ToxSci Advance Access originally published online on March 9, 2007
Toxicological Sciences 2007 97(1):4-20; doi:10.1093/toxsci/kfm026
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Preclinical Cardiovascular Risk Assessment in Modern Drug Development
Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH and Co. KG, D-88397 Biberach an der Riss, Germany
1 For correspondence via fax: +49 7351-545177. E-mail: brian.guth@bc.boehringer-ingelheim.com.
Received December 22, 2006; accepted February 9, 2007
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INTRODUCTION |
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The new guidelines including the ICH S7A and S7B (Anonymous, 2001
, 2004) have brought early safety testing of new pharmaceuticals using pharmacological models into the regulatory spotlight in the past few years. Whereas this was motivated to a large extent by a single safety issue (i.e., the proarrhythmic action of drugs that slow myocardial repolarization), the intent was to provide a comprehensive safety assessment based on pharmacodynamic end points, as opposed to histopathological end points used in traditional toxicity studies. These new guidelines were explicitly designed to protect volunteers and patients involved in clinical trials of new drugs from unexpected, life-threatening effects. As such, the emphasis is on acute, functional effects as opposed to chronic histopathological changes. This important distinction was emphasized by Zbinden (1984) some years ago. However, the implications of such testing go well beyond this primary goal and can impact on the later use of |
STEPWISE APPROACH TO CARDIOVASCULAR RISK ASSESSMENT |
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IN VITRO ELECTROPHYSIOLOGICAL ASSESSMENTS |
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"High-Throughput" hERG Assays
Competetive Binding Assays
Rubidium Flux Assays
Fluorescence Ion Channel Assays Using Voltage-Sensitive Dyes
Automated Patch-Clamp Systems
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MANUEL VOLTAGE CLAMP STUDIES ON hERG-MEDIATED POTASSIUM CHANNELS |
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Xenopus Oocytes
Stably Transfected Cells
Studies on hERG Channels in Isolated Ventricular Myocytes
Studies on Myocardial Ion Channels in Addition to hERG
hERG Channel Trafficking
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STUDIES ON THE MYOCARDIAL ACTION POTENTIAL |
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Measurement of the Concentration of Test Article in In Vitro Systems
Studies in Isolated Purkinje Fibers
Studies in Isolated Guinea Pig Papillary Muscles
Arterially Perfused Wedge of Canine Left Ventricle
Isolated Heart (Langendorff) Preparations
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THE CASE FOR EARLY IN VIVO TESTING IN RODENTS OR OTHER SMALL ANIMALS |
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Small Animal Telemetry System
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IN VIVO APPROACHES TO CARDIOVASCULAR PROFILING AND ELECTROCARDIOGRAPHIC ASSESSMENTS |
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Cardiovascular Assessments Using Anesthetized Animal Models
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CARDIOVASCULAR SAFETY STUDIES IN CONSCIOUS DOGS AND OTHER NONRODENT SPECIES |
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Correction of QT Interval for Heart Rate
Animal Reuse
Incorporating Safety Pharmacology End Points in Toxicology Studies
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DESIGNING A COMPREHENSIVE CARDIOVASCULAR ASSESSMENT APPROACH |
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