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Developmental toxicity of the class III antiarrhythmic agent almokalant in mice. Adverse effects mediated via induction of embryonic heart rhythm abnormalities.
Arzneimittelforschung. 2000 Jun; 50(6):520-5.A

Abstract

Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has been shown to be embryotoxic in rats. In the absence of human pregnancy outcome data, the human relevance of these findings in rats is unknown, and results from other species would indicate if these findings are of more universal interest. Therefore, this study was initiated to evaluate the potential effects in mice. ALM was given to three groups of pregnant mice (approximately 20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 mumol/kg. A fourth group served as a control. In addition, whole embryo culture was performed on gestation day 10 with doses of ALM ranging from 325-5200 nmol/l (approximately 17 embryos/group) in order to study if ALM had the potential to induce dysrhythmia in the embryonic mouse heart. ALM induced total embryonic death in the high dose group, and in the intermediate group the level of embryonic death was elevated and the mean foetal weights decreased. A slight increase in minor skeletal defects was observed, mainly consisting of reduced calcification of elements in the vertebral column and among the phalanges. ALM caused bradycardia in a concentration dependent manner (13-42% at 650-5200 nmol/l). Irregular heart rhythm and/or episodes of cardiac arrest were observed in one embryo at 2600 and in seven embryos at 5200 nmol/l. In conclusion, ALM caused embryotoxicity in the mouse, most likely secondary to adverse effects on the embryonic heart. The results may suggest that class III antiarrhythmics are embryotoxic also in humans.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Uppsala University, Sweden. anna-carin.skold@astrazeneca.comNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10918943

Citation

Sköld, A C., and B R. Danielsson. "Developmental Toxicity of the Class III Antiarrhythmic Agent Almokalant in Mice. Adverse Effects Mediated Via Induction of Embryonic Heart Rhythm Abnormalities." Arzneimittel-Forschung, vol. 50, no. 6, 2000, pp. 520-5.
Sköld AC, Danielsson BR. Developmental toxicity of the class III antiarrhythmic agent almokalant in mice. Adverse effects mediated via induction of embryonic heart rhythm abnormalities. Arzneimittelforschung. 2000;50(6):520-5.
Sköld, A. C., & Danielsson, B. R. (2000). Developmental toxicity of the class III antiarrhythmic agent almokalant in mice. Adverse effects mediated via induction of embryonic heart rhythm abnormalities. Arzneimittel-Forschung, 50(6), 520-5.
Sköld AC, Danielsson BR. Developmental Toxicity of the Class III Antiarrhythmic Agent Almokalant in Mice. Adverse Effects Mediated Via Induction of Embryonic Heart Rhythm Abnormalities. Arzneimittelforschung. 2000;50(6):520-5. PubMed PMID: 10918943.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Developmental toxicity of the class III antiarrhythmic agent almokalant in mice. Adverse effects mediated via induction of embryonic heart rhythm abnormalities. AU - Sköld,A C, AU - Danielsson,B R, PY - 2000/8/5/pubmed PY - 2000/9/19/medline PY - 2000/8/5/entrez SP - 520 EP - 5 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 50 IS - 6 N2 - Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has been shown to be embryotoxic in rats. In the absence of human pregnancy outcome data, the human relevance of these findings in rats is unknown, and results from other species would indicate if these findings are of more universal interest. Therefore, this study was initiated to evaluate the potential effects in mice. ALM was given to three groups of pregnant mice (approximately 20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 mumol/kg. A fourth group served as a control. In addition, whole embryo culture was performed on gestation day 10 with doses of ALM ranging from 325-5200 nmol/l (approximately 17 embryos/group) in order to study if ALM had the potential to induce dysrhythmia in the embryonic mouse heart. ALM induced total embryonic death in the high dose group, and in the intermediate group the level of embryonic death was elevated and the mean foetal weights decreased. A slight increase in minor skeletal defects was observed, mainly consisting of reduced calcification of elements in the vertebral column and among the phalanges. ALM caused bradycardia in a concentration dependent manner (13-42% at 650-5200 nmol/l). Irregular heart rhythm and/or episodes of cardiac arrest were observed in one embryo at 2600 and in seven embryos at 5200 nmol/l. In conclusion, ALM caused embryotoxicity in the mouse, most likely secondary to adverse effects on the embryonic heart. The results may suggest that class III antiarrhythmics are embryotoxic also in humans. SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/10918943/Developmental_toxicity_of_the_class_III_antiarrhythmic_agent_almokalant_in_mice__Adverse_effects_mediated_via_induction_of_embryonic_heart_rhythm_abnormalities_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-0031-1300241 DB - PRIME DP - Unbound Medicine ER -