The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

Tilmanis, Danielle; Baalen, Carel van; Oh, Ding Yuan; Rossignol, Jean‐François; Hurt, Aeron C.

doi:10.1016/j.antiviral.2017.10.002

Cited by 61 publications

(55 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nitazoxanide is an antiprotozoal drug that has previously been demonstrated to display broad antiviral activity against human and animal coronaviruses [40] as well as various strains of influenza [41,42].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, nitazoxanide is rapidly metabolised to tizoxanide in humans and this active metabolite is being investigated against SARS-CoV-2 (NCT04341493 and NCT04343248). Tizoxanide has been reported to exhibit similar activities to nitazoxanide for other viruses as well as other pathogens [43][44][45]. The mechanism of antiviral action is not fully understood for nitazoxanide, but it has been reported to affect viral genome synthesis, prevent viral entry and interfere with the N-glycosylation and maturation of the influenza hemagglutinin [46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

View full text Add to dashboard Cite

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Nitazoxanide is an antiprotozoal drug used to treat Cryptosporidium and Giardia infections. In vitro data demonstrate antiviral activity against influenza A and B strains (195,196). It acts by inhibiting influenza HA trafficking through the epithelial endoplasmic reticulum and Golgi apparatus and preventing maturation by blocking HA terminal glycosylation (197).…”

Section: Targeting Iav and S Pneumoniae At The Mucosal Barriermentioning

confidence: 99%

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

et al. 2020

View full text Add to dashboard Cite

The primary function of the respiratory system of gas exchange renders it vulnerable to environmental pathogens that circulate in the air. Physical and cellular barriers of the respiratory tract mucosal surface utilize a variety of strategies to obstruct microbe entry. Physical barrier defenses including the surface fluid replete with antimicrobials, neutralizing immunoglobulins, mucus, and the epithelial cell layer with rapidly beating cilia form a near impenetrable wall that separates the external environment from the internal soft tissue of the host. Resident leukocytes, primarily of the innate immune branch, also maintain airway integrity by constant surveillance and the maintenance of homeostasis through the release of cytokines and growth factors. Unfortunately, pathogens such as influenza virus and Streptococcus pneumoniae require hosts for their replication and dissemination, and prey on the respiratory tract as an ideal environment causing severe damage to the host during their invasion. In this review, we outline the host-pathogen interactions during influenza and post-influenza bacterial pneumonia with a focus on interand intra-cellular crosstalk important in pulmonary immune responses.

show abstract

“…Favipiravir developed and approved in Japan specifically for treatment of influenza virus infections, and its combination with neuraminidase inhibitors was shown to be effective in a mouse model [10,48]. Further interesting candidates are haloxanide/nitazoxanide, thiazolide compounds that were originally developed as antiparasitic agents, but were shown to inhibit influenza virus hemagglutinin maturation and intracellular trafficking of viral components in infected cells and that are now in clinical trials [83,138] as well as cycloheptathiophene-3-carboxamide, which interferes with the polymerase PA-PB1 subunits of influenza virus [106]. Alicyclic amines/aminoadamantanes amantadine and rimantadine, first described in 1985 as M2 protein blockers ( [60]; H + channel/viroporin; only type A viruses), are not recommended anymore for clinical use (WHO/US), due to rapid induction of viral resistance mutations: 100% of clinical isolates are resistant.…”

Section: Orthomyxoviridaementioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

View full text Add to dashboard Cite

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

show abstract

The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

Cited by 61 publications

References 27 publications

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

Antivirals in medical biodefense

Contact Info

Product

Resources

About