Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins

Abstract

Objectives: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. Methods: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1β, IL-6, IL-10, TNF, and high-sensitive C-reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. Results: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. Conclusion: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI.

Pentraxin 3 in primary percutaneous coronary intervention for ST elevation myocardial infarction is associated with early irreversible myocardial damage

“…We have previously shown that there were no statistically significant treatment effects of TRO40303 on the levels of PTX3, IL-6 or hs-CRP during the first 72 hours after primary PCI 16 (online Appendix Table 2). Therefore, the kinetics of PTX3, IL-6 and hs-CRP were analysed in all 161 patients.…”

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

“…The MITOCARE study demonstrated no effect of TRO400303 in limiting myocardial injury following reperfusion between treatment and placebo [125] or effecting pro-inflammatory cytokines at 72 hours following PCI [126].…”

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…Most of these compounds must yet undergo proof-of-concept trials and have their safety and clinical effectiveness to be scrutinized. The once-promising compound TRO40303, however, has performed poorly in more than one translational study [321,322], with its clinical relevance regarding the reduction of IRI due to percutaneous coronary intervention for acute myocardial infarction. It is worth mentioning that hydroxytyrosol, a phenolic compound found in olive oil, provided significant protection to the myocardium against IRI, by inhibiting mPTP opening although it is still unclear whether or not this effect is CyD-dependent [323].…”