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New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential.
Curr Pharm Des. 2007; 13(29):2979-88.CP

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Division of Toxicology, S-751 24, Uppsala University, Uppsala, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

17979741

Citation

Karlsson, Miriam, et al. "New Proposals for Testing Drugs With IKr-blocking Activity to Determine Their Teratogenic Potential." Current Pharmaceutical Design, vol. 13, no. 29, 2007, pp. 2979-88.
Karlsson M, Danielsson BR, Nilsson MF, et al. New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential. Curr Pharm Des. 2007;13(29):2979-88.
Karlsson, M., Danielsson, B. R., Nilsson, M. F., Danielsson, C., & Webster, W. S. (2007). New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential. Current Pharmaceutical Design, 13(29), 2979-88.
Karlsson M, et al. New Proposals for Testing Drugs With IKr-blocking Activity to Determine Their Teratogenic Potential. Curr Pharm Des. 2007;13(29):2979-88. PubMed PMID: 17979741.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential. AU - Karlsson,Miriam, AU - Danielsson,Bengt R, AU - Nilsson,Mats F, AU - Danielsson,Christian, AU - Webster,William S, PY - 2007/11/6/pubmed PY - 2008/1/3/medline PY - 2007/11/6/entrez SP - 2979 EP - 88 JF - Current pharmaceutical design JO - Curr. Pharm. Des. VL - 13 IS - 29 N2 - 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. SN - 1873-4286 UR - https://www.unboundmedicine.com/medline/citation/17979741/New_proposals_for_testing_drugs_with_IKr_blocking_activity_to_determine_their_teratogenic_potential_ L2 - http://www.eurekaselect.com/59951/article DB - PRIME DP - Unbound Medicine ER -