Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: Potential of pentoxifylline and dipyridamole

Med Hypotheses. 2020 Oct;143:110051. doi: 10.1016/j.mehy.2020.110051. Epub 2020 Jul 2.


Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline - might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals - yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium - might also improve therapeutic outcomes in COVID-19.

Publication types

  • Editorial

MeSH terms

  • Adenosine A2 Receptor Agonists / therapeutic use
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Betacoronavirus* / drug effects
  • Betacoronavirus* / immunology
  • Betacoronavirus* / physiology
  • COVID-19
  • COVID-19 Drug Treatment
  • Coronavirus Infections / complications
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / metabolism
  • Dietary Supplements
  • Dipyridamole / therapeutic use*
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Models, Biological
  • Pandemics*
  • Pentoxifylline / therapeutic use*
  • Pneumonia / etiology
  • Pneumonia / prevention & control
  • Pneumonia, Viral / complications
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / metabolism
  • Receptor, Adenosine A2A / metabolism*
  • SARS-CoV-2
  • Signal Transduction / drug effects
  • Thrombosis / etiology
  • Thrombosis / prevention & control
  • Translational Research, Biomedical
  • Virus Replication / drug effects


  • ADORA2A protein, human
  • Adenosine A2 Receptor Agonists
  • Anti-Inflammatory Agents, Non-Steroidal
  • Fibrinolytic Agents
  • Receptor, Adenosine A2A
  • Dipyridamole
  • Pentoxifylline