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COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone During SARS-Cov-2 Infection

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COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone During SARS-Cov-2 Infection pharmaceuticals Review COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection Katarzyna Kotfis 1,* , Kacper Lechowicz 1 , Sylwester Drozd˙ zal˙ 2 , Paulina Nied´zwiedzka-Rystwej 3 , Tomasz K. Wojdacz 4, Ewelina Grywalska 5 , Jowita Biernawska 6, Magda Wi´sniewska 7 and Miłosz Parczewski 8 1 Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; [email protected] 2 Department of Pharmacokinetics and Monitored Therapy, Pomeranian Medical University, 70-111 Szczecin, Poland; [email protected] 3 Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; [email protected] 4 Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, 71-252 Szczecin, Poland; [email protected] 5 Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] 6 Department of Anesthesiology and Intensive Therapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; [email protected] 7 Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland; [email protected] 8 Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; [email protected] * Correspondence: katarzyna.kotfi[email protected]; Tel.: +48-91-466-11-44 Abstract: In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared Citation: Kotfis, K.; Lechowicz, K.; a global pandemic by the World Health Organization (WHO). The clinical course of the disease is Drozd˙ zal,˙ S.; Nied´zwiedzka-Rystwej, unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to P.; Wojdacz, T.K.; Grywalska, E.; acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one Biernawska, J.; Wi´sniewska,M.; of the major long-term complications of COVID-19. In animal models, the use of spironolactone was Parczewski, M. COVID-19—The proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a Potential Beneficial Therapeutic mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide Effects of Spironolactone during significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing SARS-CoV-2 Infection. Pharmaceuticals 2021, 14, 71. pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely https://doi.org/10.3390/ph14010071 used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, Received: 1 December 2020 exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 Accepted: 14 January 2021 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It Published: 17 January 2021 has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 Publisher’s Note: MDPI stays neu- expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic tral with regard to jurisdictional clai- action, and therefore it may prove to act as additional protection for patients at highest risk of severe ms in published maps and institutio- pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential. nal affiliations. Keywords: COVID-19; SARS-CoV-2; coronavirus; pandemic; spironolactone; potassium canrenoate; ARDS (acute respiratory distress syndrome); androgen receptor antagonist; TMPRSS2 Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- 1. Introduction ditions of the Creative Commons At- In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was tribution (CC BY) license (https:// declared a global pandemic by the World Health Organization (WHO), deeming it a threat creativecommons.org/licenses/by/ to health and life [1]. Patients with SARS-CoV-2 infection include both asymptomatic 4.0/). Pharmaceuticals 2021, 14, 71. https://doi.org/10.3390/ph14010071 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 71 2 of 14 carriers and those suffering from severe acute respiratory infection (SARI) leading to acute respiratory distress syndrome (ARDS), which may be complicated by sepsis and death. The clinical course of the disease is unpredictable but has been divided into certain stages, based on severity: 1. asymptomatic patient/mild course (mild upper or genitourinary symptoms); 2. stable patients (respiratory symptoms, radiological pneumonia); 3. unsta- ble patients (respiratory failure); 4. ARDS patients (shock, multiorgan failure, impaired consciousness) [2]. In connection with the global SARS-CoV-2 infection outbreak that began in December 2019, spironolactone has become a light of potential importance in the treatment of compli- cations in patients with COVID-19 infection [3]. It has been shown in animal models that the use of spironolactone may be important in the prevention of pulmonary fibrosis [4]. In addition, it has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19 that might leave many patients debilitated and unable to return to pre-infection pulmonary fitness 5. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide signifi- cant benefits in the treatment of one of the complications of COVID-19, that is, ARDS. In addition, the primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS [5]. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). It has been proposed that spironolac- tone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Cadegiani et al. identified four major factors associated with worse prognosis in COVID-19: age, obesity, hypertension and exposure to androgen hormones, with male sex and androgen-related hair loss that may be associated with enhanced TMPRSS2 ex- pression [6]. Therefore, researchers and clinicians hypothesized that, through its complex pharmacological actions, spironolactone may have therapeutic benefits for patients during the COVID-19 pandemic. 2. Aldosterone Action and Mineralocorticoid Receptor Activation Aldosterone, physiologically, is a hormone of the adrenal cortex, a component of the renin–angiotensin–aldosterone system (RAAS) and a physiological MR activator, which binds to mineralocorticoid receptors (MRs) in the distal tubules and the collecting duct of the kidney, causing sodium reabsorption and secretion of potassium. Mineralocorticoid receptor (MR) activation is a contributing factor to the pathophysiology of many diseases [7]. It has a physiological effect on the regulation of the electrolyte and water balance in the distal tubules, thus maintaining blood pressure and extracellular fluid homeostasis, which acts mainly through cytosolic MRs in epithelial cells [8]. Additionally, stimulation of this system causes vascular stiffness and remodeling, as well as intensification of cardiac inflammation, fibrosis and remodeling [9]. Aldosterone is partly responsible for the increase in extracellular matrix turnover, which is seen in pulmonary, heart and kidney fibrosis and primarily affects the lung epithelium [10]. It is known that elevated aldosterone levels can induce hypertension, alter inflammation and fibrosis and exacerbate cardiovascular disease [11]. Aldosterone also exerts multiple actions on immune cells, which express the mineralo- corticoid receptor [7]. It has been shown that activation of MR in immune cells promotes the hyperinflammatory response. In macrophages, MR activation causes polarization towards the M1 proinflammatory phenotype (M1Mφ). In CD4+ lymphocytes, activation of the MR favors differentiation towards proinflammatory Th17 cells, while enhancing Th17-mediated immunity influences dendritic cells’ (DCs) functioning, crucial for immunological tolerance and homeostasis [12]. It also induces cytotoxic IFNγ+-CD8+ T lymphocytes [7]. This is particularly important in the light of COVID-19 infection characterized by a cytokine Pharmaceuticals 2021, 14, 71 3 of 14 storm and hyperinflammatory state, with Th17 T cells increased and increased CD8+ cells cytotoxicity [13]. 3. Mineralocorticoid Receptor Antagonist Action Experimental evidence and a literature review suggest that mineralocorticosteroid receptor (MRA) antagonists have beneficial effects on collagen metabolism [10]. Studies have shown that MRAs are effective anti-hypertensive drugs and reduce morbidity and mortality in patients with heart
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