Report: Cardiotoxicity: Issues, Technologies, and Solutions for the Future TOC

CARDIOTOXICITY
2.1. “Directly Cardiotoxic” Drugs
2.2. Mechanism of Toxicity of “Directly Cardiotoxic” Drugs
- Anthracyclines/Anthracycline-Interacting Anticancer Drugs
- Other Anticancer Drugs
- Nonsteroidal Anti-inflammatory Drugs
- Other Drugs Associated with Direct Toxicity
2.3. “Direct Cardiotoxicity”
- Predisposing Factors
- Damage Limitation
2.4. “Proarrhythmic” Drugs
2.5. Mechanism of Cardiotoxicity of Proarrhythmic Drugs
- Molecular Targets of Proarrhythmic Drugs
- Drug Interactions with Ion Channels
- Arrhythmia Generation
2.6. Proarrhythmia
- Predisposing Factors
- Damage Limitation
2.7. Summary

ASSESSING DRUG-INDUCED CARDIOTOXICITY
4.1. Surrogate Markers for Proarrhythmia
Measures of Ion Channel Flux
Action Potential Morphology and Duration
Dispersion of Action Potential Duration
- Temporal Dispersion of Action Potential Duration (Instability)
- Transmural Dispersion of Repolarization
- Spatial Dispersion of Repolarization
QT Interval Prolongation
Combinations of Measures
4.2. Preclinical Proarrhythmia Screening
In Silico Approaches
Single-Cell Methods
- Cell Types
- Non - Patch Clamp Single-Cell Assay
- Conventional Patch Clamping
- Automated Medium-/High-Throughput Patch Clamping
- Scanning Patch Clamping
Multicell Methods
- Purkinje Fiber and Papillary Muscle Systems
- Ventricular Wedge
- Whole Heart Systems
  - Langendorff Perfused Heart
  - SCREENIT Perfused Rabbit Heart
- Future Developments in Multicellular In Vitro Systems
4.3. Preclinical Proarrhythmia Screening: In Vivo Methods
Anesthetized Animals
Conscious, Telemetrized Animals
Predisposed Models
- Methoxamine-Sensitized Rabbits
- Canine Chronic Atrioventricular Block
- Canine Pharmacological IKs Block
- Other Models
4.4. Clinical Trials and Postmarketing Surveillance
- Low Frequency of Arrhythmia Complicates Trials
- Pharmacogenetics
- Measurements in the Trial Population
- Impact of QT Effects Discovered in Clinical Trials
4.5. Screening for “Direct” Cardiotoxicity
- Markers of Cardiac Damage
- Animal Models
4.6. Summary

INDUSTRY ATTITUDES AND CARDIOTOXICITY SURVEY RESULTS
5.1. Previous Surveys
5.2. Insight Pharma Reports Cardiotoxicity Survey - December 2007
- Survey Population
- Analysis of Questionnaire Responses
  - In Silico Methods
  - In Vitro Methods
  - In Vivo Methods
  - Clinical Methods
5.3. Insight Pharma Reports Expert Interviews
- Survey Population
- Analysis of Interview Responses
  - In Silico Methods
  - In Vitro Methods
    - Single-Cell Systems
    - Multicell Systems
  - In Vivo Methods
  - Clinical Methods
  - Views on the TQT Study
  - Timing and Nature of Possible Changes to S7B or E14
    - S7B
    - E14
5.4. Summary

AN OPINION: THE FUTURE OF CARDIOTOXICITY SCREENING IN DRUG DEVELOPMENT
7.1. Proarrhythmia Screening
- Early-Stage Drug Development
- Late-Stage Drug Development
7.2. Screening for “Direct” Cardiotoxicity
- Chronic Cardiotoxicity
- Acute Cardiotoxicity
7.3. Summary

EXPERT INTERVIEWS
Charles Antzelevitch, PhD, Executive Director and Director of Research, Masonic Medical Research Laboratory, Utica, NY
Ernest D. Bush, PhD, Vice President and Scientific Director, Cambridge Healthtech Associates, Needham, MA (formerly Head of Non-clinical Drug Safety Department, Hoffmann-La Roche)
Marek Malik, MD, PhD, Professor of Cardiac Electrophysiology, St. George' s Hospital, University of London, UK
Umesh Patel, PhD, Director, R&D, Ion Channel Group, BioScience Division, Millipore UK, Cambridge, UK
Katya Tsaioun, PhD, President, Apredica, Watertown, MA
Benoit Tyl, MD, Medical Director, Europe, MDS Pharma Services/Centralized Cardiac Services

Cardiotoxicity: Issues, Technologies, and Solutions for the Future