Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d.

Stockis, Armel; Bruyn, Steven De; Gengler, Christophe; Rosillon, Dominique

doi:10.5414/cpp40221

Cited by 75 publications

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“…Nevertheless, all patients completed the study, and no abnormalities of clinical chemistry parameters were related to its use. The adverse effects were very similar to those reported by other studies with NTZ in vivo (19,20), especially those noted by the patients taking a 1-g dose twice daily.…”

Section: Discussionsupporting

confidence: 88%

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Nitazoxanide in Treatment of Helicobacterpylori : a Clinical and In VitroStudy

Guttner

Windsor

Viiala

et al. 2003

Antimicrob Agents Chemother

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Nitazoxanide (NTZ) is an antibiotic with microbiological characteristics similar to those of metronidazole but without an apparent problem of resistance. The aim of this study was the prospective evaluation of NTZ given as a single agent in the treatment of Helicobacter pylori infection. Twenty culture-positive patients with dyspepsia who had previously failed at least one course of H. pylori eradication therapy were enrolled. Subjects received 1 g of NTZ twice daily for 10 days. The safety and tolerability of the drug were assessed by physical examination, monitoring of adverse events, and clinical laboratory evaluation. Urea breath tests (UBTs) were performed 6 weeks posttreatment. H. pylori was isolated from UBT-positive patients by the string test or endoscopy with biopsy, and the MICs for these isolates were compared to those for isolates obtained pretherapy. The levels of tizoxanide, the active deacylated derivative of NTZ, were measured in blood, saliva, and tissue from two patients during treatment. The UBT results were positive for all 20 patients after completion of NTZ therapy. The MIC results demonstrated that the NTZ susceptibilities of none of the strains isolated from the patients posttherapy had changed significantly. No major adverse reactions were observed, but frequent minor side effects were observed. In conclusion, NTZ did not eradicate H. pylori when it was given as a single agent.Nitazoxanide (NTZ), a nitrothiazolyl-salicylamide compound first described by Rossignol and Cavier (J. F. Rossignol and R. Cavier, Chem. Abstr. 83:28216n, 1975), has a broad spectrum of activity against microaerobic and anaerobic bacteria, anaerobic protozoa, and helminths (1, 6). It is the first antiparasitic agent reported to be effective against both protozoa and helminths, particularly in the treatment of intestinal parasitic infections (8, 13). The pharmacokinetics and metabolism of NTZ have been studied after the administration of single oral doses to healthy subjects (18), as well as after administration of radiocarbon-labeled NTZ (4). The main circulating metabolites have been identified as deacetyl-NTZ or tizoxanide (TIZ) and the corresponding acyl-glucuronide.Previous studies showed that the incidence of adverse events was dose related, while vital signs, electrocardiograms, and laboratory test results remained unchanged (19). Side effects included loose stools, diarrhea, abdominal pain, flatulence, nausea, vomiting, dyspepsia, xerostomia, discolored urine (yellow-green), and headache (19,20).NTZ was the first effective treatment for cryptosporidial diarrhea in patients with AIDS, eradicating Cryptosporidium parvum from the intestinal tract (5,7,14,21), and has been successful in the treatment of microsporidiosis in a patient with AIDS (3). Diarrhea caused by Giardia intestinalis and Entamoeba histolytica or Entamoeba dispar has also been shown to respond to NTZ (12,15). Furthermore, the drug was efficacious in a hamster model of antibiotic-induced diarrhea caused by Clostridium difficile compared to the...

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Section: Discussionsupporting

confidence: 88%

“…Side effects included loose stools, diarrhea, abdominal pain, flatulence, nausea, vomiting, dyspepsia, xerostomia, discolored urine (yellow-green), and headache (19,20).…”

mentioning

confidence: 99%

Nitazoxanide in Treatment of Helicobacterpylori : a Clinical and In VitroStudy

Guttner

Windsor

Viiala

et al. 2003

Antimicrob Agents Chemother

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“…This is below the growthinhibitory concentrations of NTZ (50) and within the range achievable in human plasma (77). Our further analysis of P pilus assembly revealed a dose-dependent decrease in the levels of pili on the bacterial surface in response to NTZ, corresponding with the decrease in HA activity.…”

Section: Discussionsupporting

confidence: 56%

Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane

Chahales

Hoffman

Thanassi

2016

Antimicrob Agents Chemother

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bMany bacterial pathogens assemble surface fibers termed pili or fimbriae that facilitate attachment to host cells and colonization of host tissues. The chaperone/usher (CU) pathway is a conserved secretion system that is responsible for the assembly of virulence-associated pili by many different Gram-negative bacteria. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and an integral outer membrane (OM) assembly and secretion platform termed the usher. Nitazoxanide (NTZ), an antiparasitic drug, was previously shown to inhibit the function of aggregative adherence fimbriae and type 1 pili assembled by the CU pathway in enteroaggregative Escherichia coli, an important causative agent of diarrhea. We show here that NTZ also inhibits the function of type 1 and P pili from uropathogenic E. coli (UPEC). UPEC is the primary causative agent of urinary tract infections, and type 1 and P pili mediate colonization of the bladder and kidneys, respectively. By analysis of the different stages of the CU pilus biogenesis pathway, we show that treatment of bacteria with NTZ causes a reduction in the number of usher molecules in the OM, resulting in a loss of pilus assembly on the bacterial surface. In addition, we determine that NTZ specifically prevents proper folding of the usher ␤-barrel domain in the OM. Our findings demonstrate that NTZ is a pilicide with a novel mechanism of action and activity against diverse CU pathways. This suggests that further development of the NTZ scaffold may lead to new antivirulence agents that target the usher to prevent pilus assembly.

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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 tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d.

Cited by 75 publications

References 0 publications

Nitazoxanide in Treatment of Helicobacterpylori : a Clinical and In VitroStudy

Nitazoxanide in Treatment of Helicobacterpylori : a Clinical and In VitroStudy

Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane

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

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