Brian G Drew1, Bronwyn A Kingwell. 1. Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia.
Abstract
BACKGROUND: Acadesine is an adenosine-regulating agent that increases bioavailability of adenosine and has important metabolic effects, partly through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase. OBJECTIVE: This review aimed to summarise and critique available data on the mechanism of action and clinical utility of acadesine, with a focus on treatment of ischaemic reperfusion injury, B-cell chronic lymphocytic leukaemia and diabetes mellitus. METHODS: The literature was acquired through numerous avenues including Medline, Pubmed, institutional libraries and relevant pharmaceutical companies using keyword search criteria for all trade and common names of acadesine and its derivatives. RESULTS: Acadesine has proven intravenous efficacy in the amelioration of ischaemic reperfusion injury associated with coronary artery bypass graft surgery in Phase III clinical trials. Acadesine is active only in metabolically stressed tissues in the presence of ATP catabolism and therefore has fewer unwanted peripheral side effects than systemic administration of adenosine. Metabolism of the drug is through the endogenous purine pathway and acadesine has been proven to be safe and well tolerated. More recently, acadesine has entered Phase I trials for B-cell chronic lymphocytic leukaemia to compete with purine antagonists that are used at present. AMPK-activating agents with high oral bioavailability have potential application in impaired glucose tolerance, insulin resistance and types 1 and 2 diabetes, however the poor oral bioavailability of acadesine precludes such application. CONCLUSIONS: This review highlights that, although limited to intravenous application, acadesine is a potentially viable therapy for ischaemic reperfusion injury following coronary artery bypass surgery. Further studies are required to determine the efficacy of acadesine for other ischaemic indications, including during percutaneous transluminal coronary angioplasty for acute myocardial infarction.
BACKGROUND:Acadesine is an adenosine-regulating agent that increases bioavailability of adenosine and has important metabolic effects, partly through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase. OBJECTIVE: This review aimed to summarise and critique available data on the mechanism of action and clinical utility of acadesine, with a focus on treatment of ischaemic reperfusion injury, B-cell chronic lymphocytic leukaemia and diabetes mellitus. METHODS: The literature was acquired through numerous avenues including Medline, Pubmed, institutional libraries and relevant pharmaceutical companies using keyword search criteria for all trade and common names of acadesine and its derivatives. RESULTS:Acadesine has proven intravenous efficacy in the amelioration of ischaemic reperfusion injury associated with coronary artery bypass graft surgery in Phase III clinical trials. Acadesine is active only in metabolically stressed tissues in the presence of ATP catabolism and therefore has fewer unwanted peripheral side effects than systemic administration of adenosine. Metabolism of the drug is through the endogenous purine pathway and acadesine has been proven to be safe and well tolerated. More recently, acadesine has entered Phase I trials for B-cell chronic lymphocytic leukaemia to compete with purine antagonists that are used at present. AMPK-activating agents with high oral bioavailability have potential application in impaired glucose tolerance, insulin resistance and types 1 and 2 diabetes, however the poor oral bioavailability of acadesine precludes such application. CONCLUSIONS: This review highlights that, although limited to intravenous application, acadesine is a potentially viable therapy for ischaemic reperfusion injury following coronary artery bypass surgery. Further studies are required to determine the efficacy of acadesine for other ischaemic indications, including during percutaneous transluminal coronary angioplasty for acute myocardial infarction.
Authors: Julian M W Quinn; Shanna Tam; Natalie A Sims; Hasnawati Saleh; Narelle E McGregor; Ingrid J Poulton; John W Scott; Matthew T Gillespie; Bruce E Kemp; B J W van Denderen Journal: FASEB J Date: 2009-09-01 Impact factor: 5.191
Authors: Susana Peralta; Sofia Garcia; Han Yang Yin; Tania Arguello; Francisca Diaz; Carlos T Moraes Journal: Hum Mol Genet Date: 2016-06-10 Impact factor: 6.150
Authors: Eric Van Den Neste; Bruno Cazin; Ann Janssens; Eva González-Barca; María José Terol; Vincent Levy; Jaime Pérez de Oteyza; Pierre Zachee; Andrew Saunders; Mercè de Frias; Clara Campàs Journal: Cancer Chemother Pharmacol Date: 2012-12-11 Impact factor: 3.333