Almroth, et al., 2011. The safety of flecainide treatment of atrial fibrillation: long-term
incidence of sudden cardiac death and proarrhythmic events. J. Intern. Medicine. 270,
281–290.
Amin, et al., 2010. Cardiac sodium channelopathy, Pflugers Arch. Eur. J. Physiol. 460,
223–237.
Ando, et al., 2017. A new paradigm for drug-induced torsadogenic risk assessment
using human iPS cell-derived cardiomyocytes. J Pharmacol Toxicol Methods. 84,
111-127.
Betzenhauser, et al., 2015. Calcium
channel
mutations
in
cardiac
arrhythmia
syndromes. Curr. Mol. Pharmacol. 8, 133–142.
Bibler, et al., 1988. Recurrent ventricular tachycardia due to pentamidine-induced
cardiotoxicity. Chest. 94, 1303–1306.
Blinova, et al., 2017. Comprehensive Translational Assessment of Human-Induced
Pluripotent Stem Cell Derived
Cardiomyocytes for Evaluating Drug-Induced
Arrhythmias. Toxicol. Sci. 155, 234–247.
Blinova, et al., 2018. International multisite study of human-induced pluripotent stem
cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep. 24,
3582-3592.
Braam, et al., 2010. Prediction of drug-induced cardiotoxicity using human embryonic
stem cell-derived cardiomyocytes. Stem Cell Res. 4, 107–116.
Brown, 2004. Drugs, hERG and sudden death. Cell Calcium. 35, 543-7.
Chen, et al., 2010. Post-transcriptional control of human ether-a-go-go-related gene
potassium channel protein by alpha-adrenergic receptor stimulation. Mol. Pharmacol.
78, 186–197.
Clements, et al., 2015. Bridging functional and structural cardiotoxicity assays using
human embryonic stem cell-derived cardiomyocytes for a more comprehensive risk
assessment. Toxicol. Sci. 148, 241–260.
Colatsky, et al., 2016. The Comprehensive in Vitro Proarrhythmia Assay (CiPA)
45
initiative - Update on progress. J. Pharmacol. Toxicol. Methods. 81, 15-20.
Conte, et al., 1986. Use of a specific and sensitive assay to determine pentamidine
pharmacokinetics in patients with AIDS. J. Infect. Dis. 154, 923–929.
Cordes, et al., 2005. Pentamidine reduces hERG expression to prolong the QT interval.
Br. J. Pharmacol. 145, 15–23.
Cubeddu, 2003. QT prolongation and fatal arrhythmias: a review of clinical
implications and effects of drugs. Am. J. Ther. 10, 452–457.
Cubeddu, 2016. Drug-induced inhibition and trafficking disruption of ion channels:
pathogenesis of QT abnormalities and drug-induced fatal arrhythmias. Curr. Cardiol.
Rev. 12, 141–154.
de Git, et al., 2013. Cardiac ion channel trafficking defects and drugs. Pharmacol Ther.
139, 24-31.
Delisle, et al., 2004. Biology of cardiac arrhythmias: ion channel protein trafficking.
Circ. Res. 94, 1418–1428.
Dennis, et al., 2007. hERG channel trafficking: novel targets in drug-induced long QT
syndrome. Biochem. Soc. Trans. 35, 1060–1063.
Dennis, et al., 2012. Molecular determinants of pentamidine-induced hERG trafficking
inhibition. Mol. Pharmacol. 81, 198–209.
Eisenhauer, et al., 1994. Incidence
of
cardiac
arrhythmias
during
intravenous
pentamidine therapy in HIV-infected patients. Chest. 105, 389-95.
Fermini, et al., 2016. A new perspective in the field of cardiac safety testing through the
comprehensive in vitro proarrhythmia assay paradigm. J. Biomol. Screen. 21, 1–11.
Ficker, et al., 2003. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of
the cardiac potassium channel HERG. Circ. Res. 92, e87–100.
Furuhama, 2007. Toxicology assessment of fluoroquinolones: a case study. In Sietsema
W K, Schwen R (ed.), Nonclinical drug safety assessment: practical considerations for
successful Registration. FDA News. Falls Church, USA. 571-88.
Gandhi, et al., 2003. Fluconazole- and levofloxacin induced torsades de pointes in an
intensive care unit patient. Am J Health Syst Pharm. 60, 2479-83.
46
Gintant, 2011. An evaluation of hERG current assay performance: Translating
preclinical safety studies to clinical QT prolongation. Pharmacol. Ther. 129, 109–119.
Giorgi, et al., 2010. QT
Interval
Prolongation:
Preclinical
and
Clinical
Testing
Arrhythmogenesis in Drugs and Regulatory Implications. Curr. Drug Saf. 5, 54–57.
Girgis, et al., 1997. A prospective study of the effect of I.V. pentamidine therapy on
ventricular arrhythmias and QTc prolongation in HIV-infected patients. Chest 112,
646–653.
Gong, et al., 2006. Mechanisms of pharmacological rescue of trafficking-defective hERG
mutant channels in human long QT syndrome. J. Biol. Chem. 281, 4069–4074.
Harris, et al., 2013. Comparison of Electrophysiological Data From Human-Induced
Pluripotent Stem Cell–Derived Cardiomyocytes to Functional Preclinical Safety Assays.
Toxicol. Sci. 134, 412–426.
Heath, et al., 2011. Translation of flecainide- and mexiletine-induced cardiac sodium
channel inhibition and ventricular conduction slowing from nonclinical models to
clinical. J. Pharmacol. Toxicol. Methods. 63, 258–268.
Hinterseer, et al., 2010. Usefulness of short-term variability of QT intervals as a
predictor for electrical remodeling and proarrhythmia in patients with nonischemic
heart failure. The Am. J. Cardiol. 106, 216-220.
Hondeghem, et al., 2011. Drug-induced QTC prolongation dangerously underestimates
proarrhythmic potential: Lessons from terfenadine. J. Cardiovasc. Pharmacol. 57, 589–
597.
Iwai, et al., 2013.Hsp90 prevents interaction between CHIP and HERG proteins to
facilitate maturation of wild-type and mutant HERG proteins. Cardiovasc. Res. 100,
520–528.
Izumi-Nakaseko, et al., 2017. Characterization
of
human
iPS
cell-derived
cardiomyocyte sheets as a model to detect drug-induced conduction disturbance. The J.
of Toxicol. Sci. 42, 183–192.
Jha, 1983.
Evaluation of diamidine compound (pentamidine isethionate) in the
treatment resistant cases of kala-azar occurring in North Bihar, India. Trans. R. Soc.
Trop. Med. Hyg. 77, 167–170.
John, et al., 2012. Ventricular arrhythmias and sudden cardiac death. The Lancet.
47
380, 1520–1529.
Kadota, et al., 2012. Devalopment of a reentrant arrhythmia model in human
pluripotent stem cell-derived cardiac cell sheets. Eur Heart J. 34 (15), 1147-1156.
Kanda, et al., 2018. Development of torsadogenic risk assessment using human
induced pluripotent stem cell-derived cardiomyocytes: Japan iPS Cardiac Safety
Assessment (JiCSA) update. J Pharmacol Sci. 138, 233-239.
Kaneko, et al., 2014. On-chip in vitro cell-network pre-clinical cardiac toxicity using
spatiotemporal human cardiomyocyte measurement on a chip. Sci Rep. 4, 4670.
Kim, et al., 2019; Scaling and correlation properties of RR and QT intervals at the
cellular level. Sci Rep. 9, 3651.
Kitaguchi, et al., 2016. CSAHi
study:
Evaluation
of
multi-electrode
array
in
combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT
prolongation and arrhythmia — Effects of 7 reference compounds at 10 facilities. J.
Pharmacol Toxicol Methods. 78, 93–102.
Kramer, et al., 2013. MICE models: Superior to the HERG model in predicting torsade
de pointes. Sci Rep. 3, 2100
Kuryshev, et al., 2005. Pentamidine-induced long QT syndrome and block of hERG
trafficking. J. Pharmacol. Exp. Ther. 312, 316–323.
Laverty, et al., 2011. How can we improve our understanding of cardiovascular safety
liabilities to develop safer medicines? Br. J. Pharmacol.
163, 675–693.
Levine, et al., 1989. Mechanisms and risk factors for proarrhythmia with type Ia
compared with Ic antiarrhythmic drug therapy. Circulation. 80:1063–1069.
Morganroth and Goin, 1991. Quinidine-related mortality in the short-to-medium-term
treatment of ventricular arrhythmias. A meta-analysis. Circ. 84, 1977–83.
Nalos, et al., 2011. Comparison of the hERG current blockers moxifloxacin, dofetilide
and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of
isolated cardiomyocytes. Br. J. Pharmacol. 165, 467–478.
Nalos, et al., 2012. Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031
in five screening models of pro-arrhythmia reveals lack of specificity of isolated
cardiomyocytes. Br. J. Pharmacol. 165, 467–478.
48
Neckers and Workman, 2012. Hsp90 molecular chaperone inhibitors: are we there yet?
Clin. Cancer Res. 18, 64–76.
Nogawa and Kawai, 2014. hERG trafficking inhibition in drug-induced lethal cardiac
arrhythmia. Eur. J. Pharmacol. 741, 336–339.
Nomura, et al., 2011. On-chip constructive cell-network study (II): on-chip quasi-in vivo
cardiac toxicity assay for ventricular tachycardia/fibrillation measurement using
ring-shaped closed circuit microelectrode with lined-up cardiomyocyte cell network. J.
Nanobiotech. 9, 39.
Norström, et al., 2006. Molecular and pharmacological properties of human embryonic
stem cell-derived cardiomyocytes. Exp. Biol. Med.
231, 1753–1762.
Nozaki, et al., 2014. Availability of human induced pluripotent stem cell-derived
cardiomyocytes in assessment of drug potential for QT prolongation. Toxicol. Appl.
Pharmacol. 278, 72–77
Nozaki, et al., 2016. CSAHi study: Validation of multi-electrode array systems
(MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS
cell-derived cardiomyocytes -assessment of inter-facility and cells lot to-lot-variability-.
Regul. Toxixol. Pharmacol. 77, 75-86.
Osadchii, 2014. Effects of Na+ channel blockers on extrasystolic stimulation-evoked
changes in ventricular conduction and repolarization. J. Cardiovasc. Pharmacol. 63,
240–251.
Paltoo, et al., 2001.Levofloxacin induced polymorphic ventricular tachycardia with
normal QT interval. PACE. 24, 895-7.
Penniman et al., 2010. Assessing use-dependent inhibition of the cardiac Na current
(INa) in the PatchXpress automated patch clamp. J. Pharmacol. Toxicol. Methods.
62(2): 10718.
Ponti, et al., 2002. Safety of non-antiarrhythmic drugs that prolong the QT interval or
induce torsade de pointes: an overview. Drug safety: an international journal of medical
toxicology and drug experience. 25, 263–286.
Rosati and McKinnon, 2004. Regulation of ion channel expression. Circ. Res. 94, 874–
883.
Sager, et al., 2014. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting
49
report from the Cardiac Safety Research Consortium. Am Heart J. 167, 292-300.
Samaha, 1999.
QTc interval prolongation and polymorphic ventricular tachycardia in
association with levofloxacin. Am J Med. 107, 528-9.
Sartipy and Björquist, 2011. Human pluripotent stem cell-based models for cardiac
and hepatic toxicity assessment. Stem Cells. 29, 744–748.
Sirenko, et al., 2013. Multiparameter in vitro assessment of compound effects on
cardiomyocyte physiology using iPSC cells. J. Biomol. Screen. 18, 39–53.
Skibsbye and Ravens, 2016. Mechanism of proarrhythmic effects of potassium channel
blockers. Card. Electrophysiol. Clin. 8, 395–410.
Solit, et al., 2007. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in
patients with advanced cancer. Clin. Cancer Res. 13, 1775–1782.
Stams, et al., 2016. Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade
de Pointes in Anesthetized Chronic Atrioventricular Block Dogs. Circ. J. 80, 1336–1345.
Suzuki, et al., 2011. Stepwise
pattern
modification
of
neuronal
network
in
photo-thermally-etched agarose architecture on multi-electrode array chip for
individual-cell-based electrophysiological measurement. Lab Chip. 5, 241–247.
Synnergren, et al., 2008. Molecular Signature of Cardiomyocyte Clusters Derived from
Human Embryonic Stem Cells. Stem Cells. 26, 1831–1840.
Takasuna et al., 2017. Comprehensive in vitro cardiac safety assessment using human
stem cell technology: Overview of CSAHi HEART initiative. J. Pharmacol. Toxicol.
Methods. 83, 42–54.
Tanaka, et al., 2009. In vitro pharmacologic testing using human induced pluripotent
stem cell-derived cardiomyocytes. Biochem. Biophys. Res. Commun. 385, 497–502.
Varkevisser, et al., 2012. Beat-to-beat variability of repolarization as a new biomarker
for proarrhythmia in vivo. Hear. Rhythm. 9, 1718–1726.
Varkevisser, et al., 2013. Structure-activity relationships of pentamidine-affected ion
channel trafficking and dofetilide mediated rescue. Br. J. Pharmacol. 169, 1322–1334.
Wagner, et al., 2015. Role of Sodium and Calcium Dysregulation in Tachyarrhythmias
in Sudden Cardiac Death. Circ. Res. 116, 1956–1970.
50
Wang, 2010. The role of microRNA in cardiac excitability. J. Cardiovasc. Pharmacol.
56, 460–470.
Waring, et al., 2015. An analysis of the attrition of drug candidates from four major
pharmaceutical companies. Nat. Rev. Drug Discov. 14, 475-486.
Wharton, et al., 1987. Torsade de pointes during administration of pentamidine
isethionate. Am. J. Med. 83, 571–576.
Woosley, et al., 2001. Pharmacology, electrophysiology, and pharmacokinetics of
mexiletine. Am. Hear. J. 107, 1058–1065.
Wyman, et al., 2004. Prevention of primary ventricular fibrillation in acute myocardial
infarction with prophylactic lidocaine. The Am. J. Cardiol. 94, 545–551.
Yamamoto, et al., 2016. Electrophysiological characteristics of human iPSC-derived
cardiomyocytes for the assessment of drug-induced proarrhythmic potential. PLoS One.
11(12): e0167348.
Yamazaki, et al., 2012. A novel method of selecting human embryonic stem cell-derived
cardiomyocyte clusters for assessment of potential to influence QT interval. Toxicol in
Vitro. 26, 335–342.
51
謝辞
本稿を終えるにあたり、終始懇篤なる御指導、御鞭撻を賜りました、早稲田大学先進理
工学部 安田 賢二 教授、ならびに、東京大学大学院薬学系研究科 關野 祐子 教授に謹ん
で感謝の意を表します。
本研究の推進にあたり、御尽力、御助言を賜りました法政大学生命科学部 金子 智行 教
授、ならびに、野村 典正氏、浜田 智代氏、東京大学大学院薬学系研究科 澤田 光平 客員
教授に深謝いたします。また、本研究の技術基盤の構築をいただくと共に研究遂行をご支
援くださいました早稲田大学 重点領域研究機構、ならびに、Waseda Bioscience Research
Institute in Singapore（WABIOS）の関係各位に心から御礼申し上げます。
本研究を遂行するにあたり、直接のご指導を賜り、多くの知識や御助言をいただきまし
た三分一所 厚司氏、Axcelead Drug Discovery Partners 株式会社 高砂 浄氏、第一三共株
式会社 阿部 泰之氏に心よりお礼申し上げます。また、細胞培養や電流測定にあたり、御
協力を賜りました第一三共 RD ノバーレ株式会社 土居 正文氏、第一三共株式会社 坂倉 智
子氏に深謝致します。
最後に、本研究の機会と御支援を与えてくださいました第一三共株式会社 高崎 渉研究
開発本部長、熊倉 誠一郎研究統括部長、森 和彦安全性研究所長、杉立 収寛スペシャルテ
ィ第一研究所長、高石 巨澄スペシャルティ第一研究所第一グループ長に深く感謝いたしま
す。そして、私の研究を支えてくださいました第一三共株式会社 研究開発本部の関係各位、
ならびに、博士号取得に対し理解し協力してくれた家族に心より感謝の意を表します。
52
...
論文の公開元へ
