Covid-19: New Use of Therapeutics

Severe acute respiratory syndrome novel virus (SARS-CoV-2), after its origin from probably bats in Wuhan, China, has spread all over the world within around 2–3 months of origin, called as Covid-19 pandemic. The virus has infected nearly 10 million people globally with over 500, 000 deaths. Industry and academia globally are involved in developing repurposed drugs and vaccines as also developing new drugs, monoclonal antibodies and vaccines. Over 1200 molecules (including monoclonal antibodies and stem cells) and 180 plus vaccines are in clinical trials or under development. Hydroxychloroquine, remdesivir, favipiravir and a number of antivirals are in clinical use to save lives. Dexamethasone, a life-saving drug, has also been used in critical patients on support system. A monoclonal antibody and about five vaccines have reached Phase II–III clinical trials;one vaccine in India has entered Phase I clinical trial. BCG, mycobacterium W and polio vaccine are also under trial to treat Covid-19. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.

Haematological changes and metabolic alterations in SARS-CoV-2 infected patients hospitalised at an Infectious Diseases Center, Ibadan, Nigeria

Introduction and aim. Following the use of repurposing drugs to successfully manage coronavirus disease 2019 (COVID-19) patients in an Infectious Diseases Center (IDC) in Nigeria, it was imperative to assess haematological changes and metabolic alterations in these patients which may inform recommendations for future use. Material and methods. Blood samples of admitted COVID-19 Nigerian patients during therapeutic management were analysed for haematological- (total white blood cells (WBC), lymphocyte, monocyte, neutrophil, eosinophil, basophil and neutrophil:lymphocyte ratio) and blood chemistry-parameters [total protein, total and conjugated bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), albumin, urea, creatinine, total cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), PO43-, Ca2+, uric acid, Na+, K+, Cl- and HCO3-] using autoanalysers. The percentages of patients having values below, within and above reference ranges were compared using Chi-square test while the mean values at admission were compared with mean values at discharge using Student t-test. Results. The mean values of total protein, albumin, Na+, HCO3-, uric acid, Ca2+, WBC, platelets, lymphocytes, eosinophils and basophils were significantly increased in COVID-19 patients at discharge compared with COVID-19 patients at admission. Also, more percentages of COVID-19 patients at discharge compared with COVID-19 patients at admission had albumin, ALP, total bilirubin, HDL, Na+, K+, Cl-, HCO3-, urea, creatinine, WBC, lymphocytes, neutrophils, monocytes, eosinophils and basophils within normal reference intervals. Conclusion. This study showed that most metabolic and haematological derangements were normalised by repurposing drugs in most of the COVID-19 patients at this IDC, thus supporting the continuous use of this therapeutic option. © 2022 Universidad Nacional de Colombia, , Department of Linguistics. All rights reserved.

Transmission, Prevention and Therapeutic Strategies for COVID-19: Updates and Challenges

Background: Almost the whole world is observing a pandemic like never before in the last century, affecting the human lifestyle and economies known as coronavirus disease-2019 (COVID-19). A new severe acute respiratory syndrome that has emerged in China in late 2019 and spread in more than 210 countries makes a global health care emergency. Objective(s): Considering the epidemiological features of COVID-19, it is crucial to prevent the spread of such a highly infectious disease through effective control methods such as early detec-tion, isolation, and treatment strategies. Conclusion(s): This review highlights the SARS-CoV-2 transmission routes among communities and control measures, improving the quarantine and isolation of infected individuals. The "gold stan-dard" molecular and other rapid diagnostic tests used to detect SARS-CoV-2 with their benefits and limitations have been reported. Several repurposed drugs, including antivirals trailed for COVID-19 patients, and supportive treatments, such as general, cellular, and immune therapies with the role of vitamins in the safe deployment for COVID-19 patients, have been discussed. Fi-nally, the review also encompasses an overview and update about the recent development of COVID-19 vaccines and ongoing clinical studies, providing further research advances.Copyright © 2021 Bentham Science Publishers.

Repositioning of Drugs as a Promising Strategy to Fight COVID-19

Background and Objective: With the initial case of corona reported in Wuhan, China on 31st December 2020, there has been an unprecedented rise in the coronavirus disease (COVID-19), with over 200 countries all across the world in less than 3 months. By the October 2020, about 40 million population of the world got infected and over one million deaths occurred. Since no WHO and FDA approved medications or vaccines for COVID-19 were available, there was an impatient bustling need to develop a drug for the treatment. Drug repurposing emerged as the easiest and fast emerging strategy to get medicine for COVID-19 with rapid approvals for the clinical trials. The purpose of this study was to evaluate the status of drug repurposing under the clinical and its impact on the development of medicine for COVID-19. Method(s): The study was undertaken to review various clinical trials from the website. www.clinicaltrials.gov. We evaluated 220 ongoing clinical trials with the strategy of 'drug repur-posing' against COVID-19, analyzed them as per their chemical structure and possible biological targets. Result(s): It was noticed that some of the early repurposed drugs like chloroquine, hydroxychloro-quine, ACE inhibitors and ARBs, did not succeed and remained controversial. While many of the antiviral drugs like remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir could be taken for the clinical trials in various countries, remdesivir could succeed to a great extent as compared to other drugs. WHO has come up with an initiative known as multi-country 'Solidarity Trial' for developing a potential drug or therapy against COVID-19.However, the most preferred drugs used for re-purposing like hydroxychloroquine and remdesivir have not shown predictable results in solidarity trials. Conclusion(s): The analyses of several ongoing and partially concluded clinical trials suggest that drug repurposing can be one of the major strategies for the treatment of COVID-19. Further, guidelines framed by the WHO through Infection Prevention and Control for monitoring the widespread of this COVID-19 across the world is another aggressive attempt to find the solution for the treatment for COVID-19.Copyright © 2021 Bentham Science Publishers.

Credible Protein Targets and Curative Strategies for COVID-19: a Review.

The pandemic of coronavirus infection 2019 (COVID-19) due to the serious respiratory condition created by the coronavirus 2 (SARS-CoV-2) presents a challenge to recognize effective strategies for management and treatment. In general, COVID-19 is an acute disease that can also be fatal, with an ongoing 10.2% case morbidity rate. Extreme illness may bring about death because of enormous alveolar damage and hemorrhage along with progressive respiratory failure. The rapidly expanding information with respect to SARS-CoV-2 research suggests a substantial number of potential drug targets. The most encouraging treatment to date is suggested to be with the help of remdesivir, hydroxychloroquine, and many such repurposed drugs. Remdesivir has a strong in vitro activity for SARS-CoV-2, yet it is not the drug of choice as affirmed by the US Food and Drug Administration and presently is being tried in progressing randomized preliminaries. The COVID-19 pandemic has been the worst worldwide general health emergency of this age and, possibly, since the pandemic influenza outbreak of 1918. The speed and volume of clinical preliminaries propelled to examine potential treatments for COVID-19 feature both the need and capacity to create abundant evidence even in the center of a pandemic. No treatments have been demonstrated as accurate and dependable to date. This review presents a concise precise of the targets and broad treatment strategies for the benefit of researchers.

Corticosteroids: A boon or bane for COVID-19 patients?

Several drugs and antibodies have been repurposed to treat COVID-19. Since the outcome of the drugs and antibodies clinical studies have been mostly inconclusive or with lesser effects, therefore the need for alternative treatments has become unavoidable. However, corticosteroids, which have a history of therapeutic efficacy against coronaviruses (SARS and MERS), might emerge into one of the pandemic's heroic characters. Corticosteroids serve an immunomodulatory function in the post-viral hyper-inflammatory condition (the cytokine storm, or release syndrome), suppressing the excessive immunological response and preventing multi-organ failure and death. Therefore, corticosteroids have been used to treat COVID-19 patients for more than last two years. According to recent clinical trials and the results of observational studies, corticosteroids can be administered to patients with severe and critical COVID-19 symptoms with a favorable risk-benefit ratio. Corticosteroids like Hydrocortisone, dexamethasone, Prednisolone and Methylprednisolone has been reported to be effective against SARS-CoV-2 virus in comparison to that of non-steroid drugs, by using non-genomic and genomic effects to prevent and reduce inflammation in tissues and the circulation. Clinical trials also show that inhaled budesonide (a synthetic corticosteroid) increases time to recovery and has the potential to reduce hospitalizations or fatalities in persons with COVID-19. There is also a brief overview of the industrial preparation of common glucocorticoids.

Therapeutics for the management of cytokine release syndrome in COVID-19.

Coronavirus disease (COVID-19) is the greatest pandemic of this era and has affected more than 10 million people across 213 nations. However, the etiology, management, and treatment of COVID-19 remain unknown. A better understanding of the novel virus would help in developing accurate diagnostic methods and efficacious drugs for the treatment of patients of all age groups. To control the pandemic urgently, many drugs are being repurposed and several clinical trials are in progress for the same. As cytokine storm has been observed to be one of the common mechanisms of immune response in COVID-19 patients, several drugs are under trials to control the cytokine storm. In this review, we discuss the different categories of drugs in clinical trials for the management of cytokine storms in COVID-19 patients. Hitherto, several promising candidates such as IL-1 and IL-6 inhibitors have failed to display efficacy in the trials. Only corticosteroid therapy has shown benefit so far, albeit limited to patients on ventilator support. Thus, it is crucial to seek novel strategies to combat hyperinflammation and increase survival in COVID-19 afflicted patients.

Repurposing of chemotherapeutics to combat COVID-19.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a novel strain of SARS coronavirus. The COVID-19 disease caused by this virus was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 mainly spreads through droplets sprayed by coughs or sneezes of the infected to a healthy person within the vicinity of 6 feet. It also spreads through asymptomatic carriers and has negative impact on the global economy, security and lives of people since 2019. Numerous lives have been lost to this viral infection; hence there is an emergency to build up a potent measure to combat SARS-CoV-2. In view of the non-availability of any drugs or vaccines at the time of its eruption, the existing antivirals, antibacterials, antimalarials, mucolytic agents and antipyretic paracetamol were used to treat the COVID-19 patients. Still there are no specific small molecule chemotherapeutics available to combat COVID-19 except for a few vaccines approved for emergency use only. Thus, the repurposing of chemotherapeutics with the potential to treat COVID-19 infected people is being used. The antiviral activity for COVID-19 and biochemical mechanisms of the repurposed drugs are being explored by the biological assay screening and structure-based in silico docking simulations. The present study describes the various US-FDA approved chemotherapeutics repositioned to combat COVID-19 along with their screening for biological activity, pharmacokinetic and pharmacodynamic evaluation.

Highlights in TMPRSS2 inhibition mechanism with guanidine derivatives approved drugs for COVID-19 treatment.

Transmembrane protease serine 2 (TMPRSS2) has been identified as a critical key for the entry of coronaviruses into human cells by cleaving and activating the spike protein of SARS-CoV-2. To block the TMPRSS2 function, 18 approved drugs, containing the guanidine group were tested against TMPRSS2's ectodomain (7MEQ). Among these drugs, Famotidine, Argatroban, Guanadrel and Guanethidine strongly binds with TMPRSS2 S1 pocket with estimated Fullfitness energies of -1847.12, -1630.87, -1605.81 and -1600.52 kcal/mol, respectively. A significant number of non-covalent interactions such as hydrogen bonding, hydrophobic and electrostatic interactions were detected in protein-ligand complexes. In addition, the ADMET analysis revealed a perfect concurrence with the aptitude of these drugs to be developed as an anti-SARS-CoV-2 therapeutics. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior and stability of protein-ligand complexes. The results obtained herein highlight the enhanced stability and good binding affinities of the Argatroban and Famotidine towards the target protein, hence might act as new scaffolds for TMPRSS2 inhibition. Communicated by Ramaswamy H. Sarma.

Brief History, Pathophysiology, Transmission of SARS-CoV-2 Virus, and Recent Advances on Transition Metal Complexes and Nanocomposites as the Potent Antiviral Agents from COVID-19 Perspectives

The outbreak of SARS-CoV-2 has resulted in an unprecedented and greatest global health crisis in the present century affecting more than 220 countries with 3.7 million deaths and 173.5 million individual infections till now. This pandemic has had an enormous impact on global healthcare, economy, and society, which has prompted extensive research on exploring the biology of SARS-CoV-2 and the discovery of new drugs for COVID-19. The lack of effective antiviral drugs for COVID-19 has initiated the effort to repurpose selected FDA-approved antiviral drugs for the treatment of COVID-19 along with plasma therapy. Vaccination has proven to be the effective prevention strategy against the SARS-CoV-2 virus, although mutations in the SARS-CoV-2 virus have become the major concern due to the decreasing effectiveness of the vaccines Therefore, an effective cure for COVID-19 is still an elusive goal. Transition metal complexes by a broad spectrum of formal charge and oxidation states, wide range of coordination number and geometry, tunable kinetic, thermodynamic, and redox properties, diverse reaction pathways have emerged as the alternative and viable tools in the medicinal domain from therapeutics to diagnostics. Several transition metal complexes proved their efficacy against various types of viruses and recent advances on the potent transition metal complexes or nanoconjugates are reviewed in this chapter. The present chapter also aims to discuss the perspectives on the potential utility of transition metal complexes or the nanoconjugates against SARS-CoV-2. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

Impact of fluvoxamine on outpatient treatment of COVID-19 in Honduras in a prospective observational real-world study.

Background: The COVID-19 pandemic has impacted millions of lives globally. While COVID-19 did not discriminate against developed or developing nations, it has been a significant challenge for third world countries like Honduras to have widespread availability of advanced therapies. The concept of early treatment was almost unheard of when early outpatient treatments utilizing repurposed drugs in Latin American countries began showing promising results. One such drug is fluvoxamine, which has shown tremendous potential in two major studies. As a direct result, fluvoxamine was added to the standard of care in a major medical center outpatient COVID-19 clinic. Methods: This is a prospective observational study performed at the Hospital Centro Médico Sampedrano (CEMESA) in San Pedro Sula, Cortes, Honduras in the COVID-19 outpatient clinic. All patients were at least 15 years of age who had presented with mild or moderate signs and symptoms of COVID-19, and who also had a documented positive SARS-CoV-2 antigen or Reverse Transcription Polymerase Chain Reaction (RT-PCR) were included in the study. These patients then were all prescribed fluvoxamine. The cohort of patients who decided to take fluvoxamine were compared for primary endpoints of mortality and hospitalization risk to the cohort who did not take fluvoxamine. Patients were then monitored for 30 days with the first follow up at 7 days and the second follow up at 10-14 days of symptom onset. Categorical variables were compared by Pearson Chi-square test. The Relative risk was calculated using regression models. Continuous variables were compared by t-test and Wilcoxon rank-sum tests. Results: Out of total 657 COVID-19 cases, 594 patients took fluvoxamine and 63 did not take fluvoxamine. A total of five patients (0.76 percent) died, with only one death occurring in the fluvoxamine group. Patients who received fluvoxamine had a significantly lower relative risk of mortality (RR 0.06, p 0.011, 95% CI 0.007-0.516). There was a lower relative risk of hospitalization in the patients who in the fluvoxamine group. (-10 vs. 30 hospitalizations, RR 0.49, p = 0.035, 95% CI 0.26-0.95). There was 73 percent reduction in relative risk of requiring oxygen in the fluvoxamine group (RR 0.27, p < 0.001, 95% CI 0.14-0.54 Mean lymphocytes count on the first follow-up visit was significantly higher in the fluvoxamine group (1.72 vs. 1.38, Δ 0.33, p 0.007, CI 0.09-0.58). Conclusion: The results of our study suggest that fluvoxamine lowers the relative risk of death, hospitalization, and oxygen requirement in COVID 19 patients.

Dynamics and binding affinity of nucleoside and non-nucleoside inhibitors with RdRp of SARS-CoV-2: a molecular screening, docking, and molecular dynamics simulation study.

In this COVID-19 pandemic situation, an appropriate drug is urgent to fight against this infectious disease to save lives and prevent mortality. Repurposed drugs and vaccines are the immediate solutions for this medical emergency until discover a new drug to treat this disease. As of now, no specific drug is available to cure this disease completely. Several drug targets were identified in SARS-CoV-2, in which RdRp protein is one of the potential targets to inhibit this virus infection. In-Silico studies plays a vital role to understand the binding nature of the drugs at the atomic level against the disease targets. The present study explores the binding mechanism of reported 53 nucleoside and non-nucleoside RdRp inhibitors and Ivermectin which are in clinical trials. These molecules were screened by molecular docking simulation; in which, the molecules are showing high binding affinity and forming interactions with the key amino acids of active site of RdRp protein are chosen for molecular dynamics simulation (MD) and binding free energy analysis. The results of molecular docking and MD simulation studies reveal that IDX184 is a stable molecule and forms strong interactions with the key amino acids and shows high binding affinity towards RdRp. Hence, IDX184 may also be considered as a potential inhibitor of RdRp after clinical study.Communicated by Ramaswamy H. Sarma.

Drug Repurposing: a Shortcut to New Biological Entities.

Drug repurposing has proved to be an efficient alternative to drug discovery owing to the facts that it is economical and risk factors being much lower or even negligible as the drug has already been approved for having safe use in humans. The contrast of drug discovery from drug repurposing, its advantages and the challenges faced during the process are the important factors to be considered in drug repurposing. The approaches in drug discovery include three methods namely computational, biological and mixed. Moreover, the recent advancement in application of drugs for COVID-19 proved drug repurposing is a vital strategy in medical science for the upcoming years.

State-of-the-art tools to elucidate the therapeutic potential of TAT-peptide (TP) conjugated repurposing drug against SARS-CoV-2 spike glycoproteins.

BACKGROUND: In late 2019, a highly infectious and pathogenic coronavirus was recognized as Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) which causes acute respiratory disease, threatening human health and public safety. A total of 448,327,303 documented cases and 6,028,576 deaths have been reported as of March 8th 2022. The COVID-19 vaccines currently undergoing clinical trials or already in use should provide at least some protection against SARS-CoV-2; however, the emergence of new variations as a result of mutations may lessen the effectiveness of the currently available vaccines. Since the efficacy of available drugs and vaccines against COVID-19 is notably lower, there is an urgent need to develop a potential drug to treat this deadly disease. The SARS-CoV-2 spike (SCoV-SG) is the foremost drug target among coronaviruses. ObjectiveL: The major objectives of the current study are to conduct a molecular docking study investigation of TAT-peptide47-57(GRKKRRQRRRP)-conjugated remodified therapeutics such as ritonavir (RTV), lopinavir (LPV), favipiravir (FPV), remdesivir (RMV), hydroxychloroquine (HCQ), molnupiravir (MNV) and nirmatrelvir (NMV) with (SCoV-SG) structure. METHODS: Molecular docking analysis was performed to study the interaction of repurposed drugs and drugs conjugated with the TAT-peptide with target SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) using AutoDock. Further docking investigation was completed with PatchDock and was visualized by discovery the studio visualizer 2020. RESULTS: TAT-peptides are well-characterized immune enhancers that are used in intracellular drug delivery. The results of molecular docking analysis showed higher efficiency and significantly enhanced and improved interactions between TP-conjugated repurposed drugs and the target sites of the SCoV-SG structure. CONCLUSION: The study concluded that TP-conjugated repurposed drugs may be effective in preventing COVID-19, and therefore, in vitro, in vivo, and clinical trial studies are required in detail.

Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues.

Coronavirus disease 2019 continues to spread worldwide. Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell-derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug-induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA-seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high-throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir-induced cardiotoxicity.

Insights on Epidemiology, Pathogenesis, Diagnosis and Possible Treatment of COVID-19 Infection.

The sudden outbreak of the novel coronavirus infection (COVID-19, SARS-CoV-2 virus) is posing a significant threat by affecting millions of people across the globe showing mild to severe symptoms of pneumonia and acute respiratory distress. The absence of precise information on primary transmission, diagnosis, prognosis, and therapeutics for patients with COVID-19 makes prevention and control tough. In the current scenario, only supportive treatment is available, which in turn possess a biggest challenge for scientists to develop specific drugs and vaccines for COVID-19. Further, India, with the second largest populated country and fluctuating climatic conditions quarterly, has high vulnerability towards COVID-19 infection. Thus, this highlights the importance of a better understanding of the COVID-19 infection, pathology, diagnosis and its treatment. The present review article has been intended to discuss the COVID-19 biology, mechanism of infection in humans with primary effects on pregnancy, the nervous system, diabetes, and cardiovascular disease. The article will also discuss the drug repurposing strategy as an alternative line of treatment and clinical practices recommended by the World Health Organization and other government agencies and represent the COVID-19 scenario with the Indian context.

Remdesivir and Its Combination With Repurposed Drugs as COVID-19 Therapeutics.

The SARS-CoV-2 virus needs multiple copies for its multiplication using an enzyme RNA-dependent RNA polymerase (RdRp). Remdesivir inhibits viral RdRp, controls the multiplication of the virus, and protects patients. However, treatment of COVID-19 with remdesivir involves adverse effects. Many ongoing clinical trials are exploring the potential of the combination of remdesivir with repurposed drugs by targeting multiple targets of virus and host human simultaneously. Better results were obtained with the remdesivir-baricitinib combination treatment for COVID-19 compared to the treatment with remdesivir alone. Notably, recovery from COVID-19 was found to be 8 days less via the remdesivir-baricitinib combination treatment as compared to remdesivir treatment alone. Furthermore, the mortality rate via the remdesivir-baricitinib combination treatment was lower compared to the remdesivir-only treatment. Remdesivir targets the SARS-CoV-2 enzyme while baricitinib targets the host human enzyme. Simultaneously, remdesivir and baricitinib as a combination inhibit their target viral RdRp and human Janus kinase, respectively. Ongoing trials for the combination of drugs will suggest in the future whether they may reduce the recovery time, reduce the mortality rate, and improve patient clinical status for noninvasive ventilation. In the future, simultaneously targeting virus replication enzymes and host human kinases may be the strategy for SARS-CoV-2 therapeutics.

A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. Secondary outcomes include mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

Difficulty in Repurposing Selective Serotonin Reuptake Inhibitors and Other Antidepressants with Functional Inhibition of Acid Sphingomyelinase in COVID-19 Infection.

The rapid spread of COVID-19 has become a health emergency causing an urgent need for drug treatments to control the outbreak, especially in more vulnerable individuals. This is reinforced by the fact that prophylactic vaccines and neutralizing monoclonal antibodies may not be fully effective against emerging variants. Despite all efforts made by the scientific community, efficient therapeutic options currently remain scarce, either in the initial, as well as in the advanced forms of the disease. From retrospective observational studies and prospective clinical trials, selective serotonin reuptake inhibitors (SSRIs), and other antidepressants with functional inhibition of acid sphingomyelinase (FIASMAs), have emerged as potential treatments of COVID-19. This has led to some prematurely optimistic points of view, promoting a large prescription of fluvoxamine in patients with COVID-19, that we think should be reasonably tempered.