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Use of Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters to Assess Potential for Chronic Treatment with compounds to Cause QT Prolongation

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Pharmacology & Pharmacy 2014年第4期5卷 364-371页

作者： Taro Hihara Kazuto Yamazaki Tomohiko Taniguchi Takashi Yoshinaga Masashi Ito Kohei Sawada Biomarkers and Personalized Medicine CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan Biopharmaceutical Assessment CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan Next Generation Systems CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan

Drug-induced QT prolongation is a serious clinical issue in developing novel drug candidates and marketing drugs. A major cause of QT prolongation is direct inhibition of human ether-à-go-go-related gene (hERG) channels. Reduction in repolarization-related channel expression levels on plasma membranes is another mechanism that induces QT prolongation. Recently, we established a system for assessing the risk of QT prolongation by using human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. Here, we examined whether this system was able to detect FPDc prolongation caused by pentamidine or probucol, both of which can induce QT prolongation after long-term treatment. hES-CMCs were treated with pentamidine or probucol, and the FPDc of the same clusters was measured 10 min, 4 h, and 24 h after the start of treatment. concentration-dependent FPDc prolongation was observed at 24 h, but not at 10 min, with pentamidine or probucol treatment. These results suggest that the hES-CMC-based assessment system can be used to detect both acute (at 10 min) and delayed (at 24 h) QT prolongation risk on the same platform by simple alteration of the extended culture period.

关键词： Human Embryonic Stem Cell-Derived Cardiomyocytes Field Potential Duration QT Prolongation Chronic Treatment Risk Assessment

Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

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Pharmacology & Pharmacy 2014年第1期5卷 117-128页

作者： Kazuto Yamazaki Taro Hihara Hiroshi Kato Tatsuto Fukushima Kazuyuki Fukushima Tomohiko Taniguchi Takashi Yoshinaga Norimasa Miyamoto Masashi Ito Kohei Sawada Biomarkers and Personalized Medicine CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan Biopharmaceutical Assessment CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan Global Discovery Research Neuroscience and General Medicine PCU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan Next Generation Systems CFU Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan

We established a QT interval assessment system that uses human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. To investigate the applicability of the hES-CMC system to drug safety assessment, we investigated short-term variability in FPDc (STVFPDc) (beat rate rhythmicity) as a marker of torsadogenic risk. We investigated the FPDc and STVFPDc of hES-CMCs treated with hERG channel blockers (E-4031 or cisapride) or with our proprietary compounds X, Y, and Z. We also evaluated the electrocardiograms and hemodynamics of dogs treated with compound X, Y, or Z. The torsadogenic hERG channel blockers increased STVFPDc and prolonged FPDc. compounds X, Y, and Z had hERG inhibitory activity. compound X prolonged FPDc with increased STVFPDc, whereas compounds Y and Z tended to shorten FPDc in the hES-CMC system. In the in vivo canine study, compound X prolonged corrected QT (QTc), and compounds Y and Z tended to shorten QTc, showing a good correlation with the results in hES-CMCs. These findings suggest that combined assessment of FPDc and STVFPDc in the hES-CMC system increases the predictability of torsadogenic risk.

关键词： Human Embryonic Stem Cell-Derived Cardiomyocytes Field Potential Duration Short-Term Variability QT Interval Torsades de Pointes Risk Assessment

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

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Pharmacology & Pharmacy 2013年第9期4卷 663-678页

作者： Yutaka Takeuchi Masayuki Namiki Yasumi Kitahara Setsuo Hasegawa Akihiro Ohnishi Nobuyuki Yasuda Takashi Inoue Richard Clark Kazuto Yamazaki Clinical Development Japan/Asia Clinical Research PCU Eisai Co. Ltd. Tokyo Japan Clinical Development Japan/Asia Clinical Research PCU Eisai Co. Ltd. Tokyo Japan Clinical Pharmacology Clinical Science SOCS CFU Eisai Co. Ltd. Tokyo Japan Department of Laboratory Medicine Daisan Hospital Jikei University School of Medicine Tokyo Japan Sekino Clinical Pharmacology Clinic Tokyo Japan Present Address: Pharmaspur Inc. Tokyo Japan Tsukuba Research Laboratories Eisai Co. Ltd. Tsukuba Japan.

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p concentration-dependent manner, but not from basophils. The structure-activity relati

关键词： Dipeptidyl Peptidase-IV Inhibitor Rash Histamine Structure-Activity Relationship

Safety, Tolerability, and Pharmacokinetics of E3030, a Novel Peroxisome Proliferator-Activated Receptor <i>α/γ</i>Dual Agonist, in Healthy Japanese Male Subjects

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Pharmacology & Pharmacy 2014年第2期5卷 139-148页

作者： Yutaka Takeuchi Yuki Nishioka Yasumi Kitahara Setsuo Hasegawa Akihiro Ohnishi Clinical Development Japan/Asia Clinical Research PCU Eisai Co. Ltd. Tokyo Japan Department of Laboratory Medicine Daisan Hospital Jikei University School of Medicine Tokyo Japan Japan Regulatory Affairs Global Regulatory CFU Eisai Co. Ltd. Tokyo Japan Sekino Clinical Pharmacology Clinic Tokyo Japan Present address: Pharmaspur Inc. Tokyo Japan

Objective: The objectives of the present study were to evaluate the safety of single oral dose E3030 in healthy Japanese male subjects, and to evaluate pharmacokinetics after single oral dose E3030 and food effect on pharmacokinetic profiles. Methods: This study was conducted in a randomized, double-blind, placebo-controlled, ascending single-dose study in 56 healthy Japanese male subjects. Subjects were orally administered E3030 (0.5-40 mg) or placebo. Results: Six of 42 (14%) subjects’ administered E3030 experienced adverse events;however, all adverse events were mild and transient, and there was no dose-dependent increase in any adverse event. Plasma samples were collected over 96 hours after dosing. After administration in the fasted state, Cmax of E3030 was achieved between 1.00 and 1.75 hours, indicating rapid absorption. Both Cmax and AUC were dose-proportional in the range of 0.5 to 40 mg. The average range of elimination half-life was 18.4-23.8 hr. CL/F and Vz/F also remained nearly constant regardless of dose levels. In addition, food effect was exploratorily evaluated in five subjects of administered E3030 (10 mg) in both fasted and fed states. The fed/fasted ratios for the geometric mean of the Cmax and AUC were 0.803 and 0.913, respectively. conclusion: E3030 was safe and well tolerated at single doses up to 40 mg. The pharmacokinetic profile showed good linearity, and food effect on pharmacokinetics of E3030 was not significant.

关键词： PPAR Agonist Phase 1 Pharmacokinetics Healthy Subjects

Egg White Protein-Bonded columns and Their Applications

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色谱 2000年第6期18卷 508-517页

作者： Yoshiya ODA (Laboratory of Seeds Finding Technology, eisai co. ltd, Tsukuba Ibaraki 300 2635, Japan) Laboratory of Seeds Finding Technology eisai co .ltd 日本 TsukubaIba 3002635

Egg white protein bonded columns were developed for HPLC. These columns can be used under aqueous mobile phase and separate various kinds of drug enantiomers. Hyphenated techniques using protein bonded columns with LC/MS and/or column switching have been recognized as integral methods in pharmaceutical research to analyze drug enantiomers. Therefore, these methods are very useful for research fields of pharmacokinetics and pharmacology.

关键词：蛋清蛋白质键合柱 HPLC LC/MS

co-Sense for BA LC/MS系统对血浆中药物的直接分析

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Co-Sense for BA LC/MS系统对血浆中药物的直接分析

The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains

第十五次全国色谱学术报告会

作者：宋苑苑 Hashi Yuki 吕冬 Masatoshi Takahashi Shin-ichi Kawano Keiko Yamabe Eiichi Yamamoto Naoki Asakawa 岛津国际贸易(上海)有限公司北京分析中心岛津国际贸易(上海)有限公司北京分析中心岛津国际贸易(上海)有限公司北京分析中心 Shimadzu corporation Japan Shimadzu corporation Japan Shimadzu corporation Japan eisai co．ltd． Japan eisai co．ltd． Japan

＜正＞本文介绍采用co-Sense for BA LC/MS系统对血浆中药物进行直接分析。该系统运用柱切换技术、含有稀释旁路与前处理柱的自动在线前处理系统以及MS检测器（电喷雾接口）。在药代动力学及代谢研究中需要对血清、血浆等生物样品中的... 详细信息

＜正＞本文介绍采用co-Sense for BA LC/MS系统对血浆中药物进行直接分析。该系统运用柱切换技术、含有稀释旁路与前处理柱的自动在线前处理系统以及MS检测器（电喷雾接口）。在药代动力学及代谢研究中需要对血清、血浆等生物样品中的药物进行分析。为防止柱子的堵塞、劣化,在保护LC/MS接口的同时提高药物的回收率,分析前需要对生物样品进行除蛋白的处理。自动在线前处理系统co-Sense for BA使用反相前处理柱（Shim-pack MAYI-ODS）和在线稀释旁路,可实现对血清、血浆等生物样品的直接进样分析。

关键词： co-Sense-LC/MS 在线前处理系统药物分析

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Neuroscience & Medicine 2014年第4期5卷 183-195页

作者： Toshiyuki Mizui Yuichiro Tanima Hiroko Komatsu Haruko Kumanogoh Masami Kojima Bio-Interface Research Group Health Research Institute National Institute of Advanced Industrial Science and Technology (AIST) Ikeda Japan core Research for Evolutional Science and Technology (CREST) Japan Science and Technology Agency (JST) Kawaguchi Japan Global Discovery Research Neuroscience and General Medicine Product Creation Unit Eisai Product Creation Systems Eisai Co. Ltd. Tsukuba Japan

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that elicits neuronal survival and differentiation, synaptic transmission, and the modulation of synaptic plasticity. The biological actions of BDNF are mediated via two distinct receptors: the high-affinity tropomyosin-related kinase B (TrkB) receptor and the low-affinity p75 neurotrophin receptor (p75NTR). Recent findings regarding the actions and mechanisms of BDNF are reviewed here. Activity-dependent synaptic plasticity, as exemplified by long-term potentiation (LTP) and long-term depression (ltd), underlies the cellular mechanism of learning and memory. An accumulating body of evidence shows that BDNF modulates synaptic plasticity. This function requires extracellular neurotrophin release, synaptic activity-dependent local protein synthesis. In addition, a precursor of BDNF, proBDNF, is emerging as a new ligand with biological activities that are distinct from those of BDNF. The proteolytic cleavage of proBDNF is also proposed as a mechanism that determines the direction of BDNF actions. This review discusses the post-translational processing of proBDNF, the modulatory roles of the human BDNF polymorphism Val66Met, recent reports of the novel mechanisms of BDNF expression, and clinical reports showing the roles of BDNF in the blood. Taken together, these data provide new insights into the biological roles of BDNF and its related molecules in the central nervous system.

关键词： component Brain-Derived Neurotrophic Factor (BDNF) Tropomyosin-Related Kinase B (TrkB) Synaptic Plasticity Polymorphism Proteolytic Cleavage

Changes in the levels of CAM kinase II and synapsin I caused by oxidative stress in the rat brain, and its prevention by vitamin E

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Advances in Bioscience and Biotechnology 2012年第8期3卷 1199-1205页

作者： Nozomi Kaneai Koji Fukui Taisuke Koike Shiro Urano Department of Applied Chemistry Graduate School of Shibaura Institute of Technology Tokyo Japan Division of Bioscience and Engineering Shibaura Institute of Technology Saitama Japan eisai Food & Chemical co. ltd. Tokyo Japan Life Support Technology Research Center Shibaura Institute of Technology Saitama Japan

To define whether oxidative stress and aging induce abnormal dissociation of neurotransmitter-enclosing synaptic vesicles in rat brain nerve terminals, we assessed the activation of Ca+/calmodulin dependent protein kinase II (CAM kinase II) and changes in the levels of synapsin I, which is a synaptic vesicle-associated protein involved in the modulation of neurotransmitter release. Assessment of young rats subjected to hyperoxia-induced oxidative stress and normal aged rats revealed that synaptic CAM kinase II in the rat brain was markedly activated through oxidative stress and aging. In accordance with the activation of CAM kinase II, the levels of phosphorylated synapsin I increased significantly in nerve terminals. Furthermore, it was found that vitamin E prevents these oxidative stress-induced abnormal processes in rat nerve terminals. These results suggest that oxidative stress and aging facilitate the mobilization of neurotransmitter-enclosing synaptic vesicles from the reserve pool in the nerve terminal, thereby inducing abnormal accumulation of synaptic vesicles in the synapse, and that vitamin E inhibits this process in the brain through its antioxidative action.

关键词： Oxidative Stress CAM Kinase II Synapsin I Neurotransmission Vitamin E

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含有促胰酶素的粗品胰泌素的鉴定法

脏器生化制药 1981年第3期 52-58页

作者：周冠新 eisai研究室 eisai Kawashima药厂常州生物化学厂

已报导,有多种方法可以利用各种麻醉动物进行胰泌素(促胰液素)的鉴定。目前,对高纯度制剂胰泌素的效价测定误差为10～15％。迄今所报导的胰泌素测定方法中,还没有一个适用于含有促胰酶素的粗品胰泌素的测定,因为促胰酶素有显著的泌水作... 详细信息

已报导,有多种方法可以利用各种麻醉动物进行胰泌素(促胰液素)的鉴定。目前,对高纯度制剂胰泌素的效价测定误差为10～15％。迄今所报导的胰泌素测定方法中,还没有一个适用于含有促胰酶素的粗品胰泌素的测定,因为促胰酶素有显著的泌水作用(Hydrelatic action),并能增强动物对胰泌素的反应。然而在早期乃至近期的胰泌素的研究中,曾作为参考标准的胰泌素,也可能含有促胰酶

关键词：胰泌素胰脏多肽促胰酶素鉴定法粗品