A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19.
Ontology highlight
ABSTRACT:
SUBMITTER: Lokhande AS
PROVIDER: S-EPMC7678434 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19.
Lokhande Amit S AS Devarajan Padma V PV
European journal of pharmacology 20201120
The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazo ...[more]
Similar Datasets
Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory 'cytokine storm'. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here, we have reviewed potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was mainly based on keywords like Coronavirus, SARS-CoV-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies.
| S-EPMC8570392 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is a current global illness triggered by severe acute respiratory coronavirus 2 (SARS-CoV-2) leading to acute viral pneumonia, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and cytokine storm in severe cases. In the COVID-19 era, different unexpected old drugs are repurposed to find out effective and cheap therapies against SARS-CoV-2. One of these elected drugs is nitazoxanide (NTZ) which is an anti-parasitic drug with potent antiviral activity. It is effectively used in the treatment of protozoa and various types of helminths in addition to various viral infections. Thus, we aimed to elucidate the probable effect of NTZ on SARS-CoV-2 infections. Findings of the present study illustrated that NTZ can reduce SARS-CoV-2-induced inflammatory reactions through activation of interferon (IFN), restoration of innate immunity, inhibition of the release of pro-inflammatory cytokines, suppression of the mammalian target of rapamycin (mTOR), and induction of autophagic cell death. Moreover, it can inhibit the induction of oxidative stress which causes cytokine storm and is associated with ALI, ARDS, and multi-organ damage (MOD). This study concluded that NTZ has important anti-inflammatory and immunological properties that may mitigate SARS-CoV-2 infection-induced inflammatory disorders. Despite broad-spectrum antiviral properties of NTZ, the direct anti-SARS-CoV-2 effect was not evident and documented in recent studies. Then, in silico and in vitro studies in addition to clinical trials and prospective studies are needed to confirm the beneficial impact of NTZ on the pathogenesis of SARS-CoV-2 infection.
| S-EPMC9465141 | biostudies-literature
Project description:Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes coronavirus-19 (COVID-19), has caused significant morbidity and mortality globally. In addition to the respiratory manifestations seen in severe cases, multi-organ pathologies also occur, making management a much-debated issue. In addition, the emergence of new variants can potentially render vaccines with a relatively limited utility. Many investigators have attempted to elucidate the precise pathophysiological mechanisms causing COVID-19 respiratory and systemic disease. Spillover of lung-derived cytokines causing a cytokine storm is considered the cause of systemic disease. However, recent studies have provided contradictory evidence, whereby the extent of cytokine storm is insufficient to cause severe illness. These issues are highly relevant, as management approaches considering COVID-19 a classic form of acute respiratory distress syndrome with a cytokine storm could translate to unfounded clinical decisions, detrimental to patient trajectory. Additionally, the precise immune cell signatures that characterize disease of varying severity remain contentious. We provide an up-to-date review on the immune dysregulation caused by COVID-19 and highlight pertinent discussions in the scientific community. The response from the scientific community has been unprecedented regarding the development of highly effective vaccines and cutting-edge research on novel therapies. We hope that this review furthers the conversations held by scientists and informs the aims of future research projects, which will potentially further our understanding of COVID-19 and its immune pathogenesis.
| S-EPMC8989408 | biostudies-literature
Project description:Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) have long been used worldwide as frontline drugs for the treatment and prophylaxis of human malaria. Since the first reported cases in Wuhan, China, in late December 2019, humans have been under threat from coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 (previously known as 2019-nCoV), subsequently declared a pandemic. While the world is searching for expedited approval for a vaccine, which may be only preventative and not a cure, physicians and country leaders are considering several concerted clinical trials suggesting that the age-old antimalarial drugs CQ/HCQ could be a potent therapeutic against COVID-19. Based on accumulating scientific reports, here we highlight the possible modes of action of CQ/HCQ that could justify its use against viral infections. Considering the global health crisis of the COVID-19 pandemic, the option of repurposing old drugs, e.g. CQ/HCQ, particularly HCQ, for the treatment of SARS-CoV-2 infection could be a good choice. CQ/HCQ has diverse modes of action, including alteration of the acidic environment inside lysosomes and late endosomes, preventing endocytosis, exosome release and phagolysosomal fusion, and inhibition of the host cytokine storm. One or more diverse mechanisms might work against viral infections and reduce mortality. As there is no cure for COVID-19, clinical testing of HCQ is urgently required to determine its potency against SARS-CoV-2, as this is the currently available treatment option. There remains a need to find other innovative drug candidates as possible candidates to enter clinical evaluation and testing.
| S-EPMC7243790 | biostudies-literature
Project description:The coronavirus disease 2019 (COVID-19) has continued to spread worldwide since late 2019. To expedite the process of providing treatment to those who have contracted the disease and to ensure the accessibility of effective drugs, numerous strategies have been implemented to find potential anti-COVID-19 drugs in a short span of time. Motivated by this critical global challenge, in this review, we detail approaches that have been used for drug repurposing for COVID-19 and suggest improvements to the existing deep learning (DL) approach to identify and repurpose drugs to treat this complex disease. By optimizing hyperparameter settings, deploying suitable activation functions, and designing optimization algorithms, the improved DL approach will be able to perform feature extraction from quality big data, turning the traditional DL approach, referred to as a "black box," which generalizes and learns the transmitted data, into a "glass box" that will have the interpretability of its rationale while maintaining a high level of prediction accuracy. When adopted for drug repurposing for COVID-19, this improved approach will create a new generation of DL approaches that can establish a cause and effect relationship as to why the repurposed drugs are suitable for treating COVID-19. Its ability can also be extended to repurpose drugs for other complex diseases, develop appropriate treatment strategies for new diseases, and provide precision medical treatment to patients, thus paving the way to discover new drugs that can potentially be effective for treating COVID-19.
| S-EPMC8843052 | biostudies-literature
Project description:Drug repurposing involves the identification of new applications for existing drugs at a lower cost and in a shorter time. There are different computational drug-repurposing strategies and some of these approaches have been applied to the coronavirus disease 2019 (COVID-19) pandemic. Computational drug-repositioning approaches applied to COVID-19 can be broadly categorized into (i) network-based models, (ii) structure-based approaches and (iii) artificial intelligence (AI) approaches. Network-based approaches are divided into two categories: network-based clustering approaches and network-based propagation approaches. Both of them allowed to annotate some important patterns, to identify proteins that are functionally associated with COVID-19 and to discover novel drug-disease or drug-target relationships useful for new therapies. Structure-based approaches allowed to identify small chemical compounds able to bind macromolecular targets to evaluate how a chemical compound can interact with the biological counterpart, trying to find new applications for existing drugs. AI-based networks appear, at the moment, less relevant since they need more data for their application.
| S-EPMC7665348 | biostudies-literature
Project description:The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.
| S-EPMC8352658 | biostudies-literature
Project description:BackgroundMany treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVID-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500?mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax: EC50roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVID-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production.MethodsA review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5–14 days in participants experiencing acute infections of any kind. Data extracted were grade 1–4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects.Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500?mg BD and a higher dose of 1100?mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries.ResultsNine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited.Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500?mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100?mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day.ConclusionNitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500?mg BD, up to $4.08 at 1100?mg TDS. Further trials in COVID-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.
| S-EPMC7332204 | biostudies-literature
Project description:AbstractBackgroundMany treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVID-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500?mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax : EC50 roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVID-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production.MethodsA review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5–14 days in participants experiencing acute infections of any kind. Data extracted were grade 1–4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects.Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500?mg BD and a higher dose of 1100?mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries.ResultsNine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited.Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500?mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100?mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day.ConclusionNitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500?mg BD, up to $4.08 at 1100?mg TDS. Further trials in COVID-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.
| S-EPMC7213070 | biostudies-literature
Project description:The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev. 2019, 119, 9478; Wang, Curr. Comput.-Aided Drug Des. 2006, 2, 287; Wang; ; Hou J. Chem. Inf. Model., 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.
| S-EPMC7197972 | biostudies-literature