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      Carvedilol and COVID-19: A Potential Role in Reducing Infectivity and Infection Severity of SARS-CoV-2

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          Abstract

          Dear Editor: Angiotensin-converting enzyme 2 (ACE 2) is expressed by several cells in the body, like the epithelial cells of the lungs and the blood vessels. It is a host receptor for severe acute respiratory syndrome coronavirus [SARS-CoV] and SARSCoV-2. 1 ACE inhibitors and angiotensin II type I receptor blockers (ARBs) cause an upregulation of ACE2. 2 Patients with hypertension and diabetes are at increased risk of COVID-19 infection. 2 This can possibly be because they are frequently treated with ACE inhibitors and ARBs, which increase the host receptor of the virus. 2 Carvedilol is a drug with vasodilating properties, initially designed for managing hypertension and coronary artery disease. Unlike ACE inhibitors that increase the expression of ACE 2, carvedilol decreases its expression. 3 This is why, ACE inhibitors or ARBs prescribed for hypertensive patients can be replaced by carvedilol during this pandemic. Moreover, not only patients on ACE inhibitors or ARBs can benefit from carvedilol. Since carvedilol decreases the expression of ACE, which is the COVID-19 host receptor, it can be useful for all COVID-19 patients. On the other hand, carvedilol can fight COVID-19 by another mechanism. Carvedilol has interleukin 6 (IL-6) suppressing properties. 4 Detectable serum SARS-CoV-2 viral load is closely associated with drastically elevated IL-6 level in critically ill COVID-19 patients. 5 So, carvedilol can be used to target IL-6, which plays a major role in the inflammatory cascade of COVID-19. In conclusion, we hypothesize that by downregulating ACE and by having anti-IL-6 properties, carvedilol has the potential to block 2 pathogenic pathways of COVID-19.

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          Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

          The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
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            Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

            The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues 1 were cerebrovascular diseases (22%) and diabetes (22%). Another study 2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, 3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study. Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. 4 The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). 4 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. 5 ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. If this hypothesis were to be confirmed, it could lead to a conflict regarding treatment because ACE2 reduces inflammation and has been suggested as a potential new therapy for inflammatory lung diseases, cancer, diabetes, and hypertension. A further aspect that should be investigated is the genetic predisposition for an increased risk of SARS-CoV-2 infection, which might be due to ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in Asian populations. Summarising this information, the sensitivity of an individual might result from a combination of both therapy and ACE2 polymorphism. We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs. Based on a PubMed search on Feb 28, 2020, we did not find any evidence to suggest that antihypertensive calcium channel blockers increased ACE2 expression or activity, therefore these could be a suitable alternative treatment in these patients. © 2020 Juan Gaertner/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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              Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

              Abstract Background Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients. Methods This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the “Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition)” issued by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load and IL-6 levels were determined. . Results Clinical characteristics analysis of 48 cases of COVID-19 showed that RNAaemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAaemia (R = 0.902). Conclusions Detectable serum SARS-Cov-2 RNA(RNAaemia) in COVID-19 patients was associated with elevated IL-6 concentration and poor prognosis. Because the elevated IL-6 may be part of a larger cytokine storm which could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response.
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                Author and article information

                Journal
                Am J Med Sci
                Am J Med Sci
                The American Journal of the Medical Sciences
                Southern Society for Clinical Investigation. Published by Elsevier Inc.
                0002-9629
                1538-2990
                28 May 2020
                September 2020
                28 May 2020
                : 360
                : 3
                : 300
                Affiliations
                [1 ]Université de Paris, Faculté de Médecine, Paris
                [2 ]Assistance Publique des Hôpitaux de Paris (APHP), Paris
                [3 ]Hôpital Henri Mondor, Créteil, France
                [4 ]Holy Spirit University of Kaslik, Lebanon
                [5 ]Centre Hospitalier Notre Dame des Secours (CHUNDS), Byblos, Lebanon
                Author notes
                [* ]Correspondence: Charbel Skayem, MD, Department of Dermatology, Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, 51 av du maréchal de Lattre de Tassigny, 94000 Créteil, France
                Article
                S0002-9629(20)30204-4
                10.1016/j.amjms.2020.05.030
                7833103
                32631576
                57f4a9cd-c991-46bc-89d4-af1e96dd8014
                © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 22 March 2020
                : 20 May 2020
                Categories
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