Screening for Acute IKr Block is Insufficient to Detect Torsades de Pointes Liability: Role of Late Sodium Current Running title: Yang et al.; Increased late sodium current by chronic IKr blockers
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Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
BACKGROUND New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr...
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The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparflox...
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BACKGROUND The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride. Although L1825P generates late sodium current typical of SCN5A-linked long-QT syndrome (LQT3) in vitro, the patient reported had a normal QT interval before administration of the drug. To address this discrepancy, we teste...
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Several anti-arrhythmic drugs, as well as medications not intended for cardiac indications, block a specific potassium channel named IKr (the rapid delayed rectifying potassium current). In the case of the anti-arrhythmic drugs, IKr channels are purposely targeted. By blocking potassium outflow currents, the anti-arrhythmic drugs prolong the action potential. This action (depicted in the electr...
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