Polytherapy with hERG-blocking antiepileptic drugs: Increased risk for embryonic cardiac arrhythmia and teratogenicity

Birth Defects Research Part A - Clinical and Molecular Teratology

Volumn 79, Issue 8, 2007, Pages 595-603

  Danielsson, Christian ^a   Azarbayjani, Faranak ^c   Sköld, Anna Carin ^b   Sjögren, Niklas ^b   Danielsson, Bengt R ^c  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^b ASTRAZENECA R AND D   (Sweden)

^c UPPSALA UNIVERSITY   (Sweden)

Author keywords

Antiepileptics; Carbamazepine; Dimethadione; Embryonic arrhythmia; hERG; Hypoxia reoxygenation damage; Phenobarbital; Phenytoin; Polytherapy; Teratogenicity

Indexed keywords

ALMOKALANT; ANTICONVULSIVE AGENT; CARBAMAZEPINE; DIMETHADIONE; PHENOBARBITAL; PHENYTOIN; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM CHANNEL HERG; POTASSIUM ION;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICONVULSANT THERAPY; ARTICLE; BRADYCARDIA; COMBINATION CHEMOTHERAPY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DEVELOPMENTAL DISORDER; DIGITALIZATION; DISEASE MARKER; EMBRYO; EMBRYO CULTURE; EMBRYOTOXICITY; FEMALE; FETUS HYPOXIA; GESTATIONAL AGE; GROWTH RETARDATION; HEART ARRHYTHMIA; HEART REPOLARIZATION; HIGH RISK POPULATION; MOUSE; NONHUMAN; POTASSIUM CURRENT; PRIORITY JOURNAL; RABBIT; RISK ASSESSMENT; SUDDEN DEATH; TERATOGENICITY;

ANIMALS; ANTICONVULSANTS; BRADYCARDIA; DIMETHADIONE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG THERAPY, COMBINATION; EMBRYO; EMBRYO CULTURE TECHNIQUES; ETHER-A-GO-GO POTASSIUM CHANNELS; FEMALE; GESTATIONAL AGE; HEART; MICE; MICE, INBRED C57BL; PHENYTOIN; POTASSIUM CHANNEL BLOCKERS; PREGNANCY;

EID: 34548102151     PISSN: 15420752     EISSN: 15420760     Source Type: Journal    
DOI: 10.1002/bdra.20378     Document Type: Article

References (40)

1. Abrahamsson C, Palmer M, Ljung B, et al. 1994. Induction of rhythm abnormalities in the fetal rat heart. A tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent almokalant. Cardiovasc Res 28:337-344.
2. Azarbayjani F, Danielsson BR. 1998. Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs? Teratology 57:117-126.
3. Azarbayjani F, Danielsson BR. 2001. Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage. Teratology 63:152-160.
4. Azarbayjani F, Danielsson BR. 2002. Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs? Epilepsia 43:457-468.
5. Biale Y, Lewenthal H, Aderet MB. 1975. Congenital malformations due to anticonvulsant drugs. Obstet Gynecol 45:439-442.
6. Brent RL, Franklin JB. 1960. Uterine Vascular Clamping: New Procedure for the Study of Congenital Malformations. Science 132:89-91.
7. Brown NA, Shull G, Fabro S. 1979. Assessment of the teratogenic potential of trimethadione in the CD-1 mouse. Toxicol Appl Pharmacol 51:59-71.
8. Butler TC, Kuroiwa Y, Waddell WJ, et al. 1966. Effects of 5,5-dimethyl-2,4-oxazolidinedione (DMO) on acid-base and electrolyte equilibria. J Pharm Exp Ther 152:62-66.
9. Chen EY, Fujinaga F, Giaccia AJ. 1999. Hypoxic Microenvironment Within an Embryo Induces Apoptosis and Is Essential for Proper Morphological Development. Teratology 60:215-225.
10. Danielson MK, Danielsson BR, Marchner H, et al. 1992. Histopathological and hemodynamic studies supporting hypoxia and vascular disruption as explanation to phenytoin teratogenicity. Teratology 46:485-497.
11. Danielsson BR, Azarbayjani F, Skold AC, et al. 1997. Initiation of phenytoin teratogenesis: pharmacologically induced embryonic bradycardia and arrhythmia resulting in hypoxia and possible free radical damage at reoxygenation. Teratology 56:271-281.
12. Danielsson BR, Johansson A, Danielsson C, et al. 2005. Phenytoin teratogenicity:hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism. Birth Defects Res A Clin Mol Teratol 73:146-153.
13. Danielsson BR, Lansdell K, Patmore L, et al. 2003a. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res 55:147-157.
14. Danielsson BR, Sköld AC, Azarbayjani F. 2001. Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Current Pharm Design 7:787-802.
15. Danielsson BR, Sköld AC, Johansson A, et al. 2003b. Teratogenicity by the hERG potassium channel blocking drug almokalant: use of hypoxia marker gives evidence for a hypoxia-related mechanism mediated via embryonic arrhythmia. Toxicol Appl Pharmacol 193:168-176.
16. Danielsson BR, Webster WS. 1997. Cardiovascular Active Drugs. In: Kavlock RJ, Daston GP, editors. Drug Toxicity in Embryonic Development II; Advances in Understanding Mechanisms of Birth Defects: Mechanistic Understanding of Human Developmental Toxicants. Berlin: Springer. p 161-190.
17. Dansky LV, Finnell RH. 1991. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 2: Human studies. Reprod Toxicol 5:301-335.
18. Davies MP, An RH, Doevendans P, et al. 1996. Developmental changes in ionic channel activity in the embryonic murine heart. Circ Res 78:15-25.
19. Fantel AG. 1996. Reactive oxygen species in developmental toxicity: review and hypothesis. Teratology 53:196-217.
20. Finnell RH, Dansky LV. 1991. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: Animal studies. Reprod Toxicol 5:281-299.
21. Grabowski CT. 1970. Embryonic oxygen deficiency - a physiological approach to analysis of teratological mechanisms. In: Woollam DHM, editor. Advances in Teratology. London: Logos Press Ltd. p 125-169.
22. Harris C. 1997. Hypoxia and Altered Redox Status in Embryo toxicity. In: Kavlock RJ, Daston GP, editors. Drug Toxicity in Embryonic Development I; Advances in Understanding Mechanisms of Birth Defects: Mechanistic Understanding of Human Developmental Toxicants. Berlin: Springer Heidelberg. p 517-546.
23. He JQ, Ma Y, Lee Y, et al. 2003. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res: 93:32-39.
24. Holmes LB, Harvey EA, Coull BA, et al. 2001. The teratogenicity of anticonvulsant drugs. N Engl J Med 344:1132-1138.
25. Hondeghem LM, Carlsson L, Duker G. 2001. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 103:2004-2013.
26. ICH E14. 2005. International Conference on Harmonization Note on the Clinical Evaluation of QT Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic drugs. p 1-14. http://www.emea.europa.eu/htms/human/ ichefficacy.htm
27. ICH S7B. 2005. International Conference on Harmonization. Topic S7B: The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarisation by Human Pharmaceuticals. p 1-9. http://www.emea.europa.eu/htms/human/ichsafety. htm
28. Langheinrich U, Vacun G, Wagner T. 2003. Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia. Toxicol Appl Pharmacol 193:370-382.
29. Leppik IE, Scherwin AL. 1979. Intravenous phenytoin and phenobarbital: anticonvulsant action, brain content, and plasma protein binding. Epilepsia 20:201-207.
30. Marks TA, Terry RD. 1996. Developmental toxicity of ibutilide fumarate in rats after oral administration. Teratology 54:157-164.
31. New DA. 1978. Whole-embryo culture and the study of mammalian embryos during organogenesis. Biol Rev Cambridge Phil Soc 53:81-122.
32. Nilsson L, Farahmand BY, Persson PG, et al. 1999. Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 353:888-893.
33. Pennell PB. 2003. The importance of monotherapy in pregnancy. Neurology 60:S31-S38.
34. Remmel RP, Sinz MW, Cloyd JC. 1990. Dose-dependent pharmacokinetics in rats: determination of the formation clearance of carbamazepine-10,11-epoxide. Pharm Res 7:513-517.
35. Sköld AC, Danielsson BR. 2001. Developmental toxicity in the pregnant rabbit by the class III antiarrhythmic drug sotalol. Pharmacol Toxicol 88:34-39.
36. Sköld AC, Danielsson C, Linder B, et al. 2002. Teratogenicity of the IKr-blocker cisapride: relation to embryonic cardiac arrhythmia. Reprod Toxicol 16:333-342.
37. Spence SG, Vetter C, Hoe CM. 1994. Effects of the class III antiarrhythmic, dofetilide (UK-68,798) on the heart rate of midgestation rat embryos, in vitro. Teratology 49:282-292.
38. Wang L, Feng ZP, Kondo CS, et al. 1996. Developmental changes in the delayed rectifier K+ channels in mouse heart. Circ Res 79:79-85.
39. Webster WS, Brown-Woodman PD, Snow MD, et al. 1996. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 53:168-175.
40. Witchel HJ, Hancox JC. 2000. Familial and acquired long QTsyndrome and the cardiac rapid delayed retired potassium current Clin Exp Pharm Phys 27:753-766.