PMID- 8761884
OWN - NLM
STAT- MEDLINE
DCOM- 19961024
LR  - 20161123
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 53
IP  - 3
DP  - 1996 Mar
TI  - Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with 
      potassium channel blocking activity.
PG  - 168-75
AB  - 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.
FAU - Webster, W S
AU  - Webster WS
AD  - Department of Anatomy, University of Sydney, NSW, Australia.
FAU - Brown-Woodman, P D
AU  - Brown-Woodman PD
FAU - Snow, M D
AU  - Snow MD
FAU - Danielsson, B R
AU  - Danielsson BR
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Anti-Arrhythmia Agents)
RN  - 0 (Phenethylamines)
RN  - 0 (Potassium Channel Blockers)
RN  - 0 (Propanolamines)
RN  - 0 (Sulfonamides)
RN  - A6D97U294I (Sotalol)
RN  - I9NG89L275 (almokalant)
RN  - R4Z9X1N2ND (dofetilide)
SB  - IM
MH  - *Abnormalities, Drug-Induced
MH  - Animals
MH  - Anti-Arrhythmia Agents/*toxicity
MH  - Cleft Palate/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Embryonic and Fetal Development/drug effects
MH  - Female
MH  - Heart Rate, Fetal/drug effects
MH  - Limb Deformities, Congenital
MH  - Male
MH  - Organ Culture Techniques
MH  - Phenethylamines/*toxicity
MH  - *Potassium Channel Blockers
MH  - Pregnancy
MH  - Pregnancy Outcome
MH  - Propanolamines/*toxicity
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sotalol/*toxicity
MH  - Sulfonamides/*toxicity
EDAT- 1996/03/01 00:00
MHDA- 2000/06/20 09:00
CRDT- 1996/03/01 00:00
PHST- 1996/03/01 00:00 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1996/03/01 00:00 [entrez]
AID - 10.1002/(SICI)1096-9926(199603)53:3<168::AID-TERA4>3.0.CO;2-0 [pii]
AID - 10.1002/(SICI)1096-9926(199603)53:3<168::AID-TERA4>3.0.CO;2-0 [doi]
PST - ppublish
SO  - Teratology. 1996 Mar;53(3):168-75. doi: 
      10.1002/(SICI)1096-9926(199603)53:3<168::AID-TERA4>3.0.CO;2-0.