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Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs.
Reprod Toxicol. 2010 Apr; 29(2):156-63.RT

Abstract

Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, Sweden. Mats.Nilsson@farmbio.uu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20144703

Citation

Nilsson, M F., et al. "Improved Methodology for Identifying the Teratogenic Potential in Early Drug Development of hERG Channel Blocking Drugs." Reproductive Toxicology (Elmsford, N.Y.), vol. 29, no. 2, 2010, pp. 156-63.
Nilsson MF, Danielsson C, Sköld AC, et al. Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs. Reprod Toxicol. 2010;29(2):156-63.
Nilsson, M. F., Danielsson, C., Sköld, A. C., Johansson, A., Blomgren, B., Wilson, J., Khan, K. M., Bengtsson, E., Kultima, K., Webster, W. S., & Danielsson, B. R. (2010). Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs. Reproductive Toxicology (Elmsford, N.Y.), 29(2), 156-63. https://doi.org/10.1016/j.reprotox.2010.01.014
Nilsson MF, et al. Improved Methodology for Identifying the Teratogenic Potential in Early Drug Development of hERG Channel Blocking Drugs. Reprod Toxicol. 2010;29(2):156-63. PubMed PMID: 20144703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs. AU - Nilsson,M F, AU - Danielsson,C, AU - Sköld,A-C, AU - Johansson,A, AU - Blomgren,B, AU - Wilson,J, AU - Khan,K M, AU - Bengtsson,E, AU - Kultima,K, AU - Webster,W S, AU - Danielsson,B R, Y1 - 2010/02/06/ PY - 2009/07/06/received PY - 2010/01/18/revised PY - 2010/01/29/accepted PY - 2010/2/11/entrez PY - 2010/2/11/pubmed PY - 2010/6/11/medline SP - 156 EP - 63 JF - Reproductive toxicology (Elmsford, N.Y.) JO - Reprod. Toxicol. VL - 29 IS - 2 N2 - Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs. SN - 1873-1708 UR - https://www.unboundmedicine.com/medline/citation/20144703/Improved_methodology_for_identifying_the_teratogenic_potential_in_early_drug_development_of_hERG_channel_blocking_drugs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0890-6238(10)00016-X DB - PRIME DP - Unbound Medicine ER -