{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:07:21Z","timestamp":1777903641108,"version":"3.51.4"},"reference-count":60,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004384","name":"Instytut Biologii Medycznej Polskiej Akademii Nauk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004384","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia\u2010induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia\u2010activated prodrug of lidocaine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The rat Langendorff\u2010perfused 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In isolated hearts, OCT2013 and lidocaine prevented ischaemia\u2010induced VF equi\u2010effectively, 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\u2010effectively; OCT2013 had no effect on cardiac output even at 64\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup> i.v., whereas lidocaine reduced it even at 1\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>. In adult rat ventricular myocytes, OCT2013 had no effect on Ca<jats:sup>2+<\/jats:sup> handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate\u2010dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi\u2010effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013\u2010perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>OCT2013 is inactive but is bio\u2010reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia\u2010activated and ischaemia\u2010selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15764","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T19:02:52Z","timestamp":1638471772000},"page":"2037-2053","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["OCT2013, an ischaemia\u2010activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine"],"prefix":"10.1111","volume":"179","author":[{"given":"Louise M.","family":"Hesketh","sequence":"first","affiliation":[{"name":"Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute, St Thomas' Hospital King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus B.","family":"Sikkel","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, ICTEM, The Hammersmith Hospital Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Mahoney\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute, St Thomas' Hospital King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Mazzacuva","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Facility King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rasheda A.","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, ICTEM, The Hammersmith Hospital Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos N.","family":"Tzortzis","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, ICTEM, The Hammersmith Hospital Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jahn","family":"Firth","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, ICTEM, The Hammersmith Hospital Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Winter","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute, St Thomas' Hospital King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth T.","family":"MacLeod","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, ICTEM, The Hammersmith Hospital Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Ogrodzinski","sequence":"additional","affiliation":[{"name":"BioTherics Ltd  Shepshed UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine D. 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