کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9012248 | 1124544 | 2005 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature](/preview/png/9012248.png)
چکیده انگلیسی
Introduction: The HERG channel is widely used for the assessment of proarrhythmic risk for new drugs. HERG channel blockers obstruct channel functions through various mechanisms, which usually show time dependence, voltage dependence, and state dependence. The voltage protocol and temperature may affect the estimation of drug potency, but limited information is available in this regard. The purpose of this study was to evaluate the influence of voltage protocol and temperature on predicting the potency of HERG channel blockers, and to determine electrophysiological approaches for new drugs screening studies. Method: Whole-cell patch-clamp electrophysiology was carried out by utilizing different voltage step protocols to examine the potency of compounds known to preferentially block the channel in the closed (ketoconazole and BeKm-1), open, and/or inactivated states (E-4031, astemizole, and terfenadine) in HEK293 cells transfected with HERG cDNA at room temperature and near-physiological temperature. Results: Drug potency determined using different voltage protocols varied dependent on the mechanisms of drug actions. For most compounds, the IC50 values obtained with a long pulse step protocol at room temperature were close to those determined with the voltage protocols designed to disclose their intrinsic potency. Relative to room temperature, the potency of E-4031, terfenadine, and ketoconazole was not changed at â¼Â 35 °C, but potency of astemizole was reduced. Discussion: The long pulse step protocol with room temperature can be selected for HERG channel safety screening studies. Alternative voltage protocols or temperatures should be considered if HERG study results are not consistent with other cardiac safety assessments.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmacological and Toxicological Methods - Volume 52, Issue 1, JulyâAugust 2005, Pages 146-153
Journal: Journal of Pharmacological and Toxicological Methods - Volume 52, Issue 1, JulyâAugust 2005, Pages 146-153
نویسندگان
Jian-An Yao, Xiaoyi Du, Daniel Lu, Robert L. Baker, Eric Daharsh, Philip Atterson,