Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19

At the onset of the COVID-19 pandemic, mortality following infection of severe acute respiratory coronavirus (SARS-CoV-2) was thought to be solely associated with aging and pre-existing conditions; however, as the pandemic ensued, several large scale epidemiological observations eluded to additional atypical risk factors, particularly hypertension, obesity, and male gender (1–11).

In a second phase, represented by the inflammatory and immunological responses to SARS-CoV-2 infection, ACE2 is downregulated due to the entry into cell cytoplasm when coupled with the virus. In opposition to the first phase, in the second phase, lung-attached ACE2 expression may be positively correlated with better clinical outcomes, since ACE2 may limit the cytokine storm that underlies the Acute Respiratory Distress Syndrome (ARDS) in COVID-19, while the balance between proinflammatory angiotensin II-angiotensin receptor type 1 (AT1) axis, and the anti-inflammatory angiotensin 1-7-G-coupled Mas receptor (angiotensin 1-7 receptor) axis may also be crucial for level of severity of the second phase (13,(15)(16)(17)(18)(19).
A pro-thrombotic state, and endothelial, hematological, kidney, hepatic, cardiovascular, gonadal, neurological, and gastrointestinal manifestations in COVID-19 are at least partially mediated by ACE2 and TMPRSS2 expressions .
In summary, aberrancies in ACE2 expression, unbalance between angiotensin II and angiotensin 1-7 levels, and overexpression of TMPRS22 seem to be key factors for the severity of clinical manifestations in COVID-19.

SPIRONOLACTONE AS A CANDIDATE AGAINST COVID-19
Drugs that address ACE2, any sight of the RAAS, or TMPRSS2 expression are potential candidates for COVID-19. In this context, the use of old drugs against COVID-19 may present major potential benefits over novel drugs for some reasons, including: (1) The well-established long-term safety profile (2) Extensively described risks and contraindications, which allows to prevent its use when contraindicated and monitor for risks directedly; and (3) The lower cost of old, non-patented drugs allows its massive use in public health systems, when clinically indicated.
These observations combined with our understanding of SARS-CoV-2 molecular mechanism of infectivity lead us to believe that spironolactone is an ideal candidate drug for the prophylactic treatment of SARS-CoV-2.
Hence, spironolactone meets corresponding epidemiological data, mechanistical plausibility, and sufficient safety profile to become a candidate against COVID-19.
For the proper management of spironolactone during COVID-19, since spironolactone mostly targets the virus entry in the cells, which is the hallmark of the first phase of Covid-19, spironolactone should be preferably started during the earlier stages of the infection, prior to the complications of respiratory manifestations, but could also be employed in the second phase, when the inflammatory and immunologic responses become clinically relevant, due to its anti-inflammatory effects (91).

CONCLUSION
Abnormal ACE2 expression, angiotensin II and angiotensin 1-7 imbalance, and TMPRSS2 androgen-mediated overactivity seem to be key regulators of SARS-CoV-2 infectivity, in accordance with epidemiological observations of hypertension, obesity, and male sex as being major risk factors. Since spironolactone is a long used safe drug that exhibits concurrent actions in the modulation of ACE2 expression that could avoid SARS-CoV-2 cell entry, attenuation of the harms caused by the overexpression of angiotensin II-AT-1 axis, discloses anti-androgenic activity that can decrease viral priming through TMPRSS2 activity, and has anti-inflammatory effects in the lungs, spironolactone seems to be a plausible candidate for the prophylactic and early treatment of SARS-CoV-2.

AUTHOR CONTRIBUTIONS
FC, CW, and AG developed the underlying theories on the present paper, wrote, and reviewed the manuscript in its final format for submission. All authors contributed to the article and approved the submitted version.

ACKNOWLEDGMENTS
We acknowledge all researchers who have provided insightful and helpful information aiming to overcome the COVID-19 pandemic, as well as all front-line health providers who are directly dealing with COVID-19 infected patients, exposing themselves at risk for this potentially severe infection.