Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart
| Autor: | Catherine D. E. Wilder, Jade S. Munro, Michael J. Curtis, Nakita Ahdi, Georgia Lytra, Niraja N. Ranadive, Patrisia Qazimi, Louise M. Hesketh |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Drug medicine.medical_specialty media_common.quotation_subject Myocardial Ischemia Ischemia lcsh:Medicine Mexiletine 030204 cardiovascular system & hematology Article Electrocardiography 03 medical and health sciences Organ Culture Techniques 0302 clinical medicine Therapeutic index In vivo Internal medicine medicine Animals Rats Wistar Drug safety lcsh:Science Adverse effect media_common Pharmacology Multidisciplinary Dose-Response Relationship Drug business.industry lcsh:R Heart Gold standard (test) medicine.disease 030104 developmental biology Ventricular Fibrillation Ventricular fibrillation Cardiology lcsh:Q business Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-11 (2020) Scientific Reports Hesketh, L M, Wilder, C D E, Ranadive, N N, Lytra, G, Qazimi, P, Munro, J S, Ahdi, N & Curtis, M J 2020, ' Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart ', Scientific Reports, vol. 10, no. 1, 8397 . https://doi.org/10.1038/s41598-020-65190-y |
| ISSN: | 2045-2322 |
| Popis: | The ‘translational therapeutic index’ (TTI) is a drug’s ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. Our aim was to evaluate a novel integrated approach for generating a TTI for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine’s beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine’s TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the TTI further, it cannot increase it. Our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine’s TTI defining the gold standard that would need to be bettered. |
| Databáze: | OpenAIRE |
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