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Coronavirus disease-19 (COVID-19) has disproportionately affected certain demographics in England, exacerbating existing health disparities. Effective therapeutics are a critical line of defence against COVID-19, particularly for patients at elevated risk for severe disease. Surveillance systems were established to monitor the usage of COVID-19 therapeutics in hospital and community settings and to inform stewardship. Three antiviral therapies—nirmatrelvir plus ritonavir (Paxlovid®), remdesivir (Veklury®), and molnupiravir (Lagevrio®)—and two neutralising monoclonal antibody therapies (nMAbs)—sotrovimab (Xevudy®) and casirivimab with imdevimab (Ronapreve®)—were in use in England between July 2020 and April 2023. This paper aims to illuminate trends in the utilisation of COVID-19 therapeutics treatment in both hospital and community settings, stratified by the Index of Multiple Deprivation (IMD) in England. Chapter 3 of the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) Report 2022 to 2023 also discusses the epidemiological surveillance of these five directly acting antiviral COVID-19 therapeutics' use in England between 2022 and 2023. [ABSTRACT FROM AUTHOR]

Introduction. On account of the generally milder symptoms in children and of the risk of remaining undiagnosed, diagnosis and treatment of children with COVID-19 remains a challenge for the medical community. The aim of this paper is to indicate the clinical characteristics of SARS-CoV-2 infection in children and also some preventive and therapeutic measures performed so far in pediatric cases. Materials and methods. In this rapid review, a comprehensive search was conducted on Scopus and PubMed databases, with the aim of observing the clinical characteristics, management, complications and treatment of pediatric cases diagnosed with COVID-19. A total number of 577 articles were found which, after eliminating the duplicates, were reduced to 544. To this end, 565 papers were screened by their title and abstract, finally 16 papers being included (only English papers were considered, the Chinese papers and databases being not analyzed). Results and discussion. Among the studies that explicitly referred to patients' clinical symptoms, the most common were fever and cough. Other less common symptoms include sore throat, throat obstruction, dyspnea and tachypnea, rhinorrhea, nasal congestion, throat erythema, sputum, cough, fatigue. Also, the most common treatments used included antiviral drugs, immune-based therapy, antibiotics and hydroxychloroquine. Conclusions. The results obtained showed that, in children, the symptoms of the disease can be different than in adults. The most common symptoms observed in children were fever, cough, gastrointestinal symptoms, runny nose, dyspnea and tachypnea. Most currently recommended were antiviral drugs, immunobased therapy, antibiotics, and hydroxychloroquine. [ABSTRACT FROM AUTHOR]

BACKGROUND: The pandemic caused by the novel coronavirus disease (COVID-19) since early 2020 is one of the most significant global health issues in history. Although there is currently no specific treatment for COVID-19, researchers have provided a whole array of potential treatments, both from the Western medicine approach, which is molecular target and pathogenesis based, and from the traditional Chinese medicine (TCM) approach, which is based on the exposure to toxins/pathogens and the balance of the body to combat them for recovery. OBJECTIVE: The aim of this research is to find combinations of Western medicine and TCM that may offer better therapeutic efficacy synergystically with a better adverse events profile. The findings of the research may provide a new insight in the development of the treatment of COVID-19. METHODS: From the Western medicine perspective, drugs target the mechanisms of viral infection, including the stages of viral entry (Arbidol, Camostat Mesylate, Convalescent Plasma therapy) and viral replication (Lopinavir/Ritonavir, Redemsivir, Ribavirin). Additional therapies target host defenses, preventing cytokine storms (Tocilizumab) and stimulating the immune system (Interferons). On the other hand, TCM also proposed a number of treatment methods for COVID-19 with new scientific approaches identifying their antiviral and immunomodulatory activities. The novel combination of Western medicine and TCM can be proposed by analyzing their respective molecular targets. RESULTS: Although TCM is not generally accepted in the Western community because of the general lack of knowledge on their detailed mechanisms, studies and clinical trials suggest that TCM could be beneficial in combating COVID-19. CONCLUSION: Based on the principle of combining TCM and Western medicine, two combinations are tested effective in clinical trials, and three possible combinations that might be effective are proposed in the paper. [ABSTRACT FROM AUTHOR]

Remdesivir (RDV) is the only antiviral drug approved for COVID-19 therapy by the FDA. Another drug LAGEVRIO™ (molnupiravir) though has not been approved yet by FDA but has been authorized on December 23, 2021, for emergency use to treat adults with mild-to moderate COVID-19 symptoms and for whom alternative COVID-19 treatment options are not clinically appropriate. The fact is that the efficacy of RDV is, however, limited in vivo though it is highly promising in vitro against SARS-CoV-2 virus. In this paper we are focusing on the action mechanism of RDV and how it can be improved in vivo. The stability of RDV alone and on encapsulation with our platform technology based polymer NV-387 (NV-CoV-2), were compared in presence of plasma in vitro and in vivo. Furthermore, a non-clinical pharmacology study of NV-CoV-2 (Polymer) and NV CoV-2 (Polymer encapsulated Remdesivir) in both NL-63 infected and uninfected rats was done. In addition, the antiviral activity of NV-CoV-2 and NV-CoV-2-R was compared with RDV in a cell culture study. The results are (i) NV-CoV-2 polymer encapsulation protects RDV from plasma-mediated catabolism in both in vitro and in vivo, studies; (ii) Body weight measurements of the normal (uninfected) rats after administration of the test materials (NV-CoV-2 and NV-CoV-2-R) showed no toxic effects. (iii) Body weight measurements and survival rates of the NL-63 infected rats were similar to the uninfected rats after treatment with NV-CoV-2 and NV-CoV-2-R. Overall, the efficacy as an antiviral regimens were found in this order as below; NV-CoV-2-R > NV-CoV-2 > RDV. Our platform technology based NV-387-encapsulated-RDV (NV-CoV-2-R) drug has a dual effect against different variants of the coronaviruses. First, NV-CoV-2 is an antiviral regimen. Secondly, RDV is protected from plasma-mediated degradation in transit. All together, NV-CoV-2-R is the safest and efficient regimen against COVID-19. [ABSTRACT FROM AUTHOR]

The corona virus disease 2019 (COVID-19) pandemic, which originated in the city of Wuhan, China, has rapidly spread to various countries, with many cases having been reported. Some existing antiviral agents showed positive results to inhibit the infection and transmission of the novel corona virus 2019 (2019-nCoV) in vitro. Covaxin is India's first indigenous COVID-19 vaccine. In this paper, we introduce the Gourava and hyper-Gourava polynomials of a graph. We compute the Gourava and hyper-Gourava polynomials of some specific class of graphs. Further, we obtain the Gourava and hyper-Gourava polynomials of some chemical structures viz., chloroquine, hydroxychloroquine, remdesivir and theaflavin which were used in the treatment of COVID-19. The Gourava and hyper-Gourava indices are investigated for the aforesaid antiviral drugs using polynomial approach. The Indian Council of Medical Research and Bharat Biotech announced that Phase 3 results of covaxin, developed by them, have shown an interim vaccine efficacy of 81 percent. So, the results obtained may be useful for finding the design of new medicine for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Kamaleldin B Said, SP 1, sp SP 2 sp Ahmed Alsolami, SP 3 sp Fayez Saud Alreshidi, SP 4 sp Anas Fathuddin, SP 5 sp Fawwaz Alshammari, SP 6 sp Fauwaz Alrashid, SP 7 sp Ahmed Aljadani, SP 3 sp Rana Aboras, SP 4 sp Fatmah Alreshidi, SP 4 sp Mohammed H Alghozwi, SP 1 sp Suliman F Alshammari, SP 1 sp Nawaf F Alharbi SP 1 sp SP 1 sp Department of Pathology and Microbiology, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia; SP 2 sp Genomics, Bioinformatics and Systems Biology, Carleton University, Ottawa, ON, K1S 5B6, Canada; SP 3 sp Department of Internal Medicine, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia; SP 4 sp Deparmtent of Family, Community Medicine, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia; SP 5 sp Department of Plastic Surgery, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia; SP 6 sp Department of Dermatology, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia; SP 7 sp Department of Surgery, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia Correspondence: Kamaleldin B Said, Department of Pathology and Microbiology, College of Medicine, University of Ha'il, Ha'il, 55476, Saudi Arabia, Tel +966500771459, Email [email protected] View the original paper by Dr Said and colleagues This is in response to the Letter to the Editor Dear editor We would like to submit a response to the Letter to the Editor, by: Sri Wahyuni Gayatri; Andi St Fahirah Arsal; Wisdawan on the Article: Said et al, Profiles of Independent Comorbidity Groups in Senior COVID-19 Patients Reveal Low Fatality Associated with Standard Care and Low-Dose Hydroxychloroquine over Antivirals. [Extracted from the article]

COVID-19 has been a major global health concern for the past three years, and currently we are still experiencing coronavirus patients in the following years. The virus, known as SARS-CoV-2, shares a similar genomic identity with previous viruses such as SARS-CoV and MERS-CoV. To combat the pandemic, modern drugs discovery techniques such as in silico experiments for docking and virtual screening have been employed to design new drugs against COVID-19. However, the release of new drugs for human use requires two safety assessment steps consisting of preclinical and clinical trials. To bypass these steps, scientists are exploring the potential of repurposing existing drugs for COVID-19 treatment. This approach involves evaluating antiviral activity of drugs previously used for treating respiratory diseases against other enveloped viruses such as HPV, HSV, and HIV. The aim of this study is to review repurposing of existing drugs, traditional medicines, and active secondary metabolites from plant-based natural products that target specific protein enzymes related to SARS-CoV-2. The review also analyzes the chemical structure and activity relationship between selected active molecules, particularly flavonol groups, as ligands and proteins or active sites of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coronavirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the Mpro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants. [ABSTRACT FROM AUTHOR]

Background: Remdesivir is the first treatment for COVID-19 to receive FDA approval. On October 22. 2020, the antiviral drug Remdesivir was approved to treat COVID-19 patients requiring hospitalization. Objectives of the study: To compare the effect of timing of Remdesivir administration on the duration of hospitalization and clinical outcome of hospitalized patients with severe COVID-19 in Imam Al-Hussain medical city, those who received Remdesivir early; in the first week, with others who received it in the second week of the onset of the symptoms. Patients and methods: A retrospective study was done in Imam al-Hussain medical city in Karbala province. The data was collected from 139 patients' registry (84 male&54 female) with severe COVID-19 infection who admitted to the isolation wards, 68(48.6%) received Remdesivir in the first week, and 71(51.1%) received it in the second week from the onset of symptoms. A comparison was made between the two groups regarding the clinical outcome and duration of hospitalization. Result: During the first week from the onset of the symptoms, about 48.9% of patients with severe infection received Remdesivir, 95.6% of them improved, and 4.4% died. The median time of recovery was six days. About 51.1% received Remdesivir during the second week, 84.5% improved, and 15.5% died. The median time of recovery was 8.5 days. Conclusions: The case fatality rate was lower in patients who received Remdesivir during the first week from the onset of symptoms than patients who received treatment in the second week. Patients in the first group recovered substantially faster than those in the second one. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ensovibep, a designed ankyrin repeat protein antiviral being evaluated as a COVID‐19 treatment, in healthy volunteers in a first‐in‐human ascending single‐dose study. Methods: Subjects were dosed intravenously, in a randomized double‐blinded manner, with either ensovibep at 3, 9 or 20 mg/kg or with placebo, and followed until Day 100. PK and safety were assessed throughout the study duration. Immunogenicity and PD via viral neutralization in serum were also assessed. Results: All adverse events were of mild to moderate severity, and no serious adverse events were observed. One subject who received the 20‐mg/kg dose presented with moderate hypersensitivity vasculitis 3 weeks after infusion, which fully resolved using standard procedures. In most subjects ensovibep showed expected mono‐exponential decline with a half‐life of around 2 weeks. Anti‐drug antibodies were detected in 15 of 17 subjects, with the earliest onset detected on Day 29. Viral neutralization assays on subject serum showed effective viral neutralization over the first 3 weeks following dosing with titre values in a dose dependent manner. Conclusion: Ensovibep proved safe in this first‐in‐human safety study and exhibited PK and PD parameters consistent with the expected treatment period required for acute COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Favipiravir and remdesivir have been included in the COVID-19 treatment guidelines panel of several countries. The main objective of the current work is to develop the first validated green spectrophotometric methods for the determination of favipiravir and remdesivir in spiked human plasma. The UV absorption spectra of favipiravir and remdesivir have shown some overlap, making simultaneous determination difficult. Due to the considerable overlap, two ratio spectra manipulating spectrophotometric methods, namely, ratio difference and the first derivative of ratio spectra, enabled the determination of favipiravir and remdesivir in their pure forms and spiked plasma. The ratio spectra of favipiravir and remdesivir were derived by dividing the spectra of each drug by the suitable spectrum of another drug as a divisor to get the ratio spectra. Favipiravir was determined by calculating the difference between 222 and 256 nm of the derived ratio spectra, while calculating the difference between 247 and 271 nm of the derived ratio spectra enabled the determination of remdesivir. Moreover, the ratio spectra of every drug were transformed to the first order derivative using ∆λ = 4 and a scaling factor of 100. The first-order derivative amplitude values at 228 and 251.20 nm enabled the determination of favipiravir and remdesivir, respectively. Regarding the pharmacokinetic profile of favipiravir (Cmax 4.43 µg/mL) and remdesivir (Cmax 3027 ng/mL), the proposed methods have been successfully applied to the spectrophotometric determination of favipiravir and remdesivir in plasma matrix. Additionally, the greenness of the described methods was evaluated using three metrics systems: the national environmental method index, the analytical eco-scale, and the analytical greenness metric. The results demonstrated that the described models were in accordance with the environmental characteristics. [ABSTRACT FROM AUTHOR]

At present, there are some differences in the research results of nirmatrelvir–ritonavir compared with other antiviral drugs for the treatment of COVID‐19 patients. We aimed to evaluate the efficacy and safety of nirmatrelvir–ritonavir compared with other antiviral drugs and the impact of different antiviral drugs on the short‐ and long‐term effects of COVID‐19. PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, Google Scholar, and MedRxiv were searched to identify relevant studies from inception to March 30, 2023. We conducted a meta‐analysis to estimate the effects of nirmatrelvir–ritonavir compared with other antiviral drugs for the treatment of COVID‐19 patients and safety outcomes. The RoB1 and ROBINS‐I were used to assess the bias risk of the included studies. Revman 5.4 software was used for meta‐analysis (PROSPERO Code No: CRD42023397816). Twelve studies were included, including 30 588 COVID‐19 patients, of whom 13 402 received nirmatrelvir–ritonavir. The meta‐analysis results showed that the nirmatrelvir–ritonavir group had a lower proportion of patients than the control group in terms of long‐term mortality (odds ratio [OR] = 0.29, 95% confidence interval [CI]: 0.13–0.66), hospitalization (OR = 0.44, 95% CI: 0.37–0.53, short term; OR = 0.52, 95% CI: 0.36–0.77, long term), and disease progression (OR = 0.56, 95% CI: 0.38–0.83, short term; OR = 0.60, 95% CI: 0.48–0.74, long term), and nirmatrelvir ritonavir showed little difference in safety compared to the control group. Nirmatrelvir–ritonavir can reduce the mortality and hospitalization of COVID‐19 patients compared with other antiviral drugs. Further large‐scale studies remain to validate these findings. [ABSTRACT FROM AUTHOR]

This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Remdesivir was the first antiviral drug to be approved for the treatment of severe COVID-19; followed by molnupiravir (another prodrug of a nucleoside analogue) and the protease inhibitor nirmatrelvir. Combination of antiviral drugs may result in improved potency and help to avoid or delay the development of resistant variants. We set out to explore the combined antiviral potency of GS-441524 (the parent nucleoside of remdesivir) and molnupiravir against SARS-CoV-2. In SARS-CoV-2 (BA.5) infected A549-Dual hACE2-TMPRSS2 cells, the combination resulted in an overall additive antiviral effect with a synergism at certain concentrations. Next, the combined effect was explored in Syrian hamsters infected with SARS-CoV-2 (Beta, B.1.351); treatment was started at the time of infection and continued twice daily for four consecutive days. At day 4 post-infection, GS-441524 (50 mg/kg, oral BID) and molnupiravir (150 mg/kg, oral BID) as monotherapy reduced infectious viral loads by 0.5 and 1.6 log10, respectively, compared to the vehicle control. When GS-441524 (50 mg/kg, BID) and molnupiravir (150 mg/kg, BID) were combined, infectious virus was no longer detectable in the lungs of 7 out of 10 of the treated hamsters (4.0 log10 reduction) and titers in the other animals were reduced by ~2 log10. The combined antiviral activity of molnupiravir which acts by inducing lethal mutagenesis and GS-441524, which acts as a chain termination appears to be highly effective in reducing SARSCoV-2 replication/infectivity. The unexpected potent antiviral effect of the combination warrants further exploration as a potential treatment for COVID-19. [ABSTRACT FROM AUTHOR]

The efforts of the scientific world directed to identifying new antiviral drugs and therapies effective against SARS-CoV-2 continue. New oral antivirals against SARS-CoV-2 such as paxlovid have recently authorized. Evidence shows that these antivirals have good efficacy in reducing the risk of hospitalization in COVID-19 positive patients. Remdesivir is an authorized antiviral for the treatment of SARS-CoV-2 infection. To date, there are still few data in the literature on the safety profile and the risk of generating antiviral-resistant SARS-CoV-2 drug variants. In this manuscript we describe the evidence in the literature on the monotherapy use of paxlovid and monotherapy use of remdesivir, and the scientific hypothesis of using nirmatrelvir and remdesivir in association with the aim of increasing treatment efficacy, reducing the risk of adverse reactions and generating antiviral drug-resistant variants. [ABSTRACT FROM AUTHOR]

A complete response to the challenge of COVID-19 requires diagnosis, prevention, and treatment strategies. Until recently, the treatment arm has included largely ineffective, often unproven medications with minimal impact on disease outcomes. The earlier experimental therapies are now giving way to approved antiviral drugs with a demonstrated capacity for SARS-CoV-2 suppression, and more are on the way. New oral antiviral drugs will expand treatment options for persons with COVID-19 and, if used early, become the first line of defense for reducing hospitalization, mortality, and virus spread. Several oral medications have been approved for treating COVID-19 on an emergency use basis in the United States (US), European Union (EU), United Kingdom (UK), China, Russia, and India, with other countries now facilitating regulatory reviews and approvals. Here, we compare the risk/benefit profiles of three leading oral antiviral drugs: Favipiravir, Molnupiravir, and Paxlovid. These compounds have distinct features supporting their targeted use by persons with COVID-19 disease. [ABSTRACT FROM AUTHOR]

Keywords: COVID-19 (Mesh), 2019-nCo V, SARS-CoV-2, treatment, treatment, clinical observation, antiviral therapy, antiviral. Chinese search terms include: novel coronavirus, novel coronavirus pneumonia, novel coronavirus, novel coronavirus pneumonia, COVID-19, antiviral, antiviral therapy, treatment, research, trials, clinical trials. Considering that they are related to the combination of the three antiviral drugs, according to the "new coronavirus pneumonia diagnosis and treatment plan (eighth edition)" promulgated by the National Health and Health Commission of China, it is not recommended to use the three drugs in combination, and the more drugs are, the heavier the gastrointestinal burden is. Keywords: COVID-19; safety; antiviral drugs EN COVID-19 safety antiviral drugs 4457 4466 10 10/04/22 20220801 NES 220801 Introduction Coronavirus Disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread in many countries and regions around the world since 2019. [Extracted from the article]

Broad-spectrum antiviral agents that are effective against many viruses are difficult to develop, as the key molecules, as well as the biochemical pathways by which they cause infection, differ largely from one virus to another. This was more strongly highlighted by the COVID-19 pandemic, which found health systems all over the world largely unprepared and proved that the existing armamentarium of antiviral agents is not sufficient to address viral threats with pandemic potential. The clinical protocols for the treatment of COVID-19 are currently based on the use of inhibitors of the inflammatory cascade (dexamethasone, baricitinib), or inhibitors of the cytopathic effect of the virus (monoclonal antibodies, molnupiravir or nirmatrelvir/ritonavir), using different agents. There is a critical need for an expanded armamentarium of orally bioavailable small-molecular medicinal agents, including those that possess dual antiviral and anti-inflammatory (AAI) activity that would be readily available for the early treatment of mild to moderate COVID-19 in high-risk patients. A multidisciplinary approach that involves the use of in silico screening tools to identify potential drug targets of an emerging pathogen, as well as in vitro and in vivo models for the determination of a candidate drug's efficacy and safety, are necessary for the rapid and successful development of antiviral agents with potentially dual AAI activity. Characterization of candidate AAI molecules with physiologically based pharmacokinetics (PBPK) modeling would provide critical data for the accurate dosing of new therapeutic agents against COVID-19. This review analyzes the dual mechanisms of AAI agents with potential anti-SARS-CoV-2 activity and discusses the principles of PBPK modeling as a conceptual guide to develop new pharmacological modalities for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments. [ABSTRACT FROM AUTHOR]

In 2018, the discovery of carcinogenic nitrosamine process related impurities (PRIs) in a group of widely used drugs led to the recall and complete withdrawal of several medications that were consumed for a long time, unaware of the presence of these genotoxic PRIs. Since then, PRIs that arise during the manufacturing process of the active pharmaceutical ingredients (APIs), together with their degradation impurities, have gained the attention of analytical chemistry researchers. In 2020, favipiravir (FVR) was found to have an effective antiviral activity against the SARS-COVID-19 virus. Therefore, it was included in the COVID-19 treatment protocols and was consequently globally manufactured at large-scales during the pandemic. There is information indigence about FVR impurity profiling, and until now, no method has been reported for the simultaneous determination of FVR together with its PRIs. In this study, five advanced multi-level design models were developed and validated for the simultaneous determination of FVR and two PRIs, namely; (6-chloro-3-hydroxypyrazine-2-carboxamide) and (3,6-dichloro-pyrazine-2-carbonitrile). The five developed models were classical least square (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm-partial least squares (GA-PLS), and artificial neural networks (ANN). Five concentration levels of each compound, chosen according to the linearity range of the target analytes, were used to construct a five-level, three-factor chemometric design, giving rise to twenty-five mixtures. The models resolved the strong spectral overlap in the UV-spectra of the FVR and its PRIs. The PCR and PLS models exhibited the best performances, while PLS proved the highest sensitivity relative to the other models. [ABSTRACT FROM AUTHOR]

The clinical manifestations associated with COVID-19 disease is mainly due to a dysregulated host response related to the overexpression of inflammatory markers. Until recently, only remdesivir had gained FDA approval for COVID-19 hospitalized patients and there are currently no evidence-based therapeutic options or options for prevention of complications that have been established. Some medical treatments such as antivirals, antibacterials, antithrombotics, antipyretics, corticosteroids, interleukin inhibitors, monoclonal antibodies, convalescent plasma, immunostimulants, and vitamin supplements have been utilized. However, there are limited data to support their effectiveness. Hence, this study was attempted to identify and evaluate the effectiveness of antibacterials and antivirals used for COVID-19 using a retrospective cross-sectional approach based on the medical records of adult patients in four hospitals. The number of antibacterials was calculated in defined daily dose (DDD) per 100 bed-days unit. Both mixed-logit regression and analysis of covariance were used to determine the effectiveness of the aforementioned agents in relation to COVID-19 outcome and patients' length of stay. The model was weighed accordingly and covariates (e.g., age) were considered in the model. Heart disease was found to be the most common pre-existing condition of COVID-19 hospitalized patients in this study. Azithromycin, an antibacterial in the Watch category list, was used extensively (33–65 DDD per 100 bed-days). Oseltamivir, an antiviral approved by the FDA for influenza was the most prescribed antiviral. In addition, favipiravir was found to be a significant factor in improving patients' COVID-19 outcomes and decreasing their length of stay. This study strongly suggests that COVID-19 patients' received polypharmacy for their treatment. However, most of the drugs used did not reach statistical significance in improving the patients' condition or decreasing the length of stay. Further studies to support drug use are needed. [ABSTRACT FROM AUTHOR]

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Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the U.S. FDA approved intravenous RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for nonhospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an intravenous administration of RDV at 10 mg/kg, an about 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed after inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with intravenous RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning about 8 hours after infection. Moreover, the efficacy of inhaled RDV was similar to that of intravenous RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV. An inhaled antiviral: The antiviral drug, remdesivir, has demonstrated clinical benefit in patients diagnosed with COVID-19. However, the requirement of intravenous delivery complicates administration of remdesivir. To address this, Vermillion et al. tested the efficacy of remdesivir when administered via inhalation. The authors treated African green monkeys infected with SARS-CoV-2 with remdesivir using a head dome, showing that it reduced viral load as compared with placebo. Further, inhaled and intravenous remdesivir showed similar efficacy when administered at the same time point. Together, these results support further clinical investigation of inhaled remdesivir for COVID-19. [ABSTRACT FROM AUTHOR]

The coronavirus disease‐19 (COVID‐19) pandemic has become a global threat since its first outbreak at the end of 2019. Several review articles have been published recently, focusing on the aspects of target biology, drug repurposing, and mechanisms of action (MOAs) for potential treatment. This review gathers all small molecules currently in active clinical trials, categorizes them into six sub‐classes, and summarizes their clinical progress. The aim is to provide the researchers from both pharmaceutical industries and academic institutes with the handful information and dataset to accelerate their research programs in searching effective small molecule therapy for treatment of COVID‐19. [ABSTRACT FROM AUTHOR]

A pandemic disease, COVID‐19, affecting over 253 million and 5.1 million deaths reported as on November 2021 from across the globe. The worst hit pandemic since a century. Scientists around the world are working towards the development of drugs for its treatment. Several existing antiviral medications have been tried for the same. Among these, Favipiravir, a broad‐spectrum antiviral drug originally developed to treat influenza, shows noted activity against an ample range of RNA viruses. It is an oral antiviral drug with good bioavailability found to be effective in the treatment of COVID‐19. This drug has acquired FDA manifestation for drug‐resistant Influenza as it has confirmed its safety profile. There has been growing evidence that it helps in early viral clearance and speedy symptomatic relief against COVID‐19. This review attempts to provide synthetic methods of favipiravir, mechanism of action and its importance in the treatment of COVID‐19 and other viruses. [ABSTRACT FROM AUTHOR]

Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a purine nucleic acid analog, which is an antiviral agent used in the treatment of influenza. Since the recent outbreak caused by 2019-novel coronavirus (nCoV), there has been a seek for effective antiviral agents to be used in the treatment of coronavirus disease 2019 (COVID-19), and favipiravir has been one of the options which provides a broad-spectrum therapy. Herein, we studied the aqueous solubility and in vitro permeability characteristics of favipiravir in order to shed light on the BCS classification of this antiviral agent used in COVID-19 therapy. The in vitro solubility was assessed using saturated solution of favipiravir in four different aqueous media and the solubility values were evaluated during 72 h at 37 oC. The solubility of favipiravir was between 4.48 to 8.5 mg/ml, which is 5.85 to 10.63 times of calculated solubility limit. Caco-2 cell monolayers were utilized for the permeability assessment, and the drug solutions in three different concentrations including the highest dose required for bioequivalence exemption of the immediate release dosage form were applied. The effect of efflux transporters on the permeability of favipiravir was also determined using a P-gp inhibitor, Verapamil HCl. According to the data obtained from the in vitro studies, favipiravir can be considered as a representative of class I compound. [ABSTRACT FROM AUTHOR]

Summary: Vaccines and drugs are the cornerstones in the fight against the SARS‐CoV‐2 pandemic. While vaccines were a success story, the development of antiviral drugs against SARS‐CoV‐2 turned out to be difficult. For an accelerated use of antivirals in the clinic, most SARS‐CoV‐2 antivirals represented repurposed drugs. The present article summarizes the outcomes of clinical trials with antiviral drugs in COVID‐19 patients. Many antiviral drugs failed to demonstrate beneficial effects or showed mixed results. One reason for the low success rate of clinical trials was shortcomings of antiviral tests in cell culture systems and another reason was the abundance of ill‐coordinated and underpowered clinical trials. However, large pragmatic clinical trials particularly of the British RECOVERY trial series demonstrated that even under emergency situation drug trials can be conducted in a timely way such that the therapy of COVID‐19 patients can be based on evidence basis instead on expert opinion or even worse on political pressure. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic and a serious respiratory disorder that is caused by coronavirus. It has produced an outbreak of acute infectious pneumonia in China and afterward all around the world. There is not a single anti-viral drug, vaccine or any kind of treatment available for this fatal disease. There are only a few options available for symptomatic relief. Thus, in China, 85% of SARS-CoV-2 infected individuals have been treated with traditional Chinese medicines (TCM). Thus, this article focused on the previous kinds of literature regarding COVID-19 and its treatment with TCM along with its applications. SARS-CoV-2 and SARS-CoV showed similarity in genes, pathological processes, and epidemiology, so these can be treated with TCM. The proof regarding treatment of SARS-CoV with TCM explicitly shows the advantages of using TCM therapy for COVID-19. Present literature explains the mode of action and efficacy of TCM and elaborates on the natural compounds introduced to treat COVID-19. [ABSTRACT FROM AUTHOR]

The United Arab Emirates permitted since the beginning of the pandemic the use of antiviral therapies which were otherwise obstructed in the United States and Australia, also in the early stages of infection [[4]]. To the Editor, Australia has prohibited to use the of COVID-19 antiviral therapies which were prohibited in Europe and North America, despite countries permitting these therapies to achieve much lower fatalities due to COVID-19 infection. [Extracted from the article]

Coronavirus disease (COVID-19) has been declared as a pandemic by the World Health Organization with rapid spread across 216 countries. COVID-19 pandemic has left its imprints on various health systems globally and caused immense social and economic disruptions. The scientific community across the globe is in a quest for digging the effective treatment for COVID-19 and exploring potential leads from traditional systems of healthcare across the world too. Ayurveda (Indian traditional system of medicine) has a comprehensive aspect of immunity through Rasayana which is a rejuvenation therapy. Here we attempt to generate the potential leads based on the classical text from Ayurveda in general and Rasayana in particular to develop effective antiviral and/or immunomodulator for potential or adjunct therapy in SARS-CoV-2. The Rasayana acts not only by resisting body to restrain or withstand the strength, severity or progression of a disease but also by promoting power of the body to prevent the manifestation of a disease. These Rasayana herbs are common in practice as immunomodulator, antiviral and protectives. The studies on Rasayana can provide an insight into the future course of research for the plausible development of effective management of COVID-19 by the utilization and development of various traditional systems of healthcare. Keeping in view the current pandemic situation, there is an urgent need of developing potential medicines. This study proposes certain prominent medicinal plants which may be further studied for drug development process and also in clinical setup under repurposing of these herbs. [ABSTRACT FROM AUTHOR]

The ongoing pandemic, COVID-19 (SARS-CoV-2), has afflicted millions of people around the world, necessitating that the scientific community work, diligently and promptly, on suitable medicaments. Although vaccination programs have been run globally, the new variants of COVID-19 make it difficult to restrict the spread of the virus by vaccination alone. The combination of vaccination with anti-viral drug formulation is an ideal strategy for tackling the current pandemic situation. Drugs approved by the United States Food and Drug Administration (FDA), such as Remdesivir, have been found to be of little or no benefit. On the other hand, re-purposing of FDA-approved drugs, such as niclosamide (NIC), has offered promise but its applicability is limited due to its poor aqueous solubility and, therefore, low bioavailability. With advanced nano-pharmaceutical approaches, re-purposing this drug in a suitable drug-carrier for a better outcome may be possible. In the current study, an attempt was made to explore the loading of NIC into exfoliated layered double hydroxide nanoparticles (X-LDH NPs); prepared NIC-X-LDH NPs were further modified with eudragit S100 (ES100), an enteric coating polymer, to make the final product, ES100-NIC-X-LDH NPs, to improve absorption by the gastro/intestinal tract (GIT). Furthermore, Tween 60 was added as a coating on ES100-NIC-X-LDH NPs, not just to enhance its in vitro and in vivo stability, but also to enhance its mucoadhesive property, and to obtain, ultimately, better in vivo pharmacokinetic (PK) parameters upon oral administration. Release of NIC from Tween 60-ES100-NIC-X-LDH NPs was found to be greater under gastro/intestinal solution within a shorter period of time than the uncoated samples. The in vivo analysis revealed that Tween 60-ES100-NIC-X-LDH NPs were able to maintain a therapeutically relevant NIC plasma concentration in terms of PK parameters compared to the commercially available Yomesan®, proving that the new formulation might prove to be an effective oral drug-delivery system to deal with the SARS-CoV-2 viral infections. Further studies are required to ensure their safety and anti-viral efficacy. [ABSTRACT FROM AUTHOR]