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

Abstract

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.

• Authors: James J DiNicolantonio, Jorge Barroso-Aranda
• Journal: Medical hypotheses (Med Hypotheses) Vol. 143 Pg. 110051 (Oct 2020) ISSN: 1532-2777 [Electronic] United States
• PMID: 32650197 (Publication Type: Editorial)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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