AMP 579, a Novel Adenosine Agonist for the Treatment of Acute Myocardial Infarction

ABSTRACT The discovery that the endogenous autocoid adenosine plays a role in the ability of the myocardium to protect itself against ischemia has prompted a significant effort to identify stable cardioprotective adenosine agonists. This review summarizes current data regarding AMP 579, a novel adenosine receptor agonist with high affinity for the A 1 ( K i = 2 nM) and A 2A ( K i = 56 nM) receptor subtypes. In models of acute myocardial infarction (MI) in rats, pigs, and dogs, AMP 579 is a highly effective cardioprotective agent, when given prior to ischemia reducing infarct size by 63, 98, and 53%, respectively, and significantly reducing the incidence of ventricular fibrillation. Moreover, in rodent and porcine models of acute MI AMP 579 is still able to reduce infarct size by greater than 50% when administered just prior to reperfusion. This cardioprotective profile suggests that intravenous AMP 579 should prove therapeutically valuable when given as an adjunct to revascularization in patients suffering MI or undergoing coronary artery bypass grafting. Importantly, preclinical toxicology studies reveal no cause for concern regarding the potential therapeutic applications of AMP 579, which will entail only an acute intravenous administration. In addition, initial clinical experience with AMP 579 has been positive with an acceptable tolerability and a favorable pharmacokinetic profile, indicating that plasma levels of the drug can be rapidly and predictably controlled. Finally, the positive data from the Acute Myocardial Study of Adenosine (AMISTAD) trial, a small phase II study, indicate adenosine is able to reduce infarct size when given as an adjunct to thrombolysis in patients with anterior MI, raising confidence that the cardioprotective effects of adenosine agonists (e.g., AMP 579) seen in preclinical studies should translate into the clinic. In this regard, AMP 579 is currently undergoing pivotal phase II studies in patients suffering acute MI. SUMMARY AND FUTURE PROSPECTS The discovery that the endogenous autocoid adenosine plays a role in the ability of the myocardium to protect itself against ischemia has prompted a significant effort to identify more stable adenosine agonists which may be used to protect the heart against those damaging effects of ischemia that occur during acute myocardial infarction and coronary artery bypass grafting. This effort is now bearing fruit, and in this review we have summarized the current available data regarding AMP 579, a novel adenosine A 1 /A 2A receptor agonist. In preclinical studies, AMP 579 is a highly effective cardioprotective agent in all species studied to date. Moreover, in models of acute myocardial infarction when AMP 579 is administered just prior to reperfusion following a damaging period of ischemia, this agonist is still able to produce significant myocardial salvage. This profile suggests that intravenous AMP 579 should prove therapeutically valuable when given as an adjunct to revascularization (percutaneous transluminal coronary angiography (PTCA) or thrombolysis) in patients suffering an acute myocardial infarction. It is predicted that the ability of AMP 579 to reduce initial infarct size will translate (in later months to years) into reduced mortality (i.e., cardiac dysfunction and heart failure). In addition, AMP 579 may well prove useful also as a myocardial protectant for cardiac surgery. Importantly, preclinical toxicology profiling reveals no cause for concern regarding the potential therapeutic applications of AMP 579 Which will entail only an acute intravenous administration. In addition, the initial clinical experience with this novel drug has been positive indicating acceptable tolerability and a favorable pharmacokinetic profile Which indicates that plasma levels of the drug can be rapidly and predictably controlled. Finally, the positive data from the AMISTAD trial (24) indicates that, in a small phase II study, adenosine was able to reduce infarct size when given as an adjunct to thrombolysis in patients with anterior acute myocardial infarction, raising confidence that the cardioprotective effects of adenosine agonists (such as AMP 579) seen in preclinical studies should translate into therapeutic reality in the clinic. In this regard, AMP 579 is currently undergoing pivotal phase II studies in patients suffering acute myocardial infarction and it is hoped that before long, this agent may be become a useful addition to the therapeutic tools available to cardiologists when dealing with this serious disease state.