uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Toxikologi)
Show others and affiliations
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. Vol. 29, no 2, 156-163 p.
Keyword [en]
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: urn:nbn:se:uu:diva-118335DOI: 10.1016/j.reprotox.2010.01.014ISI: 000276326900004PubMedID: 20144703OAI: oai:DiVA.org:uu-118335DiVA: diva2:299024
Available from: 2010-02-23 Created: 2010-02-23 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Image Filtering Methods for Biomedical Applications
Open this publication in new window or tab >>Image Filtering Methods for Biomedical Applications
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Filtering is a key step in digital image processing and analysis. It is mainly used for amplification or attenuation of some frequencies depending on the nature of the application. Filtering can either be performed in the spatial domain or in a transformed domain. The selection of the filtering method, filtering domain, and the filter parameters are often driven by the properties of the underlying image. This thesis presents three different kinds of biomedical image filtering applications, where the filter parameters are automatically determined from the underlying images.

Filtering can be used for image enhancement. We present a robust image dependent filtering method for intensity inhomogeneity correction of biomedical images. In the presented filtering method, the filter parameters are automatically determined from the grey-weighted distance transform of the magnitude spectrum. An evaluation shows that the filter provides an accurate estimate of intensity inhomogeneity.

Filtering can also be used for analysis. The thesis presents a filtering method for heart localization and robust signal detection from video recordings of rat embryos. It presents a strategy to decouple motion artifacts produced by the non-rigid embryonic boundary from the heart. The method also filters out noise and the trend term with the help of empirical mode decomposition. Again, all the filter parameters are determined automatically based on the underlying signal.

Transforming the geometry of one image to fit that of another one, so called image registration, can be seen as a filtering operation of the image geometry. To assess the progression of eye disorder, registration between temporal images is often required to determine the movement and development of the blood vessels in the eye. We present a robust method for retinal image registration. The method is based on particle swarm optimization, where the swarm searches for optimal registration parameters based on the direction of its cognitive and social components. An evaluation of the proposed method shows that the method is less susceptible to becoming trapped in local minima than previous methods.

With these thesis contributions, we have augmented the filter toolbox for image analysis with methods that adjust to the data at hand.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 852
Keyword
Digital image analysis, Image filtering, Intensity inhomogeneity correction, Empirical mode decomposition, Particle Swarm optimization, Image registration
National Category
Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-158679 (URN)978-91-554-8155-1 (ISBN)
Public defence
2011-10-25, Room 10134, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2011-10-03 Created: 2011-09-13 Last updated: 2014-07-21
2. Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
Open this publication in new window or tab >>Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
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:nbn:se:uu:diva-206882 (URN)978-91-554-8745-4 (ISBN)
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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Bengtsson, EwertKultima, Kim

Search in DiVA

By author/editor
Bengtsson, EwertKultima, Kim
By organisation
Department of Pharmaceutical BiosciencesCentre for Image AnalysisComputerized Image AnalysisDepartment of Medical Sciences
In the same journal
Reproductive Toxicology
Pharmaceutical SciencesComputer Vision and Robotics (Autonomous Systems)

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 570 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf