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                FDA發文使用iPS人源心分開肌細胞預測藥物※心肌毒性

                2018-08-20 11:01:42

                 

                FDA發文使用iPS人源心肌細胞預測藥物心肌前提是我保證你活著離開此處毒性

                ComprehensiveTranslational Assessment of Human- Induced Pluripotent Stem Cell DerivedCardiomyocytes for Evaluating Drug-Induced Arrhythmias

                導讀:

                目前藥物要趕緊破開監管部門(CFDA,FDA等)要求★新藥研發中,檢測藥物對hERG鉀離子『通道和QT的影響。此法雖︽然排除了許多會引起torsade de points(TdP,室性扭時間轉性心律失常)的“壞藥”,但此法與體內相去甚遠,仍有很多藥物╲由於心臟毒性“死於”臨』床甚至上市後,新的更接近體內的篩選方法需求迫切。

                 

                本文選取FDA明確心臟效應的25種小分子藥物,使用iPS人源心肌細胞,通過MEAVSD方法來預測藥物對心臟的影響,以驗證新方法的可轉化性。

                 

                一張表吃透這灰méngméng篇文章:

                 

                 

                MEA
                 Cor.4U

                MEA
                 iCell

                VSD
                 Cor.4U

                VSD
                 iCell

                True Positive

                15

                9

                15

                12

                False Positive

                0

                0

                0

                0

                True Negative

                6

                6

                6

                6

                False Negative

                4

                10

                4

                7

                Sensitivity

                0.79

                0.47

                0.79

                0.63

                Specificity

                1

                1

                1

                1

                 

                如果沒有吃透,請看下列知識點

                1. iPS人源心肌細胞平臺特異性極高(1

                2. MEAVSD方法均可

                3. iPS人源心肌細胞平臺敏感度很下落高,接近臨ぷ床結果(0.79

                4. 敏感度受不同生∩產廠商來源的影響

                5. FDA強力推薦

                 

                 

                關鍵詞:

                US Food and Drug Administration (FDA)  美國食品及藥物管我斷魂谷能有好下晨理局

                human induced pluripotent stem cell-derivedCardiomyocytes (iPSC-CMs) iPS人源心肌細胞

                rate-corrected action potential duration (APDc) 矯正動作電位持續時間

                rate-corrected field potential duration (FPDc) 矯正場電位持續時間

                 

                Brief summary,

                A recent researchfrom the laboratory of US Food and Drug Administration (FDA) claimedhuman induced pluripotent stem cell-derived Cardiomyocytes (iPSC-CMs) asa highly promising in vitro systemthat should be included in pro-arrhythmia assay paradigms. Their resultsconcluded that iPSC-CMs, similar to clinical trial results, demonstrated goodcorrelation between drug-induced rate-corrected action potential duration(APDc) and field potential duration (FPDc) prolongation and clinical trial QTcprolongation. Therefore, iPSC-CM in vitro system would serve as a highthrough-put and accurate drug screening system to check ion channel and insilico modeling prediction of pro-arrhythmic risk.

                       The drugscreening strategy regulatory agencies nowadays used is to determine the newdrugs’ abilities to block the human ether-a-go-go (hERG) potassium channel andprolong the QT interval on the electrocardiogram. Although, this strategy couldprevent torsade de points (TdP) inducing drug from reaching the market, thedevelopment of other potential new drugs was also terminated inappropriately.Therefore, there is an immediate need for the development of a new screeningmethod to advance regulatory science in this field.

                       This studyperformed a concentration-dependent assay using drugs that caused clinicalcardiac diseases with iPSC-CM in vitro system. The cardiotoxicity ofthose drugs was assessed by 1) their effect on multiple isolated cardiac ionchannels (hERG, L-type Calcium, sodium) using patch clamp assay; and 2) thepro-arrhythmic liability using in silico simulations to reconstruct the humanventricular action potential. Of 20 drugs that exhibited clinical QTcprolongation, 17 caused APDc prolongation and 16 caused FPDc prolongation iniPSC-CMs. Of 14 drugs associated with TdP risk, 10 drugs caused arrhythmias iniPSC-CM and lack of arrhythmic beating in the remaining 4 drugs. In conclusion,this study demonstrated that human iPSC-CMs can be used as a high through-putand accurate drug screening system.

                 

                Reference

                Blinova, K., Stohlman, J.,Vicente, J., et al. (2017).Comprehensive Translational Assessment of Human- Induced Pluripotent Stem CellDerived Cardiomyocytes for Evaluating Drug-InducedArrhythmias, 155(1), 234–247. https://doi.org/10.1093/toxsci/kfw200

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