Cardiac safety implications of hNav1.5 blockade and a framework for pre-clinical evaluation

Frontiers in Pharmacology

Volumn 3 JAN, Issue , 2012, Pages

  Erdemli, Gül ^a,b   Kim, Albert M ^a,b   Ju, Haisong ^a,b   Springer, Clayton ^a   Penland, Robert C ^c   Hoffmann, Peter K ^a,b  

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b Translational Cardiovascular Advisory Team at Novartis   (United States)

^c NOVARTIS PHARMA K K   (Japan)

Author keywords

Arrhythmia; ECG; Pre clinical; Sodium channel

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); CALCIUM CHANNEL BLOCKING AGENT; DELAYED RECTIFIER POTASSIUM CHANNEL; ENCAINIDE; FLECAINIDE; LIDOCAINE; MEXILETINE; NVP 1; NVP 10; NVP 2; NVP 3; NVP 4; NVP 5; NVP 6; NVP 7; NVP 8; NVP 9; PENTOBARBITAL; POTASSIUM CHANNEL HERG; SODIUM CALCIUM EXCHANGE PROTEIN; SODIUM CHANNEL BLOCKING AGENT; SODIUM CHANNEL NAV1.5; UNCLASSIFIED DRUG;

AH INTERVAL; AH INTERVAL PROLONGATION; ARTICLE; ATRIOVENTRICULAR BLOCK; AUTOMATION; BRUGADA SYNDROME; COMPUTER MODEL; CONCENTRATION RESPONSE; DRUG ACTIVITY; DRUG FATALITY; DRUG MEGADOSE; DRUG POTENCY; DRUG RESEARCH; DRUG SAFETY; DRUG STRUCTURE; ECG ABNORMALITY; ELECTROCARDIOGRAM; ELECTROCARDIOGRAPHY; GENE; GENE MUTATION; HEART ARRHYTHMIA; HEART CATHETERIZATION; HEART CONDUCTION; HEART DEPOLARIZATION; HEART DISEASE; HEART LEFT BUNDLE BRANCH BLOCK; HEART MUSCLE CELL; HEART MUSCLE CONDUCTION DISTURBANCE; HEART MUSCLE FIBER MEMBRANE POTENTIAL; HEART REPOLARIZATION; HEART RIGHT BUNDLE BRANCH BLOCK; HEART VENTRICLE TACHYCARDIA; HOLTER MONITORING; HUMAN; HV INTERVAL; HV INTERVAL PROLONGATION; HYDROPHOBICITY; IC 50; IN VITRO STUDY; INHIBITION KINETICS; LONG QT SYNDROME; LONG QT SYNDROME TYPE 3; MATHEMATICAL MODEL; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PATCH CLAMP; POTASSIUM CURRENT; PR INTERVAL PROLONGATION; PREDICTION; QRS COMPLEX; QRS WIDENING; QT PROLONGATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RISK ASSESSMENT; SCN5A GENE; SENSITIVITY AND SPECIFICITY; SIDE EFFECT; SINGLE DRUG DOSE; SODIUM CURRENT; SOLUBILITY; TIME TO MAXIMUM PLASMA CONCENTRATION; TORSADE DES POINTES; TOXICITY TESTING;

EID: 84864086235     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2012.00006     Document Type: Article

References (52)

1. Abriel, H. (2007). Cardiac sodium channel Nav1.5 and its associated proteins. Arch. Mal. Coeur Vaiss. 100, 787-793.
2. Adesanya, C. O., Yousuf, K. A., Co, C., Gaur, S., Ahmed, S., Pothoulakis, A., Suryaprasad, A., and Gupta, S. (2008). Is wider worse? QRS duration predicts cardiac mortality in patients with right bundle branch block. Ann. Noninvasive Electrocar- diol. 13, 165-170.
3. Balser, J. R. (2001). The cardiac sodium channel: gating function and molecular pharmacology. J. Mol. Cell. Cardiol. 33, 599-613.
4. Bode-Schnurbus, L., Bocker, D., Block, M., Gradaus, R., Heinecke, A., Breithardt, G., and Borggrefe, M. (2003). QRS duration: a simple marker for predicting cardiac mortality in ICD patients with heart failure. Heart 89, 1157-1162.
5. Bottino, D., Penland, R. C., Stamps, A., Traebert, M., Dumotier, B., Georgiva, A., Helmlinger, G., and Lett, G. S. (2006). Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems- based computer model of the heart. Prog. Biophys. Mol. Biol. 90,414-443.
6. Cao, X., Lee, Y. T., Holmqvist, M., Lin, Y., Ni, Y., Mikhailov, D., Zhang, H., Hogan, C., Zhou, L., Lu, Q., Digan, M. E., Urban, L., and Erdemli, G. (2010). Cardiac ion channel safety profiling on the IonWorks Quat- tro automated patch clamp system. Assay Drug Dev. Technol. 8, 766-780.
7. Castle, N., Printzenhoff, D., Zellmer, S., Antonio, B., Wickenden, A., and Silvia, C. (2009). Sodium channel inhibitor drug discovery using automated high throughput electrophysiology platforms. Comb. Chem. High Throughput Screen. 12, 107-122.
8. Chen, M. X., Helliwell, R. M., and Clare, J. J. (2009). In vitro profiling against ion channels beyond hERG as an early indicator of cardiac risk. Curr. Opin. Mol. Ther. 11, 269-281.
9. + channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation 105, 1208-1213.
10. Cordes, J., Li, C., Dugas, J., Austin-Lafrance, R., Lightbrown,I.,Engwall, M., Sutton, M., and Steidl-Nichols, J. (2009). Translation between in vitro inhibition of cardiac Nav1.5 channel and preclinical and clinical QRS widening. J. Pharmacol. Toxicol. Methods 60, abstr. 221.
11. Dunlop, J., Bowlby, M., Peri, R., Vasilyev, D., and Arias, R. (2008). High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology. Nat. Rev. Drug Discov. 7, 358-368.
12. Echt, D. S., Liebson, P. R., Mitchell, L. B., Peters, R. W., Obias-Manno, D., Barker, A. H., Arensberg, D., Baker, A., Friedman, L., and Greene, H. L. (1991). Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N.Engl.J.Med. 324, 781-788.
13. Freedman, R. A., and Steinberg, J. S. (1991). Selective prolongation of QRS late potentials by sodium channel blocking antiarrhythmic drugs: relation to slowing of ventricular tachycardia. Electrophysiologic study versus electrocardiographic monitoring trial (ESVEM) investigators. J. Am. Coll. Cardiol. 17, 1017-1025.
14. + channel alpha-subunit gene (SCN5A) to band 3p21. Cytogenet. Cell Gene 68, 67-70.
15. Gintant, G. A., Gallacher, D. J., and Pugsley, M. K. (2011). The 'overly- sensitive' heart: sodium channel block and QRS interval prolongation. Br. J. Pharmacol. 164, 254-259.
16. Graf, B. M. (2001). The cardiotoxicity of local anesthetics: the place of ropivacaine. Curr. Top. Med. Chem. 1, 207-214.
17. + channel and drug-induced prolon- gation of the QRS complex. Br. J. Pharmacol. 164, 260-273.
18. Harmer, A. R., Abi-Gerges, N., Easter, A., Woods, A., Lawrence, C. L., Small, B. G., Valentin, J. P., and Pollard, C. E. (2008). Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks. J. Pharmacol. Toxicol. Methods 57, 30-41.
19. Heath, B. M., Cui, Y., Worton, S., Lawton, B., Ward, G., Ballini, E., Doe, C. P., Ellis, C., Patel, B. A., and Mcmahon, N. C. (2011). Translation of flecainide- and mexiletine-induced cardiac sodium channel inhibition and ventricular conduction slowing from nonclinical models to clinical. J. Pharmacol. Toxicol. Methods 63, 258-268
20. Heist, E. K., and Ruskin, J. N. (2010). Drug-induced arrhythmia. Circulation 122, 1426-1435.
21. Hodgkin,A. L., and Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (Lond.) 117, 500-544.
22. Hondeghem, L. M. (1994). Computer aided development of antiarrhythmic agents with class IIIa properties. J. Cardiovasc. Electrophysiol. 5, 711-721.
23. Hondeghem, L. M., Lu, H. R., Van Rossem, K., and De Clerck, F. (2003). Detection of proarrhythmia in the female rabbit heart: blinded validation. J. Cardiovasc. Electrophysiol. 14, 287-294.
24. Hummel, S. L., Skorcz, S., and Koelling, T. M. (2009). Prolonged electrocardiogram QRS duration independently predicts long-term mortality in patients hospitalized for heart failure with preserved systolic function. J. Card. Fail. 15, 553-560.
25. Inoue, H., and Zipes, D. P. (1987). Changes in atrial and ventricular refractoriness and in atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length. Circ. Res. 60, 942-951.
26. 2+ exchange in negative inotropic effects of class I antiarrhythmic drugs on rabbit and rat ventricles. J. Cardiovasc. Pharmacol. 27, 355-361.
27. Jamieson, C., Moir, E. M., Rankovic, Z., and Wishart, G. (2006). Medicinal chemistry of hERG optimizations: highlights and hang-ups. J. Med. Chem. 49, 5029-5046.
28. Keating, M. T., and Sanguinetti, M. C. (2001). Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104, 569-580.
29. 2+ transient: evidence from NCX knockout mice. J. Physiol. (Lond.) 588, 3267-3276.
30. Lu, H. R., Rohrbacher, J., Vlaminckx, E., Van Ammel, K., Yan, G. X., and Gallacher, D. J. (2010). Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the 'bad' sodium current blockers. Br. J. Pharmacol. 160, 60-76.
31. Lu, H. R., Vlaminckx, E., Van De Water, A., Rohrbacher, J., Hermans, A. and Gallacher, D. J. (2007). In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation. Eur. J. Pharmacol. 577, 222-232.
32. Moreno, J. D., Zhu, Z. I., Yang, P.-C., Bankston, J. R., Jeng, M.-T., Kang, C., Wang, L., Bayer, J. D., Christini, D. J., Trayanova, N. A., Ripplinger, C. M., Kass, R. S., and Clancy, C. E. (2011). A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. Sci. Transl. Med. 3, 98ra83.
33. Noble, D., and Rudy, Y. (2001). Models of cardiac ventricular action poten- tials: iterative interaction between experiment and simulation. Philos. Trans. R. Soc. Lond. A 359, 1127-1142.
34. Papadatos, G., Alkarouri, M., Gillet, V. J., Willett, P., Kadirkamanathan, V., Luscombe, C. N., Bravi, G., Richmond, N. J., Pickett, S. D., Hussain, J., Pritchard, J. M., Cooper, A. W. J., and Macdonald, S. J. F. (2010). Lead optimization using matched molecular pairs: inclusion of contextual information for enhanced prediction of hERG inhibition, solubility, and lipophilicity. J. Chem. Inf. Model. 50, 1872-1886.
35. Piccini, J. P., Whellan, D. J., Berridge, B. R., Finkle, J. K., Pettit, S. D., Stockbridge, N., Valentin, J.-P., Vargas, H. M., Krucoff, M. W., and Group, C. H. W. (2009). Current challenges in the evaluation of cardiac safety during drug development: translational medicine meets the critical path initiative. Am.HeartJ.158, 317-326.
36. Pressler, M. L., Warner, M. R., Rubart, M., Rardon, D. P. and Zipes, D. P. (1995). In vivo and in vitro electrophysiologic effects of terodiline on dog myocardium. J. Cardiovasc. Electrophysiol. 6, 443-454.
37. Redfern, W. S., Carlsson, L., Davis, A. S., Lynch, W. G., Mackenzie, I., Palethorpe, S., Siegl, P. K., Strang, I., Sullivan, A. T., Wallis, R., Camm, A. J., and Hammond, T. G. (2003). 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. 58, 32-45.
38. Rook, M. B., Evers, M. M., Vos, M. A., and Bierhuizen, M. F. (2012). Biology of cardiac sodium channel Nav1.5 expression. Cardiovasc. Res. 93, 12-23.
39. Ruan, Y., Denegri, M., Liu, N., Bachetti, T., Seregni, M., Morotti, S., Severi, S., Napolitano, C., and Priori, S. G. (2010). Trafficking defects and gating abnormalities of a novel SCN5A mutation question genespecific therapy in long QT syndrometype3.Circ. Res. 106, 1374-1383.
40. Seger, D. L. (2006). A critical reconsideration of the clinical effects and treatment recommendations for sodium channel blocking drug cardiotoxicity. Toxicol. Rev. 25, 283-296.
41. Starmer, C. F., Colatsky, T. J., and Grant, A. O. (2003a). What happens when cardiac Na channels lose their function? 1. Numerical studies of the vulnerable period in tissue expressing mutant channels. Cardiovasc. Res. 57, 82-91.
42. Starmer, C. F., Grant, A. O., and Colatsky, T. J. (2003b). What happens when cardiac Na channel function is compromised? 2. Numerical studies of the vulnerable period in tissue altered by drugs. Cardiovasc. Res. 57, 1062-1071.
43. Starmer, C. F., Lancaster, A. R., Lastra, A. A., and Grant, A. O. (1992). Cardiac instability amplified by use- dependent Na channel blockade. Am. J. Physiol. 262, H1305-H1310.
44. Starmer, C. F., Lastra, A. A., Nesterenko, V. V., and Grant, A. O. (1991). Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments. Circulation 84, 1364-1377.
45. Sumner, G., Salehian, O., Yi, Q., Healey, J., Mathew, J., Al-Merri, K., Al-Nemer, K., Mann, J. F. E., Dagenais, G., and Lonn, E. (2009). The prognostic significance of bundle branch block in highrisk chronic stable vascular disease patients: a report from the HOPE trial. J. Cardiovasc. Electrophysiol. 20, 781-787.
46. 2+ channel blocker AH-1058 in conscious dogs assessed by telemetry. Eur. J. Pharmacol. 413, 101-108.
47. Tfelt-Hansen, J., Winkel, B., Grunnet, M., and Jespersen, T. (2010). Inherited cardiac diseases caused by mutations in the Nav1.5 sodium channel. J. Cardiovasc. Electrophysiol. 21, 107-115.
48. Thanacoody, H. K., and Thomas, S. H. (2005). Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol. Rev. 24, 205-214.
49. Van Noord, C., Eijgelsheim, M., and Stricker, B. H. C. (2010). Drug- and non-drug-associated QT interval prolongation. Br. J. Clin. Pharmacol. 70, 16-23.
50. Vaughan Williams, E. M. (1992). The relevance of cellular to clinical electrophysiology in classifying antiarrhythmic actions. J. Cardiovasc. Pharmacol. 20(Suppl. 2), S1-S7.
51. Vieweg, W. V., and Wood, M. A. (2004). Tricyclic antidepressants, QT interval prolongation, and torsade de pointes. Psychosomatics 45, 371-377.
52. Warner, B., and Hoffmann, P. (2002). Investigation of the potential of clozapine to cause torsade de pointes. Adverse Drug React. Toxicol. Rev. 21, 189-203