Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor
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- Mizuno Hiroshi
- Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd.
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- Adachi Hideyuki
- Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd.
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- Kimura Junko
- Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd.
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- Sawa Yoshio
- Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd.
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- Kakiki Motoharu
- Drug Metabolism and Pharmacokinetics Research, Eisai Co., Ltd.
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- Lansdell Kate
- Quintiles Preclinical Services, Quintiles, Ltd.
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- Saito Mamoru
- Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd.
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- Kerns William David
- Pharma Consulting, Inc.
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The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC50 value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 μg/kg/min significantly prolonged the QT interval by 10.5±1.6% from 281±2 ms to 311±6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984±78 nM, n=3) and its protein binding fraction (99.0±0.1%, n=5), the free plasma concentration was estimated at 9.8±0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.
収録刊行物
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- Biological & Pharmaceutical Bulletin
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Biological & Pharmaceutical Bulletin 26 (12), 1661-1667, 2003
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204626111104
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- NII論文ID
- 110003608369
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- NII書誌ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- NDL書誌ID
- 6766678
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- PubMed
- 14646167
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 使用不可