YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
138 巻 , 6 号
選択された号の論文の21件中1~21を表示しています
受賞総説
  • 古山 渓行
    2018 年 138 巻 6 号 p. 731-742
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     The combination of several aromatic rings and/or heterocycles can induce novel functions. This phenomenon is observed in porphyrin derivatives, commonly found in hemoglobin, in the active sites of P-450, etc. The ability of these structures to interact strongly with visible light accounts for today's increased interest in the development of rationally designed porphyrinoid-based optical materials. In the pharmaceutical sciences, designing near-IR materials can be a challenge due to the high transparency of near-IR light in biological samples. Phthalocyanines (Pcs) are robust organic dyes that are absorbed in visible light. A theoretical investigation of molecular orbitals of Pcs has revealed that the introduction of a phosphorus(V) atom into a macrocyclic core leads to a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap. Following these studies, we found that certain types of Pc phosphorus(V) complexes display main absorptions beyond 1000 nm. Additionally, phosphorus(V) complexes with other azaporphyrinoids have been designed and synthesized via a relatively simple procedure. These complexes showed novel optical properties which are potentially useful in the pharmaceutical and material sciences. Furthermore, we have overcome the problem of organic radicals and antiaromatic compounds, which are generally considered to be unstable, by using a combination of serendipitous synthetic methodologies and spectroscopic techniques. These novel azaporphyrin compounds are robust and free from transition metals. They are relatively easy to synthesize and also exhibit predictable properties.
  • 森永 紀
    2018 年 138 巻 6 号 p. 743-750
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     The scientific evaluation of crude drugs and kampo medicines (KMs) was demonstrated using the eastern blotting method with monoclonal antibodies (MAbs) against bioactive natural compounds. Scutellariae radix is one of the most important crude drugs used in KMs. Part of its pharmaceutical properties is due to the flavone glycoside baicalin (BI). A quantitative analysis method based on eastern blotting was developed for BI using an anti-BI MAb. A rapid, simple, sensitive, specific analytical system was subsequently established for BI with the eastern blotting technique using dot-blot and chemiluminescent methods. This system was useful as a high-throughput analytical method for the determination of BI in KMs as well as HPLC and enzyme-linked immunosorbent assay systems. Furthermore, an eastern blotting method was applied to the biological metabolic study of glycyrrhizic acid (GL), the major active constituent of licorice, for investigation of metabolites of GL such as 3-monoglucuronyl-glycyrrhetinic acid (3MGA) because licorice causes pseudoaldosteronism as a side effect. This approach may make it possible to determine the pathogenic agents of licorice-induced pseudoaldosteronism.
誌上シンポジウム
  • 花輪 剛久, 百 賢二, 河野 弥生, 米持 悦生, 山内 仁史
    2018 年 138 巻 6 号 p. 751-752
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
  • 百 賢二
    2018 年 138 巻 6 号 p. 753-756
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Hospital-prepared drugs (HP), known as In'Naiseizai in Japan, are custom-prepared formulations which offer medical professionals an alternative administration pathway by changing the formulation of existing drugs according to a patients' needs. Preparing the HP is one of several roles of pharmacists in providing personalized medicine at hospitals in Japan. In 2012, the Japanese Society of Hospital Pharmacists provided guidelines for the appropriate use of “Hospital-prepared drugs”. The following information was included in this guide: 1) documentation of the proper procedures, materials, prescription practices, etc., 2) required approval from the institutional review board of each HP on the risk-based classifications, and 3) to assess the stability, efficacy, and safety of each HP. However, several problems persist for pharmacists trying to prepare or use HP appropriately; the most common is insufficient manpower to both assess and prepare these drugs during routine hospital work. To resolve this problem, we are developing an evidence database for HP based on surveys of the current literature. This database has been developed for 109 drugs to date. Data-driven assessment of the stability of HP showed that 52 out of 109 drugs examined (47.7%). Notably, only 6 of the 109 HP (5.5%) in the database had all three characteristics of “stability”, “safety”, and “efficacy”. In conclusion, the application of this database will save manpower hours for hospital pharmacists in the preparation of HP. In the near future, we will make this database available to the wider medical community via the web or through literature.
  • 長岡 広香
    2018 年 138 巻 6 号 p. 757-762
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Palliative care had a role in maintaining and improving the patient's QOL. To optimize symptomatic management, that cannot be controlled using commercial formulations, in-house pharmaceutical preparations customized to meet an individual's clinical needs are sometimes administered. Despite a growing arsenal of oncology drugs, opioids, and other compounds, many elderly cancer patients have a wide spectrum of comorbid conditions that require the help of skilled pharmacists. Although drugs prepared in in-house pharmacies can be customized to the conditions of individual patients, their preparation is time- and resource-intensive, and their benefits sometimes do not outweigh the costs. In addition, it is often difficult to predict the required amount of a drug that will be dispensed to a very small number of patients via these custom formulations. However, we occasionally experience cases in which hospital formulations (HF) significantly alleviate symptoms and improve the QOL of patients with cancer. In fact, efforts to develop HF of palliative medications sometimes pave the way to new marketable products. In fact, collaborations between physicians and pharmacists have indeed produced new types of medications, which have been further developed into commercial painkillers by drug manufacturers. This article presents examples of HF used in clinical practice. It also discusses the future need for HF, taking note of the ongoing shift towards outpatient oncology care. Regarding the use of HF, we believe it is always important to ensure patient safety, to obtain informed consent, and to follow up.
  • 中島 孝則
    2018 年 138 巻 6 号 p. 763-766
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Hospital preparations (HPs) prepared by hospital pharmacists have contributed to advanced medical care which is custom tailored to various and individual medical needs. Advanced pharmaceutical knowledge and skills are needed to properly prepare HPs. Hospital pharmacists have inherited formulations and the skills to prepare them from their predecessors. However, there has been an ongoing decrease in the number of HPs prepared in hospitals due to an increase in the availability of commercial formulations. Despite this trend, it is not acceptable for hospital pharmacists to lack experience when a doctor requests an original HP. We often refer to “The Hospital Preparation Casebook” when HPs are prepared. However, evidence for drug management and clinical evaluation of HPs in the book are frequently insufficient; it is difficult to keep the information up to date. Therefore, we consider that it is the role of universities to support the supply and usage of HPs in cooperation with hospital pharmacists and pharmacies. Here we report a trial that adopted a physicopharmaceutical approach to developing a HP of a mianserin hydrochloride suppository.
  • 杉山 育美, 工藤 賢三, 佐塚 泰之
    2018 年 138 巻 6 号 p. 767-772
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Cancer chemotherapy-induced stomatitis may spread throughout a patient's entire oral cavity and decrease the patient's QOL. The therapy for stomatitis at Iwate Medical University Hospital (IMUH) includes dental treatment before chemotherapy, in addition to oral rinses or cryotherapy as a preventative measure. However, in our survey of doctors and nurses, the responses of patients “satisfied” with the present approach for stomatitis treatment reached only 5.1%. Therefore, we attempted treatment using an indomethacin spray, prepared as a hospital preparation, with pre-approval of the ethics committee and based on a previous report of its positive effect on patients at another hospital. We observed that the indomethacin spray succeeded in decreasing chemotherapy-induced oral pain, and its effect was maintained for 2 h in patients at IMUH. The ratio of female patients who rated indomethacin spray as good was higher than that of males. Comments from some patients included a complaint that the nozzle of the injection tip was too short; thus we increased the length of the nozzle from 2 to 7 cm. At present, indomethacin spray is being used to treat stomatitis patients at IMUH. Indeed, the indomethacin spray has been used since October 2011. It was used on 34 patients in 2016. In this review, we describe the collaboration between IMUH and the basic application of studies in our university laboratory.
  • 重山 昌人, 田口 真穂, 山本 浩充
    2018 年 138 巻 6 号 p. 773-780
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Mohs' paste (MP), which is widely used in medical services as a specific hospital preparation, has been considered to have demerits, such as increased hardness after preparation and marked adhesiveness. However, factors associated with variations in its physical properties have not yet been clarified. Therefore, we conducted studies to clarify the physicochemical phenomena influencing such variations, and also examined prescription drug designs of MP preparations that are difficult to use clinically due to the above-mentioned demerits, with a view to improving their usability. Furthermore, with cooperation from the director of the Department of Palliative Care and Maintenance Therapy and certified wound ostomy and continence (WOC) nurses of Yokohama Minami Kyousai Hospital, we clinically applied an improved form of MP I. We also examined the effects of an improved MP II (designed as a stable formulation) in mice. This is an example of the clinical application of basic research to design a new clinical formulation in order to meet medical needs.
  • 関根 祐子, 三浦 剛
    2018 年 138 巻 6 号 p. 781
    発行日: 2018年
    公開日: 2018/06/01
    ジャーナル フリー
  • 高野 博之
    2018 年 138 巻 6 号 p. 783-785
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     The number of patients with chronic heart failure (CHF) is increasing in Japan. Because there is a shortage of medical professionals to address the demands of an aging society, it is important for CHF patients to receive appropriate treatment from medical professionals in their own neighborhoods. Multidisciplinary care, involving physicians, nurses, pharmacists, care managers, et al., is indispensable for providing safe, appropriate home medical care for CHF patients. In multidisciplinary care, pharmacists play an important role, especially in improving patient adherence to CHF treatment regimens. Pharmacists are also expected to participate actively in the improvement of patients' quality of life and the avoidance of hospital readmission. However, team medicine for CHF treatment is in its nascent stage, and the system for providing multidisciplinary care is still under development. It is important to discuss the present situation and the issues facing multidisciplinary care for CHF treatment. In particular, we need to enhance the significance and role of pharmacists in providing successful multidisciplinary care. In this symposium, I highlight the new role of pharmacists in home medical care for CHF treatment and introduce the pharmaceutical education program of Chiba University.
  • 寺崎 展幸
    2018 年 138 巻 6 号 p. 787-789
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Pharmacists in dispensing pharmacies are initiating efforts to provide guidance on medication based on the requests of hospital pharmacists. In the present study, 10 cases in which pharmacists in dispensing pharmacies provided education to heart failure patients at home were examined. Improved medication compliance was observed in all cases. Additionally, at the time of re-exacerbation, it was possible for the patients to respond quickly. As a result, the number of hospitalizations during the 6 months before and after the interventions exhibited a decreasing trend from 1.6±0.7 to 0.1±0.3. Further, by conducting joint guidance at discharge, we were able to introduce smooth home guidance. I would like to continue working with hospital pharmacists and pharmacists at dispensing pharmacies in the future.
  • 雜賀 匡史
    2018 年 138 巻 6 号 p. 791-795
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Community pharmacists are often not included in home healthcare teams; their absence from such teams places patients undergoing transitions at risk for potential medication-related errors. However, community pharmacists can improve medication adherence and decrease heart failure (HF)-related hospital readmission rates. The expansion of home medication teaching services for patients by community pharmacists to reach as many patients as possible could only augment those benefits. Community pharmacists provide home health services including medication reconciliation and teaching. In the near future, all HF patients should be allowed to receive one in-home visit by a community pharmacist so that they can improve their lifestyles and enhance their medical treatment. Home visits and home healthcare by community pharmacists can reduce avoidable hospital readmissions of patients with HF.
  • 渡辺 德, 森川 剛, 久保田 健, 岡澤 香津子, 田中 千恵子, 堀内 三枝子
    2018 年 138 巻 6 号 p. 797-806
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Chronic heart failure (CHF) is a critical disease in the aging population. Conventional therapy in hospitals cannot cure elderly patients with CHF at the end of life. Patients and their families experience anxiety and need comfortable care at home or in a nursing facility. To improve chronic cardiovascular disease management, we developed a simplified but integrated clinical pathway to facilitate medical and nursing care teamwork in the local community. Our institution is a central hospital in the North Shinshu district, which has an approximate population of 100000. We developed a pathway for both clinical program and information provision between our hospital and neighboring clinics. A hospital team evaluates and shares patient information with a homecare medical team every 6 months using the medical staff pathway. To maintain the efficacy and security of pharmacotherapy, a hospital clinical pharmacist reviews the prescriptions and prepares a drug profile book to share drug information between patients and all medical staff. These efforts have resulted in preventing adverse effects of drugs and reduced the cost of medications. Physical activity evaluation and nutrient guidance are also useful for patients to maintain their personal lifestyles. We initiated use of the pathway from 2009 and have followed up over 500 patients since then. We have also established a community partnership council to promote face-to-face communication among multiple categories of institutions and government agencies. Members of the council collaborate to help patients with cardiovascular disease to manage their own lives at home.
  • 佐藤 薫, 池谷 裕二
    2018 年 138 巻 6 号 p. 807
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
  • 高 夢璇, 佐藤 元重, 池谷 裕二
    2018 年 138 巻 6 号 p. 809-813
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as “seizure-inducing” drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.
  • 山根 順子, 油谷 幸代, 今西 哲, 赤沼 宏美, 永野 麗子, 加藤 毅, 曽根 秀子, 大迫 誠一郎, 藤渕 航
    2018 年 138 巻 6 号 p. 815-822
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Toxicity prediction based on stem cells and tissue derived from stem cells plays a very important role in the fields of biomedicine and pharmacology. Here we report on qRT-PCR data obtained by exposing 20 compounds to human embryonic stem (ES) cells. The data are intended to improve toxicity prediction, per category, of various compounds through the use of support vector machines, and by applying gene networks. The accuracy of our system was 97.5-100% in three toxicity categories: neurotoxins (NTs), genotoxic carcinogens (GCs), and non-genotoxic carcinogens (NGCs). We predicted that two uncategorized compounds (bisphenol-A and permethrin) should be classified as follows: bisphenol-A as a non-genotoxic carcinogen, and permethrin as a neurotoxin. These predictions are supported by recent reports, and as such constitute a good outcome. Our results include two important features: 1) The accuracy of prediction was higher when machine learning was carried out using gene networks and activity, rather than the normal quantitative structure-activity relationship (QSAR); and 2) By using undifferentiated ES cells, the late effect of chemical substances was predicted. From these results, we succeeded in constructing a highly effective and highly accurate system to predict the toxicity of compounds using stem cells.
  • 小島 敦子, 宮本 憲優
    2018 年 138 巻 6 号 p. 823-828
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Use of the microelectrode array (MEA) system to record spontaneous neuron activity from networks of cultured neurons has potential as a good risk evaluation method for drug-induced seizure events. Spontaneous electrical activity in neural networks consists of action potential spikes and organized patterns of action potential bursts. In both potentiated rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons, an epileptogenic response pattern manifests as a synchronized burst from spatially separated neurons. Here, we delineate how to perform MEA experiments using cultured neurons, and how to analyze the MEA data to detect drug-induced seizurogenic abnormalities. Usually, a drug's effects, as shown by MEA data, include changes in spike frequency, inter-spike intervals (ISI), burst frequency, burst duration, spikes in a burst, etc. Subsequently, seizurogenic events are evidenced by changes in synchronized burst phenotypes from spatially separated multiple channels in an MEA probe, such as a change in the cross correlation of the spike events from all channels in an MEA probe, or a change in histogram from the sum of ISI for all channels in a probe, etc. We attempted to depict an epileptogenic marker using a histogram of the sum of spikes for all channels in an MEA probe. Verification of these metrics for drug induced abnormalities is ongoing in various collaboration organizations, including the Consortium for Safety Assessment using Human iPS Cells (CSAHi), iPS Non-clinical Experiments for the Nervous System (iNCENS). Collaboration networks for the utilization of iPSC-derived cells during drug development are also summarized here.
総説
  • 千葉 健史, 前田 智司, 工藤 賢三
    2018 年 138 巻 6 号 p. 829-836
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter. 5-HT released into milk is incorporated by the apical membrane-expressed serotonin reuptake transporter and degraded by the monoamine oxidase A enzyme. Suckling maintains 5-HT at low levels in milk. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using human mammary epithelial MCF-12A cells, shows that the expression of β-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of signal transducer and activator of transcription 5. Additionally, our results show that reduced β-casein expression in MCF-12A cells is associated with 5-HT7 receptor expression. Furthermore, we show that 5-HT7 receptor-mediated suppression of β-casein expression is involved in the activation of protein kinase A and protein-tyrosine phosphatase 1B. Thus, this mechanism might be associated with the feedback signals by 5-HT within the mammary epithelium. Hence, further research that builds on our findings should include the elucidation of the physiological roles of 5-HT present in milk synthesized by mammary epithelial cells in vivo and its effects on nursing infants.
    Editor’s picks

    Intrinsic 5-HT synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using MCF-12A cells, shows that the expression of b-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of STAT5. Additionally, our results show that reduced b-casein expression in the cells is associated with 5-HT7 receptor and PTP1B activation.

一般論文
  • 喜田 亜由美, 池田 貴幸, 瀬戸 大貴, 飯田 泰広
    2018 年 138 巻 6 号 p. 837-842
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     Only 4 classes of antifungal agents comprising 9 compounds are effective against deep mycosis in Japan, and it has been difficult to develop new antifungal specific agents. Micafungin, which has been used as an antifungal agent since 2002, inhibits β-1,3-glucan synthesis in fungal cell walls, thereby killing yeast and filamentous fungi with no septum. In this study, we constructed a pYES2-BGL2 vector to overexpress β-1,3-glucanase (BGL2) in yeast (Saccharomyces cerevisiae INVSc1) and evaluated the synergy between BGL2 overexpression and conventional antifungal agents. The recombinant yeast was incubated in SC-Ura medium, which contained galactose to induce BGL2 overexpression. The recombinant yeast with induced BGL2 overexpression was also frozen and crushed to obtain crude protein for sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which revealed robust BGL2 overexpression compared with that in the control yeast without the expression vector. Therefore, we considered that we successfully constructed the recombinant yeast to express more BGL2. Further, 3 conventional antifungal agents (amphotericin B, micafungin, and miconazole) were more effective against the recombinant yeast than against the control yeast. From this result, it is suggested that BGL2 overexpression has an enhancing effect on conventional antifungal agents. Hence, glucanase-inducing compounds could act as novel antifungal drugs by augmenting the effectiveness of conventional antifungal agents.
  • 斉藤 佑治, 安達 直生, 加藤 美紀, 灘井 雅行
    2018 年 138 巻 6 号 p. 843-851
    発行日: 2018/06/01
    公開日: 2018/06/01
    [早期公開] 公開日: 2018/03/27
    ジャーナル フリー
     In recent years, self-medication has started to receive more attention in Japan owing to increasing medical costs and health awareness among people. One of the main roles of pharmacists in self-medication is to provide appropriate information regarding OTC drugs. However, pharmacists promoting the proper use of OTC drugs have little information on their formulation properties. In this study, we performed dissolution tests on both OTC drugs and ethical drug (ED) containing famotidine, and evaluated the differences in their dissolution profiles. Marked differences in dissolution profiles of OTC drugs were observed in test solutions at pH 1.2, 4.0, and 6.8 and in water. To evaluate the differences quantitatively, we calculated the lag time and dissolution rate constant from the dissolution profiles. Significant differences in lag times and dissolution rate constants between some OTC drugs and ED were observed. We also used similarity factor (f2), to quantify the similarity between dissolution profiles of OTC drugs and ED. f2 values less than 42 were observed in some OTC drugs, suggesting that these differences might influence absorption in vivo resulting in differences in their onset time and efficacy. The findings of this study will provide useful information for the promotion of proper use of OTC drugs.
  • 宗像 千恵, 渕上 由貴, 蒔添 敬之, 三浦 雄介, 山岡 真理子, 笹原 里美, 畑 勝友, 立木 秀尚, 佐々木 均, 萩森 政頼, ...
    2018 年 138 巻 6 号 p. 853-860
    発行日: 2018/06/01
    公開日: 2018/06/01
    ジャーナル フリー
     The physicochemical compatibility between injections of different agents is very important. An injection of the antibiotic vancomycin (VCM) is acidic and its standard pH range is 2.5-4.5. In clinical treatments, VCM injections are often used with Lasix® (furosemide) injections. The Lasix® injection is alkaline and its standard pH range is 8.6-9.6. Therefore, mixing VCM injections with Lasix® injections may cause compatibility problems. We evaluated the effect of pH on the compatibility between VCM (original and two generic) and Lasix® injections. Compatibility was not observed in non-pH-adjusted VCM with Lasix® injections, but white crystals appeared when VCM injections adjusted to pH 2.5 experimentally were mixed with a Lasix® injection, suggesting that the acidic condition of VCM injections cause compatibility. However, the residual rates of VCM did not change after 24 h in all mixtures. We analyzed the crystals by mass spectrometry and 1H-NMR, and identified them to comprise furosemide.
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