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Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Erdemli, Gul and Kim, Albert and Ju, Haisong and Springer, Clayton and Penland, Robert and Hoffmann, Peter (2012) Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation. Frontiers in Pharmaceutical Medicine and Outcomes Research.

Abstract

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene), is the critical mediator of electrical excitation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity. If marked, such changes can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients, and the financial risk for the pharmaceutical industry, enabling the detection and mitigation of hNav1.5 liabilities early in drug development seems prudent. In this review, we describe a preclinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

Item Type: Article
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6337

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