Download Cardiac Action Potential Prolongation Induced by Isolated

Cardiac Action Potential Prolongation Induced by Isolated
Thioridazine Enantiomers
Cardiac Action Potential Prolongation Induced by Isolated
Thioridazine Enantiomers
by
Ask Schou Jensen
There is an urgent need for development of new treatments for infectious diseases caused
by drug-resistant strains of bacteria such as mycobacterium tuberculosis. Increasingly
resistant microbial strains are causing disease treatment to become far more difficult,
slow, and costly. The discovery of new classes of antimicrobial drugs has halted, and
there are few truly novel compounds in the pipeline. Recent discoveries have
demonstrated that the antipsychotic drug thioridazine reverses antimicrobial resistance,
and thioridazine was used successfully in combination with conventional antibiotics to
treat extensively drug-resistant tuberculosis in patients who did not respond to
conventional treatment. This indicates that thioridazine holds great potential for
antimicrobial treatment. However, thioridazine also causes risk of the potentially fatal
cardiac arrhythmia Torsades de Pointes, and branded versions for antipsychotic treatment
were withdrawn from the market. The primary indicator of arrhythmic risk is QT
prolongation in the ECG, and the QT prolonging effect of thioridazine now presents a
major obstacle to the introduction of thioridazine for antimicrobial treatment.
Ph.D. lecture
by
Ask Schou Jensen
Friday 24 October 2014
The purpose of the work presented in thesis was to investigate a possible solution to this
problem. Thioridazine is a chiral compound consisting of a racemic mixture of two
similar but chemically distinct molecules: (-)-thioridazine and (+)-thioridazine. Recent
findings show that (-)-thioridazine has a substantially reduced antipsychotic effect,
whereas the antimicrobial effects are similar. This raises the question of whether (-)thioridazine also has a reduced cardiotoxic effect. The primary determinant of QT
duration is the ventricular action potential duration (APD). In order to investigate
differences in cardiotoxic effects, an experimental setup was established to test the
effects of (-)-thioridazine, (+)-thioridazine, and racemate on the APD of the isolated
rabbit papillary muscle. The results of this study indicate that both (+)-thioridazine and
racemate cause significantly greater prolongation of the APD than does (-)-thioridazine.
Risk of Torsade de Pointes is strongly related to blockade of the cardiac IKr current in
many drugs. Further analysis of experimentally measured drug effects were carried out
using computational modeling of the rabbit ventricular action potential. The results of
this investigation indicate that differential inhibition of the IKr current may play a major
part in the difference in APD prolonging effect.
These results provide the first evidence that isolated (-)-thioridazine may have reduced
cardiotoxic side effects. Consequently, (-)-thioridazine may be a safer effective treatment
for multidrug-resistant microbial diseases including tuberculosis.
This thesis is based on
Ask Schou Jensen’s research work at:
Medical Informatics Group
Department of Health Science and Technology
Aalborg University, Denmark
To fulfill the requirements for the Ph.D. degree, Ask Schou Jensen has
submitted the thesis: Cardiac Action Potential Prolongation Induced by
Isolated Thioridazine
Enantiomers, to the Faculty Council of Medicine
at Aalborg University.
Program for Ph.D. Lecture on
Friday 24 October 2014
The Faculty Council has appointed the following adjudication committee
to evaluate the thesis and the associated lecture:
by
Dr. Jørgen Matz
Senior Director Global Safety & Pharmacovigilance
H. Lundbeck A/S
Denmark
Dr. Mary Margot C. Maleckar
Director Simula School of Research and Innovation
Oslo, Norway
Chairman:
Associate Professor Lasse Riis Østergaard
Medical Informatics Group, Aalborg University
Denmark
Moderator:
Associate Professor Claus Graff
Medical Informatics Group, Aalborg University
Denmark
Ask Schou Jensen
Cardiac Action Potential Prolongation Induced by Isolated
Thioridazine Enantiomers
Chairman:
Moderator:
Associate Professor Lasse Riis Østergaard
Associate Professor Claus Graff
13.00
Opening by the Moderator
13.05
PhD lecture by Ask Schou Jensen
13.50
Break
14.00
Questions and comments from the Committee
Questions and comments from the audience at the
Moderator’s discretion
16.00
Conclusion of the session by the Moderator
The Ph.D. lecture is public and will take place on:
Friday 24 October 2014 at 13:00
Aalborg University – Room E3-209
Fredrik Bajers Vej 7 E
9220 Aalborg East
After the session a reception will be arranged in room C1-215