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Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The potassium ion channel (hERG/IKr) is important for normal heart function and drug-induced blockade of the channel in adult humans can lead to irregular heart rhythms (arrhythmia).  The ion channel is also essential for early cardiac function in the embryo and therapeutic drugs which block this channel have been shown to cause birth defects in animal studies.  A wide range of birth defects have been seen including cleft lip/palate, distal limb defects and heart malformations.

These malformations are associated with periods of hypoxia and altered blood flow in the embryo associated with the drug-induced heart rhythm disorders and bradycardia. It is also well known that other experimental procedures causing periods of hypoxia in the embryo can give rise to similar defects as those seen with drugs that block the hERG/IKr channel. Paper I on the thesis deals with risk assessment for use in pregnancy of drugs which block hERG/IKr.   Evaluation of the risk of birth defects is largely based on the results of experimental studies on animals. Guidelines for how such standard tests are to be performed were determined by regulatory authorities several decades ago. However, there are examples where safety studies for drugs blocking hERG/IKr, although fulfilling regulatory guidelines, have been carried out at a suboptimal dose range and failed to detect teratogenicity.  A consequence of this is that the teratogenic potential of hERG/IKr blocking drugs have been missed in standard safety testing. The results of the paper I show that the teratogenic properties of the drug astemizole (withdrawn from the market several years ago because of fatal cardiac arrhythmias in adults related to the blockade of hERG/IKr) were missed in the initial safety studies.

Paper II shows that several drugs that block cardiac ion channels other than hERG/IKr can also disrupt fetal cardiac function during embryonic development. However, the concentrations required to cause these changes are much higher than is likely to occur during normal use of the medicines and based on these results that are not considered a risk when taken during pregnancy.

Paper III deals with the possible teratogenicity of erythromycin.  From the Swedish Birth Defects Register there have been signals that use of erythromycin (which has hERG/IKr-blocking properties) during pregnancy is associated with an increased risk of cardiovascular malformations. Paper III shows that the levels of erythromycin needed to disrupt fetal cardiac function during embryonic development are unlikely to occur after normal oral treatment with erythromycin.

Paper IV shows that the embryonic rat heart undergoes major changes in sensitivity to blockade of specific cardiac ion channels during the organogenic period. This is an important observation from the perspective that there may be periods during embryonic development when the embryo is more or less sensitive to the effect of drugs that affect specific ion channels.

To conclude, papers I-IV show that the study of drug effects on the gestation day 13 rat embryonic heart, together with the use of computational assisted image analysis of the cardiac response, provides an in vitro model for hazard identification of compounds with the potential to adversely affect heart function in the developing embryo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 177
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-206882ISBN: 978-91-554-8745-4 (print)OAI: oai:DiVA.org:uu-206882DiVA: diva2:645869
Public defence
2013-10-18, A1:107a, Biomedicinskt Centrum, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-09-27 Created: 2013-09-05 Last updated: 2014-01-23
List of papers
1. Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
Open this publication in new window or tab >>Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
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2010 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 29, no 2, 156-163 p.Article in journal (Refereed) Published
Abstract [en]

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 (80mg/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 20nM, and arrhythmias at 200-400nM. 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.

Place, publisher, year, edition, pages
Elsevier, 2010
Keyword
Astemizole, hERG channel, IKr, Teratogenicity, Hypoxia, Embryonic cardiac adverse effects, Embryotoxicity, Toxicology
National Category
Pharmaceutical Sciences Computer Vision and Robotics (Autonomous Systems)
Research subject
Toxicology; Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-118335 (URN)10.1016/j.reprotox.2010.01.014 (DOI)000276326900004 ()20144703 (PubMedID)
Available from: 2010-02-23 Created: 2010-02-23 Last updated: 2017-12-12Bibliographically approved
2. The effect of drugs with ion channel-blocking activity on the early embryonic rat heart
Open this publication in new window or tab >>The effect of drugs with ion channel-blocking activity on the early embryonic rat heart
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2010 (English)In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 89, no 5, 429-440 p.Article in journal (Refereed) Published
Abstract [en]

This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the IKr/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or IKr/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

Keyword
embryo/fetal physiology, in vitro screens, mechanisms of teratogenesis, pharmaceuticals
National Category
Computer Vision and Robotics (Autonomous Systems) Pharmaceutical Sciences
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-141481 (URN)10.1002/bdrb.20270 (DOI)000283911500008 ()20973055 (PubMedID)
Available from: 2011-01-12 Created: 2011-01-12 Last updated: 2017-12-11Bibliographically approved
3. Comparative effects of erythromycin and clarithromycin on rat embryonic heart function in vitro
Open this publication in new window or tab >>Comparative effects of erythromycin and clarithromycin on rat embryonic heart function in vitro
(English)Article in journal (Refereed) Submitted
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-206880 (URN)
Available from: 2013-09-05 Created: 2013-09-05 Last updated: 2014-01-23Bibliographically approved
4. The effect on rat embryonic heart rate of Na+-, K+ and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age
Open this publication in new window or tab >>The effect on rat embryonic heart rate of Na+-, K+ and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age
2013 (English)In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 98, no 5, 416-427 p.Article in journal (Refereed) Published
Abstract [en]

To determine the changes in dependence on ion channels during rat cardiac development we compared the effects of four ion channel blockers on rat embryonic heart function during the organogenic period from gestational day (GD) 10-15. Rat embryos in culture were exposed to either the hERG potassium channel blocker dofetilide (400 nM), the sodium channel blocker lidocaine (250 μM) the L-type calcium channel blocker nifedipine (1.8 μM), or the multi-channel blocker phenytoin (200 μM). Lidocaine slowed the heart rate (HR) with the effect becoming more severe with increasing GD. Dofetilide slowed the embryonic HR and caused arrhythmias with the most severe effect on GD 11-13. Nifedipine primarily caused a negative inotropic effect except on GD 10 when it stopped the heart in most embryos. Phenytoin stopped the heart of most GD 10-12 embryos while on GD 13-15 phenytoin it slowed the heart. The results demonstrate that as the rat heart develops during the organogenic period its functional dependence on ion channels changes markedly. These changes are important for understanding drug effects on the embryo during pregnancy and the methodology used provides a simple procedure for assessing drug effects on the developing heart.

National Category
Pharmacology and Toxicology
Research subject
Behavioural Neuroscience; Toxicology
Identifiers
urn:nbn:se:uu:diva-206881 (URN)10.1002/bdrb.21084 (DOI)000328470100005 ()
Available from: 2013-09-05 Created: 2013-09-05 Last updated: 2017-12-06Bibliographically approved

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