Molecular Docking Based in-Silico Approach Reveals the Potential Inhibitory Activity of Nsaids against Sars-Cov-2 Proteins

The rapid rate of mutation of the RNA genome of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is responsible for the emergence of viral variants, leading to the enhanced survivability of the virus. Hence, searching for new drugs that can restrict new viral infections by interacting with wild-type and mutated viral proteins is important. However, new drug development's economic and time-constraining nature makes drug repurposing a more viable solution to address the problem. In this work, we conducted a computational study to screen 23 Non-Steroidal Anti-Inflammatory Drugs (NSAID) interactions with 5 major viral proteins of SARS-CoV-2 that are mainly involved in host infection. Our in-silico results establish a database that shows that different NSAID ligands interact with the different viral proteins with good binding affinities. Stabilizing point mutations were introduced within the conserved amino acids involved in ligand-protein interactions. Redocking the NSAID ligands with these mutated viral proteins showed that the NSAID ligands could bind with the mutated and wild-type viral proteins with comparable binding affinities. We conclude that the NSAID ligands could be repurposed as therapeutic drugs against the SARS-CoV-2 virus. Additionally, our work generated a repository that includes binding affinities, possible modes of interaction, and specific interacting residues of the protein (wild-type and mutated) ligand complexes that could be used for future validation studies. Further, our results point to the potential of these drugs to treat other viral infections with similar disease etiology.Copyright All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research.

NSAID-induced gastropathies associated with the treatment of SARS-CoV-2 infection: how to improve therapy safety? Focus on esomeprazole

Objective — Using mFSSG questionnaire, to define the presences of gastrointestinal disturbances, associated with the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with moderate course of SARS-CoV-2 infection and to investigate ability of esomeprazole (Ezonexa, Farmak) to preventing the development of dyspeptic and reflux symptoms in these patients. Materials and methods. All patients with the established diagnosis of coronaviral disease (n = 85), hospitalized for treatment in the Centre of Therapy of Clinical Emergency Hospital in Lviv, who signed the informed consent, became the participants of an open controlled trial of Ezonexa efficacy at this pathology. The medication was administered in a dose of 20 mg/day in the morning, 30 mins before meals, used to prevent NSAID-induces gas-tropathies for 28 days. Simple blinded method was used to randomize patients into two groups. Subjects of the first group (n = 45) took esomeprazole, second group included controls (n = 40) without active prophylaxis of NSAID-induces gastropathies. The mean patients' age was 69.4 ± 2.6 years. The men age of male subjects was 66.4 ± 2.4 years, of females 72.3 ± 2.7 years. The follow up period lasted 4 weeks. All patients underwent standard examinations and survey to assess the dynamics of clinical manifestations of the disease against the background of the treatment of coronaviral infection. Besides, patients used mFSSG questionnaire to evaluate the intensity of dyspeptic and reflux symptoms. Examinations and survey were performed on the 1st, 10 — 14th and 28th days of follow up. The quality of life indices were assessed with the use of SF-36 questionnaire in all patients at baseline and 4 weeks after the study start. Results. No significant difference in mFSSG scores was reveled in the patients of both groups on the 1st day in terms of clinical manifestations of dyspepsia and reflux. At the second testing on 10 — 14th days, the assessment of dyspeptic and reflux symptoms didn't change in patients of the 1st group, whereas in 49.6 % subjects of the control group presence of the signs of NSAID-induced gastropathy with a pronounced dyspeptic and moderate reflux syndrome was registered. At 28th day, symptoms of both dyspepsia and reflux developed in 11.3 % of patients in the first group, and 78.6 % in the second group. No differences in age and gender ratio were reveled after comparative analysis. However, comorbid pathology, for which patients constantly took low doses of ace-tylsalicylic acid, was an additional aggravating risk factor of the development of NSAID-induced gastropathy. Analysis of the baseline indices of quality of life in both groups showed the significant (р < 0.05) decrease in the majority of scores, except for the scales of physical functions and pain. Positive dynamics against the background of esomeprazole treatment was defined in all indices of the quality of life, in the most extent in the scores of pain, vitality, social and role emotional functions. Conclusions. Esomeprazole in a dose of 20 mg demonstrated excellent protective effects in regard to the gastrointestinal mucosa in elderly patients from the high-risk group, who are particularly sensitive to the gastroduo-denal NSAID-induced toxicity even at short therapeutic course for coronaviral infection. Ezonexa may be considered as a drug of choice to treat NSAID-induced gastropathy;due to its prolonged and stable acid-inhibiting ability, Ezonexa promotes prompt symptoms' relief. Owing to the phenomenon of stereoselectivity, the drug has pharmacokinetic properties that ensure its high clinical efficacy in acid-dependent diseases. © 2021, Publishing Company VIT-A-POL. All rights reserved.

Anti-Inflammatory Therapy of Infections

Anti-inflammatory treatment of infections is challenging due to the heterogeneity of etiologic agents and complex immune interactions. Nevertheless, anti-inflammatory medications are commonly used in infections to reduce unpleasant symptoms and to modify host response. They may play a fundamental role in managing infection with over-inflammation by decreasing inflammatory organ damage, e.g., COVID-19. However, by its inherent inhibition of immune functions, they might also contribute to the development of serious bacterial infections. Moreover, reducing a patient's symptoms and signs may provide a false sense of security and delay diagnosing threatening infections. © 2022 Elsevier Inc. All rights reserved.

A Decade of Clinical Advances in Chronic Rhinosinusitis: 2012-2022.

The field of chronic rhinosinusitis (CRS) is constantly evolving. In the past 10 years, key advancements in basic and translational research as well as clinical studies have improved our understanding and management of CRS. Notably, treatment options have expanded to include novel therapeutic drugs, devices, and surgical techniques. Assessments of patient symptoms and their impact on quality of life have become more standardized. Progress has also been made in both determining the true prevalence of CRS and recognizing comorbidities that can impact CRS severity. Practice guidelines have also shifted from expert opinion to more data-driven analyses. This review highlights major clinical advancements made in the field of CRS over the past 10 years as well as identifies current gaps in knowledge that can form the basis for new areas of study over the next decade.

Effect of the Duration of NSAID Use on COVID-19.

Background and Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to control pain and fever. However, their effect on COVID-19 infected patients has not been fully studied. In this study, we investigated the effect of the duration of NSAIDs use on COVID-19 infection and clinical outcomes. Materials and Methods: In South Korea, 25,739 eligible patients who received COVID-19 testing between 1 January and 31 July 2020, were included in this retrospective observational cohort analysis. Based on the date of the first COVID-19 test for each patient, NSAID prescription dates were used to separate patients into two groups (short-term group: <2 weeks; long-term group: 8−12 weeks). COVID-19 infectivity and clinical outcomes were analyzed. We used the propensity score-matching (PSM) method. Results: Of the 580 patients who had taken NSAIDs before the date of COVID-19 test, 534 and 46 patients were grouped in the short- and long-term NSAID-use groups, respectively. We did not find a statistically significant increased risk of COVID-19 infection (adjustment for age and sex, p = 0.413; adjustment for age, sex, region of residence, comorbidity, Charlson Comorbidity Index, and current use of medication, p = 0.259) or change in clinical outcomes, including conventional oxygen therapy, admission of intensive care unit, artificial ventilation, or death, between the two groups in which the PSM method was applied. Conclusions: The duration of NSAIDs use did not have a statistically significant effect on COVID-19 infectivity or clinical outcomes. However, further studies looking at clinical presentation and laboratory test results in a large number of people should be performed.

Machine learning in the diagnosis of asthma phenotypes during coronavirus disease 2019 pandemic.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, it has become a pressing need to be able to diagnose aspirin hypersensitivity in patients with asthma without the need to use oral aspirin challenge (OAC) testing. OAC is time consuming and is associated with the risk of severe hypersensitive reactions. In this study, we sought to investigate whether machine learning (ML) based on some clinical and laboratory procedures performed during the pandemic might be used for discriminating between patients with aspirin hypersensitivity and those with aspirin-tolerant asthma. Methods: We used a prospective database of 135 patients with non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) and 81 NSAID-tolerant (NTA) patients with asthma who underwent OAC. Clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant and urine were extracted for the purpose of applying ML techniques. Results: The overall best ML model, neural network (NN), trained on a set of best features, achieved a sensitivity of 95% and a specificity of 76% for diagnosing NERD. The 3 promising models (i.e., multiple logistic regression, support vector machine, and NN) trained on a set of easy-to-obtain features including only clinical characteristics and laboratory data achieved a sensitivity of 97% and a specificity of 67%. Conclusions: ML techniques are becoming a promising tool for discriminating between patients with NERD and NTA. The models are easy to use, safe, and achieve very good results, which is particularly important during the COVID-19 pandemic.

Synthesis of nonsteroidal anti-inflammatory drug (NSAID) 2,4,5-trimethoxybenzaldehyde from Indonesian calamus oil and its in silico pharmacokinetic study

There is a race to search for nonsteroidal anti-inflammatory painkillers due to the escalating cases of the life-threatening COVID-19 pandemic. Those current nonsteroidal anti-inflammatory drugs (NSAIDs) used as an inflammation adjunct treatment on COVID-19 patients, including paracetamol, ibuprofen, and celecoxib, are still under dispute offering emergency development of a new potent NSAID. Meanwhile, a well-known COX-2 selective anti-inflammation 2,4,5-trimethoxybenzaldehyde (TMBA) has not been developed further in terms of its synthetic methodology and its pharmacokinetic studies. Herein, the synthesis of 2,4,5-TMBA from Indonesia sweet flag (Acorus calamus) and its pharmacokinetic properties was studied through in silico calculation. A typical Asian tetraploid calamus oil was yielded ( 90% pure) after reduced pressure distillation of the crude Indonesian sweet flag oil. Submission of that oil into a very cheap DIY ozone machine produced 95% of pure 2,4,5-TMBA just in 10 min ozonised. The in silico adsorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction using the free access ADMETlab 2.0 web server strongly recommended 2,4,5-TMBA to be an orally administered NSAID candidate.

Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients.

BACKGROUND: It is known that severe acute respiratory coronavirus 2 (SARS-CoV-2) is the viral strain responsible for the recent coronavirus disease 2019 (COVID-19) pandemic. Current documents have demonstrated that the virus causes a PGE2 storm in a substantial proportion of patients via upregulating cyclooxygenase-2 (COX-2) and downregulating prostaglandin E2 (PGE2)-degrading enzymes within the host cell. AIM: Herein, we aimed to study how short-term treatment with celecoxib (Celebrex), a selective COX-2 inhibitor, affects demographic features, early symptoms, O2 saturation, and hematological indices of cases with COVID-19. METHODS: A total of 67 confirmed COVID-19 cases with a mild or moderate disease, who had been referred to an institutional hospital in south-eastern Iran from October 2020 to September 2021, were enrolled. Demographic characteristics, symptoms, and hematological indices of the patients were recorded within different time periods. One-way ANOVA or Kruskal-Wallis tests were used to determine differences between data sets based on normal data distribution. RESULTS: O2 saturation was statistically different between the control group and patients receiving celecoxib (p = 0.039). There was no marked difference between the groups in terms of the symptoms they experienced (p > 0.05). On the first days following Celebrex therapy, analysis of complete blood counts showed that white blood cell (WBC) counts were markedly lower in patients treated with a high dose of celecoxib (0.4 g/day) than in controls (p = 0.026). However, mean lymphocyte levels in patients receiving a high dose of celecoxib (0.4 g/day) were markedly higher than in patients receiving celecoxib with half of the dose (0.2 g/day) for one week or the untreated subjects (p = 0.004). Changes in platelet count also followed the WBC alteration pattern. CONCLUSION: Celecoxib is a relatively safe, inexpensive, and widely available drug with non-steroidal anti-inflammatory properties. The therapeutic efficacy of celecoxib depends on the administrated dose. Celecoxib might improve disease-free survival in patients with COVID-19.

Effects of non-steroidal anti-inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses: EAACI task force on eicosanoids consensus report in times of COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research.

Indomethacin: an exploratory study of antiviral mechanism and host-pathogen interaction in COVID-19.

INTRODUCTION: COVID-19, a dreadful pandemic that has impacted human life like no other pathogenic invasion, has claimed the lives of over 100 million people. The need for effective treatment strategies is still a subject of intense research considering the rapidly evolving genome and continental diversity. Indomethacin is administered mostly as co-treatment for affected patients as a non-steroidal anti-inflammatory drug (NSAID). However, the underlying mechanism of action is unresolved. This study explores the basal mechanism of indomethacin and potency in alleviating the damage caused by SARS-CoV-2 and discusses the experimental and clinical efficacy in recent studies. AREAS COVERED: The literature search and system biology-based network formation were employed to describe the potent effects and risks associated with indomethacin in in-vitro, in-vivo, and clinical studies. This study also highlights the plausible mechanism of antiviral action of indomethacin with its apparent viral protein targets. The SARS-CoV-2 protein, the interacting host proteins, and the effect of indomethacin on this interactome as a standalone treatment or as part of a co-therapy strategy are particularly emphasized using network modeling. EXPERT OPINION: Indomethacin has demonstrated excellent clinical endpoint characteristics in several studies, and we recommend that it be utilized in the treatment of mild-to-moderate COVID patients.

Nonsteroidal anti-inflammatory drugs and glucocorticoids in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a wide spectrum of symptom severity, which is manifested at different phases of infection and demands different levels of care. Viral load, host innate-immune response to SARS-CoV-2, and comorbidities have a direct impact on the clinical outcomes of COVID-19 patients and determine the diverse disease trajectories. The initial SARS-CoV-2 penetrance and replication in the host causes death of infected cells, determining the viral response. SARS-CoV-2 replication in the host triggers the activation of host antiviral immune mechanisms, determining the inflammatory response. While a healthy immune response is essential to eliminate infected cells and prevent spread of the virus, a dysfunctional immune response can result in a cytokine storm and hyperinflammation, contributing to disease progression. Current therapies for COVID-19 target the virus and/or the host immune system and may be complicated in their efficacy by comorbidities. Here we review the evidence for use of two classes of anti-inflammatory drugs, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of COVID-19. We consider the clinical evidence regarding the timing and efficacy of their use, their potential limitations, current recommendations and the prospect of future studies by these and related therapies.

Protecting older patients with cardiovascular diseases from COVID-19 complications using current medications.

PURPOSE: In the pathogenesis of severe COVID-19 complications, derangements of renin-angiotensin-aldosterone system (RAAS), vascular endothelial dysfunction leading to inflammation and coagulopathy, and arrhythmias play an important role. Therefore, it is worth considering the use of currently available drugs to protect COVID-19 patients with cardiovascular diseases. METHODS: We review the current experience of conventional cardiovascular drugs [angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, anticoagulants, acetosalicylic acid, antiarrhythmic drugs, statins] as well as some other drug classes (antidiabetic drugs, vitamin D and NSAIDs) frequently used by older patients with cardiovascular diseases. Data were sought from clinical databases for COVID-19 and appropriate key words. Conclusions and recommendations are based on a consensus among all authors. RESULTS: Several cardiovascular drugs have a potential to protect patients with COVID-19, although evidence is largely based on retrospective, observational studies. Despite propensity score adjustments used in many analyses observational studies are not equivalent to randomised controlled trials (RCTs). Ongoing RCTs include treatment with antithrombotics, pulmonary vasodilators, RAAS-related drugs, and colchicine. RCTs in the acute phase of COVID-19 may not, however, recognise the benefits of long term anti-atherogenic therapies, such as statins. CONCLUSIONS: Most current cardiovascular drugs can be safely continued during COVID-19. Some drug classes may even be protective. Age-specific data are scarce, though, and conditions which are common in older patients (frailty, comorbidities, polypharmacy) must be individually considered for each drug group.

Sex-Related Differences in Drugs with Anti-Inflammatory Properties.

There is increasing evidence of sex differences in the action of anti-inflammatory drugs, with women being at significantly higher risk of adverse effects. Nevertheless, clinicians' awareness of the implications of these sex differences on dosing and adverse event monitoring in routine practice is still in need of improvement. We reviewed the literature evaluating sex differences in terms of pharmacokinetics and pharmacodynamics of anti-inflammatory drugs. The anti-thrombotic activity of selective and non-selective COX-inhibitors tends to be stronger in men than women. Side effect profiles differ with regards to gastro-intestinal, renal and hepatic complications. Glucocorticosteroids were found to be more effective in men; women were more sensitive to corticosteroids when their oestradiol levels were high, a finding important for women taking hormonal contraception. TNF-alpha inhibitors have a longer half-life in men, leading to stronger immunosuppression and this a higher incidence of infections as side effects. Although research on sex differences in the effectiveness and safety of drugs is increasing, findings are often anecdotal and controversial. There is no systematic sex-differentiated reporting from clinical trials, and women are often under-represented. As personalized medicine is gaining in importance, sex, and gender aspects need to become integral parts of future research and policy making.

Etoricoxib may inhibit cytokine storm to treat COVID-19.

The worldwide spread of COVID-19 has caused an unprecedented disaster. The emergence of COVID-19-mediated cytokine storm is one of the most important contributors to the development of acute and severe illness in patients. At present, there is an urgent need for drugs that can inhibit cytokine storm to treat COVID-19. In the absence of specific drugs and vaccines, it is important to screen existing drugs as potential treatments. This article introduces a potential repositioning of the existing drug etoricoxib, which may inhibit cytokine storm to treat COVID-19 through reducing the activity of Cyclooxygenase-2 in the conversion of arachidonic acid to prostaglandin.

Role of arachidonic cascade in COVID-19 infection: A review.

The World Health Organization has described the 2019 Coronavirus disease caused by an influenza-like virus called SARS-CoV-2 as a pandemic. Millions of people worldwide are already infected by this virus, and severe infection causes hyper inflammation, thus disrupting lung function, exacerbating breath difficulties, and death. Various inflammatory mediators bio-synthesized through the arachidonic acid pathway play roles in developing cytokine storms, injuring virus-infected cells. Since pro-inflammatory eicosanoids, including prostaglandins, and leukotrienes, are key brokers for physiological processes such as inflammation, fever, allergy, and pain but, their function in COVID-19 is not well defined. This study addresses eicosanoid's crucial role through the arachidonic pathway in inflammatory cascading and recommends using bioactive lipids, NSAIDs, steroids, cell phospholipase A2 (cPLA2) inhibitors, and specialized pro-resolving mediators (SPMs) to treat COVID-19 disease. The role of soluble epoxide hydrolase inhibitors (SEHIs) in promoting the activity of epoxyeicosatrienoic acids (EETs) and 17-hydroxide-docosahexaenoic acid (17-HDHA) is also discussed. Additional research that assesses the eicosanoid profile in COVID-19 patients or preclinical models generates novel insights into coronavirus-host interaction and inflammation regulation.

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients.

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.