Nitazoxanide: pharmacokinetics and metabolism in man

Broekhuysen, J.; Stockis, Armel; Lins, Robert; Graeve, J. De; Rossignol, Jean‐François

doi:10.5414/cpp38387

Cited by 159 publications

(131 citation statements)

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“…More recently, nitazoxanide was confirmed to be a treatment option for rotavirus diarrhea in a randomized, single-blind, controlled trial in children aged from 28 days to 24 months (36). We now describe that thiazolides, at concentrations achieved in the blood and in the gut of humans after a standard oral dose (37), exert a potent antiviral activity against rotaviruses through a novel mechanism targeting rotavirus morphogenesis. Taken together, these observations indicate that nitazoxanide and its derivatives may represent a novel class of antiviral drugs effective against rotavirus gastroenteritis.…”

Section: Discussionmentioning

confidence: 99%

Thiazolides, a New Class of Antiviral Agents Effective against Rotavirus Infection, Target Viral Morphogenesis, Inhibiting Viroplasm Formation

Frazia

Ciucci

Arnoldi

et al. 2013

J Virol

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dRotaviruses, nonenveloped viruses presenting a distinctive triple-layered particle architecture enclosing a segmented doublestranded RNA genome, exhibit a unique morphogenetic pathway requiring the formation of cytoplasmic inclusion bodies called viroplasms in a process involving the nonstructural viral proteins NSP5 and NSP2. In these structures the concerted packaging and replication of the 11 positive-polarity single-stranded RNAs take place to generate the viral double-stranded RNA (dsRNA) genomic segments. Rotavirus infection is a leading cause of gastroenteritis-associated severe morbidity and mortality in young children, but no effective antiviral therapy exists. Herein we investigate the antirotaviral activity of the thiazolide anti-infective nitazoxanide and reveal a novel mechanism by which thiazolides act against rotaviruses. Nitazoxanide and its active circulating metabolite, tizoxanide, inhibit simian A/SA11-G3P[2] and human Wa-G1P[8] rotavirus replication in different types of cells with 50% effective concentrations (EC 50 s) ranging from 0.3 to 2 g/ml and 50% cytotoxic concentrations (CC 50 s) higher than 50 g/ml. Thiazolides do not affect virus infectivity, binding, or entry into target cells and do not cause a general inhibition of viral protein expression, whereas they reduce the size and alter the architecture of viroplasms, decreasing rotavirus dsRNA formation. As revealed by protein/protein interaction analysis, confocal immunofluorescence microscopy, and viroplasm-like structure formation analysis, thiazolides act by hindering the interaction between the nonstructural proteins NSP5 and NSP2. Altogether the results indicate that thiazolides inhibit rotavirus replication by interfering with viral morphogenesis and may represent a novel class of antiviral drugs effective against rotavirus gastroenteritis. R otaviruses are complex nonenveloped viruses belonging to the Reoviridae family. The rotavirion has a distinctive triple-layered particle (TLP) architecture that surrounds a genome composed of 11 segments of double-stranded RNA (dsRNA) encoding six structural viral proteins (VPs) and six nonstructural proteins (NSPs) (1, 2). The capsid structure comprises an inner-core shell of VP2 dimers and an intermediate shell formed by trimers of the major structural protein VP6, which interacts with both the VP2 core protein and the outer shell constituted by the VP4 protein (the rotavirus spikes, which express P-serotype epitopes), and VP7 glycoprotein trimers, which express G-serotype epitopes (2). The P and G serotypes represent independently segregating neutralization epitopes imparting immunity to infection. VP7, which is the second most abundant protein in the virion, is cotranslationally glycosylated as it is inserted into the endoplasmic reticulum (ER) membrane via a cleavable signal sequence found at the N terminus of the protein (1, 2). Rotaviruses exhibit a unique morphogenetic pathway. Double-layered particles (DLPs) are assembled in the cytoplasm at special areas termed viroplasms and the...

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Section: Discussionmentioning

confidence: 99%

Thiazolides, a New Class of Antiviral Agents Effective against Rotavirus Infection, Target Viral Morphogenesis, Inhibiting Viroplasm Formation

Frazia

Ciucci

Arnoldi

et al. 2013

J Virol

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“…The mouse model has been extensively used for studies on the pathology and immunology of experimental neosporosis (1,3,4,11,12). However, comparative analysis of the pharmacokinetics of NTZ metabolites in mice (32) and humans (2) has shown that in mice tizoxanide reaches only very low levels in serum (below 1 g/ml for less than 1 h), while in humans peak tizoxanide serum levels reach 8 g/ml and remain above 4 g/ml for a time span of 5 to 6 h. Thus, the mouse model is essentially not a suitable model to investigate the efficacy of this drug against challenge infection with N. caninum tachyzoites. Therefore, it will be important to obtain detailed information on the pharmacokinetics of this drug in cattle or dogs prior to embarking on any further animal experimentation to study the in vivo efficacy of NTZ or is derivatives against neosporosis.…”

Section: Discussionmentioning

confidence: 99%

“…8B). For this, extracellular tachyzoites were resuspended in medium containing NTZ for different time spans (2,6, and 24 h) and only then were added to HFF monolayers. The overall number of tachyzoites interacting with HFF and the respective number of invaded parasites were determined in relation to controls incubated in medium alone.…”

Section: Vol 49 2005mentioning

confidence: 99%

In Vitro Efficacies of Nitazoxanide and Other Thiazolides againstNeospora caninumTachyzoites Reveal Antiparasitic Activity Independent of the Nitro Group

Esposito

Stettler

Moores

et al. 2005

Antimicrob Agents Chemother

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The thiazolide nitazoxanide [2-acetolyloxy-N-(5-nitro-2-thiazolyl)benzamide] (NTZ) exhibits a broad spectrum of activities against a wide variety of intestinal and tissue-dwelling helminths, protozoa, and enteric bacteria infecting animals and humans. The drug has been postulated to act via reduction of its nitro group by nitroreductases, including pyruvate ferredoxin oxidoreductase. In this study, we investigated the efficacies of nitazoxanide and a number of other thiazolides against Neospora caninum tachyzoites in vitro. We employed real-time-PCR-based monitoring of tachyzoite adhesion, invasion, and intracellular proliferation, as well as electron microscopic visualization of the effects imposed by nitazoxanide. In addition, we investigated several modified versions of this drug. These modifications included on one hand the replacement of the nitro group on the thiazole ring with a bromide, thus removing the most reactive group, and on the other hand the differential positioning of methyl groups on the salicylate ring. We show that the thiazole-associated nitro group is not necessarily required for the action of the drug and that methylation of the salicylate ring can result in complete abrogation of the antiparasitic activity, depending on the positioning of the methyl group. These findings indicate that other mechanisms besides the proposed mode of action involving the pyruvate ferredoxin oxidoreductase enzyme could be responsible for the wide spectrum of antiparasitic activity of NTZ and that modifications in the benzene ring could be important in these alternative mechanisms.

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“…The oral bioavailability of nitazoxanide 1 is about 30% and rises to about 50% when taken after food [32,33]. Recent data on the 5 -chloro analog 3 have demonstrated a biodisposition at least as good as 1 and likely better.…”

Section: Pharmacokinetics Of Thiazolides and Clinical Trials Datamentioning

confidence: 99%

Second-Generation Nitazoxanide Derivatives: Thiazolides are Effective Inhibitors of the Influenza a Virus

Stachulski

Piacentini

et al. 2018

Future Med. Chem.

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Aim:The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza.Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC 50 s in the range of 0.14-5.0 μM. Additionally a quantitative structure-property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified. Graphical abstract:OR 2 A number of thiazolides (R 1 = a 3, 4 or 5-substituent; R 2 = H or CH 3 CO; R 3 = a 4´ -or 5´-substituent) are active with IC 50 = 0.14-5.0 µM against a prototypical H1N1 strain of influenza A virus in MDCK cells; a QSAR regression model was developed, showing good correlation between predicted and measured in vitro activity.Since the prototype nitazoxanide has successfully completed Phase III clinical trials against acute uncomplicated influenza, this molecule series has considerable potential for future development.

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Nitazoxanide: pharmacokinetics and metabolism in man

Cited by 159 publications

References 0 publications

Thiazolides, a New Class of Antiviral Agents Effective against Rotavirus Infection, Target Viral Morphogenesis, Inhibiting Viroplasm Formation

Thiazolides, a New Class of Antiviral Agents Effective against Rotavirus Infection, Target Viral Morphogenesis, Inhibiting Viroplasm Formation

In Vitro Efficacies of Nitazoxanide and Other Thiazolides againstNeospora caninumTachyzoites Reveal Antiparasitic Activity Independent of the Nitro Group

Second-Generation Nitazoxanide Derivatives: Thiazolides are Effective Inhibitors of the Influenza a Virus

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