Mechanism and Dosage of AICAR

5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is an intermediate in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. The drug has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle.

Mechanism of action

The nucleoside form of AICAR, acadesine, is an analog of adenosine that enters cardiac cells to inhibit adenosine kinase and adenosine deaminase. It enhances the rate of nucleotide re-synthesis increasing adenosine generation from adenosine monophosphate only during conditions of myocardial ischemia.In cardiac myocytes, acadesine is phosphorylated to AICAR to activate AMPK without changing the levels of the nucleotides.AICAR is able to enter the de novo synthesis pathway for adenosine synthesis to inhibit adenosine deaminase causing an increase in ATP levels and adenosine levels.

AICAR (Acadesine) is an intermediate in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. AICAR has been used clinically to treat and protect against cardiac ischemic injury. 

Uses and Dosage

AICAR (Acadesine) 42 mg/kg diluted in normal saline to a total of 500 mL, delivered as an IV infusion over approximately 7 hours commencing within approximately 30 minutes before induction of anesthesia at a rate of 0.1 mg/kg/min (translating into 1.2 mL/min for a 500 mL solution). In addition, a 5 µg/mL cardioplegia solution of acadesine will be administered, and acadesine will be added to the priming solution (5 µg/mL) in the heart lung machine during CPB.

The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery. The drug has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle. Acadesine is an adenosine receptor agonist (ARA) in development for the treatment of ischaemia-reperfusion injury and chronic lymphocytic leukaemia. Schering-Plough is developing the compound as a cardioprotective agent in ischaemia-reperfusion injury. Avancell and Protherics are co-developing acadesine for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). 

Clinical development is underway for both indications. AICAR, an AMPK activator, results in accumulation of ZMP, which mimics the stimulating effect of AMP on AMPK and AMPK kinase. Orphan drug status has been granted for acadesine in the EU for the treatment of B-cell chronic lymphocytic leukaemia.