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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of the potentially fatal cardiac arrhythmia Torsades de Pointes, and branded versions for antipsychotic treatment were withdrawn from the market.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