key: cord-284873-m1ehdydr authors: Cadegiani, Flavio A.; Wambier, Carlos G.; Goren, Andy title: 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 date: 2020-07-28 journal: Front Med (Lausanne) DOI: 10.3389/fmed.2020.00453 sha: doc_id: 284873 cord_uid: m1ehdydr nan 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) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . The peculiarities and complexity of SARS-CoV-2 infection patterns precluded definitive findings regarding the mechanisms of infectivity. Current literature suggests that angiotensin-converting enzyme-2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) are the key for SARS-CoV-2 cell entry (12) (13) (14) (15) (16) (17) (18) (19) . While ACE2 is the coupling site of the spike protein of SARS-CoV-2, TMPRSS2 facilitates SARS-CoV-2 spikes and ACE2 for viral cell entry. Although ACE2 expression is present diffusely, up to 80% of its expression is located in the type-2 pneumocytes (12, 17) , which may explain why COVID-19 is predominantly pulmonary, although SARS-COV-2 may affect any organ and system. TMPRSS2 activity is modulated by androgens, which may justify why males are overrepresented among severe COVID-19 infected patients (20) . Current understanding of SARS-CoV-2 allows the division of COVID-19 into two phases (12) (13) (14) (15) (16) (17) (18) . In a first, early phase, which corresponds to the period of SARS-CoV-2 cell entry, lung membrane-attached ACE2 expression seems to be positively correlated with virus infectivity, while the balance between circulating ACE2, that could protect from lung infectivity by coupling with SARS-CoV-2 and precluding from the entry into the pneumocytes (13) (14) (15) (16) , and membrane-attached ACE2, may also be relevant. 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) . The Renin-Angiotensin-Aldosterone System (RAAS) has been shown to be central in COVID-19, since three of the key modulators of SARS-CoV-2 infectivity-angiotensin 1-7, ACE2, and AT1-belong to the RAAS, in addition to the TMPRSS2 expression (12) (13) (14) (15) (16) (17) (18) (19) . Disruption of RAAS and ACE2 expression abnormalities are likely the underlying mechanism that links hypertension and obesity as important risk factors for COVID-19 (21) (22) (23) (24) (25) (26) (27) (28) (29) . Conversely, TMPRSS2 overexpression in response to exposure to androgens may justify the higher occurrence of COVID-19 complications in males (30) (31) (32) (33) , which can be reinforced by the fact that males under androgen deprivation therapies such as for prostate cancer may experiment decreased risk for ARDS when compared to age-, sex-, and comorbidities-matched subjects (33) . 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. 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. Spironolactone is a safe and well-tolerated anti-hypertensive and anti-androgenic drug used since 1959, that is effective to maintain normal blood levels (61) (62) (63) , address heart function, and provide cardio-and renoprotection (64) (65) (66) (67) (68) . While spironolactone is a safe and unexpensive option, it may act in multiple sites against COVID-19, including: (1) Favorable patterns of ACE2 expression, including potential increase of circulating ACE2, enhancing its potential protective role in SARS-CoV-2, once plasma ACE2 may couple to SARS-CoV-2 and avoid its entry in the cells (24, (69) (70) (71) (72) (73) (74) ; (2) Downregulation of the androgen-mediated TMPRSS2 due to its antiandrogenic activity (75) (76) (77) , without the adverse events of male sexual castration; (3) Mitigation of the deleterious effects of obesity on the RAAS, possibly reducing obesity-related COVID-19 complications (78, 79); (4) Direct anti-inflammatory and antiviral effects that could directly avoid pulmonary complications of COVID-19 (80) (81) (82) (83) (84) (85) (86) (87) (88) (89) (90) . 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) . 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. 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. 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. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study COVID-19) from publicly reported confirmed cases: estimation and application Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019. Pneumonia in Wuhan, China Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? China medical treatment expert group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China Obesity is associated with worse outcomes in COVID-19: analysis of Early data from New York City Association of obesity with disease severity among patients with coronavirus disease Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain -a potential clue to the role of androgens in COVID-19 severity Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19) Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2 Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury 2019-nCoV) uses the SARS coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry in target cells Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis SARS-COV-2 infection is likely to be androgen mediated Estimation of RAAS-Inhibitor effect on the COVID-19 outcome: a meta-analysis Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: from basic science to clinical implications COVID-19, ACE2, and the cardiovascular consequences Weight loss and the renin-angiotensin-aldosterone system Obesity and malnutrition similarly alter the renin-angiotensin system and inflammation in mice and human adipose but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats Mineralocorticoid receptor activation in obesity hypertension Role of renin-angiotensin-aldosterone system in adipose tissue dysfunction Impact of sex and gender on COVID-19 outcomes in Europe Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D Androgen sensitivity gateway to COVID-19 disease severity Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n = 4532) Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Neurotropism of SARS-CoV 2: mechanisms and manifestations Does SARS-Cov-2 invade the brain? Translational lessons from animal models Neurologic features in severe SARS-CoV-2 infection Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong Cohort: systematic review and meta-analysis Evidence for gastrointestinal infection of SARS-CoV-2 Cutaneous manifestations in COVID-19: a first perspective COVID-19 and cutaneous manifestations Cardiovascular complications in patients with COVID-19: consequences of viral toxicities and host immune response COVID-19-related myocarditis in a 21-year-old female patient Cardiac and arrhythmic complications in patients with COVID-19 First case of COVID-19 complicated with fulminant myocarditis: a case report and insights Liver injury during highly pathogenic human coronavirus infections Gastrointestinal and liver manifestations in patients with COVID-19 Hepatic and gastrointestinal involvement in coronavirus disease Acute kidney injury in SARS-CoV-2 infected patients Acute renal impairment in coronavirus-associated severe acute respiratory syndrome Does COVID-19 affect male fertility? SARS-CoV-2 and the testis: similarity with other viruses and routes of infection Incidence of thrombotic complications in critically ill ICU patients with COVID-19 High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Pulmonary embolism in patients with COVID-19: time to change the paradigm of computed tomography Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past Mineralocorticoid antagonists in ESRD: an overview of clinical trial evidence Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways? Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension? Cardioprotective mechanisms of spironolactone associated with the angiotensinconverting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure Spironolactone exhibits direct renoprotective effects and inhibits renal reninangiotensin-aldosterone system in diabetic rats The renin-angiotensin-aldosterone system and its blockade in diabetic nephropathy: main focus on the role of aldosterone Spironolactone rescues renal dysfunction in obstructive jaundice rats by upregulating ACE2 expression Effects of aldosterone and angiotensin II receptor blockade on cardiac angiotensinogen and angiotensin-converting enzyme 2 expression in Dahl salt-sensitive hypertensive rats Effect of mineralocorticoid receptor blockade on the renal renin-angiotensin system in Dahl salt-sensitive hypertensive rats Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients Hypertension: renin-angiotensin-aldosterone system alterations The emerging role of ACE2 in physiology and disease Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies Comparison of the efficiency of anti-androgenic regimens consisting of spironolactone, Diane 35, and cyproterone acetate in hirsutism Antiandrogenic activity of spironolactone Antiandrogenic and antirenotropic effect of spironolactone Eplerenone implantation improved adipose dysfunction averting RAAS activation and cell division Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity Inflammatory monocyte/macrophage modulation by liposome-entrapped spironolactone ameliorates acute lung injury in mice Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments Cardiac macrophages and apoptosis after myocardial infarction: effects of central MR blockade The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis Pretreatment with mineralocorticoid receptor blocker reduces intestinal injury induced by ischemia and reperfusion: involvement of inhibition of inflammatory response, oxidative stress, nuclear factor κB, and inducible nitric oxide synthase Spironolactone inhibits production of proinflammatory mediators in response to lipopolysaccharide via inactivation of nuclear factor-κB Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response Specific inhibition of HIV infection by the action of spironolactone in T cells Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function Use of spironolactone in SARS-CoV-2 ARDS patients Renin-angiotensin system at the heart of COVID-19 pandemic AG is the CEO of the company Applied Biology Inc (Irvine, CA, USA). CW is part of the medical board of the company Applied Biology Inc (Irvine, CA, USA).The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2020 Cadegiani, Wambier and Goren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.