YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
141 巻, 6 号
選択された号の論文の16件中1~16を表示しています
誌上シンポジウム
  • 合田 幸広, 伊藤 美千穂
    2021 年 141 巻 6 号 p. 771-772
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー
  • 津谷 喜一郎
    2021 年 141 巻 6 号 p. 773-786
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    General views on three aspects were discussed. The first aspect is regulatory categories, which can range from “soft to hard”, an expression using the English and Japanese translation of the French term, “drogue douce” (soft drug). This categorization starts with “so-called health foods” and extends to Foods with Health Claims [Foods with Nutrient Functional Claims (FNFC); Foods with Functional Claims (FFC); Foods for Specified Health Uses (FOSHU)], OTC drugs, and ethical drugs. “The Basic Policy for New Drug Approval” (1967) made a distinction between OTC and prescription drugs. FOSHU (1991) originally included foods for “patients”, such as low allergen rice with preventive “health claims”. Foods for Medical Uses (FMU) later became an independent subcategory under Foods for Special Dietary Uses. On the other hand, manufacturers of FFC can make various “health claims” on the basis of randomized controlled trial or systematic review (2015). Products in the intermediate zone between food and drug have an annual market of over 2 trillion yen (US$ 20 billion). The second aspect is the five elements, i.e., quality, safety, efficacy, information, and cost, which are derived from WHO's “The rational use of drugs” (1985). The adoption of Sustainable Development Goals (SDGs) by the UN General Assembly (2015) led to the addition of “ecology” as the sixth element, which is applicable for herbal and animal raw materials. The third aspect is quality control and quality assurance. This initially began with manufactured products and was expanded to the service fields handled by various health workers including pharmacists.

  • 合田 幸広
    2021 年 141 巻 6 号 p. 787-791
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    The author believes that the three pillars of pharmaceutical sciences (PS) in Japan are drug development science, medical pharmacy, and quality management science. Of these, the most PS-like science is quality management science, both historically and presently. Considering the balance of safety and efficacy is the basis of PS. The definition of “quality” is the degree to which a set of inherent properties of a product, system, or process fulfills requirements in Q9 of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In our society, pharmaceutical science graduates including pharmacists, are active participants, not only in the pharmaceutical industry, including a pharmacy, but also in the food industry, especially for quality assurance and quality control. This report presents a focused overview of quality in health foods, foods with health claims, and pharmaceutical products and discusses the importance of a curriculum focusing on quality assurance, control, and management in pharmaceutical education.

  • 小松 かつ子
    2021 年 141 巻 6 号 p. 793-805
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    The role of pharmaceutical education in primary health care for self-medication needs recognition. Hence, we conducted a survey on quality assurance of foods/pharmaceuticals at 75 pharmaceutical schools in Japan, as part of a project for the Subcommittee of Clinical Pharmacy and Pharmaceutical Sciences, Science Council of Japan. The set of questions in the survey focused on two subjects, one set was related to the lectures on “foods with health claims” (I) and the other set was on quality assessment of pharmaceuticals (II). For each subject, we asked whether there were lectures on these subjects and whether all items were covered. We also asked for the title of lectures, major field of experts in charge, and class standing. We received a response from 60 schools. Thirty-two schools had lectures on subject I in which all seven items were covered. However, “regulatory sciences”, “borderline of pharmaceuticals to non-pharmaceuticals”, and “quality assurance of foods” were not explained in 22, 12, and 15 schools, respectively. Twenty-six schools had lectures on subject II in which all six items were covered. However, “definition of quality”, “quality assurance”, “classification of pharmaceuticals”, and “Chemistry, Manufacturing and Control” were not explained in 12, 11, 12, and 29 schools, respectively. The high rate of insufficient explanation for some of the items in subject I and II may be due to the lack of description about them in the “Model Core Curriculum for Pharmacy Education”. We conclude that including these items in the curriculum can have important implications for pharmaceutical education.

  • 尾上 誠良
    2021 年 141 巻 6 号 p. 807-812
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Considerable attention has been drawn to predict a photosafety hazard on new chemicals. A number of phototoxins tend to generate reactive oxygen species (ROS) via energy transfer mechanisms following UV/VIS excitation, including superoxide and singlet oxygen. Then, ROS assay has been designed to assess photoreactivity of pharmaceuticals, of which the principle is to monitor types I and II photochemical reactions of the test chemicals when exposed to simulated sunlight. This simple analytical test could be used to screen potential chemical scaffolds, leads, and candidate drugs to identify and/or select away from those having phototoxic potential. The validation study for the ROS assay has been being carried out by the Japan Pharmaceutical Manufacturers Association (JPMA), supervised by the Japanese Center for the Validation of Alternative Methods (JaCVAM). Although several false positives appeared, the ROS assay on 42 coded chemicals has provided no false negative predictions. The validation study tentatively indicates satisfactory outcomes in terms of transferability, intra- and inter-laboratory variability, and predictive capacity. Thus, a negative result in this ROS assay would indicate a very low probability of phototoxicity, whereas a positive result would be a flag for follow-up assessment. Upon international harmonization activities supported by several agencies and industrial groups, ROS assay was successfully adopted as International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S10 guideline (2014) and Organisation for Economic Co-operation and Development (OECD) test guideline 495 (2019).

  • 堤 康央
    2021 年 141 巻 6 号 p. 813-816
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    For human health and welfare, toxicology/safety science is a branch of the pharmaceutical sciences dealing with the risk or benefit of pharmaceutical products derived from organic compounds, proteins, and genes, as well as chemicals contained in cosmetics or food additives. The quality of pharmaceutical products is one of the factors that decide risk or benefit, so quality assurance based on regulatory science is an important research and education area in the field of toxicology/safety science.

  • 髙鳥 悠記, 奥山 聡
    2021 年 141 巻 6 号 p. 817-818
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー
  • 奥山 聡, 澤本 篤志, 中島 光業, 古川 美子
    2021 年 141 巻 6 号 p. 819-824
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Citrus kawachiensis (Kawachi Bankan), is a citrus species grown in Ehime, Japan, and its peel is abundant in 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF). We have recently revealed that HMF, one of the citrus flavonoids, has anti-inflammatory activity and neuroprotective abilities in the brain against global cerebral ischemia. HMF rescued neuronal cell death in the hippocampus and suppressed the activation of microglia, whose activation have been shown to significantly aggravate neurological deficit scores for ischemic mice. In the Y-maze test, HMF showed protection against ischemia-induced short-term memory dysfunction; in addition, HMF enhanced the expression of brain-derived neurotrophic factor and accelerated neurogenesis in the hippocampus. Similarly, the powder of the peel of C. kawachiensis showed anti-inflammatory activity and neuroprotective abilities in the ischemic brain. To further examine the effect of the peel of C. kawachiensis, we administered it to senescence-accelerated-mouse prone 8 (SAMP8) mice, which show memory impairment and brain inflammation, tau hyperphosphorylation, and neuronal dysfunction. The C. kawachiensis treatment inhibited microglial activation and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in SAMP8. These results suggest that HMF and the peel of C. kawachiensis have potential effects as neuroprotective and anti-dementia agents.

  • 矢野 義明
    2021 年 141 巻 6 号 p. 825-829
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    The formation of neurotoxic aggregates by amyloid-β peptide (Aβ) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous-phase aggregation of Aβ. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Fluorescence correlation spectroscopy (FCS) is a sensitive method to monitor molecular aggregation processes by measuring diffusion of fluorophore-labeled molecules. Here, we monitored the initial aggregation process of Aβ on cell membranes of SH-SY5Y neuroblastoma cells. For example, aggregation of Aβ-(1-42) was evaluated by using Aβ-(1-42) (5 μM) doped with fluorophore-Aβ-(1-42) (10 nM). A membrane-bound Aβ component was detected in FCS autocorrelation curve after 1-h incubation of the Aβs with the cells. Following incubation for ~10 h, Aβ-(1-42) formed oligomers composed of ~10 Aβ molecules. These Aβ oligomers formed on membranes did not induce activation of caspase-3, an effector caspase for apoptosis, therefore were not neurotoxic, in contrast to reported Aβ oligomers prepared in aqueous phase. Formation of larger Aβ fibrils on membranes was found to be critical for Aβ neurotoxicity. We also report that trace amounts of pyroglutaminated Aβ-(3-42), a minor species of Aβ, can enhance initial aggregation process of Aβ-(1-42) on the cell membranes. These results indicate the usefulness of FCS detection of small Aβ oligomers formed on cell surface, which can act as pathogenic seeds for amyloid fibrils responsible for neurotoxicity.

  • 喜里山 暁子
    2021 年 141 巻 6 号 p. 831-833
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    In recent years, the number of patients with Alzheimer's type dementia continues to increase year by year. As a first-line drug, cholinesterase inhibitor is used. There is a close relationship between the time course of the drug plasma concentration (pharmacokinetics; PK) and the time course of its effects and side effects (pharmacodynamics; PD). However, the relationship between PK and PD is not simply that plasma concentrations are proportional to the effects. The effect is expressed through the characteristics of various pharmacokinetic processes. Therefore, it is important to investigate the transition of effects accompanying its pharmacokinetics. We conducted a fundamental PK/PD analysis using donepezil. Time course of acetylcholine in the hippocampus was investigated with relation to its PK after donepezil administration using rats. The PK and PD characteristics of the drug, including its active metabolite, were investigated. Additionally, Alzheimer's type dementia drugs are often given in combination with antiplatelet drugs such as cilostazol. It is reported that donepezil and cilostazol interact clinically, partly due to inhibition in the efflux transporters in certain tissues. There are various transporters in the body, and interactions through them may cause unexpected changes in the effects. So, it is important to calculate the correlation between the donepezil level in plasma and tissues after their combined administration. From the PK/PD point of view, the results of this study will provide insight into the time course of effects and the characteristics of drug-drug interaction in clinical practice.

  • Mark J. Hackett, Ashley L. Hollings, Virginie Lam, 武智 隆祐, John C. L. ...
    2021 年 141 巻 6 号 p. 835-842
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Dementia has no cure and is an international health crisis. In addition to the immeasurable loss of QOL caused by dementia, the global economic cost is predicted to reach $2 trillion (USD) by 2030. Although much remains unknown about the biochemical pathways driving cognitive decline and memory loss during dementia, metals have been implicated in neurodegenerative disease. For example, total levels of Fe and Cu increase, which has been proposed to drive oxidative stress; and Fe, Cu, and Zn can bind amyloid-β, catalysing aggregation and formation of amyloid plaques. Unfortunately, despite these known facets through which metal ions may induce pathology, studies in greater detail have been hampered by a lack of microscopy methods to directly visualise metal ions, and their chemical form, within brain cells. Herein we report the use of synchrotron X-ray fluorescence microscopy to simultaneously image Fe, Cu, and Zn within neurons in ex vivo brain tissue sections. Using animal models of dementia, we now demonstrate for the first time that despite global increases in brain metal content and metal ion accumulation within amyloid plaques, key brain regions may also become metal ion deficient. Such deficiency could contribute to cognitive decline because of the essential roles metal ions play in neurotransmitter synthesis and energy metabolism. These recent findings are discussed in the context of memory loss, and the impact that metal ion dis-homeostasis may have on diagnostic and therapeutic development.

  • 泉尾 直孝, 清水 孝彦, 村上 一馬, 入江 一浩
    2021 年 141 巻 6 号 p. 843-849
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Development of therapeutics for Alzheimer's disease (AD) is an urgent research task. Amyloid β (Aβ) is one of the causative proteins of AD. Irie et al. identified a toxic conformer among the various structures of 42-mer Aβ (Aβ42). This conformer, which possesses a turn structure at the positions Glu22-Asp23, exhibits rapid oligomerization and potent neurotoxicity. By the generation of conformationally-specific antibodies against this toxic conformer of Aβ, elevation of the toxic conformer in the AD brain was strongly suggested. To investigate the pathogenic role of the toxic conformer in AD, passive immunization experiments against conventional AD model mice were conducted. Specific antibody administration improved the behavioral abnormalities observed in AD model mice without affecting senile plaque pathology. Next, knock-in mice exclusively producing the toxic conformer of Aβ were generated. These mice exhibited cognitive dysfunction and oligomerization of Aβ, which preceded the onset of the plaque deposition. Taken together, the toxic conformer of Aβ is confirmed to be involved in the pathogenesis of AD, and our knock-in mice could be useful in analyzing the Aβ oligomer-related pathology of AD.

  • 髙鳥 悠記
    2021 年 141 巻 6 号 p. 851-856
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Donepezil, the most widely used drug for the treatment of Alzheimer's disease (AD), is an acetylcholinesterase (AChE) inhibitor and is thought to improve cognition by stimulating cholinergic neurotransmission. However, no correlation has yet been established between the inhibitory role of AChE inhibitors and their therapeutic effects when used in AD patients. The cleavage pathway of amyloid precursor protein (APP) includes amyloidgenic (β, γ-cleavage) and non-amyloidgenic (α-cleavage) pathways. The intracellular transportation of APP is important in determining these cleavage pathways. It has been suggested that sorting nexin (SNX) family proteins regulates the intracellular transport of APP, thereby enhancing α-cleavage. In this study, we examined the effects of donepezil on SNX33 expression changes and APP processing in primary cultures of fetal rat cortical neurons. While donepezil treatment increased the levels of SNX33 expression and soluble APPα (sAPPα) in culture media, no changes were observed regarding full-length APP expression in the cell lysate. Donepezil also reduced the release of amyloid β (Aβ) into culture media in a concentration- and time-dependent manner. This reduction was not affected by acetylcholine receptor antagonists. The membrane surface expression of APP was elevated by donepezil. Furthermore, SNX knockdown by antisense morpholino oligos prevented the effects of donepezil. These results indicated that donepezil increased APP expression at the surface of the plasma membrane by decreasing APP endocytosis through upregulation of SNX33, suggesting donepezil might stimulate the non-amyloidogenic pathway. This new mechanism of action for the currently used anti-AD drug may provide a valuable basis for future drug discovery.

総説
  • 大塚 文徳
    2021 年 141 巻 6 号 p. 857-867
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Heavy metals, both toxic and essential, have long been an important research focus in life science. To investigate the intracellular actions of heavy metals at the molecular level, I have been exploring protein factors involved in induction of metallothionein (MT) genes by heavy metals that specifically bind to a metal responsive element (MRE) in the region upstream of the human MT-IIA gene. Purification of a zinc-dependent MRE-binding factor, and cloning of its cDNA identified a sequence identical to that of metal-responsive transcription factor-1 (MTF-1). MTF-1, which is characterized by six tandem repeats of the C2H2 type zinc finger motif, is indispensable for induction of MT gene expression by multiple types of heavy metal, but zinc is the only metal that can directly activate MTF-1 binding to the MRE, indicating that other heavy metal signals act through zinc as a second messenger. Functional analysis of various MTF-1 point mutants revealed several cysteine (Cys) residues critical for DNA binding and/or transactivation activity. Interestingly, six finger motifs seem to mediate several MTF-1 functions other than DNA binding. Immunohistochemical analyses of various mouse tissues revealed selective expression of MTF-1 in spermatocytes among the testicular cells, suggesting roles relevant to spermatogenesis. The zinc regulon, under the control of MTF-1, will likely provide good clues to aid in unraveling novel functions of intracellular zinc ions.

    Editor's pick

    MTF-1 is a transcription factor activated in response to an increase in concentration of intracellular free zinc. In this article, MTF-1 is reviewed from its discovery to unique characteristics as an intracellular zinc sensor, mainly based on the author’s research results. It is indicated that clarification of the zinc signaling system mediated by MTF-1, together with the analysis of the genes under its control, is useful for unraveling novel biological roles of essential zinc.

一般論文
  • 中田 雄一郎, 山口 瑞季, 出口 粧央里, 稲葉 一訓, 長井 紀章
    2021 年 141 巻 6 号 p. 869-876
    発行日: 2021/06/01
    公開日: 2021/06/01
    ジャーナル フリー

    Quality changes associated with physical changes in suspended eye drops are difficult to predict. In this study, we attempted to evaluate the aggregation and redispersability in commercially available suspended eye drops (fluorometholone ophthalmic solutions). The 0.1% fluorometholone ophthalmic solutions (the original product and 4 generic products) were gently mixed by hand after short-term (4 months) or long-term (40 months) storage, and the drug concentration in the first drop and physical stability (redispersability and particle size) were measured. All eye drops produced a cloudy precipitate on the bottom surface of the container, and the amount of precipitate decreased with mixing time. The drug concentration per drop in the original product was approximately 70% of the labeled value after mixing 10 times, and the drug particle size was approximately 4 μm. After mixing the generic products stored short-term 10 times, the concentration ranged from less than 50% to almost 100%. In addition, some generic products after long-term storage had a reduced redispersion ability and labeled concentration. These results suggested that at least 10 mixing were required before the using of fluorometholone original product. In addition, some generic products may not provide sufficient drug exposure even when mixed in the same manner as the original products.

  • 飯田 香緒里, 矢野 孝彦, 池森 恵, 石田 智樹, 西村 訓弘
    2021 年 141 巻 6 号 p. 877-886
    発行日: 2021/06/01
    公開日: 2021/06/01
    [早期公開] 公開日: 2021/03/01
    ジャーナル フリー
    電子付録

    Japanese pharmaceutical products continue to experience a trade deficit, since import values exceed export values. In drug discovery development, given the pace of technological innovations, there has been a major shift from low-molecular-weight compounds to biomedicine. It is anticipated that industry, academia and government will work more closely together in support of the pharmaceutical industry. Drug discovery requires much time and vast resources before the results can be put to practical use, and evidence suggests that many newly approved drugs derive from university-sourced technology. Pharmaceutical companies keep a close eye on technology evolving in universities. However, some reports state that there is a substantial difference compared to the development costs of the major Japanese pharmaceutical companies. Therefore, the authors hypothesized that there may be some issues hindering industrial-academic partnerships in drug discovery. In order to understand the actual situation and barriers to promoting industrial-academic collaboration, the Japan Pharmaceutical Manufacturers Association (JPMA), Japan Agency for Medical Research and Development (AMED), and the Medical Industry-Academia Collaboration Network (medU-net) Council will work together in issuing questionnaires and conducting an awareness survey. This survey sought the personal opinions of individuals belonging to JPMA and medU-net. Based on the results of this survey, we will introduce the issues related to industrial-academic collaboration and partnerships, and any gaps between industry and academia. Furthermore, we suggest solutions to promoting drug discovery innovation in Japan.

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