Effect of low-to-moderate dose glucocorticoids on viral clearance in COVID-19: a retrospective study.

Objective: To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance in patients with COVID-19. Methods: A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, Zhejiang University School of Medicine were recruited. All patients received oral arbidol and combination of lopinavir/ritonavir or darunavir/cobistitat for antiviral therapy, and symptomatic supportive care. Among them, 51 patients received methylprednisolone (0.75-1.50 mg.kg-1.d-1) (glucocorticoid treatment group), and 21 patients did not use glucocorticoid (control group). The time of virologic negative conversion in sputum and the time of radiologic recovery in lung since onset were compared between the two groups. The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups. Results: The median ages of the glucocorticoid group and the control group were 52 (45, 62) and 46 (32, 56) years (chi2=4.365, P<0.05). The clinical conditions at hospital admission were different between the two groups (P<0.01). The severe cases accounted for 52.0%, while moderate cases in the control group accounted for 71.4%. The median times from the onset to virologic negative conversion in the two groups were 15 (13, 20) and 14 (12, 20) days (P>0.05). The median times from onset to radiologic recovery were 13 (11, 15) and 13 (12, 17) days in the two groups (P>0.05). In moderate cases, the median times from the onset to virologic conversion in sputum were 13 (11, 18) days in the glucocorticoid group and 13 (12, 15) days in the control group (P>0.05). The median times from onset to radiologic recovery in lung were 12 (10, 15) and 13 (12, 17) days, respectively (P>0.05). Conclusion(s): Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19, and also no effect on accelerating radiologic recovery in lung, so it is not recommended.Copyright © 2020 by the Chinese Medical Association.

Effect of low-to-moderate dose glucocorticoids on viral clearance in COVID-19: a retrospective study.

Objective: To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance in patients with COVID-19. Methods: A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, Zhejiang University School of Medicine were recruited. All patients received oral arbidol and combination of lopinavir/ritonavir or darunavir/cobistitat for antiviral therapy, and symptomatic supportive care. Among them, 51 patients received methylprednisolone (0.75-1.50 mg.kg-1.d-1) (glucocorticoid treatment group), and 21 patients did not use glucocorticoid (control group). The time of virologic negative conversion in sputum and the time of radiologic recovery in lung since onset were compared between the two groups. The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups. Results: The median ages of the glucocorticoid group and the control group were 52 (45, 62) and 46 (32, 56) years (chi2=4.365, P<0.05). The clinical conditions at hospital admission were different between the two groups (P<0.01). The severe cases accounted for 52.0%, while moderate cases in the control group accounted for 71.4%. The median times from the onset to virologic negative conversion in the two groups were 15 (13, 20) and 14 (12, 20) days (P>0.05). The median times from onset to radiologic recovery were 13 (11, 15) and 13 (12, 17) days in the two groups (P>0.05). In moderate cases, the median times from the onset to virologic conversion in sputum were 13 (11, 18) days in the glucocorticoid group and 13 (12, 15) days in the control group (P>0.05). The median times from onset to radiologic recovery in lung were 12 (10, 15) and 13 (12, 17) days, respectively (P>0.05). Conclusion(s): Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19, and also no effect on accelerating radiologic recovery in lung, so it is not recommended.Copyright © 2020 by the Chinese Medical Association.

Effect of low-to-moderate dose glucocorticoids on viral clearance in COVID-19: a retrospective study.

Objective: To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance in patients with COVID-19. Methods: A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, Zhejiang University School of Medicine were recruited. All patients received oral arbidol and combination of lopinavir/ritonavir or darunavir/cobistitat for antiviral therapy, and symptomatic supportive care. Among them, 51 patients received methylprednisolone (0.75-1.50 mg.kg-1.d-1) (glucocorticoid treatment group), and 21 patients did not use glucocorticoid (control group). The time of virologic negative conversion in sputum and the time of radiologic recovery in lung since onset were compared between the two groups. The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups. Results: The median ages of the glucocorticoid group and the control group were 52 (45, 62) and 46 (32, 56) years (chi2=4.365, P<0.05). The clinical conditions at hospital admission were different between the two groups (P<0.01). The severe cases accounted for 52.0%, while moderate cases in the control group accounted for 71.4%. The median times from the onset to virologic negative conversion in the two groups were 15 (13, 20) and 14 (12, 20) days (P>0.05). The median times from onset to radiologic recovery were 13 (11, 15) and 13 (12, 17) days in the two groups (P>0.05). In moderate cases, the median times from the onset to virologic conversion in sputum were 13 (11, 18) days in the glucocorticoid group and 13 (12, 15) days in the control group (P>0.05). The median times from onset to radiologic recovery in lung were 12 (10, 15) and 13 (12, 17) days, respectively (P>0.05). Conclusion(s): Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19, and also no effect on accelerating radiologic recovery in lung, so it is not recommended.Copyright © 2020 by the Chinese Medical Association.

Knowledge, Concept on severe Acute Respiratory Syndrome Coronavirus-2(SARS-CoV-2). A Review of the Literature and Future perspective

Severe acute respiratory corona virus-2 (SARS-CoV-2) is a newly recognized pathogen and may cause severe respiratory illness among virus-infected people. The virus in the open market of Wuhan city, China was identified. The virus causative agent for the COVID-19 disease and became pandemic in December 2019 to now with no proper disease management protocols. So, the authors felt a need to bring awareness to the disease and its causative agent among worldwide.The current review article is trying to bringglance information on SARS-CoV-2 on various aspects of disease condition as Common characteristics, history, and mode of transmissions of the virus. The virus can be detected through investigations, Identified clinical manifestations for the virus, and available management used to treat the virus-infected patient. Here discussed possible preventive measures for SARS-CoV-2;to control the spread of the disease among the communities. This article information maybea help people to have an awareness of the disease.Health professional are trying hard for providing effective care to the virus affected people with minimal disease preventive protocols. People should understand the effectiveness of the vaccine and undergoing vaccination process which helps the spread of virus among the healthy people. Every individual should take initiation for the control of the disease spreads by following controlling measures.Copyright © RJPT All right reserved.

COVID-19: From the Molecular Mechanisms to Treatment

The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARS-CoV-2 bio-molecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the bio-molecular aspects of SARS-CoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.Copyright © 2022 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran.

Pathogenesis, Clinical Manifestation, Diagnosis, Pathological Findings, Treatment Options, Preventive Measures, and Risk Factors of COVID-19

Background: COVID-19 is an infectious disease caused by SARS-CoV-2. The disease has hit hard around the globe and is now a pandemic. As of April 01, 2020, a total of 875,560 cases have been reported and the figures are increasing day by day. Currently, there is no treatment or vaccine available for curing COVID-19 and pharmaceutical companies are racing toward the common goal of achieving the cure. Method(s): Scientific databases, including Science direct, Pub med, Elsevier, Scopus, and Nature, were explored. Data has also been accessed from case reports, newspaper reports, internet data, World Health Organisation (WHO) reports, and Centre of Disease Control (CDCs) reports. The US National Library of Medicine, Clinicaltrials.gov, were accessed to get information about the ongoing clinical trials. The literature survey started in the first week of February 2020 and was completed in the first week of April 2020. Additional literature survey was done in the second week of June 2020. Result(s): The epicentre of COVID-19 is Wuhan City, Hubei Province, China. Coronavirus belongs to Order Nidovirale and is subdivided into four groups alpha, beta, gamma, and delta. Coronavirus 229E, NL63, HKU1, MERS-CoV and SARS-CoV are known to infect humans. It is an enveloped, non-segmented positive-sense RNA virus of size 30-32 kb with several structural and accessory proteins. The pathogenesis of COVID-19 involves attachment of Spike (S) protein of SARS-CoV-2 to the angio-tensin-converting enzyme 2(ACE2) receptor present on the host cell membrane. Clinical manifestation of COVID-19 include fever, cough, complicated dyspnoea, pneumonia, etc. Real-time-PCR is a sensi-tive test for the detection of SARS-CoV. Remdesivir, Bevacizumab, Darunavir and cobicistat, lopinavir-ritonavir, Oseltamavir, hydroxychloroquine, Sarilumab, mRNA-1273, Ad5-nCoV are some of the drugs under the clinical phase of the trial. People with A-positive blood group, with comorbidities like diabe-tes, hypertension, chronic pulmonary obstructive disease, substance abuse disorders, immunocom-promised individuals, health care workers, and older adults are at high risk of getting infected with SARS-CoV-2 Conclusion(s): This article gives insight into the occurrence of COVID-19, classification and structure of SARS-CoV-2, pathogenesis, pathological findings, clinical manifestation, diagnosis, potential treatment options and prevention, and people at risk of COVID-19.Copyright © 2021 Bentham Science Publishers.

Liver injury caused by antiviral agents for COVID-19.

Antiviral therapy is important for COVID-19. Currently, the anti-2019-nCoV drugs in clinical trials include broad-spectrum antiviral drugs (alpha interferon and ribavirin), hemagglutinin inhibitors (arbidol), human immunodeficiency virus protease inhibitors (lopinavir/ritonavir and darunavir/cobicistat), nucleoside analogues (favipiravir and remdesivir) and antimalarial drug (chloroquine);while liver damage may occur in some patients with the medication. This article reviews the research on liver damage associated with anti-2019-nCoV drugs, aiming at promoting the safe and effective antiviral therapy for COVID-19 patients.Copyright © 2020 by the Chinese Medical Association.

Liver injury caused by antiviral agents for COVID-19.

Antiviral therapy is important for COVID-19. Currently, the anti-2019-nCoV drugs in clinical trials include broad-spectrum antiviral drugs (alpha interferon and ribavirin), hemagglutinin inhibitors (arbidol), human immunodeficiency virus protease inhibitors (lopinavir/ritonavir and darunavir/cobicistat), nucleoside analogues (favipiravir and remdesivir) and antimalarial drug (chloroquine);while liver damage may occur in some patients with the medication. This article reviews the research on liver damage associated with anti-2019-nCoV drugs, aiming at promoting the safe and effective antiviral therapy for COVID-19 patients.Copyright © 2020 by the Chinese Medical Association.

COVID-19 Infection: A Review of Summarized Clinical Trials Study for the Treatment

Background: Coronavirus Disease 2019 (COVID-19) is a widely infectious and pathogenic viral infection. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wu-han, China, and spread throughout the world. Coronavirus is indeed an enveloped RNA virus of the ge-nus Betacoronavirus, which is transmitted to birds, humans as well as other mammals. The fastest human to human transition has been generally established. On July 19, 2020, the WHO has reported total confirmed cases: 1,40, 43,176, total confirmed new cases: 1,66,735, total deaths: 5,97,583, and total new deaths: 4,496 globally. Material(s) and Method(s): In this review, the Clinical trial database is analyzed and systematically summarized drugs which are in the recruiting phase and the completion phase of the clinical trial. Result(s): Total 383 clinical trials are listed, involving more than 350 medicines such as Deferoxamine, Favipiravir, DAS181, Tocilizumab Injection, Sarilumab, Placebo, Sildenafil citrate tablets, Sargramo-stim, Lopinavir/ritonavir, Remdesivir, Bevacizumab, Tetrandrine, Fingolimod, Methylprednisolone, Plaquenil, Tocilizumab, Hydroxychloroquine, Abidol hydrochloride, Bevacizumab Injection, Methyl-prednisolone, Amoxicillin-clavulanate, Moxifloxacin, Sarilumab, Darunavir, Cobicistat, etc. Conclusion(s): There is no commercially authorized antiviral treatment or vaccine suitable for use against COVID-19. However, clinical trials represent an effective approach because they facilitate the development of new types of pharmaceutical drugs.Copyright © 2021 Bentham Science Publishers.

SARS-CoV-2 Infection-Of Music and Mechanics of Its Spikes! A Perspective.

The COVID-19 pandemic has been inflicted upon humanity by the SARS-CoV-2 virus, the latest insidious incarnation of the coronaviruses group. While in its wake intense scientific research has produced breakthrough vaccines and cures, there still exists an immediate need to further understand the origin, mechanobiology and biochemistry, and destiny of this virus so that future pandemics arising from similar coronaviruses may be contained more effectively. In this Perspective, we discuss the various evidential findings of virus propagation and connect them to respective underpinning cellular biomechanical states leading to corresponding manifestations of the viral activity. We further propose avenues to tackle the virus, including from a "musical" vantage point, and contain its relentless strides that are currently afflicting the global populace.

In Silico Study of Five SARS CoV-2 Target Proteins on Known Drugs

COVID-19 is an infectious disease that started at the end of 2019 in China then became pandemic worldwide. A number of crystal structures of coronavirus proteins are available in the Protein Data Bank. In this paper, we reported results from the virtual screening of databases including 2701 FDA approved drugs against five known coronavirus protein targets. Our results showed a wide range of scores for different drugs of which some were predicted to be active against one or some of the proteins. Among all of the compounds with higher scores, tannic acid and cobicistat showed to be active against four and two of the studied proteins respectively. Tannic acid which was reported to be an antiviral and potent inhibitor of hepatitis C virus activity and cobicistat with anti-HIV activity might be useful for the cure of COVID-19. According to the results, we suggest more studies on these valuable potential drugs. © 2021, Iranian Association of Pharmaceutical Scientists. All rights reserved.

The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters.

Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.

ORAL BACTERIOTHERAPY IN PATIENTS WITH COVID-19: A RETROSPECTIVE COHORT STUDY

Oral bacteriotherapy with SAB51 has been previously evidenced as support of standard care in treating patients hospitalized for SARS-CoV2 pneumonia and associated gastrointestinal symptoms leading to a significantly decreased risk of developing respiratory failure. This study aimed to compare the rate of mortality, the need for ICU hospitalization, and the length of hospitalization in patients with severe COVID-19 pneumonia who received the best available therapy in Italy (BAT) versus patients treated with BAT and supplemented with SLAB51. 200 adults (≥18 years) hospitalized from March 6 until April 26, 2020 with severe COVID-19 pneumonia and needing oxygen support were investigated. All patients received therapeutic regimens including hydroxychloroquine (200 mg twice a day for 7 days), azithromycin (500 mg once a day for 7 days), lopinavir–ritonavir (400/100 mg twice a day) or darunavir–cobicistat (800/150 mg once a day) for 14 days, and low molecular weight heparin. Out of the 200 patients, 112 received BAT without oral bacteriotherapy and 88 BAT with SLAB51. Crude mortality was 22%. Significantly higher mortality has been observed in the group of patients managed only with BAT (30%) to that treated with BAT plus SLAB51 (11%). In both groups, the highest mortality was registered for the combination of Tocilizumab and hydroxychloroquine and Tocilizumab. By multivariate analysis, the age >65 years, PCR >41.8 mg/L, Platelets <150.000 mmc, and CV events were associated with increased mortality risk. Overall results evidenced that oral bacteriotherapy with SLAB51 was an independent variable associated with a reduced risk for death.(Image presented) Death probability. Kaplan-Meier curves displaying Best Available therapy (BAT) versus BAT and oral bacteriotherapy.

Oral Bacteriotherapy In The Managemente Of Fatigue In Covid-19 Patients

Prolonged Fatigue, have been reported in many Covid-19 patients. There is a mounting suspicion that SARS-CoV2 acts as a catalyst for a condition known as chronic fatigue syndrome (CFS). Oral bacteriotherapy with SAB51 has been previously evidenced as support of standard care in ameliorating SARS-CoV2 pneumonia and associated gastrointestinal symptoms. This study aimed to evaluate the effectiveness of SLAB51 in preventing or contrasting CFS in patients hospitalized for SARS-CoV2 infection. 65 hospitalized adults with severe COVID-19 pneumonia have been enrolled. All patients received the best available therapy (BAT), including hydroxychloroquine, azithromycin, lopinavir–ritonavir, or daru-navir–cobicistat for 7 days, and low molecular weight heparin. In addition to the above treatments, 32 randomly chosen patients initiated oral bacteriotherapy with the multistrain probiotic SLAB51. Before starting therapies, a venous blood sample was collected to evaluate a complete set of biochemical features, including asparagine and lactate levels. A second blood sample has been collected after 7 days of treatment. At hospital discharge, patients were administered with the Fatigue Assessment Scale (FAS) according to that previously reported by De Vries and colleagues in 2004. Discharged subjects were asked to compile a second FAS relative to conditions experimented at admittance. A value of FAS≥21 was considered to assess the presence of chronic fatigue. At admittance, no significant differences were determined between the group of patients treated only with BAT and that additionally administered with oral bacteriotherapy for age, sex, the prevalence of Fatigue, and levels of biochemical features. Obtained results evidenced a significant increase of asparagine and lactate levels in the group of patients administered with SLAB51 after a 7 days treatment. In contrast, no significant differences were observed for the group of subjects receiving only BAT. Observed levels of asparagine and lactate were significantly higher in subjects administered with oral bacteriotherapy to those observed for the patients treated with BAT only. Notably, at hospital discharge, the group of patients receiving only BAT, presented a considerable increase in the proportion of subjects positive for CFS. In comparison, an invariant prevalence of CFS positive patients were observed in the group administered with SLAB51. Furthermore, a significant association between CFS development and the lack of oral bacteriotherapy supplementation has been observed. Obtained results strongly evidenced that oral bacteriotherapy could represent a promising therapeutic strategy in reducing fatigue and preventing CFS development above all in fragile subjects. Furthermore, our findings contribute to stress the importance of the modulation of gut microbiota in influencing the outcome of Covid-19 patients. (Figure Presented)

Data on the stability of darunavir/cobicistat suspension after tablet manipulation.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia.

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment.

Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can only be given by intravenous route, and there is a pressing medical need for oral antivirals. Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated. We performed an in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) assessment to examine the potential of RDV, and particularly GS-441524, as oral drugs. In our in vitro assessments, RDV exhibited prohibitively low stability in human liver microsomes (HLMs, t 1/2 = âˆ¼1 min), with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety. This observation is poorly aligned with any potential oral use of RDV, though in the presence of cobicistat, the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH. Conversely, GS-441524 showed excellent metabolic stability in human plasma and HLMs. In further in vivo studies in CD-1 mice, GS-441524 displayed a favorable oral bioavailability of 57%. Importantly, GS-441524 produced adequate drug exposure in the mice plasma and lung, and was effectively converted to the active triphosphate, suggesting that it could be a promising oral antiviral drug for treating COVID-19.

The Use of Antiviral Agents against SARS-CoV-2: Ineffective or Time and Age Dependent Result? A Retrospective, Observational Study among COVID-19 Older Adults.

BACKGROUND: Our aim was to investigate the impact of therapeutics with antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mortality of older adults affected by coronavirus disease 2019 (COVID-19), taking into consideration the time interval from symptoms onset to drugs administration. METHODS: Data from 143 COVID-19 patients over 65 years of age admitted to the Humanitas Clinical and Research Center Emergency Department (Milan, Italy) and treated with Lopinavir/ritonavir (LPV/r) or Darunavir/cobicistat (DVR/c) associated to Hydroxychloroquine (HCQ) were retrospectively analyzed. Statistical analysis was performed by using a logistic regression model and survival analysis to assess the role of different predictors of in-hospital mortality, including an early (<6 days from symptoms onset) vs. late treatment onset, signs and symptoms at COVID-19 presentation, type of antiviral treatment (LPV/r or DVR/c) and patients' age (65-80 vs. >80 years old). RESULTS: Multivariate analysis showed that an older age (OR: 2.54) and dyspnea as presenting symptom (OR: 2.01) were associated with higher mortality rate, whereas cough as presenting symptom (OR: 0.53) and a timely drug administration (OR: 0.44) were associated with lower mortality. Survival analysis demonstrated that the timing of drug administration had an impact on mortality in 65-80 years-old patients (p = 0.02), whereas no difference was seen in those >80 years-old. This impact was more evident in patients with dyspnea as primary symptom of COVID-19, in whom mortality decreased from 57.1% to 38.3% due to timely drug administration (OR: 0.5; p = 0.04). CONCLUSIONS: There was a significant association between the use of a combined antiviral regimen and HCQ and lower mortality, when timely-administered, in COVID-19 patients aged 65-80 years. Our findings support timely treatment onset as a key component in the treatment of COVID-19.

Use of Darunavir-Cobicistat as a Treatment Option for Critically Ill Patients with SARS-CoV-2 Infection.

We retrospectively reviewed patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who were admitted to an intensive care unit in Daegu, South Korea. The outcomes of patients who did (cases) or did not (controls) receive darunavir-cobicistat (800-150 mg) therapy were compared. Fourteen patients received darunavir-cobicistat treatment, and 96 received other antiviral therapy (controls). Overall, the darunavir-cobicistat group comprised patients with milder illness, and the crude mortality rate of all patients in the darunavir-cobicistat group was lower than that in the controls [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.04-0.89, p=0.035]. After 1:2 propensity-score matching, there were 14 patients in the darunavir-cobicistat group, and 28 patients in the controls. In propensity score-matched analysis, the darunavir-cobicistat group had lower mortality than the controls (OR 0.07, 95% CI 0.01-0.52, p=0.009). In conclusion, darunavir-cobicistat therapy was found to be associated with a significant survival benefit in critically ill patients with SARS-CoV-2 infection.

Identification of potential drug candidates to combat COVID-19: a structural study using the main protease (mpro) of SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19 has become a global pandemic that is spreading rapidly and has caused a global health emergency. Hence, there is an urgent need of the hour to discover effective drugs to control the pandemic caused by this virus. Under such conditions, it would be imperative to repurpose already known drugs which could be a quick and effective alternative to discovering new drugs. The main protease (Mpro) of SARS-COV-2 is an attractive drug target because of its essential role in the processing of the majority of the non-structural proteins which are translated from viral RNA. Herein, we report the high-throughput virtual screening and molecular docking studies to search for the best potential inhibitors against Mpro from FDA approved drugs available in the ZINC database as well as the natural compounds from the Specs database. Our studies have identified six potential inhibitors of Mpro enzyme, out of which four are commercially available FDA approved drugs (Cobicistat, Iopromide, Cangrelor, and Fortovase) and two are from Specs database of natural compounds (Hopeaphenol and Cyclosieversiodide-A). While Cobicistat and Fortovase are known as HIV drugs, Iopromide is a contrast agent and Cangrelor is an anti-platelet drug. Furthermore, molecular dynamic (MD) simulations using GROMACS were performed to calculate the stability of the top-ranked compounds in the active site of Mpro. After extensive computational studies, we propose that Cobicistat and Hopeaphenol show potential to be excellent drugs that can form the basis of treating COVID-19 disease.Communicated by Ramaswamy H. Sarma.