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138 巻, 8 号
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誌上シンポジウム
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畝山 寿之, 竹内 孝治2018 年 138 巻 8 号 p. 1001
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーPDF形式でダウンロード (150K) -
堀江 俊治, 田嶋 公人, 松本 健次郎2018 年 138 巻 8 号 p. 1003-1009
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーCapsaicin is a constituent of chili pepper, and induces the burning sensation on the tongue. The site of action for capsaicin has been discovered as transient receptor potential vanilloid receptor subtype 1 (TRPV1) that resides on the membranes of pain- and heat-sensing primary afferent nerves. The immunohistochemical study on the stomach revealed that nerve fibers expressing TRPV1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers. High numbers of TRPV1-immunoreactive axons were observed in the rectum and distal colon. Therefore, capsaicin stimulates TRPV1 not only on the tongue but also in the gut. In this review, the mechanism of gastrointestinal mucosal defense enhanced by capsaicin was summarized. TRPV1 plays a protective role in gastrointestinal mucosal defensive mechanism. Hypersensitivity of afferent fibers occurs during gastrointestinal inflammation. Abnormalities of primary afferent nerve fibers are strongly associated with the visceral hypersensitive state in inflammatory bowel disease (IBD). The alteration of TRPV1 channels in mucosa contributes to the visceral hypersensitivity in colitis model mice. TRPV1-expressing neurons in the gut are thought to be extrinsic sensory afferent neurons that operate to maintain gastrointestinal functions under physiological and inflammatory states.
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駒井 三千夫, 後藤 知子, 大日向 耕作, 神戸 大朋, 真柳 祐希, 白川 仁2018 年 138 巻 8 号 p. 1011-1016
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーWe investigated the role of zinc in regulation of food intake using male SD rats during early-stage of zinc deficiency (the 3rd day of the feeding) without decreased zinc concentrations in tissues (hypothalamus and liver). As a result, we found that orally but not intraperitoneal administered zinc stimulates food intake in the short-term zinc-deficient rats. The mRNA expressions of hypothalamic peptides, such as orexin (OX) and neuropeptide Y (NPY), were increased after oral administration of zinc to increase food intake. Pretreatment with an antagonist for the NPY Y1 receptor or the orexin OX1 receptor blocked orexigenic activity by zinc administration. The stimulation of food intake by oral administration of zinc was also abolished by vagotomy. Taken together, our results indicate that zinc stimulates food intake in short-term zinc-deficient rats through the afferent vagus nerve followed by activating the hypothalamic peptide associated with food intake regulation. This study showed the first evidence that gastrointestinal zinc signal is indispensable for the food appetite induction in the experimentally anorexigenic rat. However, since it has not yet been clarified the mechanism involved in zinc sensing by the epithelial membrane of the gastrointestinal tract, further detailed investigations are necessary.
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上田 陽一2018 年 138 巻 8 号 p. 1017-1024
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーVarious neuropeptides play an essential role in the nutrient sensing mechanism and related homeostasis. Nesfatin-1 is a newly identified neuropeptide having anorectic activity, and nesfatin-1-containing neurons are widely distributed in the brain, including the hypothalamus and brain stem. Our previous study showed that dehydration-induced anorectic effects are mediated via the central nesfatin-1 pathway in rats. Our recent studies have also shown that peripheral anorectic peptides (cholecystokinin-8, glucagon-like peptide-1, and leptin) and an antineoplastic agent (cisplatin) caused inhibition of feeding via the central nesfatin-1 pathway in rats. Nesfatin-1-containing neurons in the central nervous system, in particular the hypothalamus and the brain stem, may mediate peripheral nutrient signals and regulate feeding behavior.
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松丸 尊紀, 安田 大輔2018 年 138 巻 8 号 p. 1025-1026
発行日: 2018/08/01
公開日: 2018/08/01
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山下 智大, 津田 誠, 齊藤 秀俊, 井上 和秀2018 年 138 巻 8 号 p. 1027-1031
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーNeuropathic pain associated with cancer, diabetic neuropathy, and postherpetic neuralgia is a type of intractable chronic pain characterized by mechanical allodynia and abnormal pain hypersensitivity evoked by innocuous stimuli. However, this disorder has no specific treatment. We previously showed that the purinergic receptor P2X4 (P2X4R), a subtype of ATP-gated nonselective cation channels, is highly upregulated in spinal microglia after peripheral nerve injury, and blocking the function of P2X4R reverses mechanical allodynia. In the present study, we screened a chemical library of 1979 clinically approved compounds (a gift from the Drug Discovery Initiative at the University of Tokyo) aimed at achieving “Eco-Pharma,” which refers to seeking new effects of existing drugs. We demonstrated that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rat and human P2X4R. In rat primary cultured microglial cells, duloxetine also inhibited P2X4R-mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain reversed nerve injury-induced mechanical allodynia. Based on those results, we suggest that the inhibition of P2X4R expressed in microglial cells may be involved in the antiallodynic effect of duloxetine in neuropathic pain. Furthermore, in this review, we discuss a new strategy for drug discovery called “Green Pharma” (a merger of “Eco-Pharma” and “Green chemistry” and referring to the development of eco-friendly pharmaceuticals).
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長門石 曉, Jose M. M. Caaveiro, 津本 浩平2018 年 138 巻 8 号 p. 1033-1041
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーIn small molecule drug discovery, researchers must find specific binders that interact with a target protein and inhibit its function in connection with human diseases. It is of critical importance to know the binding mode of compounds interacting with a target protein to assure hit validation and optimization. Biophysical analysis is a powerful quantitative approach to evaluate the binding modes of such candidates. Since the level of sensitivity of biophysical analysis is suitable to quantitatively detect the binding of fragment compounds, and because of the remarkable success of compound libraries of small molecules, the development and adaptation of biophysical analysis for these applications is in great demand. Herein, we describe the technical developments of biophysical methods, especially thermodynamic and kinetic analysis, for the purpose of screenings which employ small molecules. In addition, we discuss the interaction mechanisms of small molecules to find hit compounds based on these biophysical analyses.
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藤川 雄太, 井上 英史2018 年 138 巻 8 号 p. 1043-1048
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーInsect growth regulators (IGRs) are chemicals that adversely affect the physiological processes associated with insect development and cause abnormalities that impair insect survival. Ecdysone, an insect steroid hormone originally identified as a molting hormone, plays an essential role in developmental transition, such as during molting and metamorphosis. Recently, a member of the epsilon class of glutathione S-transferases (GST), GSTe14, also called Noppera-bo (Nobo), has been identified as essential for regulating the biosynthesis of ecdysone. Knockout or knockdown of the nobo gene causes ecdysone deficiency, leading to either death or arrested phenotype development at the larval stage. It is therefore considered that Nobo is potentially well suited as a target for novel IGRs. In this review, we focus on the development of a high-throughput screening strategy for Nobo inhibitors using a GST fluorogenic substrate.
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吉田 優2018 年 138 巻 8 号 p. 1049-1058
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーTarget identification of screening hit compounds with unknown mechanisms of action obtained from chemical libraries by phenotypic assays has played an important role in the development of innovative drugs that work based on novel mechanisms. To improve the usability of the target identification based on the photoaffinity labeling method, we have studied the “diazido probe” method, wherein a photoreactive aromatic azido and relatively photostable aliphatic azido groups are sequentially used for photoreaction and introduction of a latent detectable tag via the Staudinger ligation or click reactions, and related synthetic methods that enable expeditious preparation of molecular probes. To facilitate the development of diazido probes, we established short synthetic routes to diazido building blocks with different connectable groups based on sequential iridium-catalyzed C-H borylation and copper-catalyzed azidation of 1,3-disubstituted benzenes, and subsequent diverse functional group transformations leaving the azido groups untouched. To improve the utility of click chemistry for efficient introduction of a latent detectable tag, we developed a transient protection method of cyclooctynes from cycloaddition with an azide by 1 : 1 complexation with a cationic copper(I) salt. Application of this protection method using a cationic copper salt to a cyclooctyne bearing a terminal alkyne allowed for the selective click conjugation with an azide at the terminal alkyne moiety, which rendered functionalized cyclooctyne derivatives easily synthesizable.
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安田 大輔, 小畠 りか, 髙橋 恭子, 大江 知之, 増野 匡彦2018 年 138 巻 8 号 p. 1059-1065
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーIn the process of recent hit-to-lead studies, not only in industry but also in academia, early evaluation of metabolic properties has been one of the key aspects supporting a higher probability of success in drug discovery. In this review, we introduce the development of chemical seeds targeting the Kelch-like ECH-associated protein-1 (Keap1) as an example of an academic hit-to-lead study considering metabolic stability. Keap1 regulates the function of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces various antioxidative or detoxification proteins. An inhibitor of protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 is expected to be a novel target for drug discovery. However, Nrf2 is also activated in several cancers, such as human hepatocellular carcinoma, and causes chemoresistance, which is mediated by phosphorylated p62/Sqstm1 (p-p62), an autophagy-related protein that also undergoes a PPI with Keap1. In this case, an Nrf2 suppressor could be used to attenuate drug resistance. We discovered inhibitors against the Nrf2-Keap1 PPI and p-p62-Keap1 PPI using high-throughput screening and established the synthetic routes for the hit compounds and their derivatives. Furthermore, we assessed the metabolic stability of both of the PPI inhibitors in human liver microsomes and identified the metabolic sites.
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総説
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今中 常雄2018 年 138 巻 8 号 p. 1067-1083
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーPeroxisomes are organelles that are present in almost all eukaryotic cells. These organelles were first described in 1954, in the cytoplasm of the proximal tubule cells in the mouse kidney, using electron microscopy by Rhodin and referred to as “microbodies”. Then, de Duve and Baudhuin isolated microbodies from rat liver using density gradient centrifugation, defined the microbodies as membrane-bound organelles containing several H2O2-producing oxidases and H2O2-degrading catalase, and named them peroxisomes. At present, the biogenesis of peroxisomes in mammals involves three different processes: the formation of pre-peroxisomes from the endoplasmic reticulum, the import of peroxisomal membrane and matrix proteins to the pre-peroxisomes, and the growth and division of the peroxisomes. These organelles are involved in a variety of metabolic processes, including the β-oxidation of very long chain fatty acids, and the synthesis of ether phospholipids and bile acids in mammals. These metabolic pathways require the transport of metabolites in and out of peroxisomes. The transport of such metabolites is facilitated in part by the ATP-binding cassette (ABC) transporter. Impairment of the biogenesis and function of peroxisomes causes severe peroxisomal disorders. Since I began peroxisome research at Professor de Duve's laboratory in 1985, I have studied the biogenesis and function of peroxisomes and peroxisome diseases for more than 30 years, with a focus on ABC transporters. Here, I review the biogenesis of peroxisomes, the targeting of ABC transporters to the peroxisome, and the function of ABC transporters in physiological and pathological processes, including X-linked adrenoleukodystrophy, a neurodegenerative disease.
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一般論文
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清水 忠, 西村 奏咲, 上田 昌宏2018 年 138 巻 8 号 p. 1085-1093
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーRecently, it has been reported that only a small number of sixth-year students who had undergone a long-term pre-clinical training in the fifth year found organic chemistry useful. To explain this, we hypothesized that pharmacists are unable to utilize the knowledge of organic chemistry to solve clinical problems. With the aim of addressing this problem, we conducted a workshop consisting of a series of lectures and exercises on structural similarity, solubility, absorption, and metabolism of drugs based on a chemical structural formula. Then, we administered a questionnaire survey to 253 participants who had participated in our workshop. The questionnaire comprised 17 questions, and free descriptions were analyzed using text mining. Results showed that, although about 45% of the participants confirmed the chemical structural formula described in the medical package insert, and about 22% of the participants had the opportunity to check the metabolites described in the drug interview form, more than 90% of the participants were interested in the workshop contents. Thus, pharmacists may want to learn how the process of utilizing the chemical structural formula can be applied to their clinical practice.
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畠山 史朗, 鈴木 規子, 安部 一弥, 金野 昇, 金子 俊幸, 豊口 禎子, 白石 正2018 年 138 巻 8 号 p. 1095-1101
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーChemotherapy-induced nausea and vomiting (CINV) is the most unbearable adverse effect of chemotherapy. The antiemesis guidelines of the National Comprehensive Cancer Network indicate that hyponatremia is a risk factor for CINV, although the relationship between the incidence of CINV and hyponatremia has not been sufficiently studied. This two-center prospective observational study evaluated whether low serum sodium concentrations were a risk factor for CINV. The study included 34 patients who were scheduled to receive first-line carboplatin- or oxaliplatin-based chemotherapy for gynecological or colorectal cancers. Patient diaries were used to record the daily incidences of CINV events during a 5-day period. The patients were divided based on the median serum sodium concentration into a low Na+ group (<141 mEq/L) and a high Na+ group (≥141 mEq/L). The incidences of delayed nausea were 27.8% in the high Na+ group and 62.5% in the low Na+ group (p=0.042), with complete control rates (no vomiting, rescue medication, or grade 2 nausea) of 77.8% and 43.8%, respectively (p=0.042). The time to complete control failure in each group was analyzed using the Kaplan-Meier method, which revealed a significantly shorter time in the low Na+ group (p=0.03). Therefore, these results indicate that low serum sodium concentrations may increase the risk of CINV.
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溝口 優, 三浦 剛, 小嶋 文良2018 年 138 巻 8 号 p. 1103-1110
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーWhen handling high risk medications, such as anticancer agents, at home, it is necessary to take measures to prevent children from accidentally ingesting these drugs. In this study, we investigated pediatric characteristics such as literacy ability and finger function in Japanese subjects and examined the usefulness of child-resistant (CR) packaging technologies used in the U.S. when given to children in Japan. The survey covered 104 Japanese children aged 37-84 months. The results of the survey revealed that of the five types of CR packaging technologies, that which leveraged the differences in hand size and muscle mass between children and adults was effective against children aged 3-6 years. However, the CR packaging styles that rely on literacy, the ability to use tools, and the ability to perform complex operations are only applicable to children of a certain age. This suggests that the differences in the language, culture, and preschool education between Japan and the U.S. have a significant influence on pediatric characteristics. Based on the results of this study, it is possible to adopt CR packaging for Japanese children, which is expected to decrease the number of cases of accidental drug ingestion by children in Japan.
抄録全体を表示Editor's pickThis study investigated pediatric characteristics such as literacy ability and finger function in Japanese subjects and examined the usefulness of child-resistant (CR) packaging technologies. The authors indicated that the CR packaging styles that rely on literacy, the ability to use tools, and the ability to perform complex operations are only applicable to children of a certain age. These results may help to adopt CR packaging for Japanese children, and may be reduce accidental drug ingestion by children in Japan.
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長井 紀章, 上野 祥奈, 石井 美有, 福岡 侑也, 大竹 裕子2018 年 138 巻 8 号 p. 1111-1117
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーThe ophthalmic application is the main route for the therapy of glaucoma, and is well-accepted by glaucoma patients. Therefore, it is important to measure the drug behavior in lacrimal fluid after instillation of eye drops. In this study, we used ophthalmic formulation (eye drops) containing timolol maleate (TM), in anti-glaucoma eye drops, and attempted to measure the drug behavior after instillation of TM eye drops. First, we collected the lacrimal fluid (5 μL) every 10 time after instillation using micropipette, and measured by the HPLC method. The TM concentration in lacrimal fluid was 21.2 μg/mL at 5 min after the instillation, and the TM was remained for 30 min after the instillation. Next, we collected the lacrimal fluid via the dialysis prove, and measured by the HPLC method. The retention of TM in lacrimal fluid was observed for 45 min after the instillation, and the measurement accuracy was enhanced by system with an automatic injection of TM solution via dialysis prove (microdialysis-HPLC method). In addition, the measurement accuracy increased more by using a capillary liquid chromatography (CLC) instead of an HPLC (microdialysis-CLC method), and the retention time of TM in lacrimal fluid was extended to 75 min after the instillation. In conclusion, we showed that the microdialysis-CLC method was suitable to measure the drug behavior in lacrimal fluid after instillation. These findings provide significant information that can be used in the design and evaluation of ophthalmic formulation.
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三島 脩太, 大塚 青海, 松内 省太, 橋川 直也, 井上 健一, 橋川 成美2018 年 138 巻 8 号 p. 1119-1126
発行日: 2018/08/01
公開日: 2018/08/01
ジャーナル フリーCalcitonin gene-related peptide (CGRP) plays an important role in several physiological processes such as vasodilation, cardiovascular homeostasis and transmission of pain. Here we report the generation of a transgenic mouse overexpressing αCGRP and the impact of this on baseline physiological responses. αCGRP transgenic mice displayed significantly increased αCGRP mRNA levels in the kidney, heart and hippocampus. To assess cardiovascular physiology, we measured arterial pressure using a tail cuff system. Heart rate, systolic pressure, mean arterial pressure and diastolic pressure were significantly lower in αCGRP transgenic mice than wild-type mice. To assess pain, a hot plate test was performed and the latency of response was used as an indicator of supraspinal response. In addition, a tail immersion test was performed to assess thermal nociception. A significant increase in latency was observed in the αCGRP transgenic mice when compared with wild-type mice in both tests. These results suggest that αCGRP overexpression causes an increase in thermal reaction and downregulation of the cardiovascular system, presumably due in increased levels of αCGRP.
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