Chemocentric Informatics Analysis: Dexamethasone Versus Combination Therapy for COVID-19

Abstract

COVID-19 is a biphasic infectious disease with no approved vaccine or pharmacotherapy. The first drug that has shown promise in reducing COVID-19 mortality in severely-ill patients is dexamethasone, a cheap, well-known anti-inflammatory glucocorticoid, approved for the treatment of inflammatory conditions including respiratory diseases such as asthma and tuberculosis. However, about 80% of COVID-19 patients requiring oxygenation, and about 67% of patients on ventilators, are not responsive to dexamethasone therapy mainly. Additionally, using higher doses of dexamethasone for prolonged periods of time can lead to severe side effects and some patients may develop corticosteroid resistance leading to treatment failure. In order to increase the therapeutic efficacy of dexamethasone in COVID-19 patients, while minimizing dexamethasone-related complications that could result from using higher doses of the drug, we applied a chemocentric informatics approach to identify combination therapies. Our results indicated that combining dexamethasone with fast long-acting beta-2 adrenergic agonists (LABAs), such as formoterol and salmeterol, can ease respiratory symptoms hastily, until dexamethasone’s anti-inflammatory and immunosuppressant effects kick in. Our studies demonstrated that LABAs and dexamethasone (or other glucocorticoids) exert synergistic effects that will augment both anti-inflammatory and fibronectin-mediated anticoagulant effects. We also propose other alternatives to LABAs that are supported by sound systems biology evidence, such as nitric oxide. Other drugs such as sevoflurane and treprostinil interact with the SARS-CoV-2 interactome and deserve further exploration. Moreover, our chemocentric informatics approach provides systems biology evidence that combination therapies for COVID-19 will have higher chances of perturbing the SARS-CoV-2 human interactome, which may negatively impact COVID-19 disease pathways.

Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients

“…Based on research findings presented here, we suggest that increasing the time interval between the first and second vaccines doses could potentially reduce or eliminate myocarditis adverse events by reducing the chances of unfavorable synergism on interferon-gamma secretion resulting from the successive waves of primary responses. We also prioritize the use of glucocorticoids (e.g., dexamethasone) for post-COVID-19 vaccine myocarditis for the following reasons: (1) glucocorticoids has been used successfully for the treatment of acute and chronic myocarditis, including viral myocarditis [ 27 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ], (2) glucocorticoids lead to the inhibition of IFN-gamma by regulating STAT1 expression [ 19 ], (3) dexamethasone is one of the drugs that reduces COVID-19 mortality.…”

“…We developed an informatics workflow ( Figure 1 ), based on the methods developed by Hajjo et al [ 16 , 17 , 18 , 19 ], to interrogate the network pharmacology of myocarditis/pericarditis to derive a testable mechanistic hypothesis that could explain post-vaccine cardiac adverse events. First, we started by searching VAERS using the following VAERS indexing terms for events: “myocarditis” and “pericarditis”.…”

The effectiveness of dexamethasone as a combination therapy for COVID-19

“…COVID-19 is a biphasic illness necessitating distinct treatments in each phase (50). The effect of a single therapeutic agent is limited compared to promising drug combinations for COVID-19.…”

A review on function and side effects of systemic corticosteroids used in high-grade COVID-19 to prevent cytokine storms

“…Due to the weakening of immune mechanisms and the possibility of reduced virus clearance after dexamethasone, its combined use with intravenous immunoglobulin and beta interferon may be a viable option (Abdolahi et al, 2020[ 1 ]). Concomitant use of dexamethasone with long-acting beta-2 adrenergic agonists such as salmeterol and formoterol relieves respiratory symptoms and together synergistically improves the anti-inflammatory and anticoagulant effects (Hajjo et al, 2020[ 46 ]). Also, in a controlled study with a treatment regimen consisting of inhaled corticosteroids along with remdesivir and dexamethasone, 5 out of 6 patients survived (Yatam Ganesh and Nachimuthu, 2020[ 146 ]).…”