5-Aminoimidazol-4-Carboxamida Ribonucleótido

Otros Nombres

5'-Phosphoribosyl-5-amino-4-imidazolecarboxamide5'-Phosphoribosyl-5-aminoimidazole-4-carboxamide5-Amino-1-beta-D-ribofuranosylimidazole-4-carboxamide 5'-monophosphate5-Amino-4-imidazolecarboxamide (AICA) ribonucleotide5-Amino-4-imidazolecarboxamide ribonucleotide5-Aminoimidazole-4-carboxamide ribonucleosideAICA ribonucleotideAICA ribotideAICA-Riboside-5'-phosphateAICARAICAR monophosphateAminoimidazole carboxamide ribonucleotideN1-(beta-D-5'-Phosphoribofuranosyl)-5-aminoimidazole-4-carboxamideNSC 283955NSC 292227Z-nucleotideZMP

Sinopsis

5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR / Acadesine): A Comprehensive Reference

1. Identity, Nomenclature, and Chemical Character

Names and Identifiers

AICAR, also known as 5-aminoimidazole-4-carboxamide ribonucleotide, AICA-ribonucleotide, ZMP, and acadesine, is an intermediate metabolite in the de novo synthesis pathway of inosine monophosphate. The compound exists under a cluster of related names that reflect its distinct chemical forms: the dephosphorylated nucleoside (the freely cell-permeable form used in research) is formally called 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, often abbreviated AICAr or AICA riboside, and given the pharmaceutical name acadesine. AICAR typically refers to AICA riboside, whereas ZMP refers to AICA ribotide. Acadesine, which is also referred to as 5-amino-1-D-ribofuranosyl-1H-imidazole-4-carboxamide, 5-aminoimidazole-4-carboxamide riboside, AICA riboside and AICAR, is a natural substance with CAS RN 2627-69-2; acadesine 5′-monophosphate, which is also called AICAR ribotide or ZMP, has CAS RN 3031-94-5 and it is a naturally occurring active metabolite of acadesine.

Structural Classification

5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is an intermediate in the generation of inosine monophosphate and an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. AICAR is the abbreviated name for 5-aminoimidazole-4-carboxamide ribonucleoside, also known by its pharmaceutical name acadesine and the experimental code AICA-riboside. It is a nucleoside analog — a synthetic compound structurally related to adenosine — not a peptide.

Endogenous Occurrence and Natural Sources

AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate) is a natural metabolic intermediate of purine biosynthesis that is present in all organisms. Endogenous AICAR is an intracellular intermediate in the de novo purine biosynthesis pathway that is known to accumulate in Lesch–Nyhan syndrome and other purine synthesis disorders. The compound is therefore not a botanical extract or plant-derived ingredient; it is a ubiquitous cellular metabolite. In urine of healthy humans, considerable amounts (up to 7,500 ng/mL) were present due to the natural occurrence of AICAR as a by-product of purine biosynthesis. In micro-organisms, AICAR is also synthesized as a by-product of the histidine biosynthesis pathway.

Common Forms and Preparations

AICAR is not commercially available as a licensed drug or regulated dietary supplement in any major jurisdiction. It is produced and distributed as a research-grade chemical compound. Phase III trials have been carried out with acadesine, indicating that it is safe when administered orally and intravenously. In experimental and clinical-trial contexts, the compound has been formulated for intravenous infusion; the oral form has also been investigated but oral bioavailability considerations are an active area of pharmaceutical development. Acadesine, once inside a cell and phosphorylated to ZMP, is ion-trapped inside the cell. ZMP will thus accumulate inside red blood cells and endothelial cells until it causes toxicity, rather than reaching other cell types where it may be needed. Therefore, IV administration of large doses of the nucleoside acadesine will produce very small systemic exposure of the active species ZMP, along with toxic effects in RBCs and endothelial cells. Research-grade AICAR is generally available as a lyophilized powder, and subcutaneous injection protocols have been employed in some animal studies.

2. Traditional and Historical Use

AICAR has no recorded history of traditional or ethnobotanical use in any culture or time period. As an endogenous metabolic intermediate discovered and characterized through twentieth-century biochemistry, it has no pre-modern therapeutic tradition. Its entry into applied medicine is entirely a product of laboratory science.

It was first used in 1992 as a method of protection against cardiac ischemic injury during surgery. Later, AICAR was developed by PeriCor Therapeutics as an adenosine-regulating agent and licensed to Schering-Plough in 2007. AICAR was originally developed in the 1990s by Acadesine Inc. (later Schering-Plough) as a candidate cardioprotective agent for coronary artery bypass surgery — the compound completed Phase III trials but did not gain regulatory approval.

The first study of the safety and tolerance of AICAr was done in 1991, much before the recognition of AICAr as an AMPK agonist, to establish pharmacokinetics of a drug that raised interest as a novel adenosine-regulating agent. Adenosine is a potent vasodilator that plays a key role in reducing ischemia/reperfusion injury, but the applications for systemic adenosine are limited owing to peripheral hemodynamic actions. The rationale was that acadesine, by increasing extracellular adenosine concentrations at sites of ischemic injury, could selectively protect cardiac tissue during the hemodynamic stress of open-heart surgery.

The recognition of AICAR's ability to activate AMPK — and thus to mimic metabolic features of exercise — emerged only after 1995, when laboratory tools for studying the AMPK cascade were being developed. Its identity as an "exercise mimetic" is thus a scientific-era phenomenon with no traditional antecedent.

3. Key Constituents and Active Compounds

The AICAr/ZMP Relationship

The pharmacological activity of exogenously administered AICAR depends on a critical intracellular transformation. AICAr enters the cell through adenosine transporters and becomes phosphorylated by adenosine kinase into 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR; also termed ZMP), which acts as an AMP mimetic. This phosphorylation step is essential: most of the described AICAR effects require its metabolic conversion to the monophosphate form ZMP by adenosine kinase. As an intermediate of the purine de novo pathway, ZMP is naturally present in cells at low concentration.

AMPK — The Primary Molecular Target

Incubation of rat hepatocytes with AICAR results in accumulation of ZMP within the cell. ZMP mimics both activating effects of AMP on AMPK: direct allosteric activation and promotion of phosphorylation by AMPK kinase. ZMP is an AMP mimetic that binds to the gamma subunit of AMPK, promoting allosteric activation and protecting the activating phosphorylation on Thr172 of the alpha subunit from dephosphorylation by protein phosphatases. A key practical distinction: unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP.

Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known AMPK target (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two known target pathways: fatty acid and sterol synthesis. Activated AMPK facilitates catabolic pathways, like glycolysis and fatty acid oxidation, and decreases anabolic pathways, like protein and fatty acid syntheses, which makes AMPK an attractive target to modulate metabolism.

AMPK-Independent Mechanisms

A growing body of research has established that not all AICAR effects operate via AMPK. There is an increasing number of studies showing that numerous AICAr effects, previously attributed to AMPK activation, are in fact AMPK-independent. For example, the anti-leukemic effect of acadesine in CML cells did not involve apoptosis but required rather induction of autophagic cell death, and AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. AICAr-mediated differentiation in myeloid leukemia cells was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage–associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion.

Additionally, AICAR treatment can lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent manner. Thus, ATM may function as a potential AMPK kinase in response to AICAR treatment.

NF-κB Inhibition and Adenosine Signaling

AICAR, an intermediate in nucleoside metabolism, inhibits signalling by NF-κB in multiple cell types, including bovine aortic endothelial cells. Transfection of active AMPK into endothelial cells reduced NF-κB reporter activity, suggesting that part of the ability of AICAR to inhibit NF-κB signalling is due to activation of AMPK. Inhibition of NF-κB signalling may be important in the anti-inflammatory action of drugs such as sulfasalazine and methotrexate, which led to the accumulation of AICAR within target cells.

AICAR also modulates purine metabolism in a manner that amplifies adenosine tone: AICAr shares structural similarities with adenosine, and therefore can increase the extracellular concentrations of adenosine by competing for the nucleoside transporter. In addition, AICAR increases intracellular concentrations by inhibiting adenosine deaminase and increasing the production of adenosine rather than inosine from ATP catabolism.

Purine Biosynthesis Role and One-Carbon Metabolism

AICAR is an intermediate metabolite in the purine de novo synthesis pathway; it is synthesized from succinyl-AICAR (SAICAR) by adenylosuccinate lyase (ASL), an enzyme inhibited by AICAR through a feedback regulation. In the de novo purine synthesis pathway, AICAR is further metabolized to IMP by successive action of AICAR-Transformylase and IMP Cyclohydrolase, two enzymatic activities which are generally carried on a single protein named ATIC. This dual-enzyme activity (ATIC) makes AICAR central to one-carbon (folate) metabolism as well as nucleotide biosynthesis.

4. Scientific Evidence by Area of Use

4.1 Cardioprotection

Clinical evidence — the most extensive human dataset available for AICAR.

The original clinical rationale was adenosine regulation during myocardial ischemia. A 1992 study by Bolling and colleagues in the Annals of Thoracic Surgery provided the preclinical cardioprotection rationale, showing that acadesine improves postischemic cardiac recovery. Acadesine (the clinical-trial name for AICAR) completed two large Phase III trials for cardioprotection in coronary artery bypass surgery (CABG) in the 1990s. The trials did not demonstrate statistically significant reductions in the primary composite endpoint (myocardial infarction, stroke, cardiovascular death), and the development programme was discontinued.

A meta-analysis of five large international randomized, double-blind, placebo-controlled trials examined acadesine in CABG patients. Clinical studies in patients undergoing coronary artery bypass graft surgery demonstrate that treatment with acadesine before and during surgery can reduce early cardiac death and myocardial infarction (Mangano, Journal of the American Medical Association 1997, vol. 277, pp. 325–332). Despite promising signals in this analysis, the pivotal Phase III programmes did not meet regulatory standards for approval, and development was halted.

Evidence strength: Moderate. Multiple large randomized controlled trials were conducted but yielded a mixed efficacy signal; no approved indication was achieved. The compound demonstrated an acceptable safety profile in more than 4,000 cardiac patients at doses used in perioperative settings.

4.2 Metabolic Disease and Glucose Homeostasis

Preclinical evidence — substantial; human evidence — limited and mechanistically complex.

AICAR has been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle. At the mechanistic level, AMPK activation by AICAR drives GLUT4 translocation to the plasma membrane independently of insulin signalling, and phosphorylates and inactivates acetyl-CoA carboxylase, thereby promoting fatty acid oxidation and suppressing lipogenesis.

One human study examined AICAR's effect on skeletal muscle glucose uptake across three groups. In healthy young men, AICAR stimulates human muscle 2-deoxyglucose uptake without detectable activation of muscle AMPK but with ERK1/2 activation. This was also tested in healthy older subjects and subjects with type 2 diabetes. Six healthy young subjects (23 ± 3 yr), eight older subjects (59 ± 4 yr), and eight subjects with type 2 diabetes (62 ± 4 yr) received a 6-hour 2DG infusion and AICAR (10 or 20 mg·kg⁻¹·h⁻¹) from 3 to 6 hours. This study revealed that AICAR-stimulated glucose uptake was blunted with aging regardless of diabetic status, complicating the simple narrative of AMPK-driven insulin sensitization in humans.

Evidence strength: Weak for human clinical benefit. Effects in animal models are robust and well-replicated, but human studies are few, small, and reveal unexpected complexity (age-dependent blunting, AMPK-independent signalling).

4.3 Exercise Mimicry and Skeletal Muscle Adaptation

Preclinical evidence — landmark study; human evidence — none published as of 2026.

The characterization of AICAR as an "exercise mimetic" derives primarily from a landmark 2008 study published in Cell from the Salk Institute. Because training activates AMPK and PGC-1α, researchers tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that the AMPK–PPARδ pathway can be targeted by drugs to enhance training adaptation or endurance.

Treatment with AICAR for 14 days significantly decreased the proportion of glycolytic fast-twitch (type IIB) myofibers and simultaneously caused larger increases in the more oxidative, slower-twitch fiber types. These fiber-type shifts are hallmarks of classical endurance training adaptation.

The molecular basis of these endurance effects involves multiple pathways: both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a modulator of mitochondrial biogenesis. All three energy-sensing network components — pAMPK, PGC-1α, and GLUT4 — were upregulated in muscle to a similar extent by AICAR and exercise after 14 days of treatment.

As of April 2026, no human trial data for AICAR in endurance, exercise performance, or metabolic optimization has been published. The entire body of exercise-mimicry evidence is derived from rodent studies.

Evidence strength: Preclinical only. The 2008 Cell paper is widely cited as proof-of-concept but does not constitute human evidence. Translation to humans remains entirely undemonstrated.

4.4 Oncology and Hematological Malignancies

In vitro and animal evidence — extensive; human evidence — one Phase I/II trial completed.

Acadesine can inhibit proliferation and induce apoptosis in multiple myeloma, neuroblastoma, glioblastoma, childhood acute lymphoblastic leukemia (ALL), colon cancer, and breast and prostate cancer cell lines. In particular, acadesine exerts a pro-apoptotic activity in a wide range of B lymphoid malignancies, with cells from chronic lymphocytic leukemia (CLL) being the most sensitive to this agent.

In 2003, Campas et al. reported that AICAr activates AMPK and induces apoptosis in primary samples of B-cell chronic lymphocytic leukemia (CLL) in vitro.

The single completed human oncology trial was a multicenter Phase I/II study in relapsed or refractory CLL. A Phase I/II multicenter open-label trial by Van Den Neste, Cazin, Janssens, and colleagues published in Cancer Chemotherapy and Pharmacology in 2013 evaluated acadesine in 24 patients with relapsed or refractory B-cell CLL (18 in Part I dose-escalation at 50–315 mg/kg; 6 in Part II at 210 mg/kg), establishing a maximum tolerated dose of 210 mg/kg with a manageable safety profile — although grade ≥2 hyperuricemia was common and required prophylactic allopurinol. Observed trends included reductions in peripheral CLL cell counts and lymphadenopathy in some participants, but the small cohort limits any efficacy conclusions. The program was subsequently abandoned.

Preclinical work also showed potential in mantle cell lymphoma (MCL): acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab.

The complexity of AICAR's oncological profile is underscored by a nuanced mechanistic point: although it would be expected that AMPK, acting as a downstream target of LKB1, has tumor suppressor activity, the results from many studies point that the role of AMPK in cancer is much more complex; AMPK may suppress tumor growth before tumorigenesis, but once cancer has arisen, AMPK may instead support the survival of cancer cells.

Evidence strength: Preclinical evidence is strong and mechanistically well-characterized. Human clinical evidence is limited to one small Phase I/II dose-escalation trial; the programme was not advanced. No oncological indication has been approved.

4.5 Inflammation

Preclinical evidence — compelling; human evidence — indirect (via methotrexate pharmacology).

Activation of NF-κB is one of the most important pro-inflammatory mechanisms in disease. AICAR inhibits signalling by NF-κB in multiple cell types, including bovine aortic endothelial cells. This NF-κB inhibition is at least partly attributable to AMPK activation by ZMP.

Importantly, AICAR accumulation appears to mediate part of the anti-inflammatory action of established drugs: methotrexate polyglutamates, as potent inhibitors of the enzyme AICAR transformylase, promote the accumulation of AICAR in tissues. The continuous action of MTX polyglutamates results in intracellular accumulation of AICAR by AICART inhibition. AICAR has an ability to diminish activity of adenosine deaminase (ADA) and adenosine monophosphate (AMP) deaminase as well. An MTX-mediated excess of AICAR promotes the AMP and adenosine increase and subsequent release of these adenine derivatives outside the cell. This cascade is now considered a key mechanistic contribution to methotrexate's anti-inflammatory effect in rheumatoid arthritis.

Evidence strength: Mechanistic (cell/animal) evidence is strong; direct human anti-inflammatory trials of exogenous AICAR have not been conducted.

4.6 Neuroprotection and Cognitive Function

Preclinical evidence only — animal studies in rodents.

In young sedentary animals, pharmacological activation of AMPK enhanced spatial memory function and endurance. A study investigated effects of AMPK agonist AICAR on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young transgenic mice with muscle-specific mutated AMPK α2-subunit. Mice were injected with AICAR (500 mg/kg) for 3–14 days, followed by testing in the Morris water maze, rotarod, and open field.

In the brain, AMPK protein levels were upregulated in the dentate gyrus by exercise and AICAR to a similar extent as in muscle at the longer time-point (14 days). Thirty days of running elevates hippocampal PGC-1α levels, and eight weeks of treadmill training elevates PGC-1α and Sirtuin 1, increasing brain mitochondrial biogenesis. The beneficial effects of AICAR and exercise on the brain (increased dentate gyrus cell genesis and BDNF levels at 7 days) precede brain energy metabolism protein level changes (at 14 days), indicating these may be unnecessary for enhancement of neural plasticity.

Both exercise training and AICAR increased the protein level of PGC-1α, a modulator of mitochondrial biogenesis. Compound C (an AMPK inhibitor) abolished the exercise-induced effects on memory, AMPK phosphorylation, autophagy, mitophagy, and mitochondrial fission in the aged hippocampus.

Research into AICAR for diabetic neuropathy is also emerging: exercise mimetics could play a crucial role as therapy in diabetic polyneuropathy (DPN), but this would require further clinical trials in humans. AICAR directs AMPK activation and transport via ENT1, making it an intriguing candidate for further investigation to develop isoform-specific AMPK activators in the nervous system.

Evidence strength: Preliminary preclinical only. All neuroprotection and cognitive data in the published literature are from animal models; no human clinical trials have been conducted or published.

4.7 Retinal and Ocular Research

5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP, is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. A published PMC study reported that AICAR inhibits the growth of retinoblastoma in vivo by decreasing angiogenesis and inducing apoptosis in xenograft models. This work is in the preclinical (animal/cell) domain and has not been advanced to clinical study.

Evidence strength: Preclinical only.

4.8 Liver Protection

AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyroptosis, protecting rats from sodium taurocholate-induced pancreatitis-associated liver injury (PALI). AICAR inhibits hepatic oxidative stress and inflammation by promoting AMPK phosphorylation partially via Nrf2-mediated antioxidant effects and inhibition of NLRP3 inflammasome activation.

Evidence strength: Animal model data only.

5. Body Systems and Health Areas Associated with AICAR

Cardiovascular system: Cardioprotection during ischemia-reperfusion, reduction of perioperative myocardial infarction (clinical trials conducted, Phase III not meeting primary endpoint).
Skeletal muscle and metabolism: AMPK-driven glucose uptake, fatty acid oxidation, mitochondrial biogenesis, fiber-type reprogramming (primarily animal evidence).
Endocrine/metabolic: Insulin sensitivity, glucose homeostasis, type 2 diabetes research target (animal evidence; limited human data).
Oncology/hematology: Pro-apoptotic effects in B-cell malignancies, CLL, MCL, ALL; anti-proliferative effects in solid tumors (cell/animal evidence, one Phase I/II CLL trial).
Nervous system: Potential neuroprotection via AMPK and PGC-1α; hippocampal neurogenesis, BDNF, cognitive function (animal evidence only).
Immune and inflammatory systems: NF-κB inhibition, adenosine-mediated immunomodulation, indirect role in methotrexate anti-inflammatory pharmacology.
Hepatic system: Nrf2-mediated antioxidant protection, NLRP3 inflammasome inhibition (animal evidence).
Purine and folate metabolism: Central hub in de novo purine synthesis; modulation by antifolate drugs (methotrexate, pemetrexed).

6. Dosage Forms and Dosages Reported in Studies

No regulatory-approved human dosage exists. The following represent doses as specifically stated in the cited literature:

Perioperative cardioprotection (human, IV): In the cardiac surgery trials, acadesine (AICAR) was administered intravenously at 0.1 mg/kg/min for 7 hours, totaling approximately 42 mg/kg.
CLL Phase I/II oncology trial (human, IV): Dose-escalation from 50 to 315 mg/kg in Part I; 6 patients received 210 mg/kg in Part II, establishing a maximum tolerated dose of 210 mg/kg.
Human tolerability data: In humans, doses up to 210 mg/kg IV are well tolerated. At doses up to 100 mg/kg, only mild and transient side effects are reported equally in placebo and drug groups.
Rodent exercise-mimicry studies: Treating mice with AICAR alone for over 4 weeks (in the landmark Narkar et al. study) upregulated gene expression of several proteins involved in oxidative metabolism while also increasing running endurance by 44%.
Rodent cognitive studies: Mice were injected with AICAR at 500 mg/kg for 3–14 days in the cognitive function study.
Skeletal muscle aging study (subcutaneous injection in rat): Muscles were harvested 1 hour after AICAR injection at 1 mg/g body weight subcutaneously.

Important caveat: Animal doses are provided solely as documentation of published research protocols. They do not represent guidance for human use and cannot be extrapolated across species without formal pharmacokinetic analysis.

7. Safety Considerations and Drug Interactions

Overall Human Tolerability

AICAR was well tolerated in more than 4,000 cardiac patients across the perioperative trials. This forms the largest safety dataset for the compound in humans.

Dose-Dependent Adverse Effects

At doses greater than 200 mg/kg, adverse effects included hyperuricemia that occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant).

Higher dose studies examining AICAR for hematologic malignancies used repeated infusions up to 210 mg/kg per infusion, with up to 6 infusions within 12 days. At these elevated doses, an increased risk of kidney toxicity emerged, leading to discontinuation of therapy in some subjects. This nephrotoxicity at high doses represents the clearest documented safety signal from human administration.

Hyperuricemia

Uric acid, which rises as a byproduct of purine metabolism, may be influenced by AICAR's nucleoside pharmacology and is an independent cardiovascular and metabolic risk marker. As noted above, grade ≥2 hyperuricemia was common in the oncology trial at doses of 210 mg/kg and required routine prophylaxis with allopurinol.

Cell-Trapping and Erythrocyte Toxicity

Acadesine, once inside a cell and phosphorylated to ZMP, is ion-trapped inside the cell. ZMP will thus accumulate inside red blood cells and endothelial cells until it causes toxicity, rather than reaching other cell types where it may be needed. Therefore, IV administration of large doses of the nucleoside acadesine will produce very small systemic exposure of the active species ZMP, along with toxic effects in RBCs and endothelial cells.

Risks of Supraphysiological AMPK Activation

The United States Anti-Doping Agency (USADA) cautioned that excess AMPK activation, or activation in the wrong tissue, "can cause serious side effects, including neurodegeneration, or preventing cells from dividing." The agency added that the "accumulation of naturally-occurring AICAR in the body is also associated with metabolic disorders in humans."

Endogenous Accumulation in Disease States

In humans, AICAR accumulates in several metabolic diseases, but its contribution to the symptoms has not yet been elucidated. Endogenous AICAR is known to accumulate in Lesch–Nyhan syndrome and other purine synthesis disorders.

Drug Interactions

Methotrexate and antifolates: Methotrexate, a well-known cytostatic drug, inhibits purine de novo synthesis and potentiates the ability of exogenous AICAr to increase the level of ZMP by inhibiting AICART. Consequently, methotrexate enhances the ability of AICAr to activate AMPK and to inhibit the growth of human cancer cell lines, and to promote glucose uptake and lipid oxidation in skeletal muscle. This pharmacokinetic interaction means that co-administration of AICAR with methotrexate or pemetrexed would be expected to dramatically amplify AICAR's intracellular effects and could increase toxicity.

Adenosine transport competitors: In nucleoside-free media, AICAR stimulated AMPK activation, increased glucose uptake, and suppressed cell proliferation. Conversely, these effects were blunted or completely blocked in media containing nucleosides. Addition of adenosine or 2'-deoxyadenosine to nucleoside-free media also suppressed AICAR action. This indicates that compounds competing for adenosine transporters — including exogenous adenosine — may antagonize AICAR's cellular effects.

Regulatory and Doping Status

The World Anti-Doping Agency included AICAR on their list of prohibited substances in 2009 due to its performance-enhancing capabilities, and doping control laboratories started to establish methods for detecting AICAR-abuse. Metabolic modulators including PPARδ–AMPK axis agonists (e.g. AICAR) are banned under WADA regulations. Because AICAR is also an endogenous metabolite, detection is complex: urinary concentrations of AICAR have been determined and reference-based thresholds were suggested due to the fact that AICAR is an endogenously produced substance and occurs in every urine specimen. The observed biological variability in urinary concentration was high, and endogenously produced AICAR can potentially be found beyond the reference limit in rare cases. To address this, in analogy to steroids, the carbon isotope ratio determination is the method of choice to distinguish endogenous from exogenous/administered AICAR.

AICAR (acadesine) has not received FDA approval for any therapeutic indication. Acadesine was studied in Phase 3 cardiovascular trials in the 1990s and Phase I/II oncology trials in the 2000s; none resulted in approval.

Long-Term Safety

The long-term safety profile of AICAR in healthy humans is not well-established. All human exposure data come from acute surgical settings (hours of infusion) or short-course oncology protocols (days to weeks). No chronic administration studies in healthy humans have been conducted.

References

Condiciones de Salud

Condiciones de salud que 5-Aminoimidazol-4-Carboxamida Ribonucleótido puede ayudar a apoyar.

HisteriaCientífico
5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) is a cell-permeable AMP analog that activates AMPK (AMP-activated protein kinase), the master cellular energy sensor. AMPK activation by AICAR mimics energy deficiency signals, triggering mitochondrial biogenesis, glucose uptake, and fatty acid oxidation to restore cellular ATP levels.
Olor de piesCientífico
5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR), the cell-permeable precursor to AICA riboside (acadesine), directly activates AMPK, stimulating skeletal muscle glucose uptake independent of insulin. Human studies confirm AICAR infusion acutely improves glucose disposal, making it a direct insulin sensitivity tool in research and clinical contexts.
Circulación (deficiente)Científico
AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) is a cell-permeable activator of AMP-activated protein kinase (AMPK) that mimics the low-energy state (elevated AMP/ATP ratio) and triggers mitochondrial biogenesis via PGC-1α. It is widely used in research to study and activate mitochondrial biogenesis pathways.

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