Defining candidate drug characteristics for Long-QT (LQT3) syndrome
Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Over the past decade, detailed Markov models of the action potential of cardiac cells have been developed. In such models, the effects of a drug ca...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
AIMS Press
2011-05-01
|
| Series: | Mathematical Biosciences and Engineering |
| Subjects: | |
| Online Access: | https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.861 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832590202581811200 |
|---|---|
| author | Aslak Tveito Glenn T. Lines Pan Li Andrew McCulloch |
| author_facet | Aslak Tveito Glenn T. Lines Pan Li Andrew McCulloch |
| author_sort | Aslak Tveito |
| collection | DOAJ |
| description | Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Over the past decade, detailed Markov models of the action potential of cardiac cells have been developed. In such models, the effects of a drug can be treated as alterations in on- and off rates between open and inactivated states on one hand, and blocked states on the other hand. Our aim is to compute the rates specifying a drug in order to: (a) restore the steady-state open probability of the mutant channel to that of normal wild type channels; and (b) minimize the difference between whole cell currents in drugged mutant and wild type cells. The difference in the electrochemical state vector of the cell can be measured in a norm taking all components and their dynamical properties into account. Measured with this norm, the difference between the state of the mutant and wild-type cell was reduced by a factor of 36 after the drug was introduced and by factors of 4 over mexitiline and 25 over lidocaine. The results suggest the potential to synthesize more effective drugs based on mechanisms of action of existing compounds. |
| format | Article |
| id | doaj-art-9a97f68fc21947778fdfa6eb34c56966 |
| institution | Kabale University |
| issn | 1551-0018 |
| language | English |
| publishDate | 2011-05-01 |
| publisher | AIMS Press |
| record_format | Article |
| series | Mathematical Biosciences and Engineering |
| spelling | doaj-art-9a97f68fc21947778fdfa6eb34c569662025-01-24T02:01:59ZengAIMS PressMathematical Biosciences and Engineering1551-00182011-05-018386187310.3934/mbe.2011.8.861Defining candidate drug characteristics for Long-QT (LQT3) syndromeAslak Tveito0Glenn T. Lines1Pan Li2Andrew McCulloch3Center for Biomedical Computing, Simula Research Laboratory, P.O. Box 134, Lysaker 1325Center for Biomedical Computing, Simula Research Laboratory, P.O. Box 134, Lysaker 1325Center for Biomedical Computing, Simula Research Laboratory, P.O. Box 134, Lysaker 1325Center for Biomedical Computing, Simula Research Laboratory, P.O. Box 134, Lysaker 1325Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Over the past decade, detailed Markov models of the action potential of cardiac cells have been developed. In such models, the effects of a drug can be treated as alterations in on- and off rates between open and inactivated states on one hand, and blocked states on the other hand. Our aim is to compute the rates specifying a drug in order to: (a) restore the steady-state open probability of the mutant channel to that of normal wild type channels; and (b) minimize the difference between whole cell currents in drugged mutant and wild type cells. The difference in the electrochemical state vector of the cell can be measured in a norm taking all components and their dynamical properties into account. Measured with this norm, the difference between the state of the mutant and wild-type cell was reduced by a factor of 36 after the drug was introduced and by factors of 4 over mexitiline and 25 over lidocaine. The results suggest the potential to synthesize more effective drugs based on mechanisms of action of existing compounds.https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.861optimization.markov modelscardiac arrhythmiadrug design |
| spellingShingle | Aslak Tveito Glenn T. Lines Pan Li Andrew McCulloch Defining candidate drug characteristics for Long-QT (LQT3) syndrome Mathematical Biosciences and Engineering optimization. markov models cardiac arrhythmia drug design |
| title | Defining candidate drug characteristics for Long-QT (LQT3) syndrome |
| title_full | Defining candidate drug characteristics for Long-QT (LQT3) syndrome |
| title_fullStr | Defining candidate drug characteristics for Long-QT (LQT3) syndrome |
| title_full_unstemmed | Defining candidate drug characteristics for Long-QT (LQT3) syndrome |
| title_short | Defining candidate drug characteristics for Long-QT (LQT3) syndrome |
| title_sort | defining candidate drug characteristics for long qt lqt3 syndrome |
| topic | optimization. markov models cardiac arrhythmia drug design |
| url | https://www.aimspress.com/article/doi/10.3934/mbe.2011.8.861 |
| work_keys_str_mv | AT aslaktveito definingcandidatedrugcharacteristicsforlongqtlqt3syndrome AT glenntlines definingcandidatedrugcharacteristicsforlongqtlqt3syndrome AT panli definingcandidatedrugcharacteristicsforlongqtlqt3syndrome AT andrewmcculloch definingcandidatedrugcharacteristicsforlongqtlqt3syndrome |