AICAR
Also known as: Acadesine, AICA riboside, AICA-riboside, 5-aminoimidazole-4-carboxamide ribonucleoside, ZMP precursor
Not approved for any indication; acadesine was investigational; prohibited by WADA (metabolic modulators)
5 notable studies · 5 references
TLDR
AICAR (acadesine) is a nucleoside that cells turn into ZMP, an AMP mimic that activates the energy sensor AMPK; it boosted endurance in sedentary mice and acutely affected glucose and fat metabolism in short human IV studies, but a large heart-surgery trial was stopped for futility, it is not approved for any use, and WADA prohibits it in sport.
At a Glance
Classification: Synthetic adenosine analog (nucleoside, not a peptide); cell-permeable precursor of ZMP, an AMP mimetic; AMP-activated protein kinase (AMPK) activator
AICAR (acadesine) is a small nucleoside molecule, not a peptide. Inside cells it is converted to ZMP, which mimics AMP and activates AMPK, the cell's energy-sensing enzyme. It is best known from a 2008 mouse study in which four weeks of AICAR increased running endurance by 44% in sedentary mice, which led to it being called an "exercise mimetic". In humans it has been studied as an IV infusion for: • Muscle glucose uptake • Glucose and fat metabolism in type 2 diabetes • Heart protection during bypass surgery (acadesine) • Chronic lymphocytic leukemia. It is not an approved drug. A large heart-surgery trial was stopped for futility. AICAR is prohibited in sport by the World Anti-Doping Agency (WADA) as a metabolic modulator.
What Is AICAR?
AMPK is an enzyme that switches on when cellular energy is low, increasing glucose uptake and fat burning and switching off energy-costly processes. AICAR → enters cells → phosphorylated to ZMP → ZMP mimics AMP and activates AMPK. ZMP also acts on other AMP-sensitive enzymes, so not every AICAR effect is due to AMPK. Metformin and exercise also activate AMPK, but through different routes.
What Are Researchers Studying?
Endurance / exercise mimetic
In sedentary mice, four weeks of AICAR switched on metabolic genes and increased treadmill running endurance by 44%. This has not been shown in humans.
Muscle glucose uptake
In 29 healthy men, IV AICAR roughly doubled muscle 2-deoxyglucose uptake over three hours, compared with about a 4.7-fold increase from cycling. Whole-body glucose disposal rose only about 7%, and AMPK activation in muscle was not detected.
Type 2 diabetes metabolism
In 10 men with type 2 diabetes, IV AICAR lowered blood glucose, mainly by reducing liver glucose output, and reduced whole-body fat breakdown (lipolysis).
Cardiac surgery (acadesine)
The RED-CABG trial randomized 3,080 intermediate- to high-risk bypass-surgery patients to acadesine or placebo. It was stopped for futility: the primary outcome occurred in 5.1% versus 5.0%.
Blood cancers
A phase I/II study in 24 patients with relapsed or refractory CLL defined a maximum tolerated single IV dose and saw signs of activity, with hyperuricemia, transient blood-count drops, kidney impairment and infusion-related low blood pressure among adverse events.
How Does It Work?
AICAR (acadesine) ↓ cellular uptake via nucleoside transporters ↓ adenosine kinase converts it to ZMP ↓ ZMP mimics AMP → AMPK activation (plus AMPK-independent effects) ↓ increased glucose uptake and fatty-acid oxidation, reduced liver glucose output and lipolysis, shifts in muscle gene expression (in animals).
What Does the Research Show?
Human research
LIMITED and short-term. Human studies are acute IV infusion studies (metabolic physiology) and clinical trials of acadesine in heart surgery and CLL. No human study shows improved endurance, body composition or fat loss. The largest human trial (RED-CABG) was negative.
Animal research
MODERATE: rodent studies show endurance and metabolic effects, which are the source of exercise-mimetic claims.
In-vitro research
EXTENSIVE: AICAR is a standard laboratory tool for activating AMPK in cells, with known off-target effects.
Notable Studies
AMPK and PPARdelta agonists are exercise mimetics
animalJournal: Cell. In sedentary mice, four weeks of AICAR alone induced oxidative metabolic genes and increased running endurance by 44%. A PPARδ agonist combined with training also increased endurance.
Limitations: Mouse study; doses and exposure not directly translatable.
View publication →5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men
humanJournal: Diabetes. In 29 healthy men, IV AICAR increased muscle glucose (2DG) uptake about 2.1-fold after three hours versus about 4.7-fold with cycling exercise. Muscle AMPK activity and phosphorylation were unchanged, and whole-body glucose disposal rose only 7%.
Limitations: Acute IV infusion; small; healthy young men; mechanism in muscle unclear because AMPK activation was not detected.
View publication →Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients
humanJournal: Diabetologia. In 10 men with type 2 diabetes, continuous IV AICAR lowered plasma glucose mainly by reducing hepatic glucose output and reduced plasma fatty-acid appearance and levels. Muscle AMPK phosphorylation was not increased.
Limitations: Ten participants; single acute infusion; no long-term or clinical outcomes.
View publication →Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial
humanJournal: JAMA. Double-blind RCT in intermediate- to high-risk patients undergoing on-pump CABG. Stopped for futility after 3,080 of a planned 7,500 patients; the composite of death, stroke, or severe left-ventricular dysfunction occurred in 5.1% with acadesine versus 5.0% with placebo.
Limitations: Perioperative cardioprotection setting; says nothing about metabolic or performance uses.
View publication →Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study
humanJournal: Cancer Chemotherapy and Pharmacology. 24 patients with relapsed/refractory CLL received IV acadesine. 210 mg/kg was the maximum tolerated dose; hyperuricemia was common, and adverse events included transient anemia/thrombocytopenia, renal impairment and infusion-related hypotension. Some reductions in CLL cells and lymph nodes were seen.
Limitations: Small, open-label, uncontrolled early-phase study.
View publication →What We Still Don't Know
• Whether AICAR has any endurance, fat-loss or body-composition effect in humans • Effects of repeated or long-term dosing in people • How much of AICAR's action is AMPK-dependent versus off-target • Safety outside closely monitored IV clinical-trial settings (hyperuricemia, kidney and blood-pressure effects were seen in CLL) • Oral or subcutaneous exposure in people, which is poorly characterized
Related Compounds
Recent publications
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Sources & References
- Narkar VA et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008.
- Cuthbertson DJ et al. 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes. 2007.
- Boon H et al. Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia. 2008.
- Newman MF et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA. 2012.
- Van Den Neste E et al. Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. Cancer Chemotherapy and Pharmacology. 2013.
Supplier Listings
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