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1.
Br J Pharmacol ; 179(13): 3250-3267, 2022 07.
Article in English | MEDLINE | ID: covidwho-1764898

ABSTRACT

Vaccines have reduced the transmission and severity of COVID-19, but there remains a paucity of efficacious treatment for drug-resistant strains and more susceptible individuals, particularly those who mount a suboptimal vaccine response, either due to underlying health conditions or concomitant therapies. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics, such as COVID-19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti-helminth already in human use as a treatment for COVID-19. In addition, its potent antiviral activity, niclosamide has shown pleiotropic anti-inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous preclinical and early clinical studies. The advantages and rationale for nebulized and intranasal formulations of niclosamide, which target the site of the primary infection in COVID-19, are reviewed. Finally, we give an overview of ongoing clinical trials investigating niclosamide as a promising candidate against SARS-CoV-2.


Subject(s)
COVID-19 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning/methods , Humans , Niclosamide/pharmacology , Niclosamide/therapeutic use , Pandemics , SARS-CoV-2
2.
JAMA Netw Open ; 5(2): e2144942, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1676319

ABSTRACT

Importance: Oral anthelmintic niclosamide has potent in vitro antiviral activity against SARS-CoV-2. Repurposed niclosamide could be a safe and efficacious COVID-19 therapy. Objective: To investigate whether niclosamide decreased SARS-CoV-2 shedding and duration of symptoms among patients with mild to moderate COVID-19. Design, Setting, and Participants: This randomized, placebo-controlled clinical trial enrolled individuals testing positive for SARS-CoV-2 by polymerase chain reaction with mild to moderate symptoms of COVID. All trial participants, investigators, staff, and laboratory personnel were kept blind to participant assignments. Enrollment was among individuals reporting at Tufts Medical Center and Wellforce Network in Massachusetts for outpatient COVID-19 testing. The trial opened to accrual on October 1, 2020; the last participant enrolled on April 20, 2021. Trial exclusion criteria included hospitalization at time of enrollment or use of any experimental treatment for COVID-19, including vaccination. Enrollment was stopped before attaining the planned sample size when COVID-19 diagnoses decreased precipitously in Massachusetts. Data were analyzed from July through September 2021. Interventions: In addition to receiving current standard of care, participants were randomly assigned on a 1:1 basis to receive niclosamide 2 g by mouth daily for 7 days or identically labeled placebo at the same dosing schedule. Main Outcomes and Measures: Oropharyngeal and fecal samples were self-collected for viral shedding measured by reverse-transcriptase-polymerase-chain-reaction on days 3, 7, 10, and 14, and an additional fecal sample was collected on day 21. A telehealth platform was developed to conduct remote study visits, monitor symptoms, and coordinate sample collection via couriers. The primary end point was the proportion of participants with viral clearance in respiratory samples at day 3 based on the intention-to-treat sample. Mean times to viral clearance and symptom resolution were calculated as restricted mean survival times and accounted for censored observations. Results: Among 73 participants, 36 individuals were enrolled and randomized to niclosamide and 37 individuals to placebo. Participant characteristics were similar across treatment groups; among 34 patients receiving placebo and 33 patients receiving niclosamide in the intention-to-treat sample, mean (SD) age was 36.0 (13.3) years vs 36.8 (12.9) years and there were 21 (61.8%) men vs 20 (60.6%) men. The overall mean (SD) age was 36.4 (13.0) years. For the primary end point, 66.67% (95% CI, 50.74% to 81.81%) of participants receiving niclosamide and 55.88% (95% CI, 40.27% to 72.73%) of participants receiving placebo had oropharyngeal SARS-CoV-2 clearance at day 3 (P = .37). Among 63 participants with symptoms, niclosamide did not significantly shorten symptom duration, which was 12.01 (95% CI, 8.82 to 15.2) days in the niclosamide group vs 14.61 (95% CI, 11.25 to 17.96) days in the placebo group (mean difference, -2.6 [95% CI, -7.23 to 2.03] days). Niclosamide was well-tolerated; the most commonly reported adverse events in the placebo and niclosamide groups were headaches (11 patients [32.4%] vs 7 patients [21.2%]; P = .31) and cough (8 patients [23.5%] vs 7 patients [21.2%]; P = .82). Conclusions and Relevance: In this randomized clinical trial, there was no significant difference in oropharyngeal clearance of SARS-CoV-2 at day 3 between placebo and niclosamide groups. Confirmation in larger studies is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04399356.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Niclosamide/therapeutic use , SARS-CoV-2/drug effects , Virus Shedding/drug effects , Adult , Female , Humans , Male , Massachusetts , Middle Aged , Symptom Assessment , Treatment Outcome
3.
PLoS One ; 16(12): e0260958, 2021.
Article in English | MEDLINE | ID: covidwho-1546973

ABSTRACT

SARS-CoV-2 variants are emerging with potential increased transmissibility highlighting the great unmet medical need for new therapies. Niclosamide is a potent anti-SARS-CoV-2 agent that has advanced in clinical development. We validate the potent antiviral efficacy of niclosamide in a SARS-CoV-2 human airway model. Furthermore, niclosamide remains its potency against the D614G, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. Our data further support the potent anti-SARS-CoV-2 properties of niclosamide and highlights its great potential as a therapeutic agent for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Niclosamide/therapeutic use , SARS-CoV-2/drug effects , Animals , Caco-2 Cells , Chlorocebus aethiops , Humans , Inhibitory Concentration 50 , Respiratory Mucosa/virology , Vero Cells
4.
Mol Biol Rep ; 48(12): 8195-8202, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1474055

ABSTRACT

AIM/PURPOSE: Niclosamide (NCL) is an anthelminthic drug, which is widely used to treat various diseases due to its pleiotropic anti-inflammatory and antiviral activities. NCL modulates of uncoupling oxidative phosphorylation and different signaling pathways in human biological processes. The wide-spectrum antiviral effect of NCL makes it a possible candidate for recent pandemic SARS-CoV-2 infection and may reduce Covid-19 severity. Therefore, the aim of the present study was to review and clarify the potential role of NCL in Covid-19. METHODS: This study reviewed and highlighted the protective role of NCL therapy in Covid-19. A related literature search in PubMed, Scopus, Web of Science, Google Scholar, and Science Direct was done. RESULTS: NCL has noteworthy anti-inflammatory and antiviral effects. The primary antiviral mechanism of NCL is through neutralization of endosomal PH and inhibition of viral protein maturation. NCL acts as a proton carrier, inhibits homeostasis of endosomal PH, which limiting of viral proliferation and release. The anti-inflammatory effects of NCL are mediated by suppression of inflammatory signaling pathways and release of pro-inflammatory cytokines. However, the major limitation in using NCL is low aqueous solubility, which reduces oral bioavailability and therapeutic serum concentration that reducing the in vivo effect of NCL against SARS-CoV-2. CONCLUSIONS: NCL has anti-inflammatory and immune regulatory effects by modulating the release of pro-inflammatory cytokines, inhibition of NF-κB /NLRP3 inflammasome and mTOR signaling pathway. NCL has an anti-SARS-CoV-2 effect via interruption of viral life-cycle and/or induction of cytopathic effect. Prospective clinical studies and clinical trials are mandatory to confirm the potential role of NCL in patients with Covid-19 concerning the severity and clinical outcomes.


Subject(s)
COVID-19/drug therapy , Niclosamide/therapeutic use , SARS-CoV-2/drug effects , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/metabolism , Humans , Niclosamide/metabolism , Pandemics , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects
5.
J Cell Biochem ; 123(2): 155-160, 2022 02.
Article in English | MEDLINE | ID: covidwho-1473858

ABSTRACT

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.


Subject(s)
Antiviral Agents/pharmacology , Artesunate/pharmacology , Autophagy/drug effects , COVID-19/drug therapy , Drug Repositioning , Imatinib Mesylate/pharmacology , Infliximab/pharmacology , Pandemics , SARS-CoV-2/drug effects , Antidepressive Agents/pharmacology , Antiviral Agents/therapeutic use , Artesunate/therapeutic use , Chloroquine/pharmacology , Drug Development , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/physiology , Endoplasmic Reticulum/virology , Endosomes/drug effects , Endosomes/virology , Humans , Hydroxychloroquine/pharmacology , Imatinib Mesylate/therapeutic use , Infliximab/therapeutic use , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Intracellular Membranes/virology , Ivermectin/pharmacology , Macrolides/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Niclosamide/pharmacology , Niclosamide/therapeutic use , RNA, Viral/metabolism , SARS-CoV-2/physiology , Virus Replication
6.
Curr Top Med Chem ; 20(26): 2362-2378, 2020.
Article in English | MEDLINE | ID: covidwho-789061

ABSTRACT

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Betacoronavirus/ultrastructure , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive/methods , Ivermectin/therapeutic use , Models, Molecular , Niclosamide/therapeutic use , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Protein Interaction Domains and Motifs/drug effects , Protein Structure, Secondary , SARS Virus/drug effects , SARS Virus/immunology , SARS Virus/pathogenicity , SARS Virus/ultrastructure , SARS-CoV-2 , Severe Acute Respiratory Syndrome , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/biosynthesis
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