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Synthesis and BK channel-opening activity of novel N-acylhydrazone derivatives from dehydroabietic acid

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Chinese Chemical Letters 2013年第11期24卷 1023-1026页

作者： Xia-Shi Lv Yong-Mei Cui He-Yun Wang Hai-Xia Lin Wei-Ya Ni Tomohiko Ohwada Katsutoshi Ido kohei sawada Department of Chemistry College of Sciences Shanghai University Graduate School of Pharmaceutical Sciences The University of Tokyo Tsukuba Research Laboratories Eisai Co. Ltd

A series of hydrazone and N-acylhydrazone derivatives of dehydroabietic acid were synthesized and evaluated for BK channel-opening activities in an assay system of CHO-K1 cells expressing hBKa *** assay results indicated that the activities of the investigated compounds were influenced by the physicochemical properties of the substituent at hydrazone moiety.

关键词： BK channels Openers Dehydroabietic acid N-Acylhydrazone

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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

Frequency and Voltage-dependent Inhibition of Delayed Outward Potassium Current by Flecainide in Isolated Atrial Cell of Guinea Pig Heart

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哈尔滨医科大学学报 1993年第3期 222-222页

作者： kohei sawada Department of Pharmacology Eisai Tshikuba Laboratories 1-3 5-Chome Ibaraki Japan

Effects of flecanide on membrane currents were studied using an isolated single atrial cell from guinea pig hearts. The tightseal cell clamp technique was used. In the current clamp condition, flecainide prol（?）nged significantly the atrial action potential （APD） with frequency *** outward K current （I） and outward tail current were specifically inhibited by flecainide in a frequency and concentration fashion. Flecainide inhibit（?）d Imore strongly as the membrane potential become more positive from+10mV to+*** value of Iwas attenuated to 0.973 nA from 1.105 nA of control and the value of tail current was reduced to 0.113 nA from 0.288 nA of control at 60 mV. The drug did not affect on the holding *** effects of flecainide on the action potential and transmembrane ionic currents strongly suggest that the main mechanism of action of this agent is to inhibit Voltage-dependent potassium current. In the Voltage clamp condition, flecainide affected neither the conventional L type Cacurrent nor the Icurrent significantly. Our research proved that F1e was not completely consistent with class Ic agents, because F1e could markedly increase the APD in the experiment.

关键词： Flecainide Voltage Clamp Action pontential Delayed outward potassium current

Risk and Protective Factors Associated with Depression and Anxiety among Pregnant Women during the COVID-19 Pandemic

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Health 2024年第1期16卷 37-51页

作者： Maiko Manaka Miyako Tsuda Moe Fujitani Ai sawada Nanae Akatsuka Ayako Sasaki Faculty of Nursing Osaka Medical and Pharmaceutical University Takatsuki Japan Osaka City Juso Hospital Osaka Japan Osaka City General Hospital Osaka Japan

Background: The coronavirus disease (COVID-19) pandemic has impacted perinatal women’s mental health. However, protective factors associated with depression among pregnant Japanese women during the pandemic have not been reported. Purpose: The present study investigated the risk and protective factors associated with depression and anxiety among pregnant women during the COVID-19 pandemic. Methods: An online questionnaire was administered to 157 pregnant women between October 2022 and May 2023 at two general hospitals in Japan. The Japanese versions of the Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) were used to assess symptoms of depression and anxiety. The χ2 test or Fisher’s exact test and multivariate logistic regression model were used to examine factors associated with depression and anxiety among pregnant women. Results: Overall, 47.1% and 35.7% of the pregnant women reported depressive and anxiety symptoms, respectively. A “history of mental illness” was a risk factor for depression and anxiety among pregnant women during the COVID-19 pandemic. Additionally, unmarried status was a risk factor for anxiety among pregnant women, whereas outdoor and indoor exercises were protective factors against depression and anxiety, respectively. Conclusions: Exercise may have protected pregnant women from depression and anxiety during the COVID-19 pandemic. Encouraging exercise may help maintain the mental health of pregnant women who do not have exercise restrictions.

关键词： Depression Anxiety Factors Pregnancy COVID-19 Pandemic

日本百年石质文物保护:从技术演进到大遗址保护的全景探析

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华夏考古 2024年第3期 125-129页

作者： [日]泽田正昭雷欣怡(译) 日本奈良文化财研究所成都博物馆四川成都市610015

人类创造并传承至今的历史,启示着人类社会的理想状态和前进方向。此中,文化遗产更被誉为人类社会的指南针,是历史的重要物证。尤其近年来,政府极力主张它们应作为旅游资源被有效利用,许多地方率先加强行政效能到地方文化的振兴中,依托... 详细信息

人类创造并传承至今的历史,启示着人类社会的理想状态和前进方向。此中,文化遗产更被誉为人类社会的指南针,是历史的重要物证。尤其近年来,政府极力主张它们应作为旅游资源被有效利用,许多地方率先加强行政效能到地方文化的振兴中,依托当地历史文化,通过世界遗产名录活动的开展和文化遗产的认定,达到地方振兴的目的。像这样将文化遗产作为媒介,举办地域认同感的文化活动也成为近年的趋势。

关键词：世界遗产名录文化遗产石质文物保护日本百年大遗址保护技术演进重要物证指南针

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study

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Neural Regeneration Research 2022年第2期17卷 427-432页

作者： Hiroki Okawara Syoichi Tashiro Tomonori sawada Keiko Sugai kohei Matsubayashi Michiyuki Kawakami Satoshi Nori Osahiko Tsuji Narihito Nagoshi Morio Matsumoto Masaya Nakamura Department of Orthopaedic Surgery Keio University School of MedicineTokyoJapan Department of Rehabilitation Medicine Keio University School of MedicineTokyoJapan Department of Orthopedic Surgery National Hospital OrganizationMurayama Medical CenterTokyoJapan

Body weight-supported treadmill training with the voluntary driven exoskeleton(VDE-BWSTT) has been shown to improve the gait function of patients with chronic spinal cord injury. However, little is known whether VDE-BWSTT can effectively improve the trunk function of patients with chronic spinal cord injury. In this open-label, single-arm study, nine patients with chronic spinal cord injury at the cervical or thoracic level(six males and three females, aged 37.8 ± 15.6 years, and time since injury 51.1 ± 31.8 months) who underwent outpatient VDE-BWSTT training program at Keio University Hospital, Japan from September 2017 to March 2019 were included. All patients underwent twenty 60-minute gait training sessions using VDE. Trunk muscular strength, i.e., the maximum force against which patient could maintain a sitting posture without any support, was evaluated in four directions: anterior, posterior, and lateral(right and left) after 10 and 20 training sessions. After intervention, lateral muscular strength significantly improved. In addition, a significant positive correlation was detected between the change in lateral trunk muscular strength after 20 training sessions relative to baseline and gait speed. The change in trunk muscular strength after 20 training sessions relative to baseline was greatly correlated with patient age. This suggests that older adult patients with chronic spinal cord injury achieved a greater improvement in trunk muscle strength following VDE-BWSTT. All these findings suggest that VDE-BWSTT can improve the trunk function of patients with chronic spinal cord injury and the effect might be greater in older adult patients. The study was approved by the Keio University of Medicine Ethics Committee(IRB No. 20150355-3) on September 26, 2017.

关键词： body weight-supported treadmill training gait disorders hybrid assistive limb neurologic neurophysiotherapy postural balance precision medicine robot-assisted gait training robotics spinal cord injury trunk

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Bayesian optimization with experimental failure for high-throughput materials growth

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npj Computational Materials 2022年第1期8卷 1746-1754页

作者： Yuki K.Wakabayashi Takuma Otsuka Yoshiharu Krockenberger Hiroshi sawada Yoshitaka Taniyasu Hideki Yamamoto NTT Basic Research Laboratories NTT CorporationAtsugiKanagawa243-0198Japan NTT Communication Science Laboratories NTT CorporationSoraku-gunKyoto619-0237Japan

A crucial problem in achieving innovative high-throughput materials growth with machine learning,such as Bayesian optimization(BO),and automation techniques has been a lack of an appropriate way to handle missing data due to experimental ***,we propose a BO algorithm that complements the missing data in optimizing materials growth *** proposed method provides a flexible optimization algorithm that searches a wide multi-dimensional parameter *** demonstrate the effectiveness of the method with simulated data as well as in its implementation for actual materials growth,namely machine-learning-assisted molecular beam epitaxy(ML-MBE)of SrRuO_(3),which is widely used as a metallic electrode in oxide *** the exploitation and exploration in a wide three-dimensional parameter space,while complementing the missing data,we attained tensile-strained SrRuO3 film with a high residual resistivity ratio of 80.1,the highest among tensile-strained SrRuO3 films ever reported,in only 35 MBE growth runs.

关键词： optimization strained resistivity

Ultrasound-guided rectus sheath block for anterior cutaneous nerve entrapment syndrome after laparoscopic surgery:A case report

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World Journal of Clinical Cases 2022年第7期10卷 2357-2362页

作者： Ryuji sawada Kunitaro Watanabe Joho Tokumine Alan Kawarai Lefor Tadao Ando Tomoko Yorozu Department of Pain Clinic NTT Medical Center TokyoHigashigotanda 141-8625TokyoJapan Department of Anesthesiology Hino Municipal HospitalTamadaira 191-0062TokyoJapan Department of Anesthesiology Kyorin University School of MedicineMitaka 181-8611TokyoJapan Department of Surgery Jichi Medical UniversityShimotsuke 329-0498TochigiJapan

BACKGROUND Anterior cutaneous nerve entrapment syndrome is defined as abdominal pain due to entrapped intercostal *** is the first report of a patient successfully treated for anterior cutaneous nerve entrapment syndrome after laparoscopic surgery with an ultrasound-guided rectus sheath *** rectus sheath block physically lysed adhesions and relieved pain from anterior cutaneous nerve entrapment *** SUMMARY The patient is a 44-year-old man who presented with severe left upper abdominal pain at an operative scar one month after laparoscopic ulcer *** and treatment were performed using an ultrasound-guided rectus sheath block with 0.1%lidocaine 20 *** pain was relieved after the *** diagnosis was anterior cutaneous nerve entrapment *** sheath block may be effective for patients with anterior cutaneous nerve entrapment *** Ultrasound-guided rectus sheath block is a promising treatment modality for patients with postoperative anterior cutaneous nerve entrapment syndrome due to adhesions.

关键词： Anterior cutaneous nerve entrapment syndrome Rectus sheath block Hydrodissection Laparoscopic surgery Case report