San-Martín-Martínez Daniel, Serrano-Lemus Dayanara, Cornejo Vicente, Gajardo Abraham I J, Rodrigo Ramón
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Avda. Independencia 1027, CP 8380453, Santiago, Región Metropolitana, Chile.
Clin Pharmacokinet. 2022 Sep;61(9):1203-1218. doi: 10.1007/s40262-022-01151-0. Epub 2022 Jul 25.
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.
急性心肌梗死治疗的主要目标是实现受影响心肌组织的再灌注，经皮冠状动脉腔内血管成形术是金标准治疗方法。然而，这种策略与一种名为“致死性再灌注损伤”的额外心脏损伤有关，这种损伤导致了最终梗死面积的一半。在可能解释这种损伤的潜在机制中，研究表明氧化应激起关键作用。尽管在大多数研究中这尚未转化为临床益处，但最近的临床前研究报告了有前景的结果以及维生素C（VC）、N - 乙酰半胱氨酸（NAC）和去铁胺（DFO）联合使用可能产生的协同作用。然而，要对患者实施这些药物的联合治疗需要进一步研究以了解它们的药代动力学特性。临床试验的现有数据在设计中未通过研究药代动力学来验证。因此，本文介绍并比较了每种药物在心脏保护中的给药方案的疗效证据、它们的药代动力学特性以及用于对抗“致死性再灌注损伤”的作用机制。为了在再灌注开始前使用新的药理学策略实现心脏保护作用，考虑每种药物的药代动力学是有帮助的。在这方面，为了设计一种快速且短效的药理学治疗策略，理论上VC和DFO的浓度可以用单室模型模拟，而NAC可以用具有初始短半衰期的三室模型模拟。
