title: Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings.
abstract: Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials.
authors: The Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors: Gilad D
authors: GD
authors: Birnbaum
authors: The Section of Cardiology, Baylor College of Medicine, MS: BCM620, One Baylor Plaza, Houston, TX, 77030, USA.
authors: Itamar
authors: I
authors: Birnbaum
authors: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors: Yumei
authors: Y
authors: Ye
authors: The Section of Cardiology, Baylor College of Medicine, MS: BCM620, One Baylor Plaza, Houston, TX, 77030, USA. ybirnbau@bcm.edu.|The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. ybirnbau@bcm.edu.
authors: Yochai
authors: Y
authors: Birnbaum
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000592:standards*; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: Adenosine; Animal models; Clinical trials; Cyclooxygenase-2; Diabetic drugs; Drug interaction; Infarct size; Morphine; Statins