AICAR dosage protocol

What the compound is

Acadesine (AICA-riboside) is a purine nucleoside analog, meaning it is a synthetic compound resembling natural building blocks of DNA and RNA. It is also known as AICAR (PMID 8227467, PMID 20367195). It is classified as an adenosine-regulating agent (PMID 8227467, PMID 18671468).

In humans, purine nucleotide biosynthesis de novo (PNB) requires two folate-dependent enzymes, one of which is 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylase. This enzyme introduces carbon 2 (C2) into the purine ring using 10-formyltetrahydrofolate (PMID 26374178). Acadesine is metabolized through the endogenous purine pathway (PMID 18671468).

How it is thought to work

Acadesine increases the bioavailability of adenosine and has significant metabolic effects, partly by activating AMP-activated protein kinase (AMPK) (PMID 20367195, PMID 18671468). AMPK is a key enzyme that regulates metabolism within cells.

Studies on human retinal pigment epithelial (RPE) cells showed that acadesine suppresses the induction of complement component 3 (C3) by TNF-α. This effect required acadesine to enter the cell, but did not appear to depend on its conversion to AMP or subsequent AMPK activation, suggesting an AMPK-independent pathway for this specific action (PMID 33362238, cells).

AICAR is identified as an activator of SIK1 (Salt-inducible kinase 1), an enzyme involved in immune regulation (PMID 40616103). In vitro experiments showed that AICAR suppressed inflammatory responses by modulating glucose and lipid metabolism in macrophages (PMID 40616103, cells).

Acadesine's activity is primarily observed in metabolically stressed tissues where ATP (adenosine triphosphate) is being broken down, which may contribute to fewer unwanted effects in other parts of the body compared to systemic adenosine administration (PMID 18671468).

What laboratory and animal studies report

In a pig model of hemorrhagic shock and abdominal sepsis, resuscitation with acadesine (5 mg/kg bolus + 1 mg/kg x 60 min intravenous infusion) increased cardiac index, systemic oxygen delivery, and systemic oxygen consumption compared to vehicle. It also reduced lipopolysaccharide-evoked tumor necrosis factor (TNF) production in whole blood ex vivo (PMID 10199538, animals).

Acadesine induced programmed cell death, or apoptosis, in various models of leukemia, including B-cell chronic lymphocytic leukemia (CLL) cells. This effect was observed in both resting and proliferative leukemia cells, including those with resistance to other treatments, and did not rely on a functional p53 pathway (PMID 20367195, cells).

In melanoma cells, AICAR (acadesine) acted as an inducer of CD137L, a protein that enhances anti-tumor immunity by promoting the survival of CD8+ T cells. AICAR showed synergistic effects with PD-1 or CTLA-4 blockade (PMID 41006211, cells and animals).

A novel nanoliposome composite hydrogel containing AICAR (Gel@Lipo@AICAR) demonstrated potential for mitigating osteoarthritis progression when administered intra-articularly in animals (PMID 40616103, animals).

Human evidence so far

Acadesine has been studied for preventing adverse cardiovascular outcomes during coronary artery bypass graft (CABG) surgery, reaching Phase 3 clinical trials (PMID 8227467, humans). It has shown intravenous efficacy in reducing ischemic reperfusion injury associated with CABG surgery (PMID 18671468, humans).

In healthy males (n=4) given a 15-minute intravenous infusion of 25 mg/kg 2-14C-acadesine, total 14C concentrations in plasma declined multiexponentially, with a terminal half-life of approximately one week. Intact acadesine was measurable for 2 hours post-infusion (PMID 8227467, humans).

Acadesine has been reported to be safe and well-tolerated in healthy subjects and during CABG surgery (PMID 20367195, humans). Plasma protein binding was negligible (approximately 1%) (PMID 8227467, humans). Uric acid was the primary metabolite of acadesine in plasma and urine, with small amounts of hypoxanthine also found in urine. Acadesine 5'-monophosphate was present in red blood cells but not in plasma (PMID 8227467, humans).

Open questions and limitations

While acadesine has shown promise in intravenous applications, its poor oral bioavailability limits its application in conditions like impaired glucose tolerance, insulin resistance, and types 1 and 2 diabetes (PMID 18671468).

Further studies are needed to determine acadesine's efficacy for other ischemic conditions, such as during percutaneous transluminal coronary angioplasty for acute myocardial infarction (PMID 18671468).

In the pig model of shock and sepsis, while acadesine showed some benefits, its acute positive effects were potentially overwhelmed by the polymicrobial sepsis, suggesting a need for further research on its role as an adjuvant to boost host defense in such complex conditions (PMID 10199538, animals).