An Initial Multicenter, Randomized Controlled Trial on the Safety and Efficacy of Acadesine in Patients Undergoing Coronary Artery Bypass Graft Surgery

Abstract

Acadesine (5-amino-4-imidazole carboxamide riboside) is a purine nucleoside analog that has been shown in animals to reduce myocardial ischemic injury by selectively increasing the availability of adenosine in ischemic tissues. Because patients undergoing coronary artery bypass graft (CABG) surgery are especially vulnerable to developing myocardial ischemia, we investigated whether perioperative use of this adenosine-regulating drug with potential anti-ischemic properties could modify the incidence and severity of perioperative myocardial ischemia. The goals of this study were to evaluate safety and the effects of acadesine on myocardial ischemia, left ventricular function, and, secondarily, on adverse clinical outcomes (myocardial infarction, heart failure, life-threatening dysrhythmias, and death) in patients undergoing CABG surgery. One hundred sixteen patients were randomized to receive one of three continuous intravenous dosing regimens (placebo [control] or one of two doses of acadesine [high- and low-dose infusion]) in double-blind fashion intraoperatively and in the early postoperative period (total infusion time was 7 h). Multidose cold crystalloid cardioplegia (each containing either acadesine or placebo) was used for myocardial protection. All were monitored for potentially drug-related adverse events and the presence of myocardial ischemia was assessed by continuous Holter electrocardiography (ECG) and transesophageal echocardiography (TEE). All patients received standardized anesthetic, surgical, and hemodynamic management during the intraoperative period. All research data (ECG, TEE, outcome data) were evaluated at the coordinating center (San Francisco) in blinded fashion to ensure that uniform data analysis criteria were employed. The administration of acadesine was safe: mild increases in plasma uric acid (a metabolite of acadesine) occurred only in patients receiving high doses (mean increase 1.6 +/- 0.2 mg/dL) and were without clinical sequelae. Before drug administration in the preoperative period (baseline), the incidence and severity of ECG ischemia did not differ among the three groups (placebo = 18%; low-dose = 14%; high-dose = 14%). During prebypass, the incidence of ECG ischemia was similar in all three groups (0%, 3%, 3%, respectively). The incidence of TEE ischemia was numerically lower in the two acadesine groups (high-dose = 6%, low-dose = 15%) than in the control group (19%), but this was not statistically significant (P = 0.22). During postbypass, the incidence of ECG ischemia was 11% in the high-dose group, 22% in the low-dose group, and 18% in the control group (P = 0.42), and TEE ischemia was similar in incidence in all groups (placebo = 29%; low dose = 27%; high-dose = 24%) (P = 0.86).(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolic Stress Boosts Humoral Responses In Vivo Independently of Inflammasome and Inflammatory Reaction

“…Finally, several clinical trials, designed to evaluate the antiinflammatory effect of AICAR in preventing the adverse effects of a coronary artery bypass graft, demonstrated that this drug was well tolerated in humans, with no apparent side effects (35,36). Therefore, although additional work is required to understand the molecular mechanism by which AICAR promotes the development of T cells endowed with B cell helper capacity, the present approach may pave the way to novel and safer adjuvants to promote humoral responses in vivo.…”

“…Recently, this compound has been shown to cause a significant decrease in intracellular ATP levels in several human and murine cell lines (32)(33)(34). Despite the lack of precise information concerning its mode of action, AICAR has been used extensively in animals and human clinical studies as a putative agent thought to protect the heart, lung, and small intestine against ischemic damage (35,36), and the safety, tolerance, and pharmacokinetics of this compound are well described (37). The ability of AICAR to increase T cell-dependent humoral responses in vivo therefore was evaluated.…”

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

“…Patients with AICAR orally or intravenously administrated during clinical trials revealed that the bioavailability of AICAR is <5% and its half-life is just ∼2 h [121]. More importantly, patients treated with AICAR have adverse side effects that they exhibit significant increases in the production of lactic and uric acid [121][122][123]. Although AICAR is an important research tool for investigating the effects of AMPK activation and mTOR inhibition on tumorigenesis, it is obviously not suitable for clinical use yet.…”

Reperfusion Injury after Intestinal Ischemia

“…Schoenberg et al [99] showed that acadesine 5-amino-4-imidazolecarboxamide riboside, a purine nucleoside analogue, in creases the availability of adenosine in the intestinal tis sue and inhibits the accumulation of leukocytes in the mucosal layer of the postischemic intestine. Since acade sine is a safe and well-tolerated compound in healthy young men and already used during cardiac bypass sur gery in order to protect the myocardium, 5-amino-4-imidazolecarboxamide riboside seems to be an interesting option for the treatment of postischemic tissue damage [100,101].…”