Tags

Type your tag names separated by a space and hit enter

Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity.
Teratology. 1996 Mar; 53(3):168-75.T

Abstract

Drugs with class III antiarrhythmic activity are potential human teratogens because of their ability to cause bradycardia in the embryo during the organogenic period. Three drugs with class III antiarrhythmic activity, almokalant, dofetilide and d-sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration-dependent bradycardia in 11- or 13-day rat embryos. For each drug the effective concentration was considerably greater than the human therapeutic plasma concentration. The reproductive outcome was also compared in vivo in Sprague-Dawley rats by oral administration of almokalant or dofetilide on single days during the organogenic period. Both drugs caused increased resorptions and the same stage-dependent malformations. Dosing on gestational day (GD) 11 was associated with right-sided oblique cleft lip and short tail, while dosing on day 13 caused digital hypoplasia and/or amputation. Susceptibility to these drugs started on GD 9 when the embryonic heart starts beating and ended on GD 15. The malformations were preceded by hemorrhage; which is consistent with the proposed pathogenesis that the drug-induced bradycardia caused embryonic hypoxia/ischemia. This study indicates that the induction of malformations/embryonic death by class III antiarrhythmic drugs which inhibit Ikr is a class effect secondary to a common pharmacological action on the embryonic heart.

Authors+Show Affiliations

Department of Anatomy, University of Sydney, NSW, Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

8761884

Citation

Webster, W S., et al. "Teratogenic Potential of Almokalant, Dofetilide, and D-sotalol: Drugs With Potassium Channel Blocking Activity." Teratology, vol. 53, no. 3, 1996, pp. 168-75.
Webster WS, Brown-Woodman PD, Snow MD, et al. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology. 1996;53(3):168-75.
Webster, W. S., Brown-Woodman, P. D., Snow, M. D., & Danielsson, B. R. (1996). Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology, 53(3), 168-75.
Webster WS, et al. Teratogenic Potential of Almokalant, Dofetilide, and D-sotalol: Drugs With Potassium Channel Blocking Activity. Teratology. 1996;53(3):168-75. PubMed PMID: 8761884.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. AU - Webster,W S, AU - Brown-Woodman,P D, AU - Snow,M D, AU - Danielsson,B R, PY - 1996/3/1/pubmed PY - 2000/6/20/medline PY - 1996/3/1/entrez SP - 168 EP - 75 JF - Teratology JO - Teratology VL - 53 IS - 3 N2 - Drugs with class III antiarrhythmic activity are potential human teratogens because of their ability to cause bradycardia in the embryo during the organogenic period. Three drugs with class III antiarrhythmic activity, almokalant, dofetilide and d-sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration-dependent bradycardia in 11- or 13-day rat embryos. For each drug the effective concentration was considerably greater than the human therapeutic plasma concentration. The reproductive outcome was also compared in vivo in Sprague-Dawley rats by oral administration of almokalant or dofetilide on single days during the organogenic period. Both drugs caused increased resorptions and the same stage-dependent malformations. Dosing on gestational day (GD) 11 was associated with right-sided oblique cleft lip and short tail, while dosing on day 13 caused digital hypoplasia and/or amputation. Susceptibility to these drugs started on GD 9 when the embryonic heart starts beating and ended on GD 15. The malformations were preceded by hemorrhage; which is consistent with the proposed pathogenesis that the drug-induced bradycardia caused embryonic hypoxia/ischemia. This study indicates that the induction of malformations/embryonic death by class III antiarrhythmic drugs which inhibit Ikr is a class effect secondary to a common pharmacological action on the embryonic heart. SN - 0040-3709 UR - https://www.unboundmedicine.com/medline/citation/8761884/Teratogenic_potential_of_almokalant_dofetilide_and_d_sotalol:_drugs_with_potassium_channel_blocking_activity_ L2 - https://doi.org/10.1002/(SICI)1096-9926(199603)53:3<168::AID-TERA4>3.0.CO;2-0 DB - PRIME DP - Unbound Medicine ER -