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Pharmacological Basis for Abrogating Myocardial Reperfusion Injury Through a Multi-Target Combined Antioxidant Therapy

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Abstract

The main goal of the treatment for acute myocardial infarction is to achieve reperfusion of the affected myocardial tissue, with percutaneous coronary angioplasty being the gold standard procedure. However, this strategy has been associated with additional heart damage termed “lethal reperfusion injury,” which is responsible for up to half of the final infarct size. Among the possible underlying mechanisms that are likely to explain this damage, studies suggest that oxidative stress plays a key role. Although this has not been translated into clinical benefits in most studies, recent preclinical studies reported promising results and a possible synergy with the combined use of vitamin C (VC), N-acetylcysteine (NAC), and deferoxamine (DFO). However, to implement a combined therapy with these drugs for patients requires further studies to understand their pharmacokinetic properties. Available data of the clinical trials have not been validated by looking into the pharmacokinetics in their design. Therefore, this article presents an update and comparison of the evidence for the efficacy of these administration schemes for each drug in cardioprotection, their pharmacokinetic properties and mechanisms of action for their use against “lethal reperfusion injury.” To achieve a cardioprotective effect using a new pharmacological strategy before the onset of reperfusion, it is helpful to consider the pharmacokinetics of each drug. In this regard, to design a fast and short pharmacologic therapeutic strategy, theoretically VC and DFO concentrations could be modeled by a one-compartment model whereas NAC could be modeled by a three-compartment model with an initial short half-life.

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Acknowledgments

The authors would like to thank Dr. Mabel Catalán and Dr. Raúl Vivar for their ideas, help, and support in conceptual understanding of pharmacological aspects. We also want to thank Julio Arellano for revising the final version and giving feedback to the authors.

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Authors and Affiliations

  1. Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Avda. Independencia 1027, CP 8380453, Santiago, Región Metropolitana, Chile

    Daniel San-Martín-Martínez, Dayanara Serrano-Lemus, Vicente Cornejo, Abraham I. J. Gajardo & Ramón Rodrigo

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  1. Daniel San-Martín-Martínez
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  2. Dayanara Serrano-Lemus
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  3. Vicente Cornejo
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  4. Abraham I. J. Gajardo
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  5. Ramón Rodrigo
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Corresponding author

Correspondence to Ramón Rodrigo.

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Funding

This work was supported by the Agencia Nacional de Investigación y Desarrollo (ANID) for a project of the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, Grant No. 1211850).

Conflict of interest

Daniel San-Martín-Martínez, Dayanara Serrano-Lemus, Vicente Cornejo, Abraham IJ. Gajardo, and Ramón Rodrigo declare that they have no potential conflicts of interest that might be relevant to the contents of this article.

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Availability of data and material

Datasets and explanation of code generated to establish comparisons between trials and to design Figs. 1 and 2 are available in the FIGSHARE repository, https://doi.org/10.6084/m9.figshare.18551417.v3.

Code availability

Code generated to establish comparisons between trials and to design Figs. 1 and 2 are available in the FIGSHARE repository, https://doi.org/10.6084/m9.figshare.18551417.v3.

Authors contributions

R.R. and A.I.J.G contributed to conceptualization, supervision, validation and writing review and editing; D.S.-M.-M., D.S.-L., and V.C. contributed to investigation collecting evidence, data curation, writing the original draft, and visualization; D.S.-M.-M. contributed to software code development.

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San-Martín-Martínez, D., Serrano-Lemus, D., Cornejo, V. et al. Pharmacological Basis for Abrogating Myocardial Reperfusion Injury Through a Multi-Target Combined Antioxidant Therapy. Clin Pharmacokinet 61, 1203–1218 (2022). https://doi.org/10.1007/s40262-022-01151-0

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  • DOI: https://doi.org/10.1007/s40262-022-01151-0

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