Imperial College London
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ProfessorNicholasPeters

Faculty of Medicine, National Heart & Lung Institute

Professor of Cardiac Electrophysiology
 
 
 
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Contact

 

+44 (0)20 7594 1880n.peters Website

 
 
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Assistant

 

Ms Anastasija Schmidt +44 (0)20 7594 1880

 
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Location

 

NHLI officesSir Michael Uren HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hesketh:2022:10.1111/bph.15764,
author = {Hesketh, LM and Sikkel, MB and Mahoney-Sanchez, L and Mazzacuva, F and Chowdhury, RA and Tzortzis, KN and Firth, J and Winter, J and MacLeod, KT and Ogrodzinski, S and Wilder, CDE and Patterson, LH and Peters, NS and Curtis, MJ},
doi = {10.1111/bph.15764},
journal = {British Journal of Pharmacology},
pages = {2037--2053},
title = {OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine},
url = {http://dx.doi.org/10.1111/bph.15764},
volume = {179},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 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 anesthetised 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 mass spectrometry 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 bioreduced 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.
AU  - Hesketh,LM
AU  - Sikkel,MB
AU  - Mahoney-Sanchez,L
AU  - Mazzacuva,F
AU  - Chowdhury,RA
AU  - Tzortzis,KN
AU  - Firth,J
AU  - Winter,J
AU  - MacLeod,KT
AU  - Ogrodzinski,S
AU  - Wilder,CDE
AU  - Patterson,LH
AU  - Peters,NS
AU  - Curtis,MJ
DO  - 10.1111/bph.15764
EP  - 2053
PY  - 2022///
SN  - 0007-1188
SP  - 2037
TI  - OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine
T2  - British Journal of Pharmacology
UR  - http://dx.doi.org/10.1111/bph.15764
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34855992
UR  - https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15764
UR  - http://hdl.handle.net/10044/1/93424
VL  - 179
ER  -
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