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

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MARC

Danielsson, Bengt R.Uppsala universitet,Institutionen för farmaceutisk biovetenskap (author)

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

Article/chapterEnglish2007

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Elsevier BV,2007
printrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-104298
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-104298URI
https://doi.org/10.1016/j.reprotox.2007.04.005DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:115754202URI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
Reactive oxygen species
Embryonic arrhythmia
IKr blocking drugs
Hypoxia
Malformation
hERG
PHARMACY
FARMACI

Added entries (persons, corporate bodies, meetings, titles ...)

Danielsson, Christian (author)
Nilsson, Mats F.Uppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)manil343 (author)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

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In:Reproductive Toxicology: Elsevier BV24:1, s. 42-560890-62381873-1708

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

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By the university: Uppsala University; Karolinska Institutet

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