Targeting myocardial reperfusion injuries with cyclosporine in the CIRCUS Trial - pharmacological reasons for failure
| Autor: | Gaëlle Aubertin-Kirch, Laurent Monassier, Atul Pathak, Estelle Ayme-Dietrich |
|---|---|
| Přispěvatelé: | Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (LPTNC), Université de Strasbourg (UNISTRA) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Calcineurin Inhibitors Cmax Ischemia Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Mitochondrial Membrane Transport Proteins Mitochondria Heart 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Humans Pharmacology (medical) Myocardial infarction Pharmacology Mitochondrial Permeability Transition Pore business.industry Calcineurin Myocardium MPTP medicine.disease 3. Good health Blockade 030104 developmental biology Mitochondrial permeability transition pore chemistry Cyclosporine Cardiology business [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology TIMI |
| Zdroj: | Fundamental and Clinical Pharmacology Fundamental and Clinical Pharmacology, 2016, 30 (2), pp.191-193. ⟨10.1111/fcp.12177⟩ |
| ISSN: | 0767-3981 1472-8206 |
| DOI: | 10.1111/fcp.12177 |
| Popis: | The mitochondrial permeability transition (mPTP) is a key feature of cardiac cell death in ischemia-reperfusion injury (I/R). The mPTP blocker, cyclosporine A (CsA), has been shown to give protection against reperfusion-induced myocardial necrosis and troubles generated by acute coronary artery repermeabilization. Nevertheless, the results of the CIRCUS trial (Does Cyclosporine Improve Clinical Outcome in ST-Elevation Myocardial Infarction Patients) seem to go against this hypothesis. Pharmacological reasons linked to CsA pharmacokinetics and pharmacodynamics could be suggested. First, it could be explained by a limited diffusion of the drug in the area at risk, due to the only inclusion of patients with a TIMI 0 or 1 coronary blood flow in the anterior territory and the absence of collateral perfusion. Second, to explain a low tissue diffusion of the compound, blood cell capture and high metabolism could be suggested. Moreover, CsA is highly metabolized by cytochrome P450 3A4 (CYP3A4), a polymorphic enzyme leading to variations of Cmax and AUC between 10-20% in patients using CsA. Finally, CsA blocks calcineurin, a protein implied in I/R damage but calcineurin inhibition could contribute to protection towards I/R damage only when Rcan1, a calcineurin natural inhibitor, expression is low. The results of the CIRCUS trial are disappointing and could contribute to the withdrawal of the mPTP blockade pharmacological strategy as a way to protect the myocardium from I/R lesions. Nevertheless, many pharmacological insights could have contributed to an increased variability and, as a consequence, an important reduction of the pharmacological power of the study. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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