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

DiNicolantonio, James J.; Barroso-Aranda, Jorge

doi:10.1016/j.mehy.2020.110051

Cited by 26 publications

(26 citation statements)

References 100 publications

(103 reference statements)

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“…NAC is approved by FDA under various formulations and is popular as a health supplement, this molecule having been proposed as a nutraceutical that might aid the control of RNA viruses including influenza and coronavirus. [64][65][66] Almost 60 years of experience in the prophylaxis and therapy of a variety of clinical conditions have established the safety of this drug, even at very high doses and for long-term treatments. Drug repurposing is the fastest strategy toward an effective and accessible treatment against COVID-19 before a vaccine is available, 67 and molecules working via multiple mechanisms of action, such as NAC, are more likely to be effective as compared with drugs having a single target.…”

Section: Discussionmentioning

confidence: 99%

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Balansky²,

2020

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COVID‐19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID‐19 patients. N‐ Acetyl‐L‐cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin‐converting enzyme 2 thereby hampering penetration of SARS‐CoV‐2 into cells. Based on a broad range of antioxidant and anti‐inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID‐19, as it was previously demonstrated for influenza and influenza‐like illnesses. Moreover, high‐dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID‐19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.

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Section: Discussionmentioning

confidence: 99%

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Balansky²,

2020

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“…Given that prostacyclin has beneficial effects in platelets and the endothelium by increasing cAMP levels, other oral agents that raise cAMP levels in these cell types might also be potential therapeutic strategies for COVID-19. These include the phosphodiesterase 3 inhibitors, such as dipyridamole and cilostazil, which are currently used for stroke prevention and peripheral vascular disease [251][252][253] . A small study has suggested a benefit of dipyridamole in patients with COVID-19, showing a reduction in biomarkers of disease severity (such as d-dimer levels) and improved clinical outcomes 252 .…”

Section: Potential Therapeutic Approachesmentioning

confidence: 99%

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation

et al. 2020

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The unprecedented outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO, with >34 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and with>1 million COVID-19-related deaths worldwide 1. COVID-19 can lead to a disease spectrum ranging from mild respiratory symptoms to acute respiratory distress syndrome (ARDS) and death 2-4. SARS-CoV-2 is now the third highly pathogenic and transmissible coronavirus identified in humans. Human coronaviruses were first dis covered in the 1960s 5 , but it was not until the 21st century that coronaviruses were recognized as major threats to public health. SARS-CoV 6-9 , Middle East respiratory syndrome coronavirus (MERS-CoV) 10 and SARS-CoV-2 all cause severe respiratory tract infections and have been associated with global pandemics. SARS-CoV was first reported in China in 2003 and infected >8,000 indivi duals, causing 774 deaths worldwide 11. A decade later, MERS was first reported in Saudi Arabia and infected >2,494 individuals and caused 858 deaths, with an extremely high death rate of 34% in part owing to the lack of effective therapies 12,13. SARS-CoV, MERS-CoV and SARS-CoV-2 belong to the Betacoronavirus genus, which is one of four genera of coronavirus 14. Phylogenetic analysis revealed that SARS-CoV-2 is closely related to two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 (with around 88% sequence identity), SARS-CoV (approximately 79% sequence identity) and MERS-CoV (approximately 50% sequence identity) 15. Homology modelling revealed that the receptor-binding domain structures in SARS-CoV and SARS-CoV-2 are similar, despite some amino acid variations 15. MERS-CoV infects human cells by binding to the dipeptidyl peptidase 4 receptor 16 , whereas both SARS-CoV 17 and SARS-CoV-2 (refs 18,19) use angiotensin-converting enzyme 2 (ACE2) as a receptor to infect cells. For SARS-CoV-2 infection, in addition to ACE2, one or more proteases including transmembrane protease serine 2 (TMPRSS2), basigin (also known as CD147) and potentially cathepsin B or cathepsin L are required 18,19. Acute respiratory distress syndrome (ArDs). A syndrome characterized by severe acute respiratory failure arising from inflammation and fluid build-up in the lungs.

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“…Modulation of TNFα , IL1, IL6, ICAM1, VCAM1 and TNF, as well as inactivation of PDE and prevention of platelet aggregation are among the proposed mechanisms that could aid as treatment options for moderate to severe COVID-19 patients. (5,6,8,13,25,26) PTX has proven to be useful in patients with ARDS, from different etiologies and to improve pulmonary function and control pulmonary fibrosis. (27)(28)(29), Furthermore, the potential of pentoxifylline as a therapeutic agent is warranted as there is little to no downside in using this drug because of a safe adverse effect profile and a low cost.…”

Section: Discussionmentioning

confidence: 99%

“…(4) As a result, investigators have proposed alternative drugs with multiple mechanisms of action in light of finding a lower rate of complications from this disease, and potentially lower the mortality. Pentoxifylline (PTX) is a methylxanthine derivative, currently used for peripheral vascular disease, with anti-inflammatory and immunomodulatory properties (5)(6)(7). Moreover, the main pharmacodynamic properties of this drug are aimed at improving circulation by increasing erythrocyte deformability.…”

Section: Introductionmentioning

confidence: 99%

Pentoxifylline and Covid-19: A Systematic Review

Ramonfaur

González-Assad²,

Paredes-Vázquez³

2020

Preprint

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At more than 10 months after the first case of COVID-19 was documented, the understanding of the pathogenesis of this viral illness is growing on a daily basis. A massive pro-inflammatory response on infected individuals involving several cytokines seems to play a key role on disease. As a result, therapeutic efforts have focused on anti-inflammatory strategies to ameliorate the disease, in sight of a lack of a truly effective anti-viral agent. Pentoxifylline (PTX) has been proposed by multiple authors as a potential therapeutic ally, targeting a variety of mechanisms as it has been shown to have antiviral, anti-inflammatory and hemodynamic effects. Importantly, anti-inflammatory effects center on down-regulation of cytokines such as interleukins and tumor necrosis factor. In pre-pandemic studies, PTX has demonstrated to change the clinical course of inflammatory diseases such as acute respiratory distress syndrome, which is a hallmark of severe COVID-19. Researchers agree it is pertinent to experimentally evaluate the effect this drug has on COVID-19 patients. The objective of this review is to summarize all the proposed mechanisms by which PTX may aid in the treatment of COVID-19, as well as prevent its deadly complications. Our interpretation of the literature is that the benefits PTX may bring to a patient with COVID-19 outweigh the risks this drug might pose on them. As a result, there is consensus regarding the evaluation of PTX in further experimental studies to better characterize its effects on COVID-19 patients.

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

Cited by 26 publications

References 100 publications

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation

Pentoxifylline and Covid-19: A Systematic Review

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