Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion

Autor: 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
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Redox Biology, Vol 73, Iss , Pp 103167- (2024)
Druh dokumentu: article
ISSN: 2213-2317
DOI: 10.1016/j.redox.2024.103167
Popis: 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
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