Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization

Rossignol, Jean‐François; Cb, Matthew; Jb, Oaks; Bg, Bostick; Kn, Vora; Fulgencio, Jessica; Mogelnicki, Dena; Bréchot, Christian

doi:10.1101/2021.04.19.21255441

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…This has the potential to mask the effects of proxalutamide or to introduce imbalances in the application of usual care medication. However, in the usual care treatment, only nitazoxanide has been shown to have potential efficacy in placebo-controlled trials (29)(30)(31) and this drug was offered to all new patients. Further, the randomization of patients to each trial study arm would mitigate any uneven distribution of usual care medications, if they existed.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

McCoy¹,

Goren²,

Cadegiani³

et al. 2021

Front. Med.

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Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (clinicaltrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200 mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization. A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P < 0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03–0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost during follow-up, and 2 patients died from acute respiratory distress syndrome. Here we demonstrate the hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

McCoy¹,

Goren²,

Cadegiani³

et al. 2021

Front. Med.

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show abstract

“…Interestingly nitazoxanide was also found to be effective against different animal and human coronaviruses, including MERS-CoV [26,35,36] and, more recently, SARS-CoV-2 in-vitro [37][38][39] and in COVID-19 patients [39][40][41][42].…”

Section: Introductionmentioning

confidence: 99%

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Riccio

Santopolo

Rossi

et al. 2021

Preprint

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The emergence of the highly-pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 (coronavirus disease-2019), has caused an unprecedented global health crisis, as well as societal and economic disruption. The SARS-CoV-2 spike (S), a surface-anchored trimeric class-I fusion glycoprotein essential for entry into host cells, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of several SARS-CoV-2 spike variants that facilitate virus spread and may affect the efficacy of recently developed vaccines, creates great concern and highlights the importance of identifying antiviral drugs to reduce SARS-CoV-2-related morbidity and mortality. Nitazoxanide, a thiazolide originally developed as an antiprotozoal agent with recognized broad-spectrum antiviral activity in-vitro and in clinical studies, was recently shown to be effective against several coronaviruses, including SARS-CoV-2. Using biochemical and pseudovirus entry assays, we now demonstrate that nitazoxanide interferes with the SARS-CoV-2 spike biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage, and hindering its fusion activity in human cells. Besides membrane fusion during virus entry, SARS-CoV-2 S-proteins in infected cells can also trigger receptor-dependent formation of syncytia, observed in-vitro and in COVID-19 patients tissues, facilitating viral dissemination between cells and possibly promoting immune evasion. Utilizing two different quantitative cell-cell fusion assays, we show that nitazoxanide is effective in inhibiting syncytia formation mediated by different SARS-CoV-2 spike variants in human lung, liver and intestinal cells. The results suggest that nitazoxanide may represent a useful tool in the fight against COVID-19 infections, inhibiting SARS-CoV-2 replication and preventing spike-mediated syncytia formation.

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“…Despite nitazoxanide not accelerating symptom resolution, the viral load was reduced significantly with no serious adverse events [70]. A recent study by Rossignol et al, not yet peer-reviewed, showed evidence of disease progress reduction in mild and moderate cases of COVID-19 by early treatment with nitazoxanide in a double-blind randomized multicenter study with 379 patients [71].…”

Section: Nitazoxanidementioning

confidence: 99%

Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

Santos

Martins

Bregadiolli

et al. 2021

Journal of Heterocyclic Chem

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A virus outbreak challenges the economic, medical, and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure-activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2.

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Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization

Cited by 12 publications

References 23 publications

RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

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