Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

Abstract

SummaryAcadesine is a ribose-substituted imidazole with antithrombotic properties mediated by adenosine. In view of the beneficial effects of antiplatelet agents on thrombolysis and post-thrombolytic reocclusion, we studied the effects of acadesine on t-PA induced coronary reperfusion and continued patency in anesthetized dogs with electrically-induced coronary artery thrombosis. In 4 groups of dogs we examined the effects of saline and 3 doses of acadesine (0.5,1.0,2.0 mg/kg/min, i.v.) on time to reperfusion, and incidence and time to reocclusion following infusion of t-PA (10 μg/kg/min, i.v.). Acadesine had no effect on time to reperfusion, but significantly (p <0.05) reduced the incidence of reocclusion and prolonged the time to reocclusion at the highest dose tested. In saline treated animals vessels reoccluded in 6 of 7 animals (86%) at 33 ± 6 min after reperfusion. With the lowest dose of acadesine (0.5 mg/kg/min) vessels reoccluded in 3 of 3 animals (100%) at 18 ± 7 min. In animals treated with 1.0 mg/kg/min acadesine, the incidence of reocclusion was reduced, but not significantly (p<0.1) to 2 of 6 (33%), and time to reocclusion was prolonged to 59 ± 11 min (p<0.1). At the highest dose (2.0 mg/kg/min) of acadesine, only 2 of 8 (25%) animals reoccluded (p<0.05), and time to occlusion was prolonged to 80 ± 13 min (p<0.05). Acadesine had no effect on hemodynamics. These results suggest that acadesine might prove beneficial in clinical settings of platelet activation and prothrombotic conditions, such as occur during thrombolysis with t-PA.

5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…Once inside the cell, AICAR is phosphorylated by adenosine kinase to ZMP, which mimics AMP and activates AMPK without altering the cellular levels of ATP, ADP, or AMP (13). Activation of AMPK has been reported to be associated with a variety of beneficial effects on the cardiovascular system, including increasing the regional blood flow and local adenosine concentration (15), inhibiting neutrophil activation (16), suppressing platelet activation and intracoronary thrombosis (17), preventing oxidant-induced injury (18), and potentiating the protective mechanisms induced by myocardial preconditioning (19). Several clinical trials have been conducted to evaluate the beneficial effect of AICAR in preventing adverse effects of coronary artery bypass grafting surgery, and the results have been reported to be significant (20 -22).…”

Acadesine Inhibits Tissue Factor Induction and Thrombus Formation by Activating the Phosphoinositide 3-Kinase/Akt Signaling Pathway

“…1,2 The mechanisms underlying these beneficial effects remain ill-defined but may involve the inhibitory effects of acadesine on platelet aggregation 3,4 neutrophil activation, 5 and thrombus formation. 6 …”

2022 Update of the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) Domain 6: Defining rational use of thrombolytics

“…A large number of publications report the use of thrombolytics in experimental arterial thrombosis models in dogs (LOE 3), but lack suitable controls thereby precluding their use to address the PICO question 26–86 . In most of these studies, thrombolytics were administered within 60 minutes of thrombosis, 10,18,26–29,31,33,34,36,39–41,45–58,61,64–69,73–76,78–82,84,85,87–94 with fewer studies investigating thrombolytics administered 90 minutes, 43,44,86,95 2 hours, 30,38,62,72,77 3 hours, 63,70 or 6 hours 96 after thrombosis.…”

“…Nonetheless, there was little consistency in findings across the studies supporting the PICO question precluding any conclusions supporting one drug over another. The vast majority of the experimental literature of arterial thrombolysis in dogs involved the use of rt‐PA and lacked comparisons with other commercially available thrombolytics 9,13,19,24,25,28–31,33,36,38–48,51,52,54,55,57–59,61,63,64,67–71,73,76,78–80,82–90,92–95,100–102 …”