© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications
Report on a Policy Conference of the European Society of Cardiology
* Corresponding author. Tel.: +49-251-834-7617; fax: +49-251-834-7864 breithg@uni-muenster.de
Received 27 April 2000; accepted 28 April 2000
| The first 150 words of the full text of this article appear below. |
 |
1 Preamble1 |
|---|
The Policy Conference on The Potential for QT Prolongation and Pro-arrhythmia by Non-anti-arrhythmic Drugs. Clinical and Regulatory Implications was held at the European Heart House in Sophia Antipolis, France, on the initiative of Günter Breithardt, FESC, FACC, on June 24th and 25th, 1999 after formal approval by the Board of the European Society of Cardiology (ESC).
The conference was organised under the auspices of the ESC Committee for Scientific and Clinical Initiatives by Günter Breithardt and Wilhelm Haverkamp, Münster, Germany, with participation of representatives of the Working Group on Arrhythmias of the ESC, the American College of Cardiology, the American Heart Association, the World Heart Federation, the European Agency for the Evaluation of Medicinal Products, the Medicines Control Agency (UK), the Food and Drug Administration (USA), the National Heart, Lung and Blood Institute (USA), the Federal Institute for Drugs and Medical Devices (Germany), and the Medical Products Agency (Sweden).
The
|
2 The problem |
|---|
|
3 Mechanisms of QT prolongation and TdP |
|---|
|
4 Detecting drug-induced effects on repolarization |
|---|
4.1 In vitro models
4.2 In-vivo animal models
|
5 Clinical assessment of drug effects on repolarization |
|---|
5.1 Phase I/II studies
5.2 Phase III studies
5.3 Post-marketing surveillance
|
6 Regulatory perspectives |
|---|
|
7 Conclusions |
|---|
|
Appendix A |
|---|
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Morabito, M. C. Piccirillo, F. Falasconi, G. De Feo, A. Del Giudice, J. Bryce, M. Di Maio, E. De Maio, N. Normanno, and F. Perrone Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinases: Current Status and Future Directions Oncologist, April 1, 2009; 14(4): 378 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Emul, M Dalkiran, S Samim, E Yildirim, R Bayar, I Balcioglu, and I Keles The influences of depression and venlafaxine use at therapeutic doses on atrial conduction J Psychopharmacol, March 1, 2009; 23(2): 163 - 167. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Eckardt, G&#x.;n. Breithardt, and S. Hohnloser CHAPTER 30 Ventricular Tachycardia and Sudden Cardiac Death ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Myokai, S. Ryu, H. Shimizu, and S. Oiki Topological Mapping of the Asymmetric Drug Binding to the Human Ether-a-go-go-Related Gene Product (HERG) Potassium Channel by Use of Tandem Dimers Mol. Pharmacol., June 1, 2008; 73(6): 1643 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ritz and C. Wanner The Challenge of Sudden Death in Dialysis Patients Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 920 - 929. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Darbar, J. Kimbrough, A. Jawaid, R. McCray, M. D. Ritchie, and D. M. Roden Persistent Atrial Fibrillation Is Associated With Reduced Risk of Torsades de Pointes in Patients With Drug-Induced Long QT Syndrome J. Am. Coll. Cardiol., February 26, 2008; 51(8): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hinterseer, M. B. Thomsen, B.-M. Beckmann, A. Pfeufer, R. Schimpf, H.-E. Wichmann, G. Steinbeck, M. A. Vos, and S. Kaab Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study Eur. Heart J., January 2, 2008; 29(2): 185 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Strevel, D. J. Ing, and L. L. Siu Molecularly Targeted Oncology Therapeutics and Prolongation of the QT Interval J. Clin. Oncol., August 1, 2007; 25(22): 3362 - 3371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Guth Preclinical Cardiovascular Risk Assessment in Modern Drug Development Toxicol. Sci., May 1, 2007; 97(1): 4 - 20. [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Thomsen, A. Oros, M. Schoenmakers, J. M. van Opstal, J. N. Maas, J. D.M. Beekman, and M. A. Vos Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation Cardiovasc Res, February 1, 2007; 73(3): 521 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kirchhof, G. Breithardt, and L. Eckardt Primary prevention of sudden cardiac death Heart, December 1, 2006; 92(12): 1873 - 1878. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hinterseer, M. Irlbeck, L. Ney, B.-M. Beckmann, A. Pfeufer, G. Steinbeck, and S. Kaab Acute respiratory distress syndrome with transiently impaired left ventricular function and Torsades de Pointes arrhythmia unmasking congenital long QT syndrome in a 25-yr-old woman Br. J. Anaesth., August 1, 2006; 97(2): 150 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Gintant, Z. Su, R. L. Martin, and B. F. Cox Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety Toxicol Pathol, January 1, 2006; 34(1): 81 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Morganroth, J. P. DiMarco, A. Anzueto, M. S. Niederman, S. Choudhri, and the CAPRIE Study Group A Randomized Trial Comparing the Cardiac Rhythm Safety of Moxifloxacin vs Levofloxacin in Elderly Patients Hospitalized With Community-Acquired Pneumonia Chest, November 1, 2005; 128(5): 3398 - 3406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rademacher, R. Dietz, and W. Haverkamp QT prolongation and syncope with methadone, doxepin, and a {beta}-blocker Ann. Pharmacother., October 1, 2005; 39(10): 1762 - 1763. [Full Text] [PDF]
|
|
|
|
|
|
C. M. Beasley Jr, M. I. Mitchell, A. A. Dmitrienko, J. T. Emmick, W. Shen, T. M. Costigan, A. W. Bedding, M. A. Turik, A. Bakhtyari, M. R. Warner, et al. The Combined Use of Ibutilide as an Active Control With Intensive Electrocardiographic Sampling and Signal Averaging as a Sensitive Method to Assess the Effects of Tadalafil on the Human QT Interval J. Am. Coll. Cardiol., August 16, 2005; 46(4): 678 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. T. Beery The Genetics of Cardiac Arrhythmias Biol Res Nurs, April 1, 2005; 6(4): 249 - 261. [Abstract] [PDF]
|
|
|
|
|
|
D. L Nykamp, C. L Blackmon, P. E Schmidt, and A. G Roberson QTc Prolongation Associated with Combination Therapy of Levofloxacin, Imipramine, and Fluoxetine Ann. Pharmacother., March 1, 2005; 39(3): 543 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Royer, S. Demolombe, A. El Harchi, K. Le Quang, J. Piron, G. Toumaniantz, D. Mazurais, C. Bellocq, G. Lande, C. Terrenoire, et al. Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity Cardiovasc Res, January 1, 2005; 65(1): 128 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch, L. Belardinelli, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, and G. Thomas Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties Circulation, August 24, 2004; 110(8): 904 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Barriere, F. Genter, E. Spencer, M. Kitt, D. Hoelscher, and J. Morganroth Effects of a New Antibacterial, Telavancin, on Cardiac Repolarization (QTc Interval Duration) in Healthy Subjects J. Clin. Pharmacol., July 1, 2004; 44(7): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Thomsen, P. G. A. Volders, M. Stengl, R. L. H. M. G. Spaatjens, J. D. M. Beekman, U. Bischoff, M. A. Kall, K. Frederiksen, J. Matz, and M. A. Vos Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 776 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zicha, I. Moss, B. Allen, A. Varro, J. Papp, R. Dumaine, C. Antzelevich, and S. Nattel Molecular basis of species-specific expression of repolarizing K+ currents in the heart Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1641 - H1649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sarapa, M. R. Britto, B. Cotton, S. R. Cox, S. F. Francom, N. Jin, E. D. Polasek, S. M. Sainati, S. L. Crosby-Sessoms, and J. C. Fleishaker Valdecoxib, a COX-2-Specific Inhibitor, Does Not Affect Cardiac Repolarization J. Clin. Pharmacol., September 1, 2003; 43(9): 974 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Di Diego, L. Belardinelli, and C. Antzelevitch Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation Circulation, August 26, 2003; 108(8): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.N. M. N. Obreztchikova, E.A. E. A. Sosunov, A. Plotnikov, E.P. E. P. Anyukhovsky, R. Z. Gainullin, P. Danilo Jr., Z.-H. Yeom, R. B. Robinson, and M. R. Rosen Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia Cardiovasc Res, August 1, 2003; 59(2): 339 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Martell, J. H. Arnsten, B. Ray, and M. N. Gourevitch The Impact of Methadone Induction on Cardiac Conduction in Opiate Users Ann Intern Med, July 15, 2003; 139(2): 154 - 155. [Full Text] [PDF]
|
|
|
|
|
|
S. Kaab, M. Hinterseer, M. Nabauer, and G. Steinbeck Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome--a case-control pilot study using i.v. sotalol Eur. Heart J., April 1, 2003; 24(7): 649 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.S. Redfern, L. Carlsson, A.S. Davis, W.G. Lynch, I. MacKenzie, S. Palethorpe, P.K.S. Siegl, I. Strang, A.T. Sullivan, R. Wallis, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development Cardiovasc Res, April 1, 2003; 58(1): 32 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Pereon, G. Lande, S. Demolombe, S. Nguyen The Tich, D. Sternberg, H. Le Marec, and A. David Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization Neurology, January 28, 2003; 60(2): 340 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Milberg, L. Eckardt, H.-J. Bruns, J. Biertz, S. Ramtin, N. Reinsch, D. Fleischer, P. Kirchhof, L. Fabritz, G. Breithardt, et al. Divergent Proarrhythmic Potential of Macrolide Antibiotics Despite Similar QT Prolongation: Fast Phase 3 Repolarization Prevents Early Afterdepolarizations and Torsade de Pointes J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 218 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Fossa, M. J. DePasquale, D. L. Raunig, M. J. Avery, and D. J. Leishman The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 828 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Roden The problem, challenge and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death J. Am. Coll. Cardiol., July 17, 2002; 40(2): 357 - 359. [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. McALLISTER-WILLIAMS and I. N. FERRIER Rapid tranquillisation: time for a reappraisal of options for parenteral therapy The British Journal of Psychiatry, June 1, 2002; 180(6): 485 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Gbadebo, R. W. Trimble, M. S.C. Khoo, J. Temple, D. M. Roden, and M. E. Anderson Calmodulin Inhibitor W-7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes Circulation, February 12, 2002; 105(6): 770 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Eckardt, G. Breithardt, and W. Haverkamp Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 64 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Zarate Jr and J. Patel Sudden Cardiac Death and Antipsychotic Drugs: Do We Know Enough? Arch Gen Psychiatry, December 1, 2001; 58(12): 1168 - 1171. [Full Text] [PDF]
|
|
|
|
|
|
P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates Cardiovasc Res, May 1, 2001; 50(2): 386 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Pham, E. A. Sosunov, R. Z. Gainullin, P. Danilo Jr, and M. R. Rosen Impact of Sex and Gonadal Steroids on Prolongation of Ventricular Repolarization and Arrhythmias Induced by IK-Blocking Drugs Circulation, May 1, 2001; 103(17): 2207 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.G Hammond, L Carlsson, A.S Davis, W.G Lynch, I MacKenzie, W.S Redfern, A.T Sullivan, and A.J Camm Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey Cardiovasc Res, March 1, 2001; 49(4): 741 - 750. [Abstract] [Full Text] [PDF]
|
|