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The teratogenic effect of dofetilide during rat limb development and association with drug-induced bradycardia and hypoxia in the embryo.
Birth Defects Res B Dev Reprod Toxicol. 2013 Apr; 98(2):144-53.BD

Abstract

BACKGROUND

Dofetilide is an antiarrhythmic drug that blocks the cardiac repolarizing current IKr ((IKr, rapid component of the delayed rectifying potassium current). Previous studies have shown that (a) IKr is essential for normal cardiac function of the embryonic heart and (b) dofetilide is teratogenic in rodents. This study was undertaken to examine the mechanism by which dofetilide causes limb defects on gestational day 13 (GD 13) in the rat.

METHODS

Rats were treated with dofetilide (single oral dose, 5 mg/kg) on GD 13 and embryonic heart rates assessed by ultrasound (Vevo770, VisualSonics, Toronto, Ontario, Canada) 2 hr later. Fetuses were examined for malformations on GD 20. In a separate experiment, dofetilide treatment of GD 13 rats was followed 2, 4, 12, or 24 hr with iv dosing with the hypoxia marker, pimonidazole (60 mg/kg). Embryos were collected and heart rates were assessed in vitro and hypoxia in embryo limbs analyzed.

RESULTS

A teratogenic dose of dofetilide at a susceptible stage of development (GD 13) resulted in a period of bradycardia and arrhythmia of the embryonic heart and hypoxia in the developing limbs (GD 13) resulting in limb malformations (GD 20).

CONCLUSIONS

Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens.

Authors+Show Affiliations

Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23504928

Citation

Ritchie, Helen E., et al. "The Teratogenic Effect of Dofetilide During Rat Limb Development and Association With Drug-induced Bradycardia and Hypoxia in the Embryo." Birth Defects Research. Part B, Developmental and Reproductive Toxicology, vol. 98, no. 2, 2013, pp. 144-53.
Ritchie HE, Ababneh DH, Oakes DJ, et al. The teratogenic effect of dofetilide during rat limb development and association with drug-induced bradycardia and hypoxia in the embryo. Birth Defects Res B Dev Reprod Toxicol. 2013;98(2):144-53.
Ritchie, H. E., Ababneh, D. H., Oakes, D. J., Power, C. A., & Webster, W. S. (2013). The teratogenic effect of dofetilide during rat limb development and association with drug-induced bradycardia and hypoxia in the embryo. Birth Defects Research. Part B, Developmental and Reproductive Toxicology, 98(2), 144-53. https://doi.org/10.1002/bdrb.21050
Ritchie HE, et al. The Teratogenic Effect of Dofetilide During Rat Limb Development and Association With Drug-induced Bradycardia and Hypoxia in the Embryo. Birth Defects Res B Dev Reprod Toxicol. 2013;98(2):144-53. PubMed PMID: 23504928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The teratogenic effect of dofetilide during rat limb development and association with drug-induced bradycardia and hypoxia in the embryo. AU - Ritchie,Helen E, AU - Ababneh,Deena H, AU - Oakes,Diana J, AU - Power,Carl A, AU - Webster,William S, Y1 - 2013/03/15/ PY - 2012/11/15/received PY - 2012/12/19/accepted PY - 2013/3/19/entrez PY - 2013/3/19/pubmed PY - 2013/11/12/medline SP - 144 EP - 53 JF - Birth defects research. Part B, Developmental and reproductive toxicology JO - Birth Defects Res. B Dev. Reprod. Toxicol. VL - 98 IS - 2 N2 - BACKGROUND: Dofetilide is an antiarrhythmic drug that blocks the cardiac repolarizing current IKr ((IKr, rapid component of the delayed rectifying potassium current). Previous studies have shown that (a) IKr is essential for normal cardiac function of the embryonic heart and (b) dofetilide is teratogenic in rodents. This study was undertaken to examine the mechanism by which dofetilide causes limb defects on gestational day 13 (GD 13) in the rat. METHODS: Rats were treated with dofetilide (single oral dose, 5 mg/kg) on GD 13 and embryonic heart rates assessed by ultrasound (Vevo770, VisualSonics, Toronto, Ontario, Canada) 2 hr later. Fetuses were examined for malformations on GD 20. In a separate experiment, dofetilide treatment of GD 13 rats was followed 2, 4, 12, or 24 hr with iv dosing with the hypoxia marker, pimonidazole (60 mg/kg). Embryos were collected and heart rates were assessed in vitro and hypoxia in embryo limbs analyzed. RESULTS: A teratogenic dose of dofetilide at a susceptible stage of development (GD 13) resulted in a period of bradycardia and arrhythmia of the embryonic heart and hypoxia in the developing limbs (GD 13) resulting in limb malformations (GD 20). CONCLUSIONS: Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens. SN - 1542-9741 UR - https://www.unboundmedicine.com/medline/citation/23504928/The_teratogenic_effect_of_dofetilide_during_rat_limb_development_and_association_with_drug_induced_bradycardia_and_hypoxia_in_the_embryo_ L2 - https://doi.org/10.1002/bdrb.21050 DB - PRIME DP - Unbound Medicine ER -