The development and characterisation of a novel class of antiarrhythmic prodrugs

Abstract

Sudden cardiac death, caused by the lethal arrhythmia ventricular fibrillation during acute myocardial ischaemia and infarction, is a leading cause of death worldwide. Currently available antiarrhythmic drugs have failed to provide comprehensive protection against sudden cardiac death because the benefit afforded by these drugs is offset by systemic adverse effects, resulting in an unacceptably narrow therapeutic index. Consequently, they are used only sparingly in those at highest risk of sudden cardiac death and are not considered safe and effective enough for use in larger lower-risk populations, and thus a novel antiarrhythmic drug with a large therapeutic index is required.
The purpose of this research was to examine lidocaine N-oxide, a novel putative ischaemia-activated antiarrhythmic prodrug. The project aimed to test the hypothesis that lidocaine N-oxide is pharmacologically inactive prior to its hypoxia-activated conversion to lidocaine during myocardial ischaemia, affording the drug antiarrhythmic effectiveness in the absence of adverse effects. In ex vivo and in vivo rat models of acute myocardial ischaemia, it was shown that lidocaine N-oxide exhibited antiarrhythmic effectiveness without adverse effects, generating a translational therapeutic index far greater than that of lidocaine. Using a range of different techniques in the rat isolated heart, lidocaine N-oxide was shown to exhibit a portfolio of effects on arrhythmias and conduction that was identical to that of lidocaine and attributable to INa block, differing only in terms of lidocaine N-oxide’s absolute dependency on the presence of ischaemia to exert an effect. In the rat isolated heart model, using a newly developed UHPLC-MS/MS analysis method, it was shown that lidocaine N-oxide was reduced to lidocaine selectively in the ischaemic myocardium.
The results generated in this thesis justify further preclinical and clinical development of lidocaine N-oxide as an ischaemia-activated antiarrhythmic prodrug for the prevention of sudden cardiac death.

Date of Award	1 Jul 2021
Original language	English
Awarding Institution	King's College London
Supervisor	Michael Curtis (Supervisor)