Embryonic cardiac arrhythmia and generation of reactive oxygen species: common teratogenic mechanism for IKr blocking drugs

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Fältnamn	Indikatorer	Metadata
000		03668naa a2200433 4500
001		oai:DiVA.org:uu-104298
003		SwePub
008		090528s2007 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:prod.swepub.kib.ki.se:115754202
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1042982 URI
024	7	a https://doi.org/10.1016/j.reprotox.2007.04.0052 DOI
024	7	a http://kipublications.ki.se/Default.aspx?queryparsed=id:1157542022 URI
040		a (SwePub)uud (SwePub)ki
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Danielsson, Bengt R.u Uppsala universitet,Institutionen för farmaceutisk biovetenskap4 aut
245	1 0	a Embryonic cardiac arrhythmia and generation of reactive oxygen species :b common teratogenic mechanism for IKr blocking drugs
264	1	b Elsevier BV,c 2007
338		a print2 rdacarrier
520		a In the adult organism, it is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage. There is also considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent, and timing of the hypoxic event. It is the contention of this paper that drugs that block the potassium channel IKr, either as an intended pharmacologic effect or as an unwanted side-effect, are potentially teratogenic by a common ROS related mechanism. Drugs blocking the IKr channel, such as almokalant, dofetilide, phenytoin, cisapride and astemizole, do all produce a similar pattern of hypoxia-related malformations. Mechanistic studies show that the malformations are preceded by embryonic cardiac arrhythmia and periods of hypoxia/reoxygenation in embryonic tissues. Pretreatment or simultaneous treatment with radical scavengers with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses result in high incidences of embryonic death due embryonic cardiac arrhythmia, thus masking their teratogenic potential. Instead, single dosing on specific days is proposed to be a better way to characterize the teratogenic potential of Ikr blocking drugs.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653		a Reactive oxygen species
653		a Embryonic arrhythmia
653		a IKr blocking drugs
653		a Hypoxia
653		a Malformation
653		a hERG
653		a PHARMACY
653		a FARMACI
700	1	a Danielsson, Christian4 aut
700	1	a Nilsson, Mats F.u Uppsala universitet,Institutionen för farmaceutisk biovetenskap4 aut0 (Swepub:uu)manil343
710	2	a Uppsala universitetb Institutionen för farmaceutisk biovetenskap4 org
773	0	t Reproductive Toxicologyd : Elsevier BVg 24:1, s. 42-56q 24:1<42-56x 0890-6238x 1873-1708
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-104298
856	4 8	u https://doi.org/10.1016/j.reprotox.2007.04.005
856	4 8	u http://kipublications.ki.se/Default.aspx?queryparsed=id:115754202

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Av författaren/redakt...: Danielsson, Beng ...; Danielsson, Chri ...; Nilsson, Mats F.

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