OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine
Louise M Hesketh1, Markus B Sikkel2, Laura Mahoney-Sanchez1
1Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute, St Thomas' Hospital, King's College London, London, UK.
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.
Insights
A new drug, OCT2013, acts as an ischemia-activated prodrug of lidocaine, effectively suppressing ventricular fibrillation without adverse effects. This novel antiarrhythmic agent offers a safer alternative for treating sudden cardiac death due to myocardial ischemia.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Sudden cardiac death (SCD) from acute myocardial ischemia and ventricular fibrillation (VF) remains a significant therapeutic challenge.
- Lidocaine is effective against VF but has a narrow therapeutic index and adverse effects.
Purpose of the Study:
- To characterize OCT2013, a potential ischemia-activated prodrug of lidocaine.
- To compare the antiarrhythmic effectiveness, adverse effects, and mechanism of action of OCT2013 with lidocaine.
Main Methods:
- Studies utilized Langendorff-perfused isolated hearts, anesthetized rats, and rat ventricular myocytes.
- Experiments involved blinded, randomized comparisons of OCT2013 and lidocaine.
Main Results:
- OCT2013 and lidocaine showed equivalent efficacy in preventing ischemia-induced VF and increasing survival in rats.
- OCT2013 did not cause the adverse effects (PR widening, bradycardia, negative inotropy) associated with lidocaine.
- OCT2013 was inactive in normoxic conditions but converted to lidocaine in ischemic myocardium, demonstrating ischemia-selectivity.
Conclusions:
- OCT2013 functions as an ischemia-activated, ischemia-selective antiarrhythmic prodrug.
- It mimics lidocaine's benefits in treating VF without its associated toxicities, offering a wider therapeutic index.
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