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Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview.
MedLine Citation:
PMID:  21805209     Owner:  NLM     Status:  Publisher    
Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core battery mandatory studies. This critical review aims at discussing the usefulness, relevance, advantages, and limitations of some preclinical in vivo, in vitro, and in silico models, with high predictive values and currently used in supplemental safety studies.
Sandra Picard; Sonia Goineau; Philippe Guillaume; Joël Henry; Jean-Luc Hanouz; René Rouet
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-30
Journal Detail:
Title:  Cardiovascular toxicology     Volume:  -     ISSN:  1559-0259     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-8-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101135818     Medline TA:  Cardiovasc Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Groupe Coeur et Ischémie, EA 3212, Université de Caen, Esplanade de la Paix, 14000, Caen, France,
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