Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion
Thomas W. Johnson,
James Holt,
Anna Kleyman,
Shengyu Zhou,
Eva Sammut,
Vito Domenico Bruno,
Charlotte Gaupp,
Giacomo Stanzani,
John Martin,
Pietro Arina,
Julia Deutsch,
Raimondo Ascione,
Mervyn Singer,
Alex Dyson
Affiliations
Thomas W. Johnson
Translational Biomedical Research Centre (TBRC), Faculty of Health Science, University of Bristol, UK
James Holt
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
Anna Kleyman
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
Shengyu Zhou
Institute of Pharmaceutical Science, King's College London, London, UK; Centre for Pharmaceutical Medicine Research, King's College London, London, UK
Eva Sammut
Translational Biomedical Research Centre (TBRC), Faculty of Health Science, University of Bristol, UK
Vito Domenico Bruno
Translational Biomedical Research Centre (TBRC), Faculty of Health Science, University of Bristol, UK
Charlotte Gaupp
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
Giacomo Stanzani
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
John Martin
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
Pietro Arina
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
Julia Deutsch
Translational Biomedical Research Centre (TBRC), Faculty of Health Science, University of Bristol, UK
Raimondo Ascione
Translational Biomedical Research Centre (TBRC), Faculty of Health Science, University of Bristol, UK
Mervyn Singer
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK; Corresponding author. Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK.
Alex Dyson
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK; Institute of Pharmaceutical Science, King's College London, London, UK; Centre for Pharmaceutical Medicine Research, King's College London, London, UK; Corresponding author. Institute of Pharmaceutical Science, King's College London, London, UK.
Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.
