title: Dipyridamole augments the antiinflammatory response during human endotoxemia.
abstract: BACKGROUND
  In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.
  
  
  METHODS
  In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.
  
  
  RESULTS
  Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.
  
  
  CONCLUSIONS
  Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.
  
  
  BACKGROUND
  ClinicalTrials (NCT): NCT01091571.
authors: Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands.
authors: Bart P
authors: BP
authors: Ramakers
authors: Niels P
authors: NP
authors: Riksen
authors: Thijmen H
authors: TH
authors: Stal
authors: Suzanne
authors: S
authors: Heemskerk
authors: Petra
authors: P
authors: van den Broek
authors: Wilbert H M
authors: WH
authors: Peters
authors: Johannes G
authors: JG
authors: van der Hoeven
authors: Paul
authors: P
authors: Smits
authors: Peter
authors: P
authors: Pickkers
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D003404:Creatinine / Q000652:urine; D004176:Dipyridamole / Q000627:therapeutic use*; D004311:Double-Blind Method; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology; D004731:Endotoxins / Q000494:pharmacology; D033705:Equilibrative Nucleoside Transport Proteins / Q000037:antagonists & inhibitors*; D005542:Forearm / Q000098:blood supply; D005982:Glutathione Transferase / Q000652:urine; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000382:microbiology; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D055815:Young Adult
chemical_list: D004731:Endotoxins; D033705:Equilibrative Nucleoside Transport Proteins; D009599:Nitroprusside; D004176:Dipyridamole; C044101:endotoxin, Escherichia coli; D003404:Creatinine; D005982:Glutathione Transferase; D000109:Acetylcholine; D009638:Norepinephrine