Cardiac safety

QT prolongation is a surrogate marker used in cardiac safety studies, but several lines of experimental evidence indicate that it is a poor surrogate of TdP a number of drugs, because of their complex pharmacological profile, can prolong the QTc with a relatively low proarrhythmic risk (e.g. amiodarone). 

Hancox, J.C. and Mitcheson, J.S. (2006) Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine a case-study in cardiac safety pharmacology. British Journal of Pharmacology, 149, 457 159. 

Cavero, 1. and Crumb, W.J. (2001) Native and cloned ion channels from human heart laboratory models for evaluating the cardiac safety of new drugs. European Heart Journal Supplements, 3, K53-K63. 

Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart. Progress in Biophysics and Molecular Biology, 90, 414-443. 

Bottino, D., Penland, R.C., Stamps, A., Traebert, M., Dumotier, B., Georgiva, A., Helmlinger, G. and Lett, G.S. (2006) Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart. Progress in Biophysics and Molecular Biology, 90, 414-443. 

Following the discovery and clinical use of chloroform in 1847, The Royal Medical and Chirurgical Society (later to become The Royal Society of Medicine) had already set up in 1864 a committee to enquire into the uses and the physiological, therapeutical and toxicological effects of chloroform. There had been 109 fatalities following administration of chloroform. A critical relationship had been demonstrated between the dose and effect of this anaesthetic. The committee commented on the need for animal experiments to compare chloroform with ether and also on the relative cardiac safety of ether. 

Meyer, T, Sartipy P., Blind, F., Leisgen, C. and Guenther, E. (2007) New cell models and assays in cardiac safety profiling. Expert Opinion on Drug Metabolism and Toxicology, 3 (4), 507—517. 

Nondinical assessment of cardiac safety must be performed for a compound to qualify to be submitted to the health authorities to begin studies in man. For this purpose the regulatory bodies require that the cardiosafety assays should follow the principles of GLP wherever possible. The following assays/technologies are frequently used to predict potential clinical QT liability. 

Hanton, G. (2007) Preclinical cardiac safety assessment of drugs. Drugs R D, 8, 213-228. 

Taglialatela M and Annunziato L. Evaluation of the cardiac safety of second-generation antihistamines. Allergy 2000 55 Suppl 60 22-30. 

Bivalrudin (Angiomax, Angiox) [10,11] Cardiac Safety pharmacology studies appear to have been done separately 1 month (rat) 1 month (cyno)c No Standard battery Synthetic FDA-2000 EMEA-2004... 

Nesiritide Cardiac Cardiac safety pharmacology No Ames only Recombinant FDA-2001... 

Turner JR, Durham TA. Nonclinical Development Integrated Cardiac Safety Assessment Methodologies for Non-cardiac Drugs in Discovery, Development, and Postmarketing Surveillance. John Wiley Sr Sons Inc. Hoboken, New Jersey. 2009 111-134. 

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