The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study.

PURPOSE: Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID. METHODS: This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection. RESULTS: A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16-8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30-3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21-0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25-0.92). CONCLUSIONS: We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.

Current clinical status of new COVID-19 vaccines and immunotherapy.

COVID-19, caused by SARS-CoV-2, is a positive-strand RNA belonging to Coronaviridae family, along with MERS and SARS. Since its first report in 2019 in Wuhan, China, it has affected over 530 million people and led to 6.3 million deaths worldwide until June 2022. Despite eleven vaccines being used worldwide already, new variants are of concern. Therefore, the governing bodies are re-evaluating the strategies for achieving universal vaccination. Initially, the WHO expected that vaccines showing around 50-80% efficacy would develop in 1-2 years. However, US-FDA announced emergency approval of the two m-RNA vaccines within 11 months of vaccine development, which enabled early vaccination for healthcare workers in many countries. Later, in January 2021, 63 vaccine candidates were under human clinical trials and 172 under preclinical development. Currently, the number of such clinical studies is still increasing. In this review, we have summarized the updates on the clinical status of the COVID-19 and the available treatments. Additionally, COVID-19 had created negative impacts on world's economy; affected agriculture, industries, and tourism service sectors; and majorly affected low-income countries. The review discusses the clinical outcomes, latest statistics, socio-economic impacts of pandemic and treatment approaches against SARS-CoV-2, and strategies against the new variant of concern. The review will help understand the current status of vaccines and other therapies while also providing insights about upcoming vaccines and therapies for COVID-19 management.

COVID-19 therapies: do we see substantial progress?

The appearance of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its spread all over the world is the cause of the coronavirus disease 2019 (COVID-19) pandemic, which has recently resulted in almost 400 million confirmed cases and 6 million deaths, not to mention unknown long-term or persistent side effects in convalescent individuals. In this short review, we discuss approaches to treat COVID-19 that are based on current knowledge of the mechanisms of viral cell receptor recognition, virus-host membrane fusion, and inhibition of viral RNA and viral assembly. Despite enormous progress in antiviral therapy and prevention, new effective therapies are still in great demand.

Computational Prediction of the Potential Target of SARS-CoV-2 Inhibitor Plitidepsin via Molecular Docking, Dynamic Simulations and MM-PBSA Calculations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the interaction between the viral proteins and the human translation machinery. The cytotoxic peptide plitidepsin was found to inhibit CoV-2 up to 90 % at a concentration of 0.88 nM. In vitro studies suggest that this activity may be attributed to the inhibition of the eukaryotic translation elongation factor 1A (eEF1A). However, recent reports raised the potential for other cellular targets which plitidepsin may use to exert its potent antiviral activity. The lack of data about these potential targets represents a major limitation for its structural optimization. This work describes the use of a molecular modeling approach to rationalize the in vitro antiviral activity of plitidepsin and to identify potential cellular targets. The developed protocol involves an initial molecular docking step followed by molecular dynamics and binding free energy calculations. The results reveal the potential for plitidepsin to bind to the active site of the key enzyme SARS-CoV-2 RdRp. The results also highlight the importance of van der Waals interactions for proper binding with the enzyme. We believe that the results presented in this study could provide the grounds for the optimization of plitidepsin analogs as SARS-CoV-2 inhibitors.

Establishing a Distribution Network for COVID-19 Monoclonal Antibody Therapy Across a Large Health System During a Global Pandemic.

Emergency authorized coronavirus disease 2019 (COVID-19)-neutralizing monoclonal antibodies can aid outpatients with mild to moderate COVID-19 infection. Many report barriers to adequate distribution and uptake. We present our model for distribution in a large health system as well as early lessons learned.

Pharmacogenomic landscape of COVID-19 therapies from Indian population genomes.

Aim: Numerous drugs are being widely prescribed for COVID-19 treatment without any direct evidence for the drug safety/efficacy in patients across diverse ethnic populations. Materials & methods: We analyzed whole genomes of 1029 Indian individuals (IndiGen) to understand the extent of drug-gene (pharmacogenetic), drug-drug and drug-drug-gene interactions associated with COVID-19 therapy in the Indian population. Results: We identified 30 clinically significant pharmacogenetic variants and 73 predicted deleterious pharmacogenetic variants. COVID-19-associated pharmacogenes were substantially overlapped with those of metabolic disorder therapeutics. CYP3A4, ABCB1 and ALB are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four CYP inhibitor drugs. Conclusion: Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

In silico identification of novel SARS-COV-2 2'-O-methyltransferase (nsp16) inhibitors: structure-based virtual screening, molecular dynamics simulation and MM-PBSA approaches.

The novel coronavirus disease COVID-19, caused by the virus SARS CoV-2, has exerted a significant unprecedented economic and medical crisis, in addition to its impact on the daily life and health care systems all over the world. Regrettably, no vaccines or drugs are currently available for this new critical emerging human disease. Joining the global fight against COVID-19, in this study we aim at identifying a potential novel inhibitor for SARS COV-2 2'-O-methyltransferase (nsp16) which is one of the most attractive targets in the virus life cycle, responsible for the viral RNA protection via a cap formation process. Firstly, nsp16 enzyme bound to Sinefungin was retrieved from the protein data bank (PDB ID: 6WKQ), then, a 3D pharmacophore model was constructed to be applied to screen 48 Million drug-like compounds of the Zinc database. This resulted in only 24 compounds which were subsequently docked into the enzyme. The best four score-ordered hits from the docking outcome exhibited better scores compared to Sinefungin. Finally, three molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for our proposed approach. The MD and MM-PBSA outputs revealed compound 11 as the best potential nsp16 inhibitor herein identified, as it displayed a better stability and average binding free energy for the ligand-enzyme complex compared to Sinefungin.

Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign.

Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients.

Most of drugs could have certain mucocutaneous reactions and COVID-19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti-viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug-induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life-threatening reactions may occur. Better management strategies could achieve by knowing more about drug-induced mucocutaneous presentations of COVID-19.