Key papers ✓ 3✗ 3~ 1? 1

• ✗ Negative human RCTJAMA · 2012

  Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial.

  Humans3,080 peopleRandomizedPlacebo-controlledDouble-blind28 days postoperative

  Randomized, double-blind, placebo-controlled, parallel-group trial (RED-CABG), stopped for futility

  RED-CABG trial (3,080 bypass surgery patients): IV acadesine did not reduce death, stroke or severe heart failure versus placebo (5.1% vs 5.0%); stopped early for futility.

  Key resultPrimary outcome in 75 of 1493 (5.0%) placebo vs 76 of 1493 (5.1%) acadesine (OR 1.01, 95% CI 0.73-1.41)

  Study details

  Studied

  Intermediate- to high-risk patients (median age 66) undergoing non-emergency on-pump CABG, 300 sites in 7 countries

  Compared with

  Placebo

  Main outcome

  Composite of all-cause mortality, nonfatal stroke or mechanical support for severe LV dysfunction

  Sample

  3080 CABG patients randomized (1493 per group analysed)

  Authors' conclusion

  Acadesine did not reduce the composite of all-cause mortality, nonfatal stroke or severe LV dysfunction in CABG patients.

  Limitations

  Stopped early for futility after 3080 of 7500 planned.

  DOI 10.1001/jama.2012.7633PubMed 22782417
• ✓ Positive meta-analysisJAMA · 1997

  Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

  Humans4,043 people5 trials pooledRandomized trials

  Individual patient-data meta-analysis of 5 placebo-controlled double-blind RCTs

  Patient-level meta-analysis of 5 RCTs (4,043 bypass surgery patients): acadesine cut perioperative myocardial infarction by 27% and early cardiac death by 50%; stroke was not significantly reduced.

  Key resultAcadesine reduced perioperative MI by 27% (OR 0.69; 95% CI 0.51-0.95; P=.02) and combined MI, stroke or cardiac death by 26% (OR 0.73; 95% CI 0.57-0.93; P=.01); stroke not significantly reduced (P=.10)

  Study details

  Studied

  Patients undergoing CABG surgery in 5 trials at 81 centers

  Compared with

  Placebo

  Main outcome

  Perioperative myocardial infarction, cardiac death, stroke

  Sample

  5 randomized trials, 4043 patients

  Authors' conclusion

  Acadesine before and during CABG can reduce early cardiac death, MI and combined adverse cardiovascular outcomes.

  DOI 10.1001/jama.277.4.325PubMed 9002496
• ✗ Negative human RCTCardiovasc Drugs Ther · 1994

  Effect of acadesine, a new metabolic agent, on exercise-induced myocardial ischemia in chronic stable angina.

  Humans12 peopleRandomizedPlacebo-controlledDouble-blind

  Five-way randomized double-blind crossover-type comparison of four acadesine doses with placebo

  Randomized crossover study in 12 people with stable angina: IV acadesine at four doses did not improve time to ischemia, angina or exercise time versus placebo.

  Key resultPlacebo-adjusted change in time to 1-mm ST depression was -0.1 ± 6.2%, 11.1 ± 13.8%, 12.9 ± 8.6%, -3.2 ± 6.8% at 6, 12, 24, 48 mg/kg (p = NS vs. baseline)

  Study details

  Studied

  Patients with chronic stable angina

  Compared with

  Placebo

  Main outcome

  Time to 1 mm ST-segment depression and exercise tolerance

  Sample

  12 patients with stable angina

  Authors' conclusion

  Acadesine did not consistently alter exercise tolerance in stable angina; the exercise-induced ischemia may have been insufficient to show an antiischemic effect.

  Limitations

  Only 12 patients.

  DOI 10.1007/BF00877327PubMed 7918131
• ✓ Positive human trialDiabetologia · 2008

  Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients.

  HumansTen male type 2 diabetic patients

  Intravenous AICAR vs saline infusion with stable isotope methodology and muscle biopsies

  In 10 men with type 2 diabetes, IV AICAR reduced liver glucose output and lowered blood glucose and free fatty acids compared with saline.

  Key resultGlucose disposal as percent of appearance increased and plasma glucose fell more with AICAR (both p < 0.001); plasma NEFA appearance and disappearance were reduced

  Study details

  Studied

  Male type 2 diabetic patients (age 64 ± 2 years, BMI 28 ± 1)

  Compared with

  NaCl 0.9% control test

  Main outcome

  Glucose and fatty acid kinetics

  Authors' conclusion

  IV AICAR reduced hepatic glucose output and lowered blood glucose in type 2 diabetes, and may stimulate hepatic fatty acid oxidation and/or inhibit lipolysis.

  Limitations

  Small sample; muscle AMPK phosphorylation was not increased.

  DOI 10.1007/s00125-008-1108-7PubMed 18709353
• ~ Mixed human trialDiabetes · 2007

  5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men.

  Humans29 people3 hours AICAR

  Human trial of AICAR vs exercise with 2-deoxyglucose uptake and euglycemic-hyperinsulinemic clamp

  In 29 healthy men, IV AICAR doubled muscle glucose uptake (exercise more than quadrupled it) but raised whole-body glucose disposal by only 7%.

  Key result2DG uptake rose 2.1 ± 0.8-fold with AICAR and 4.7 ± 1.7-fold with bicycle exercise; whole-body glucose disposal rose 7% with AICAR (P < 0.05)

  Study details

  Studied

  Healthy men (age 26 ± 8 years, BMI 25 ± 4)

  Compared with

  Bicycle exercise

  Main outcome

  Muscle 2-deoxyglucose uptake

  Sample

  29 healthy men

  Authors' conclusion

  In healthy people AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.

  Limitations

  AMPK activity/phosphorylation was unchanged with AICAR.

  DOI 10.2337/db06-1716PubMed 17513706
• ✗ Negative human trialJ Clin Pharmacol · 2011

  Intravenous AICAR during hyperinsulinemia induces systemic hemodynamic changes but has no local metabolic effect.

  HumansTen participants (paired data n = 8)Placebo-controlled120-minute clamp, AICAR over last 60 minutes

  Two euglycemic hyperinsulinemic clamps with AICAR or placebo infusion

  In 10 healthy volunteers, IV AICAR during an insulin clamp did not change whole-body or forearm glucose uptake but raised heart rate and lowered blood pressure.

  Key resultNo difference in glucose infusion rate or forearm glucose uptake; heart rate rose from 58 ± 3 to 70 ± 3 vs 60 ± 4 to 63 ± 4 bpm with placebo (P < .05)

  Study details

  Studied

  Healthy humans

  Compared with

  Saline placebo

  Main outcome

  Whole-body glucose infusion rate and forearm glucose uptake

  Authors' conclusion

  AICAR does not seem to have a direct effect on systemic or local glucose uptake in humans; it increases heart rate and decreases blood pressure, probably by systemic vasodilation.

  Limitations

  Small sample.

  DOI 10.1177/0091270010382912PubMed 21148051
• ? Inconclusive human trialCancer Chemother Pharmacol · 2013

  Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study.

  Humans24 patients (18 in Part I, 6 in Part II)Open-labelNo control group

  Multicenter phase I/II open-label study

  Phase I/II study in 24 patients with relapsed CLL: IV acadesine had a manageable safety profile and variable signs of anti-leukemic activity.

  Key resultMaximum tolerated dose was 210 mg/kg single dose; efficacy trends included reduced peripheral CLL cells and lymphadenopathy

  Study details

  Studied

  Patients with relapsed/refractory chronic lymphocytic leukemia

  Main outcome

  Safety, tolerability, maximum tolerated dose

  Authors' conclusion

  Acadesine had a manageable safety profile and might be a valuable agent for relapsed/refractory CLL.

  Limitations

  Small population and variable doses; efficacy results variable, open-label, no control.

  DOI 10.1007/s00280-012-2033-5PubMed 23228986Free full text
  Fig. 1
• ✓ Positive animalCell · 2008

  AMPK and PPARdelta agonists are exercise mimetics.

  Animalssize not reported4 weeks AICAR

  Mouse treadmill endurance experiments with AMPK and PPARdelta agonists

  In sedentary mice, 4 weeks of AICAR switched on muscle metabolic genes and increased running endurance by 44%.

  Key result4 weeks of AICAR alone enhanced running endurance by 44% in sedentary mice

  Study details

  Studied

  Sedentary and trained adult mice in treadmill running tests

  Compared with

  Untreated sedentary mice

  Main outcome

  Running endurance

  Authors' conclusion

  The AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or increase endurance without exercise.

  Limitations

  Mouse study.

  DOI 10.1016/j.cell.2008.06.051PubMed 18674809Free full text

Reported side effects

• commonRaised blood uric acid [ref] [ref]
• reportedTransient low blood pressure during infusion [ref] [ref]
• reportedIncreased heart rate [ref]
• reportedTransient anemia or low platelets [ref]
• reportedKidney impairment [ref]

Human safety data come from IV hospital use (heart surgery, leukemia, metabolic studies); there are no safety data for self-administered use.

1 registered human trial (0 active)

✓ positive · ✗ negative · ~ mixed · ? inconclusive, judged on each paper's own main outcome. Grades: A strong human evidence → D little or none. Papers and verdicts are drawn from PubMed, Europe PMC and Russian journals (CyberLeninka); not medical advice.