YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
141 巻, 11 号
選択された号の論文の12件中1~12を表示しています
受賞総説
  • 藤井 拓人
    2021 年 141 巻 11 号 p. 1217-1222
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    P-type ion pumps (P-type ATPases) are involved in various fundamental biological processes. For example, the gastric proton pump (H+,K+-ATPase) and sodium pump (Na+,K+-ATPase) are responsible for secretion of gastric acid and maintenance of cell membrane potential, respectively. In this review, we summarize three topics of our studies. The first topic is gastric H+,K+-ATPase associated with Cl-transporting proteins (Cl/H+ exchanger ClC-5 and K+-Cl cotransporter KCC4). In gastric parietal cells, we found that ClC-5 is predominantly expressed in intracellular tubulovesicles and that KCC4 is predominantly expressed in the apical membrane. Gastric acid (HCl) secretion may be accomplished by the two different complexes of H+,K+-ATPase and Cl-transporting protein. The second topic focuses on the Na+,K+-ATPase α1-isoform (α1NaK) associated with the volume-regulated anion channel (VRAC). In the cholesterol-enriched membrane microdomains of human cancer cells, we found that α1NaK has a receptor-like (non-pumping) function and that binding of low concentrations (nM level) of cardiac glycosides to α1NaK activates VRAC and exerts anti-cancer effects without affecting the pumping function of α1NaK. The third topic is the Na+,K+-ATPase α3-isoform (α3NaK) in human cancer cells. We found that α3NaK is abnormally expressed in the intracellular vesicles of attached cancer cells and that the plasma membrane translocation of α3NaK upon cell detachment contributes to the survival of metastatic cancer cells. Our results indicate that multiple functions of P-type ion pumps are generated by different membrane environments and their associated proteins.

  • 内山 博雅
    2021 年 141 巻 11 号 p. 1223-1228
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    The coamorphous formation between naringenin (NRG) and hesperetin (HPT) was investigated with the aim of enhancing their solubility and membrane permeability. In addition, application to emulsion of coamorphous was investigated. The melt-quenched particles (MQPs) of NRG and HPT were prepared in a range of molar ratios of NRG/HPT (3/1 to 1/3). All MQPs showed the amorphous state and single glass transition temperature. MQPs of NRG/HPT (1/1) could kept the amorphous state under storage. On the other hand, other MQPs recrystallized from the compound with a higher molar ratio. These results indicated that NRG and HPT formed the coamorphous at a molar ratio of 1 to 1. The coamorphous formation enhanced the apparent solubilities of NRG and HPT in aqueous media. Furthermore, MQPs of NRG/HPT (1/1) increased a permeated amount of NRG and HPT via the synthetic membrane in Franz Cell. When the solubility of NRG and HPT in oil components were investigated, the MQPs of NRG/HPT (1/1) enhanced the solubility of both compounds. This study highlighted the importance of coamorphous formation as a formulation to enhance solubility in oil components and aqueous media, and membrane permeability of both NRG and HPT.

  • 幸 龍三郎
    2021 年 141 巻 11 号 p. 1229-1234
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Epithelial-mesenchymal transition (EMT) is an important program in epithelial cancer cells to acquire the motility and invasion, which promotes cancer metastasis to remote organs. EMT is induced by various secreted factors, such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF). TGF-β ligand activates Smad-dependent and -independent pathways by binding to TGF-β receptors. In Smad-dependent pathway, the activated TGF-β receptor phosphorylates Smad2/3 and accelerates its association with Smad4, leading to their nuclear translocation. Smad2/3-4 complex promotes the expression of EMT-inducing transcription factors, such as Snail and Slug. In Smad-independent pathway, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are activated and required for TGF-β-induced EMT. Smad-independent pathway is similar to downstream of receptor tyrosine kinases, and therefore EGFR signaling is known to induce EMT synergize with TGF-β signaling. We explored a new mechanism of EGFR-mediated activation of TGF-β signaling and found that c-Abl kinase activates TGF-β signaling. Based on our proteomic analysis, we identified several TGF-β signaling molecules as nuclear c-Abl substrates, including transcriptional intermediary factor 1-γ (TIF1γ/TRIM33/Ectodermin), a suppressor of TGF-β signaling. c-Abl-mediated phosphorylation of TIF1γ inhibits its binding to Smad3, thereby increasing Smad3's transcriptional activity and promoting EMT. TIF1γ phosphorylation is also involved in the EGFR-caused aberrant activation of TGF-β signaling, suggesting that EGFR/c-Abl pathway activates TGF-β signaling through phosphorylation of nuclear substrates and promotes EMT. Our findings provide new insights into the activation machinery of TGF-β signaling, and further studies are required to clarify the clinical significance of the EGFR/c-Abl pathway in cancer metastasis.

  • 井上 大輔
    2021 年 141 巻 11 号 p. 1235-1240
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    The nasal drug application has drawn much attention as the strategy for the delivery route of many drug modalities such as the poorly absorbed drugs, peptides, nucleic acid, and central nervous system drugs. The absorption of drug after intranasal (IN) application depends on the nasal residence time of applied drug, affected by mucociliary clearance (MC). MC is a decisive factor in the nasal absorption of drug. We describe the establishment of in vitro evaluation system of nasal MC via the moving velocity of a marker particle on nasal mucosa, and the development of the pharmacokinetic model to which in vitro parameters on nasal MC was incorporated to enable the prediction of drug absorption after IN application. Moreover, the pharmacokinetics of norfloxacin after IN application was investigated using MC-modified rats pretreated with MC modulators. Nasal absorption fluctuated due to changes in the nasal residence time of drug in response to changes in MC. The prediction system enables quantitative evaluation of changes in drug absorption associated with MC fluctuations. In addition, for a precise prediction system for drug absorption after IN application from the drug absorption model, the relationships between in vitro drug permeability through Calu-3 layers, in vivo transnasal permeation of drug and in vivo bioavailability after IN application were evaluated. The significant correlations between these parameters were obtained, suggesting that transnasal permeability and drug absorption after IN application can be predicted from in vitro membrane permeability.

  • 安藤 英紀
    2021 年 141 巻 11 号 p. 1241-1245
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    In the development of drug delivery system (DDS)-based anticancer drugs, the techniques for the intratumor mapping and quantification of active pharmaceutical ingredients (API) in pharmaceuticals must be pivotal for predicting pharmacological effects and adverse events. X-ray fluorescence spectrometry (XRF) is a potent analytical tool for mapping/quantifying platinum pharmaceutics such as oxaliplatin (l-OHP) and its liposomal formulation. In recent studies, we employed XRF to visualize the intratumor micro-distribution of l-OHP in a tumor-bearing model mouse intravenously injected with either free l-OHP or l-OHP liposomes. The intratumor distribution of l-OHP within tumor sections could be determined by XRF to detect platinum atoms. After treatment with the liposomal formulation, the l-OHP was localized near the tumor vessels and, via repeated injections, increasingly accumulated in tumors by a much greater degree than treatment with free l-OHP. The repeated injections of l-OHP liposomes improved the vascular permeability via inducing the apoptosis of tumor cells near the tumor vessels, which should improve the tumor microenvironment and enhance the intratumor accumulation of repeated doses of l-OHP liposomes. The proposed process was also used to visualize the intratumor distribution of l-OHP in rectal cancer specimens resected from a patient who had received l-OHP-based preoperative chemotherapy. We further revealed that neutralization of an acidic tumor microenvironment via oral administration with NaHCO3 could improve the therapeutic efficacy of weakly basic anticancer agent-encapsulating liposomes. Collectively, mapping/quantifying the intratumor API in DDS drugs and/or improving the tumor microenvironment would be an effective means to accelerate the clinical development of DDS-based anticancer drugs.

誌上シンポジウム
  • 塩田 有史, 三鴨 廣繁, 松元 加奈
    2021 年 141 巻 11 号 p. 1247-1248
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー
  • 塩田 有史, 三鴨 廣繁
    2021 年 141 巻 11 号 p. 1249-1251
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Since 2018, high expectations have been placed on the efforts of pharmacists in infectious disease diagnostic aid via Japan's antimicrobial stewardship team (AST). We will explain this while describing the process of diagnostic aid at our institution, a university hospital, and taking into account the point of view of what is required of pharmacist by infection control doctors when performing infectious disease diagnostic aid as well. At our hospital, we implement AST rounds as infectious disease diagnostic aid for positive blood cultures, bacterial culture results, fever, long-term administration of anti-bacterial medication, example consultation cases, etc. The number of rounds has been increasing over time, totaling 5654 cases in 2018. When performing infectious disease diagnostic aid, failure to also bear in mind infection control measures can result in failed treatment and outbreaks, so AST must coordinate with infection control team (ICT). Furthermore, when engaging in infectious disease diagnostic aid, pharmacists must also participate in clinical research in order to improve the quality of treatment. Although it also depends on the facility environment they are affiliated with, it would seem to be necessary for pharmacists to verify the knowledge obtained from clinical data using a fundamental approach. Moreover, conducting education for the doctor, pharmacist, and nurse trainees who make up their fellow and future staff is another vital role of AST pharmacists.

  • 吉長 尚美, 久斗 章広, 北井 見和, 久光 由香, 三五 裕子, 吉田 耕一郎
    2021 年 141 巻 11 号 p. 1253-1255
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Over the last decade, many public institutions have emphasized the importance of antimicrobial stewardship (AS) in reducing the spread of antimicrobial resistance. In our facility, we have tackled AS that has adapted to clinical practices since 2015. In many facilities, especially university hospitals, multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing bacteria, may cause infections. Considering this, we recommend prompt treatment with suitable antibiotics and dosage. In AS teams, pharmacists are responsible for administering pharmacotherapy, including optimal dosage for each patient. Therefore, they should assess their patients carefully, implement thorough therapeutic drug monitoring, and utilize the information obtained from these assessments to administer optimal pharmacotherapy. However, optimal pharmacotherapy also requires a correct diagnosis. Although diagnostic stewardship is not a pharmacist's work, it is a great opportunity for pharmacists to learn how expert physicians think. Based on the type of situation above, we train younger pharmacists on the job.

  • 山口 智江, 平松 久典, 宮原 兼二, 伊藤 功治, 中根 茂喜
    2021 年 141 巻 11 号 p. 1257-1260
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Since 1997, Chubu Rosai Hospital has been establishing the proper use of various antibacterial drugs through the activities of an infection control team (ICT), introduction of a notification system for specific antibacterial drug use, and intervention of ward pharmacists for individual cases. There is no infectious disease department, and we have been working closely with each other on multiple occupations. As an initiative, we established the Nagoya Southern Infection Countermeasures Meeting in 2006 and conducted antimicrobial use and resistance (AUR) surveys to promote the proper use of antimicrobial agents within the area. In April 2018, we formed an antimicrobial stewardship team (AST) and initiated activities. In addition, an AST pharmacist can share the AST results with the ward pharmacist, for proper use of antibacterial drugs and for early monitoring of infectious disease treatment and appropriate intervention, thus improving the efficiency of the ward pharmacist's work. This program will also lead to the development of training programs for the younger generation of pharmacists.

  • 片山 歳也, 松田 浩明
    2021 年 141 巻 11 号 p. 1261-1265
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    At small or mid-sized medical institutions, such as Japanese community hospitals, adequate infectious disease physicians (IDP) are lacking, mainly due to shortages of full-time pharmacists and IDPs who support antimicrobial stewardship team (AST) activities. With our hospital AST, we developed a multidisciplinary approach based on the interim reports of culture results or detected resistant bacteria for physicians, which are written by pharmacists and clinical laboratory technicians. At the AST conference, a pharmacist works as a chairman and reviews abstracts of cases which need to be discussed. We performed a retrospective analysis of the process and outcome of AST implementation, and introduced the use of reduction data for our hospital, obtained from Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE). This program is important for pharmacists to promote the diagnostic process and comprehensive judgment necessary for bedside practice with infectious disease cases. We offer opportunities for pharmacy students to participate in the AST conference to learn how pharmacists consult with doctors about diagnosis and treatment. At present, the cooperation between AS and diagnostic stewardship (DS) has been emphasized, and improvements in a pharmacist's overall judgment regarding infectious disease cases are required to appropriate antimicrobial use. In addition, improving communication skills is essential for building a multidisciplinary approach. Regardless of the size of the facility, the role of pharmacists in AST should be implemented for the guidance of pharmacy students, which will help develop and secure future human resources at the facility.

総説
  • 鎌田 祥太郎, 石井 功
    2021 年 141 巻 11 号 p. 1267-1274
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and β/δ) with distinct physiological functions and ligand recognition. PPARs regulate energy metabolism and therefore become therapeutic targets for various metabolic diseases. While PPARα agonists are used as anti-dyslipidemia drugs and PPARγ agonists as anti-type 2 diabetes drugs, PPAR dual/pan agonists (that acts on two or three subtypes) are expected to treat non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, etc. Structural analyses of PPAR-ligand-binding domain (LBD)-ligand co-crystals using X-ray crystallography have been done mainly on PPARγ, in which ligand-free apocrystals were prepared; however, the information on PPARα-LBD and PPARδ-LBD is limited. Recently, we succeeded to obtain 34 novel co-crystal structures of PPARα-LBD and various PPARα ligands (including fibrates) using various co-crystallization techniques. This procedure is applicable to preparation of PPARδ-LBD co-crystals, and contributes to molecular design of new PPAR targeted drugs based on all three PPAR-LBD structures.

    Editor's pick

    Three subtypes of peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARβ/δ) are attracting much attention as molecular targets of drugs to treat various metabolic diseases including dyslipidemia, type 2 diabetes, and non-alcoholic fatty liver disease; however, the structural information regarding their ligand binding pockets has been lacking, especially in PPARα. Kamata and Ishii give an overview of their recent success in obtaining 34 novel PPARα-ligand structures that supplement 21 previously PDB-deposited structures using their sophisticated crystallization techniques. 

一般論文
  • 岡田 浩, 鈴木 渉太, 西村 亜佐子, 池田 裕美枝, 阿部 圭子, 中山 健夫
    2021 年 141 巻 11 号 p. 1275-1279
    発行日: 2021/11/01
    公開日: 2021/11/01
    ジャーナル フリー

    Emergency contraceptive (EC) pills are used to prevent pregnancy after unprotected sexual intercourse. Levonorgestrel is an EC pill, which has been only approved in Japan; it is more effective the sooner it is used after intercourse and safe without serious side effects. EC pills are already available at accessible community pharmacies in more than 90 countries around the world. In Japan, citizens have signed a petition calling for the sale of emergency contraceptives at community pharmacies. However, little is known about the thoughts of pharmacists who engage with patients and sell medicines at pharmacies. Therefore, we conducted a web-based cross-sectional survey to determine the level of preparation in community pharmacies and the awareness of pharmacists regarding the sale of EC pills. A total of 1338 pharmacists responded to the survey from November 7, 2020, to December 16, 2020. In terms of the level of preparation for selling EC pills at pharmacies, 1067 (83.9%) respondents cited “lack of preparation of medical questionnaires and explanatory materials”, and 975 (76.7%) respondents cited “lack of knowledge of pharmacists” as the most common reasons that were “barriers to EC pill sales at pharmacies”. In terms of confidence level, only 289 (22.7%) respondents were confident about conducting the necessary checks while administering medicine. On the other hand, 944 (74.3%) respondents agreed to be able to sell EC pills at their pharmacies. The survey revealed that most of the pharmacists who participated in the survey believe that it is possible to sell EC pills in pharmacies.

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