Beta-blockers could potentially be used to treat COVID-19

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Beta-blockers could potentially be used to treat COVID-19, according to a new international study by Italian and Australian scientists.

University of South Australia cancer researcher, Dr. Nirmal Robinson, working with a team in Naples, has found evidence in animal models that the beta-blocker Propranolol helps suppress the spread of cancer in the lung which has an inflammatory profile very similar to COVID-19.

The scientists have presented their findings in a paper published in Frontiers in Immunology, calling for clinical trials to support their research.

Dr. Robinson, head of the Cellular-Stress and Immune Response Laboratory at the Center for Cancer Biology, says Propranolol is commonly used to treat heart conditions, anxiety and migraine. Recent clinical trials have shown its effectiveness for other conditions, including cancer.

Patients with COVID-19 suffer from many abnormalities, including inflammation, because the SARS-CoV-2 virus disrupts the body’s immune system. Beta-2 blockers could potentially reduce this inflammation and help rebalance the immune system,” Dr. Robinson says.

Beta-blockers including Propranolol are medicines that work by temporarily stopping or reducing the body’s natural “fight-or-flight” response. In return, they reduce stress on certain parts of the body, such as the heart and blood vessels in the brain.

They have also been suggested as a treatment option for autoimmune diseases such as rheumatoid arthritis.

SARS-Cov-2 enters the human cells through the protein ACE2, infecting the lower respiratory tract, causing profound inflammation and multi-organ failure. Patients with comorbidities, such as high blood pressure, diabetes and heart disease, are at much higher risk,” he says.

Other inflammation suppressors, including Tocilizumab (an immunosuppressive drug prescribed for arthritis) and Ruxolitinib (a drug used to treat the rare bone marrow blood cancer, myelofibrosis) have already been used to treat the more serious COVID-19 cases, the researchers say.

“We believe the beta-2-adrenergic pathway should be more deeply investigated as a possible target to reduce the inflammatory symptoms related to COVID-19. The next step is to perform clinical trials to explore an alternative therapy to treat COVID-19, based on the lessons we have learned from cancer,” Dr. Robinson says.


At present, there is no effective drug against the present coronavirus disease 2019 (COVID-19) pandemic. It is known that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to human angiotensin-converting enzyme 2 (ACE2), which acts as a receptor, and binding to ACE2 is crucial for the cellular entry of SARS-COV-2 [1]. Any drug that interrupts the binding of spike protein with the ACE2 receptor will be useful in the treatment of COVID-19.

Renin-Angiotensin-Aldosterone System (RAAS) plays a crucial role in the regulation of blood pressure, sodium level, extracellular fluid volume, etc. Along with the classic pathway which produces effects like vasoconstriction and inflammation, one more pathway with opposing actions to classic pathway exist which produces effects like vasorelaxation and it is anti-inflammatory. Unlike the classic RAAS pathway which uses ACE, the vasorelaxation arm uses ACE2 [1].

It is known that COVID-19 patients exhibit pneumonia, and severe cases had complications like acute respiratory distress syndrome (ARDS), respiratory failure and septic shock which carries a high mortality rate [2]. Recent studies showed that beta-adrenergic blockers reduced the mortality in septic shock patients [3]. Beta-adrenergic blockers also showed beneficial effects in ARDS and respiratory failure patients [4], [5]. Beta-adrenergic blockers by its inhibitory action on the sympathetic system negatively regulate renin release by Juxtaglomerular (JG) cells in the kidney. A decrease in renin may reduce the activity in both arms of RAAS and may decrease ACE2, which may decrease the SARS-CoV-2 virus entry into the host cell.

Considering the potential role of beta-adrenergic blockers in decreasing the SARS-CoV-2 entry into the cells by downregulating ACE2 receptors, and its role in reducing the mortality in respiratory failure, ARDS and septic shock conditions, it may be a good candidate drug for treating COVID-19 patients (Fig. 1 ). I propose that beta-adrenergic blockers may be beneficial in COVID-19 patients with hypertension comorbidity, by regulation of blood pressure and decreasing SARS-CoV-2 cellular entry. In low doses, beta-adrenergic blockers may be beneficial in COVID-19 patients with normal blood pressure, as it may decrease the SARS-CoV-2 entry into the cell. I suggest doing a retrospective study on the COVID-19 patients, who were already on beta-adrenergic blockers for their previous cardiovascular illness and its effect on mortality. The proposed retrospective study will test the validity of the hypothesis and clarify the role of beta-adrenergic blockers in COVID-19 patients.

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Fig. 1
Beta-adrenergic blockers effect on RAAS and COVID-19. A) Beta-adrenergic blockers by its inhibitory action on the sympathetic system decrease the renin release by Juxtaglomerular (JG) cells in the Kidney. A decrease in renin may reduce the activity in both arms and may decrease ACE2 receptors. B) Decreased ACE2 receptors will affect the SARS-CoV-2 cellular entry and thereby reduce the viral infectivity. Beta-adrenergic blockers have been shown to reduce the mortality rate in ARDS, septic shock and respiratory failure. Beta-adrenergic blockers will be beneficial in COVID-19 patients in two ways, by reducing the SARS-CoV-2 virus cellular entry and by reducing the complications like ARDS, Septic shock and respiratory failure in severe cases.

References

  • 1. Zhang H., Penninger J.M., Li Y., Zhong N., Slutsky A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;3:1–5. [PMC free article] [PubMed] [Google Scholar]
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  • 5. Noveanu M., Breidthardt T., Reichlin T., Gayat E., Potocki M., Pargger H. Effect of oral beta-blocker on short and long-term mortality in patients with acute respiratory failure: results from the BASEL-II-ICU study. Crit Care. 2010;14(6):R198. [PMC free article] [PubMed] [Google Scholar]

More information: Antonio Barbieri et al. Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?—Lessons Learned From Cancer, Frontiers in Immunology (2020). DOI: 10.3389/fimmu.2020.588724

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