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hERG Assay, QT Liability, and Sudden Cardiac Death

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Cardiac Safety of Noncardiac Drugs

Abstract

Since the late 1990s, several blockbuster, noncardiac drugs including terfenadine (Seldane) (1,2), cisapride (Propulsid) (3,4), and grepafloxacin (Raxar) (5) have been associated with prolongation of the QT interval of the electrocardiogram (ECG), polymorphic ventricular tachycardia, torsades de pointes (TdP), and sudden cardiac death. Regulatory agencies such as the Food and Drug Administration (FDA) responded initially with severe labeling restrictions, but ultimately these drugs were withdrawn from the marketplace. Not surprisingly, sudden cardiac death owing to noncardiac drugs has become a major safety issue for the pharmaceutical industry and the agencies that regulate it. TdP is linked to defective repolarization and prolongation of the QT interval of the ECG. At the cellular level, the duration of the cardiac action potential duration (APD) is prolonged. The major membrane currents and channels that are involved are shown in Fig. 1 along with the action potential they generate (6).

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References

  1. Morganroth J, Brown AM, Critz S, et al. Variability of the QTc interval: impact on defining drug effect and low-frequency cardiac event. Am J Cardiol 1993;72:26B–31B.

    Article  PubMed  CAS  Google Scholar 

  2. Woosley RL, Chen Y, Froiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532–1536.

    Article  PubMed  CAS  Google Scholar 

  3. Rampe D, Roy ML, Dennis A, Brown AM. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel hERG. FEBS Lett 1997;417:28–32.

    Article  PubMed  CAS  Google Scholar 

  4. Mohammad S, Zhou Z, Gong Q, January CT. Blockage of the hERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol 1997;273:H2534–H2538.

    PubMed  CAS  Google Scholar 

  5. Kang J, Wang L. Cai F, Rampe D. High affinity blockade of the hERG cardiac K(+) channel by the neoruleptic pimozide. Eur J Pharmacol 2000;392(3):137–140.

    Article  PubMed  CAS  Google Scholar 

  6. Brown AM. Cardiac Potassium Channels in Health and Disease. Trends Cardiovasc Med 1997;7(4):118–124.

    Article  CAS  Google Scholar 

  7. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80(5):1–20.

    Article  Google Scholar 

  8. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81:299–307.

    Article  PubMed  CAS  Google Scholar 

  9. Roy M-L, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 1996;94(4):817–823.

    PubMed  CAS  Google Scholar 

  10. Lacerda AE, Kramer J, Shen K-Z, Thomas D, Brown AM. Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs. Eur Heart J Supplements 2001;3:K23–K30.

    Article  CAS  Google Scholar 

  11. Ficker E, Dennis AT, Wang L, Brown AM. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel hERG. Circ Res 2003;92:e87–e100.

    Article  PubMed  CAS  Google Scholar 

  12. Ficker E, Kuryshev Y, Dennis AT, et al. Arsenic-induced prolongation of cardiac repolarization and block of hERG trafficking. Mol Pharmacol 2004;66:33–44.

    Article  PubMed  CAS  Google Scholar 

  13. Roden DM. Current status of class III antiarrhythmic drug therapy. Am J Cardiol 1993;72:44B–49B.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang S; Zhou Z; Gong Q; Makielski JC; January CT. Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res 1999;89:989–998.

    Google Scholar 

  15. Kang J, Chen XL, Wang H, et al. Cardiac ion channel effects of tolterodine. J Pharmacol Exp Ther. 2004;308:935–940.

    Article  PubMed  CAS  Google Scholar 

  16. Kirsch GE, Trepakova ES, Brimecombe JC, et al. Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. 2004 J Pharmacol Toxicol Methods. Accepted.

    Google Scholar 

  17. Redfern WS, Carlsson L, Davis AS, et al. Relationships between non-clinical 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 2003;58(1):32–45. Review.

    Article  PubMed  CAS  Google Scholar 

  18. Chouabe C, Drici MD, Romey G, Barhanin J. Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs. Therapie 2000;55:195–202.

    PubMed  CAS  Google Scholar 

  19. Crumb WJ. Loratadine blockade of K+ channels in human heart: comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther 2000;292:261–264.

    PubMed  CAS  Google Scholar 

  20. Daleau P, Lessard E, Groleau MF, Turgeon J. Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes. Circulation 1995;91:3010–3016.

    PubMed  CAS  Google Scholar 

  21. Drolet B, Vincent F, Rail J, et al. Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current. J Pharmacol Exp Ther 1999;288:1261–1268.

    PubMed  CAS  Google Scholar 

  22. Ekins S, Crumb WJ, Sarazan RD, Wikel JH, Wrighton SA. Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. J Pharmacol Exp Ther 2002;301:427–434.

    Article  PubMed  CAS  Google Scholar 

  23. Hanada E, Ohtani H, Hirota M, et al. Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide. J Pharm Pharmacol 2003;55:995–1002.

    Article  PubMed  CAS  Google Scholar 

  24. ICH Expert Working Group. Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) By Human Pharmaceuticals. (Accessed in February 2002 at http://www.ich.org).

  25. Khalifa M, Drolet B, Daleau P, et al. Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. J Pharmacol Exp Ther 1999;288:858–865.

    PubMed  CAS  Google Scholar 

  26. Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur J Pharmacol 2002;450:37–41.

    Article  PubMed  CAS  Google Scholar 

  27. Kupershmidt S, Yang IC, Hayashi K, et al. The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines. FASEB Journal 2003;17:2263–2265.

    PubMed  CAS  Google Scholar 

  28. Le Grand B, Talmant JM, Rieu JP, Patoiseau JF, Colpaert FC, John GW. Investigation of the mechanism by which ketanserin prolongs the duration of the cardiac action potential. J Cardiovasc Pharmacol 1995;26:803–809.

    Article  PubMed  Google Scholar 

  29. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and dl-sotalol block of hERG. Circ Res 2000;87:1012–1018.

    PubMed  CAS  Google Scholar 

  30. Po SS, Wang DW, Yang IC, Johnson JP Jr, Nie L, Bennett PB. Modulation of hERG potassium channels by extracellular magnesium and quinidine. J Cardiovasc Pharmacol 1999;33:181–185.

    Article  PubMed  CAS  Google Scholar 

  31. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990;96:195–215.

    Article  PubMed  CAS  Google Scholar 

  32. Wang J, Della Penna K, Wang H, Karczewski J, et al. Functional and pharmacological properties of canine ERG potassium channels. Am J Physiol 2003;284:H256–H267.

    CAS  Google Scholar 

  33. Wang JC, Kiyosue T, Kiriyama K, Arita M. Bepridil differentially inhibits two delayed rectifier K+ currents, IKr and IKs, in guinea-pig ventricular myocytes. Br J Pharmacol 1999;128:1733–1738.

    Article  PubMed  CAS  Google Scholar 

  34. Weerapura M, Nattel S, Chartier D, Caballero R, Hebert TE. A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J Physiol 2002;540:15–27.

    Article  PubMed  CAS  Google Scholar 

  35. Witchel HJ, Milnes JT, Mitcheson JS, Hancox JC. Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes. J Pharmacol Toxicol Methods 2002a;48:65–80.

    Article  PubMed  CAS  Google Scholar 

  36. Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC. Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett 2002b;512:59–66.

    Article  PubMed  CAS  Google Scholar 

  37. Zhou Z, Gong Q, Ye B, et al. Properties of hERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 1998;74:230–241.

    Article  PubMed  CAS  Google Scholar 

  38. Hanson, L. Literature Reports of IC50’s IKr Blockade. 2003 Barnett International QT Prolongation Conference 2003.

    Google Scholar 

  39. Moss AJ. Measurement of the QT Interval and the Risk Associated with QTc Interval Prolongation: A Review. Am J Cardiol 1993;72:23B–25B.

    Article  PubMed  CAS  Google Scholar 

  40. (Accessed at http://www.eudravigilence.org.)

  41. Gintant GA, Limberis JT, McDermott JS, Wegner CD, Cox BF. The canine Purkinje fiber: an in vitro model aystem for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol 2001;37:607–618.

    Article  PubMed  CAS  Google Scholar 

  42. Kirk Schroeder; Brad Neagle; Derek J. Trezise; Jennings Worley. Ionworks(tm) HT: A New High Throughput Electrophysiology Measurement Platform. J Biomol Screen 2003;1:50–64.

    Article  CAS  Google Scholar 

  43. Asmild M, Oswald N, Krzywkowski KM, et al. Upscaling and automation of electrophysiology: toward high throughput screening in ion channel drug discovery. Receptors Channels 2003;9:49–58.

    Article  PubMed  CAS  Google Scholar 

  44. Tang W, Kang J, Wu X, et al. Development and evaluation of high throughput functional assay methods for HERG potassium channel. J Biomol Screen 2001;6:325–331.

    Article  PubMed  CAS  Google Scholar 

  45. Wible BA, Hawryluk P, Ficker E, Brown AM. HERG-Lite(tm), a novel high throughput hERG cardiac safety test. 2003 Society for Biomolecular Screening Annual Meeting, abstract.

    Google Scholar 

  46. Ficker E, Obejero-Paz CA, Zhao S, Brown AM. The binding site for channel blockers that rescue misprocessed LQT2 hERG mutations. J Biol Chem 2002;277:4989–4998.

    Article  PubMed  CAS  Google Scholar 

  47. Ohnishi K, Yoshida H, Shigeno K et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 2000;133:881–885.

    PubMed  CAS  Google Scholar 

  48. Unnikrishnan D, Dutcher JP, Varshneya N et al. Torsade de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001;97:1514–1516.

    Article  PubMed  CAS  Google Scholar 

  49. Drolet B, Simard C, Roden DM. Unusual effects of a QT-prolonging drug, arsenic trioxide, on cardiac potassium currents. Circulation 2004;109:26–29.

    Article  PubMed  CAS  Google Scholar 

  50. Imredy JP, Irving WD, Clouse HK; Salata JJ. Electrophysiological and pharmacological characterization of a cell line stably expressing hKCNQ1 and hKCNE1 potassium channels. 2004 Biophysical Society Annual Meeting, abstract.

    Google Scholar 

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Authors and Affiliations

  1. Physiology and Biophysics, Case Western Reserve University, MetroHealth Campus, Cleveland, OH, USA

    Arthur M. Brown MD, PhD (Professor, Chairman and CEO)

  2. ChanTest, Inc., Cleveland, OH, USA

    Arthur M. Brown MD, PhD (Professor, Chairman and CEO)

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  1. Arthur M. Brown MD, PhD
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Editors and Affiliations

  1. eResearchTechnology Inc., Philadelphia, PA, USA

    Joel Morganroth MD (Chief Scientist, Clinical Professor of Medicine) (Chief Scientist, Clinical Professor of Medicine)

  2. University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Joel Morganroth MD (Chief Scientist, Clinical Professor of Medicine) (Chief Scientist, Clinical Professor of Medicine)

  3. Global Medical Affairs, eResearchTechnology Inc., Bridgewater, NJ

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

  4. UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

  5. Journal of Electrocardiology, Bridgewater, NJ, USA

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

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© 2005 Humana Press Inc., Totowa, NJ

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Brown, A.M. (2005). hERG Assay, QT Liability, and Sudden Cardiac Death. In: Morganroth, J., Gussak, I. (eds) Cardiac Safety of Noncardiac Drugs. Humana Press. https://doi.org/10.1007/978-1-59259-884-7_4

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