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Title: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Furthermore, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [5] ;  [2] ;  [6]
  1. U.S. Food and Drug Administration, Silver Spring, MD (United States); Univ. of Zaragoza, Zaragoza (Spain)
  2. U.S. Food and Drug Administration, Silver Spring, MD (United States)
  3. Univ. of Utah, Salt Lake City, UT (United States); Spaulding Clinical Research, West Bend, WI (United States)
  4. Stanford Univ., Palo Alto, CA (United States)
  5. Univ. of Zaragoza, Zaragoza (Spain); Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza (Spain)
  6. Univ. at Buffalo - The State Univ. of New York, Buffalo, NY (United States)
Publication Date:
Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Research Org:
U.S. Food and Drug Administration, Silver Spring, MD (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; electrocardiography; potassium channels; biomarkers; heart rate; decision tree; ion channels; Phase I clinical investigation; calcium channels
OSTI Identifier:
1377847