OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

Article


Hesketh, L. M., Sikkel, M. B., Mahoney-Sanchez, L., Mazzacuva, F., Chowdury, R. A., Tzortzis, K. N., Firth, J., MacLeod, K. T., Ogrodzinski, S., Wilder, C. D. E., Pattersone, L. H., Peters, N. S. and Curtis, M. J. 2022. OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine. British Journal of Pharmacology. 179 (9), pp. 2037-2053. https://doi.org/10.1111/bph.15764
AuthorsHesketh, L. M., Sikkel, M. B., Mahoney-Sanchez, L., Mazzacuva, F., Chowdury, R. A., Tzortzis, K. N., Firth, J., MacLeod, K. T., Ogrodzinski, S., Wilder, C. D. E., Pattersone, L. H., Peters, N. S. and Curtis, M. J.
Abstract

Background and Purpose
Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine.

Experimental Approach
The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine.

Key Results
In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg⁻¹ i.v., whereas lidocaine reduced it even at 1 mg·kg⁻¹. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⁺ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable.

Conclusions and Implications
OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.

JournalBritish Journal of Pharmacology
Journal citation179 (9), pp. 2037-2053
ISSN1476-5381
Year2022
PublisherWiley for British Pharmological Society
Publisher's version
License
File Access Level
Anyone
Digital Object Identifier (DOI)https://doi.org/10.1111/bph.15764
Publication dates
Online02 Dec 2021
PrintMay 2022
Publication process dates
Deposited22 Feb 2024
FunderMedical Research Council (MRC)
The Academy of Medical Sciences
Copyright holder© 2021, The Authors
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https://repository.uel.ac.uk/item/8x55v

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