PMID- 17979741
OWN - NLM
STAT- MEDLINE
DCOM- 20080102
LR  - 20190728
IS  - 1873-4286 (Electronic)
IS  - 1381-6128 (Linking)
VI  - 13
IP  - 29
DP  - 2007
TI  - New proposals for testing drugs with IKr-blocking activity to determine their 
      teratogenic potential.
PG  - 2979-88
AB  - Drugs blocking the potassium current IKr, either as an intended pharmacologic 
      effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted 
      side-effect (eg antihistamine astemizole, propulsive drug cisapride, 
      antidepressive drugs and macrolide antibiotics) are potential human teratogens. 
      It is the contention of this paper that the existing repeat dose regimen used in 
      teratology studies to fulfil regulatory requirements, does not properly identify 
      the teratogenic risk of these drugs. Results from conventional studies for 
      dofetilide and almokalant showed high rates of postimplantation embryonic death 
      with few malformed fetuses. For astemizole and cisapride only embryonic death was 
      seen. These latter results were not considered important because they occurred 
      either in the presence of maternal toxicity and/or at high doses. Subsequent 
      studies have shown that IKr-blockers are highly teratogenic when administered on 
      single gestational days (GD) during a sensitive period of rat pregnancy (GD 
      10-14) when they induce a high incidence of stage-specific malformations. This 
      teratogenic activity of astemizole and cisapride was missed in the original 
      teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia 
      of the embryonic heart and while an embryo may be able to survive a single day 
      exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. 
      With this review we suggest that new drugs identified at the preclinical stage of 
      development as having IKr-blocking properties, should undergo more comprehensive 
      teratology testing including single GD dosing and studies using embryo culture. 
      This would further help identify and characterise their teratogenic potential.
FAU - Karlsson, Miriam
AU  - Karlsson M
AD  - Department of Pharmaceutical Biosciences, Division of Toxicology, S-751 24, 
      Uppsala University, Uppsala, Sweden.
FAU - Danielsson, Bengt R
AU  - Danielsson BR
FAU - Nilsson, Mats F
AU  - Nilsson MF
FAU - Danielsson, Christian
AU  - Danielsson C
FAU - Webster, William S
AU  - Webster WS
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United Arab Emirates
TA  - Curr Pharm Des
JT  - Current pharmaceutical design
JID - 9602487
RN  - 0 (Potassium Channel Blockers)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (Teratogens)
SB  - IM
MH  - *Abnormalities, Drug-Induced/prevention & control
MH  - Animals
MH  - Drug Evaluation, Preclinical/methods/trends
MH  - Female
MH  - Humans
MH  - Potassium Channel Blockers/*toxicity
MH  - Potassium Channels, Inwardly Rectifying/*antagonists & inhibitors/physiology
MH  - Pregnancy
MH  - Teratogens/toxicity
RF  - 87
EDAT- 2007/11/06 09:00
MHDA- 2008/01/03 09:00
CRDT- 2007/11/06 09:00
PHST- 2007/11/06 09:00 [pubmed]
PHST- 2008/01/03 09:00 [medline]
PHST- 2007/11/06 09:00 [entrez]
AID - 10.2174/138161207782110471 [doi]
PST - ppublish
SO  - Curr Pharm Des. 2007;13(29):2979-88. doi: 10.2174/138161207782110471.