclusion of the on-site training, a survey was conducted on the program's efficacy. Through information sharing during group discussions, and in case conferences, continuous patient follow up was possible regardless of students' training schedules in wards or in the central pharmacy. After introducing the LTCR, the mean satisfaction level for case conferences (as scored using a 5-point Likert-type scale) increased from 3.4 to 4.3. Students' levels of understanding also improved. Statistically significant increases in students' self-evaluation scores on professional awareness, presentation skills, and logical thinking were also observed. We concluded that the program helped students to gain practical experience, made them more aware of clinical issues, and improved their presentation skills. Through this program, the students gained clinical competency through a deep understanding of the clinical courses of diseases and patient-oriented pharmaceutical care.
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ケースレポート
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山村 恵子, 矢野 亨治, 廣岡 芳樹, 平敷 安希博, 室原 豊明, 山田 清文2015 年 135 巻 7 号 p. 925-927
発行日: 2015/07/01
公開日: 2015/07/01
[早期公開] 公開日: 2015/04/24ジャーナル フリーTo avoid major bleeding events in warfarin and S-1 combination therapy, PT-INR levels should be monitored frequently to allow for precise adjustments of the warfarin dose and to verify any side effects reported by the patient. We therefore developed a support system where outpatients obtain a home-measured PT-INR value using the CoaguChek® system and submit it along with details of any side effects to us via the Internet using their mobile phone. A 59-year-old man was started on warfarin (1.5 mg/d) and S-1 (100 mg/d), a combination preparation of tegafur, gimeracil, and oteracil potassium, to treat cholangiocarcinoma. The patient sent his data to the hospital pharmacist every two days after starting S-1 therapy. When the PT-INR was outside the target range of 1.5-2.7, the pharmacist, after consulting the physician, instructed the patient to change his warfarin dose by 0.5 mg. On day 24 after starting S-1, PT-INR had increased from 1.6 to 2.8, so the dose was decreased by 0.5 mg. Thereafter, the dose was adjusted by 0.5-1.0 mg during the observation period so that the patient was able to maintain the therapeutic range approximately 90% of the time. We anticipate this system can be applied to S-1 which interact with warfarin, thereby enabling safer anticoagulation therapy.
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