YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
140 巻, 11 号
選択された号の論文の14件中1~14を表示しています
受賞総説
  • 飯塚 怜
    2020 年 140 巻 11 号 p. 1299-1303
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    The author has developed several methodological approaches that use nanophotonic and microfluidic devices to accelerate pharmaceutical research and development. Here, the author describes two of these approaches and provides practical examples. The first is a nanophotonic approach to break the concentration limit of diffusing fluorophore-labeled molecules in single-molecule imaging. Although single-molecule imaging is highly useful in characterizing the kinetics of biomolecular interactions, it requires nanomolar concentrations of labeled molecules in solution. Zero-mode waveguides are nanophotonic structures that reduce the illumination volume by more than three orders of magnitude relative to conventional fluorescence microscopy, thereby allowing single-molecule investigations at micromolar to millimolar concentrations of fluorescent molecules i.e., under near-physiological conditions. The second approach is microfluidic microdroplet-based, allowing the discovery of novel biomolecules with the desired activities. Microfluidics allows the ultrarapid production of monodisperse microdroplets such as water-in-oil microdroplets. Each microdroplet serves as a nano/picoliter-volume test tube, which increases assay sensitivity by increasing the effective concentration of molecules and decreasing the time required to reach detection thresholds. I hope you find this review helpful in your research.

  • 佐藤 秀行
    2020 年 140 巻 11 号 p. 1305-1312
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Recently, biologics including peptides, proteins, antibodies, and nucleic acids have attracted interest as drug candidates for new modalities, since these compounds can act on target molecules that are not be affected by conventional drugs with a small molecular weight to promote greater selectivity, potency, and safety. Generally, to administer biologics, parenteral routes like intravenous and intramuscular injections have been mainly selected due to their poor oral absorbability and stability in the gastrointestinal tract, which can adversely affect patient compliance. Depending on the target diseases, inhalable formulations can be used to achieve both topical effects in the respiratory tracts and systemic actions due to the characteristics of the pulmonary site, including a large surface area, abundant capillary network, thin membrane with adequate permeability for macromolecules, reduced enzymatic degradation, and a lack of first-pass metabolism. In this study, to achieve desirable delivery of peptide drugs with an inhalable formulation to target sites in the respiratory tract and/or absorption sites in the lung, peptide-loaded inhalable formulations were designed by the application of flash nanoprecipitation, one of the precipitation methods to prepare functional nanoparticles, and the fine droplet drying process, a powderization technique using printing technology, to control the pharmacokinetic behavior. From the findings of the study, the strategic applications of these techniques could contribute to provide peptide-loaded inhalable formulations to enhance their biopharmaceutical potentials.

  • 松岡 純平
    2020 年 140 巻 11 号 p. 1313-1322
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki-Miyaura coupling), C2 (acylation), N3 (alkylation) and C5 positions (Ullmann coupling) provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.

  • 肱岡 雅宣
    2020 年 140 巻 11 号 p. 1323-1327
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Intracerebral hemorrhage (ICH) results from blood vessels rupture in the brain, forming a blood clot in the brain parenchyma. Leakage of blood constituents causes detrimental tissue damages, ensuing long-lasting neurological deficits; however, effective therapeutic approaches are not yet developed to date. In this study, leukotriene B4 (LTB4) and its receptor leukotriene B4 receptor 1 (BLT1) are proposed as novel therapeutic targets for ICH therapy. After the onset of ICH, the LTB4 content in the brain transiently elevated. Microglia are considered as the source of LTB4 production. Thrombin, a blood constituent, activated the BV-2 microglia and increased the LTB4 secretion from the BV-2 cells. Microglia-released LTB4 promoted its own microglial activation and neutrophil-like differentiated HL-60 cell migration activity. LTB4 receptors comprised of two types: BLT1 and BLT2, with BLT1 known to be a high-affinity receptor associated with chemotaxis. BLT1 knockout mice showed decreased neutrophil invasion, attenuating sensorimotor dysfunction after ICH. Furthermore, therapeutic administration of ONO-4057, an orally active LTB4 receptor antagonist, attenuated neutrophil invasion, microglial activation, axonal fragmentation, and sensorimotor deficits induced by ICH. These results suggest that LTB4 and its receptor BLT1 can be potential promising therapeutic targets that prevent tissue damages following ICH.

  • 池田 義人
    2020 年 140 巻 11 号 p. 1329-1334
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Biliary lipids primarily consist of bile salts, phospholipids, and cholesterol. Bile salts have potent detergent properties and deleterious effects on the cell membrane and are cytotoxic to hepatocytes. We have previously reported that phosphatidylcholine (PC), the predominant bile phospholipid, protects hepatocytes from the cytotoxicity of bile salts, whereas cholesterol reverses the cytoprotective effects of PC against bile salts. ABCB4, a member of the ATP-binding cassette transporter family, secretes biliary phospholipids, especially PC, from the hepatocytes into the bile. Using Abcb4 knockout mice and HEK293 cells that stably expressed ABCB4, we examined the effects of taurine- or glycine-conjugated cholate, ursodeoxycholate, and hyodeoxycholate on the ABCB4-mediated efflux of PC. We observed that the biliary secretion of PC in wild-type mice significantly increased following infusion of all the tested bile salts, especially taurohyodeoxycholate. On the other hand, the biliary secretion of PC in Abcb4 knockout mice was not affected by the bile salt infusions. The results also demonstrated that the efflux of PC from ABCB4-expressing HEK293 cells was significantly stimulated by taurohyodeoxycholate, which has a strong potential to form mixed micelles with PC. Furthermore, the results of our study emphasized the possibility that the specific interactions of bile salts with ABCB4 are necessary for the release of PC molecules from the binding pocket of ABCB4 into the aqueous environment. Further understanding of this mechanism will aid in the development of novel therapeutic agents for cholestatic liver diseases.

  • 渡邊 政博
    2020 年 140 巻 11 号 p. 1335-1341
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Advanced glycation end products (AGEs) are non-enzymatically formed from sugars or their metabolites with biomolecules. These molecules are formed in vivo, and the formation of AGEs on functional biomolecules was demonstrated to alter their properties. In addition, AGEs were reported to elicit inflammatory reactions by stimulating their endogenous receptors. However, the relationship between AGEs and these phenomena remains unclear. To understand the pathophysiological roles of AGEs, we investigated their action mechanisms at the molecular level. In this study, we found that AGEs can directly interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), the cytokine that controls tumor necrosis factor-α (TNF-α)-stimulated inflammatory reactions. This interaction inhibited the action of TWEAK and subsequently increased TNF-α-induced proinflammatory cytokine expression. This raised the possibility that AGEs trap other cytokines and alter their activities. We named this hypothesis “AGE-mediated cytokine trapping”. To assess this hypothesis, we next examined the mechanism of AGE-TWEAK interaction. The pull-down assay using the deletion mutant revealed that a relatively large region of TWEAK functions in the interaction with AGEs, suggesting that it is difficult to explore other cytokines capable of interacting with AGEs using TWEAK sequence similarity. Therefore, to find novel AGE-cytokine interactions, we performed comprehensive screening using a protein array and found several candidates. To generalize “AGE-mediated cytokine trapping”, detailed studies using these candidates are now in progress.

  • 安川 圭司
    2020 年 140 巻 11 号 p. 1343-1350
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Disruption of redox balance due to the overproduction of free radicals and reactive oxygen species (ROS) could cause protein denaturation, lipid peroxidation, and DNA mutation. These lead to an induction of gastrointestinal diseases such as gastric ulcers induced by long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) and ulcerative colitis. Magnetic resonance technique, which is non-invasive and free of radiation exposure, is a promising tool for evaluating redox status in the living body. This study investigated ROS production in rats with gastric ulcers induced by a typical NSAIDs indomethacin using in vivo ESR/spin probe technique. The ESR signal intensity of membrane-permeable nitroxyl probe in the indomethacin group showed enhanced decay compared with the vehicle group, but the enhancement was not observed in the presence of a membrane-permeable ROS scavenger, suggesting the intracellular ROS production. The imaging analysis using Overhauser-enhanced MRI (OMRI) with dual probes labeled with 14N and 15N enabled visualization of ROS production in the glandular stomach of rat with indomethacin-induced gastric ulcers. The intracellular ROS production in the distal and proximal colon in the initiation stage and intra- and extra-cellular ROS production of the advanced stage of colitis induced by dextran sodium sulfate (DSS) using the OMRI/dual-probe technique was observed. Furthermore, nitration of src homology protein tyrosine phosphatase 2 in macrophages might be involved in the activation of Toll-like receptor 4 and NF-κB, inducing infiltration of activated neutrophils into colonic mucosa to produce ROS in DSS-induced colitis mice.

総説
  • 田村 悦臣
    2020 年 140 巻 11 号 p. 1351-1363
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the effects of coffee, we analyzed molecular response upon exposure to coffee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the effect of coffee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coffee induced proteasomal degradation of IRS-1, leading to reduction of PPARγ expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60% coffee for 7 weeks. As for Alzheimer's disease, we analyzed the effect of coffee on amyloid β (Aβ) production in human neuronal SH-SY5Y cells. We found a 20% reduction in Aβ production when treated with 2.5% coffee for 2 d. This reduction was due to proteasomal degradation of BACE1 (β-secretase), which was activated by protein kinase A. In addition, coffee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFκB activity and Nrf2 activation. Roasted coffee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coffee, also reduced Aβ production and exhibits anti-inflammatory effects by a similar mechanism as coffee. Our results suggest that roasting coffee beans to generate pyrocatechol is necessary for the preventive effects of coffee intake on the chronic diseases.

  • 若子 直也, 山浦 克典
    2020 年 140 巻 11 号 p. 1365-1372
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Japan's health care system can be regarded as one of the best worldwide, provided it remains sustainable. It has relatively low costs, short wait times, low disease incidence, and high life expectancy. However, universal coverage in Japan faces financial challenges due to the country's rapidly aging population. Canada is another of the few developed countries that have universal health coverage. In contrast to Japan, Canada's health care spending is still sustainable according to recent studies. Effective cost control by payers has played a major role, with providers being steered toward evidence-based and cost-effective drug therapies. Furthermore, expanded pharmacy services have been important in suppressing spending on prescription drugs and minor health care services such as vaccination, government-funded smoking cessation, and medication review programs. This article outlines the services provided by Canadian pharmacists with expanded scope of practice. The pharmaceutical profession and its advocacy body in Canada have not only played a role in regulatory changes, but also put in place technological infrastructure called PharmaNet and contributed to appropriate prescribing. Given the current economic situation and demographic trends in Japan, more options should be explored in order to maintain universal health coverage by meeting the funding gap. Utilizing community pharmacies and pharmacists is proposed as one option.

一般論文
  • 須永 登美子, 東野 真弓, 木村 綾沙, 馬場 康彦, 谷岡 利裕, 渡邊 徹, 佐々木 忠徳
    2020 年 140 巻 11 号 p. 1373-1380
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    The treatment of acute ischemic stroke usually involves argatroban administration by continuous infusion for 2 d and by intravenous infusion twice a day for 5 d after that. However, the appropriate dose of argatroban to be administered is not clear. Therefore, no studies have been reported a comparison of intravenous and continuous argatroban infusion after day 3 for acute ischemic stroke patients. We aimed to identify the connection between differences in argatroban administration and worsening of symptoms after day 3 in ischemic stroke patients. We retrospectively evaluated the data of 107 ischemic stroke patients who received treatment with argatroban. The study endpoint was defined as the worsening of symptoms from days 3 to 7. Logistic regression analysis was used to determine the risk factors that were significantly associated with worsening of symptoms. Patients were administered argatroban, with rates of 72.0%, and 28.0% for continuous, and intravenous infusion, respectively. A total of 10 (9.3%) patients experienced worsening of symptoms. In the single logistic regression analysis, carotid stenosis [non-adjusted odds ratio (OR) 5.775, 95% confidence interval (CI) 1.486-22.442, p=0.011] was only significantly associated with worsening of symptoms. Worsening of symptoms was not related to either intravenous or continuous infusion group (16.7% vs. 6.5%, p=0.104). Bleeding was also not associated with either group (6.7% vs. 3.9%, p=0.618). We suggest that the differences in the mode of argatroban administration were not related to the worsening of symptoms in ischemic stroke patients. We also found that safety was equivalent regardless of the administration route.

    Editor's pick

    The authors investigated the connection between differences in argatroban administration and worsening of symptoms after day 3 in ischemic stroke patients. Worsening of symptoms was not related to either intravenous or continuous infusion group. Bleeding was also not associated with either group. They suggest that the differences in the mode of argatroban administration were not related to the worsening of symptoms in ischemic stroke patients. They also found that safety was equivalent regardless of the administration route.

  • 立浪 良介, 村尾 優, 佐藤 恵亮
    2020 年 140 巻 11 号 p. 1381-1388
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Epalrestat (EPS), approved in Japan, is currently the only aldose reductase inhibitor that is available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH, the most abundant non-protein thiol antioxidant in cells, is important for protection against oxidative stress. Oxidative stress is associated with the development and progression of many pathological conditions, such as atherosclerosis, diabetes, and neurodegeneration. In this study, we tested the hypothesis that EPS enhances resistance to oxidative stress, by using rat Schwann cells. To determine whether EPS protects Schwann cells from oxidative stress, we performed experiments by using radical generators, drugs, and heavy metals as the source of oxidative stress. EPS reduced the cytotoxicity induced by 2,2-azobis-[2-(2-imidazolin-2-yl) propane] dihydrochloride, 6-hydroxydopamine, cisplatin, palmitate, cadmium chloride, and manganese (II) sulfate, indicating that EPS plays a role in protecting cells from oxidative stress. We suggest that EPS has the potential to prevent the development and progression of disorders caused by oxidative stress.

ノート
  • 山本 大介, 伊藤 智夫, 鈴木 順子
    2020 年 140 巻 11 号 p. 1389-1396
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー
    電子付録

    A questionnaire survey was conducted with pharmacy students to obtain useful information for preparing teaching materials in the field of pharmaceutical laws. We conducted a customer satisfaction (CS) analysis by asking pharmacy students to evaluate whether the teaching materials used in the Pharmaceutical Laws class at Kitasato University were effective in promoting learning and understanding. In addition, we asked them about their impressions of attending the Pharmaceutical Laws class and analyzed their freely described answers. The CS analysis suggested teaching materials that included case studies of pharmaceutical law judgments and violations may have been useful for learning this subject. Furthermore, the text analysis showed many of the participants believed the contents of the teaching materials were difficult. Therefore, it is necessary to redesign the contents so that learning can progress step by step from the basic items. In addition, since some students recognized that the subject could be memorized, it is possible they can convey only what they remember and not what they had learned or what knowledge they could use in other contexts and situations. Therefore, it is necessary to clearly present the learning objectives for each item in lesson's teaching materials.

  • 山本 緑, 石井 祐次
    2020 年 140 巻 11 号 p. 1397-1403
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Pharmacological cognitive enhancement (PCE) usually refers to the use of medical substances by healthy individuals to improve mental performance. Given that certain substances have been frequently used for years, the long-term effectiveness and safety are essential to know but particularly difficult and costly to determine. Although PCE is a widespread and frequent phenomenon among university students in other countries, PCE prevalence in Japan has not been elucidated. The present study aimed to investigate the prevalence of and the attitude toward PCE among Japanese undergraduates over 3 years (2017-2019). Almost no student had ever used prescription drugs for cognitive enhancement. When asked, “Would you like to use drugs to enhance your cognitive performance?” 68.6-72.0% of the students answered, “No,” 25.4-26.7% answered, “I couldn't say,” and 2.5-4.8% answered, “Yes.” These answers were associated with sex (2017-2018) and stress sensitivity (2019) but not with drinking, smoking, or stress of academic performance. Half of the students had used energy drinks for neural enhancement prior to an examination, which is similar to Western usage. The users of soft enhancers, such as energy drinks, are more likely to use other drugs. Given that caffeine can be a gateway for cognitive enhancement, future education addressing PCE among students should emphasize the side effects of prescription drugs as well as health risks of caffeine products.

  • 田中 理恵, 河村 麻衣子, 袴塚 高志, 花尻(木倉) 瑠理
    2020 年 140 巻 11 号 p. 1405-1413
    発行日: 2020/11/01
    公開日: 2020/11/01
    ジャーナル フリー

    Lysergic acid diethylamide (LSD) is a hallucinogen, synthesized from ergot alkaloid, and controlled as a narcotic in Japan. Recently, LSD derivatives have appeared as designer drugs, all over the world. In previous study, we reported identification and analysis of four LSD derivatives in four paper sheet products. In this study, we detected three additional LSD derivatives from three paper sheet products, which were obtained from September 2019 to March 2020 in Japan. We extracted the compounds from paper sheet products with methanol for LC-MS, high-resolution MS and GC-MS analyses. The compounds were identified as 4-cyclopropionyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1cP-LSD), N-methyl-N-isopropyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (MIPLA), 4-butyryl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1B-LSD), by GC-MS, LC-MS, LC-Q-TOF-MS and NMR analyses. As well as other N1-acylated LSD derivatives, 1cP-LSD and 1B-LSD were easily deacylated to LSD during GC-MS analysis, we have to be careful to analyze these compounds.

feedback
Top