AICAR

Also known as: Acadesine, AICA riboside, AICAr, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, ARA 100, GP 1 110

Evidence: Preclinical

PeptideLab is an educational platform for learning about peptides. The information here is for educational and research purposes only. It is not medical advice, diagnosis, or treatment, and PeptideLab does not claim to diagnose, treat, cure, or prevent any disease or health condition. Many peptides discussed have not been approved for human use by the FDA or other regulatory bodies. Consult a qualified healthcare professional before making any health-related decision.

Overview

Nucleoside AMPK activator (AICA riboside) that mimics exercise signalling, increasing glucose uptake, fat oxidation and running endurance in mice.

AICAR (acadesine, AICA riboside) is a nucleoside that is phosphorylated inside cells to ZMP, an AMP mimetic that activates AMPK. In sedentary mice, 4 weeks of AICAR raised running endurance 44% and induced oxidative metabolic genes (Narkar 2008). Human work is all intravenous: in 10 men with type 2 diabetes an infusion lowered hepatic glucose output and suppressed whole-body lipolysis (Boon 2008); muscle 2-deoxyglucose uptake rose 1.6 to 2.9-fold, less in older men (Babraj 2009); under a hyperinsulinaemic clamp it raised heart rate and lowered blood pressure with no added glucose uptake (Bosselaar 2011). It was developed as a cardioprotective agent and failed a 3080-patient cardiac surgery RCT (Newman 2012), and reached phase 1/2 in leukaemia (Van Den Neste 2013). Not approved anywhere; prohibited in sport.

Benefits

Running endurance and fat oxidation (mouse), lower hepatic glucose output and suppressed lipolysis (human IV infusion), prohibited in sport

Dosing reference

Research dose: 150-500 mg daily (research-community range; no published human study used this dose or the subcutaneous route)
Range: 150000 to 500000 mcg, 1x daily
Reconstitution: 3 mL bacteriostatic water
Common vial sizes: 50 mg

Human studies used intravenous dosing only: 10-100 mg/kg single doses in healthy men (Dixon 1991), 0.75 mg/kg/min continuous infusion in type 2 diabetes (Boon 2008), 10-20 mg/kg/h for 3 h (Babraj 2009), 50-315 mg/kg (210 mg/kg was the maximum tolerated dose) over 4 h in leukaemia with 210 mg/kg as the maximum tolerated dose (Van Den Neste 2013) and 0.1 mg/kg/min for 7 h in cardiac surgery (Newman 2012). Oral solution is under 5% bioavailable (Dixon 1991). The mouse endurance work used 4 weeks of daily injection (Narkar 2008). AICAR is prohibited in sport and urinary concentrations above about 2000 ng/mL trigger isotope-ratio confirmation (Sobolevsky 2019).

Mechanism

AICAR is taken into cells by nucleoside transporters and phosphorylated by adenosine kinase to ZMP, which mimics AMP and activates AMP-activated protein kinase (Narkar 2008). In mice, 4 weeks of treatment induced an oxidative gene program through AMPK and PPAR-delta and raised running endurance without training (Narkar 2008). In humans, AICAR infusion reduced hepatic glucose output and plasma NEFA appearance and raised acetyl-CoA carboxylase phosphorylation in muscle, while muscle AMPK phosphorylation itself did not rise (Boon 2008); muscle glucose uptake rose with ERK1/2 rather than AMPK activation (Babraj 2009). It also causes systemic vasodilation, probably nitric-oxide dependent (Bosselaar 2011), and has documented AMPK-independent actions. Not a peptide; included for reference.

Evidence

Preclinical: animal or in vitro data only

Four weeks of AICAR in sedentary mice raised treadmill running endurance 44% and induced oxidative metabolic genes (Narkar et al., 2008)
IV infusion (0.75 mg/kg/min) in 10 men with type 2 diabetes reduced hepatic glucose output and suppressed whole-body lipolysis (Boon et al., 2008)
IV AICAR (10-20 mg/kg/h) raised muscle 2-deoxyglucose uptake 2.9-fold in young men and 1.6-1.8-fold in older men and men with type 2 diabetes, without detectable muscle AMPK activation (Babraj et al., 2009)
Under a hyperinsulinaemic clamp in 10 healthy adults, AICAR (67 mg/kg) raised heart rate and lowered blood pressure but did not increase glucose uptake (Bosselaar et al., 2011)
RED-CABG, 3080 patients undergoing on-pump bypass surgery: a 7-hour infusion did not reduce death, stroke or severe left ventricular dysfunction at 28 days (Newman et al., 2012)
Human-trial status: phase 1 PK in healthy men (Dixon 1991), a phase 1/2 leukaemia study with a 210 mg/kg maximum tolerated dose (Van Den Neste et al., 2013) and a negative phase 3 cardiac surgery RCT. No approval anywhere and no human trial of the endurance or body-composition uses

References

Side effects

Human IV studies report transient infusion-related hypotension with a rise in heart rate (Bosselaar 2011), grade 2 or higher hyperuricaemia, transient anaemia or thrombocytopenia and renal impairment at 50-210 mg/kg (Van Den Neste 2013), and mild transient effects at 10-100 mg/kg in healthy men (Dixon 1991). The 3080-patient cardiac surgery RCT found no excess of serious adverse events (Newman 2012). There is no oral or chronic human data, and the effects of sustained AMPK activation in humans are unknown. AICAR is prohibited in sport (Sobolevsky 2019).

Storage

Storage: Refrigerate 2-8°C (36-46°F); general lyophilised-powder guidance, no compound-specific CoA located
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: ~1.4 h terminal (human, IV; harmonic mean t1/2-beta across 10-100 mg/kg, n=16; Dixon 1991)
Bioavailability: Oral <5% in solution (human; Dixon 1991). Not protein bound, taken up rapidly by erythrocytes and phosphorylated to ZMP (human; Dixon 1991, Bosselaar 2011). No subcutaneous bioavailability data.
Molecular weight: 258.23 Da
Sequence: N/A - nucleoside analog (not a peptide)