Identification

Name
Nitazoxanide
Accession Number
DB00507  (APRD00558)
Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Description

Nitazoxanide belongs to the class of drugs known as thiazolides. Nitazoxanide (NTZ) is a broad-spectrum anti-infective drug that markedly modulates the survival, growth, and proliferation of a range of extracellular and intracellular protozoa, helminths, anaerobic and microaerophilic bacteria, in addition to viruses. This drug is effective in the treatment of gastrointestinal infections including Cryptosporidium parvum or Giardia lamblia in healthy subjects. It is generally well tolerated. Nitazoxanide is a first-line, standard treatment for illness caused by C. parvum or G. lamblia infection in healthy (not immunosuppressed) adults and children and may also be considered in the treatment of illnesses caused by other protozoa or helminths [2]. Recently, this drug has been studied as a broad-spectrum antiviral agent due to its ability to inhibit the replication of several RNA and DNA viruses [3].

Structure
Thumb
Synonyms
  • Nitaxozanid
  • Nitaxozanide
  • Nitazoxanida
  • Nitazoxanidum
External IDs
PH 5776 / PH-5776
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AliniaPowder, for suspension100 mg/5mLOralLupin Pharma2013-10-09Not applicableUs
AliniaTablet500 mg/1OralRomark Laboratories, L.C.2004-07-21Not applicableUs
AliniaTablet500 mg/1OralAvera Mc Kennan Hospital2015-05-262018-06-18Us
AliniaPowder, for suspension100 mg/5mLOralRomark Laboratories, L.C.2002-11-22Not applicableUs
International/Other Brands
Alinia / Alpex Nizox (Alpex Pharmaceutical) / ANNITA (Alpex Pharmaceutical) / Azoxanid (G&R) / Celectan (Farma) / Colufase (Roemmers) / Coluquim (Quilab) / Daxon (Siegfried) / Dianide (General Pharma) / Diar (ACI) / Famidox (Lafrancol) / Kaside (Lafrancol) / Kazide (Lafrancol) / Larvisol (Armofar) / Lumbris (Farmedic) / Mixel (California) / Niazid (Apex) / Nitax (Delta) / Nitaxide (Beximco) / Nitazet (Glenmark) / Nitazofin (Bussié) / Nodik / Omniparax
Categories
UNII
SOA12P041N
CAS number
55981-09-4
Weight
Average: 307.282
Monoisotopic: 307.026291103
Chemical Formula
C12H9N3O5S
InChI Key
YQNQNVDNTFHQSW-UHFFFAOYSA-N
InChI
InChI=1S/C12H9N3O5S/c1-7(16)20-9-5-3-2-4-8(9)11(17)14-12-13-6-10(21-12)15(18)19/h2-6H,1H3,(H,13,14,17)
IUPAC Name
2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl acetate
SMILES
CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C(S1)[N+]([O-])=O

Pharmacology

Indication

For the treatment of diarrhea in adults and children caused by the protozoa Giardia lamblia, and for the treatment of diarrhea in children caused by the protozoan, Cryptosporidium parvum [Label].

Nitazoxanide has not been shown to be superior to placebo medication for the management of diarrhea caused by Cryptosporidium parvum in patients with HIV/immunodeficiency [Label].

Associated Conditions
Pharmacodynamics

The general effect of this medication is the prevention of microbe activity through disruption of important energy pathways for survival and proliferation [Label]. Nitazoxanide exhibits antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction, an essential reaction need for anaerobic energy metabolism of various microorganisms. Sporozoites of Cryptosporidium parvum and trophozoites of Giardia lamblia are therefore inhibited, relieving symptoms of diahrrea [10]. Interference with the PFOR enzyme-dependent electron transfer reaction may only be one of the many pathways by which nitazoxanide exhibits antiprotozoal activity [Label].

Mechanism of action

The most widely accepted mechanism of NTZ is believed to be the disruption of the energy metabolism in anaerobic microbes by inhibition of the pyruvate: ferredoxin/flavodoxin oxidoreductase (PFOR) cycle [5]. In parasitic-protozoa, Nitazoxanide also induces lesions in the cell membranes and depolarizes the mitochondrial membrane while inhibiting quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase enzymes. In addition, this drug also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates the Avr-14 gene, encoding for the alpha-type subunit of glutamate-gated chloride ion channel present in nematodes. Aside from its well understood non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also demonstrates various other antibacterial mechanisms. It inhibits pyruvate dehydrogenase in E Coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria, and stimulates host macrophage autophagy in tuberculosis patients [2]. NTZ also suppresses viral replication by inhibiting the maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Lastly, NTZ exhibits an inhibitory effect on tumor cell progression by altering drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activity, and c-Myc inhibition [2].

TargetActionsOrganism
APyruvate-flavodoxin oxidoreductase
antagonist
inhibitor
Desulfovibrio africanus
Absorption

The relative bioavailability of the suspension compared to the tablet was 70%. When administered with food the AUC and Cmax increased by two-fold and 50%, respectively, for the tablet and 45 to 50% and ≤ 10%, respectively, for the oral suspension [Label].

Volume of distribution
Not Available
Protein binding

Very High (greater than 99%), bound to proteins in the plasma [Label].

Metabolism

The active metabolite of this drug is tizoxanide (desacetyl-nitazoxanide). The initial reaction in the metabolic pathway of Nitazoxanide is hydrolysis to tizoxanide, followed by conjugation, primarily by glucuronidation to tizoxanide glucuronide.

The oral suspension bioavailability of this drug is not equivalent to that of the oral tablets. Compared to the to the tablet, the bioavailability of the suspension was 70% [Label].

When administered with food, the AUCt of tizoxanide and tizoxanide glucuronide in plasma is increased to almost two-fold and the maximum concentration is increased by almost 50% compared to when ingested without food [Label].

When the oral suspension was ingested with food, the AUC of tizoxanide and tizoxanide glucuronide increased by approximately 50% and the Cmax increased by less than 10% [Label].

Route of elimination

Tizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in urine and bile. Approximately 2/3 of the oral dose of nitazoxanide is excreted in the faeces and 1/3 in the urine [Label].

Half life

7.3h [8]

Clearance

Nitazoxanide is cleared in the urine and feces. The metabolite, tizoxanide, is also found in the urine, plasma, and breastmilk [9]. The drug is not found unchanged in the urine [9].

Toxicity

Data on nitazoxanide overdosage is not available [Label]. In studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. One-time oral doses of up to 4000 mg nitazoxanide have been given to healthy adult volunteers without severe adverse effects. Gastric lavage may be appropriate soon after oral administration if overdose occurs. Supportive and symptomatic treatment should also be administered [Label].

According to previous studies [Label], less than 1% of the patients age 12 years and older participating in clinical trials with NTZ suffered from the following adverse effects: Systemic: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, fever, flu-like syndrome. Central Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia. Gastrointestinal System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst. Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia. Metabolic & Nutrition: increased SGPT. Hemic & Lymphatic Systems: anemia, leukocytosis. Skin: rash, pruritus. Special Senses: eye discoloration, ear ache. Respiratory System: epistaxis, lung disease, pharyngitis. Cardiovascular System: tachycardia, syncope, hypertension. Muscular System: myalgia, leg cramps, spontaneous bone fracture.

Affected organisms
  • Mycobacterium tuberculosis
  • Helminthic Microorganisms
  • Bacteria and protozoa
  • Escherichia coli
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

Synthesis Reference
US3950351
General References
  1. Anderson VR, Curran MP: Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs. 2007;67(13):1947-67. [PubMed:17722965]
  2. Shakya A, Bhat HR, Ghosh SK: Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent. Curr Drug Discov Technol. 2017 Jul 27. pii: CDDT-EPUB-85034. doi: 10.2174/1570163814666170727130003. [PubMed:28748751]
  3. Rossignol JF: Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014 Oct;110:94-103. doi: 10.1016/j.antiviral.2014.07.014. Epub 2014 Aug 7. [PubMed:25108173]
  4. Balamurugan K, Said HM: Role of reduced folate carrier in intestinal folate uptake. Am J Physiol Cell Physiol. 2006 Jul;291(1):C189-93. doi: 10.1152/ajpcell.00594.2005. Epub 2006 Feb 22. [PubMed:16495369]
  5. Broekhuysen J, Stockis A, Lins RL, De Graeve J, Rossignol JF: Nitazoxanide: pharmacokinetics and metabolism in man. Int J Clin Pharmacol Ther. 2000 Aug;38(8):387-94. [PubMed:10984012]
  6. Nitazoxanide, Pub Chemistry [Link]
  7. EPA Chemistry Dashboard: Nitazoxanide [Link]
  8. Nitazoxanide: A New Thiazolide Antiparasitic Agent [Link]
  9. Validated and optimized high-performance liquid chromatographic determination of tizoxanide, the main active metabolite of nitazoxanide in human urine, plasma and breast milk. [Link]
  10. Pharmacology review, Nitazoxanide [Link]
External Links
Human Metabolome Database
HMDB0014649
KEGG Drug
D02486
PubChem Compound
41684
PubChem Substance
46507813
ChemSpider
38037
BindingDB
50075050
ChEBI
94807
ChEMBL
CHEMBL1401
Therapeutic Targets Database
DAP001293
PharmGKB
PA164754874
HET
NTI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Nitazoxanide
ATC Codes
P01AX11 — Nitazoxanide
PDB Entries
3v35
FDA label
Download (150 KB)
MSDS
Download (57.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedPreventionHepatitis C Recurrence1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1, 2Active Not RecruitingTreatmentHelminth Infection / Protozoan Infections / Ulcerative Colitis (UC) / Ulcerative Colitis Exacerbation1
1, 2CompletedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection4
2CompletedTreatmentClostridium Difficile1
2CompletedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHepatitis C Infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentInfections, Rotavirus / Viral Gastroenteritis Due to Rotavirus1
2CompletedTreatmentTuberculosis1
2CompletedTreatmentAcute, severe Respiratory Illness1
2Not Yet RecruitingTreatmentGastroenteritis Norovirus1
2RecruitingTreatmentGastroenteritis1
2TerminatedTreatmentCrohn's Disease (CD)1
2TerminatedTreatmentFlu caused by Influenza1
2Unknown StatusTreatmentHCV Coinfection / Human Immunodeficiency Virus (HIV) Infections1
2Unknown StatusTreatmentHepatic Encephalopathy1
2WithdrawnTreatmentBronchiolitis1
2, 3CompletedTreatmentAdenoviridae Infections / Infections, Rotavirus / Norovirus Infections1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
2, 3CompletedTreatmentFlu caused by Influenza1
2, 3CompletedTreatmentHepatitis C Viral Infection1
2, 3RecruitingTreatmentCognitive Development / Enteric Pathogens / Malnutrition / Stunting1
2, 3RecruitingTreatmentHepatic Encephalopathy1
3CompletedTreatmentAmebiasis2
3CompletedTreatmentClostridium Enterocolitis / Pseudomembranous Colitis1
3CompletedTreatmentDiarrhea1
3CompletedTreatmentFlu caused by Influenza2
3Not Yet RecruitingTreatmentEnterovirus / Rhinovirus1
3RecruitingTreatmentFlu caused by Influenza1
3RecruitingTreatmentHelicobacter-associated Gastritis1
3RecruitingTreatmentIndigestion1
3TerminatedTreatmentClostridium Infections1
3TerminatedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Type 2 Diabetes Mellitus1
4CompletedTreatmentIrritable Bowel Syndrome (IBS)1
4Unknown StatusTreatmentChronic Hepatitis C Virus (HCV) Infection1
Not AvailableCompletedTreatmentDiarrhea / Infections, Rotavirus1
Not AvailableCompletedTreatmentHepatic Cirrhosis / Minimal Hepatic Encephalopathy1
Not AvailableUnknown StatusTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
  • Romark laboratories
Packagers
  • Industriale Chimica S.R.L.
  • Laboratoria Qualiphar NV SA
  • Murfreesboro Pharmaceutical Nursing Supply
  • Romark Pharmaceuticals
Dosage forms
FormRouteStrength
Powder, for suspensionOral100 mg/5mL
TabletOral500 mg/1
Prices
Unit descriptionCostUnit
Alinia 500 mg tablet23.22USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5387598No1995-02-072012-02-07Us
US5968961No1997-05-072017-05-07Us
US5965590No1997-07-032017-07-03Us
US6117894No1997-05-072017-05-07Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)202 °C [L1417]
boiling point (°C)394[L1417]
water solubility1.89e-04[L1417]
logP1.63 [L1417]
Predicted Properties
PropertyValueSource
Water Solubility0.00755 mg/mLALOGPS
logP2.14ALOGPS
logP2.12ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)8.3ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area114.11 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity73.89 m3·mol-1ChemAxon
Polarizability27.54 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9045
Blood Brain Barrier+0.7175
Caco-2 permeable-0.5571
P-glycoprotein substrateNon-substrate0.7978
P-glycoprotein inhibitor INon-inhibitor0.8874
P-glycoprotein inhibitor IINon-inhibitor0.9836
Renal organic cation transporterNon-inhibitor0.9228
CYP450 2C9 substrateNon-substrate0.7438
CYP450 2D6 substrateNon-substrate0.8431
CYP450 3A4 substrateNon-substrate0.5596
CYP450 1A2 substrateNon-inhibitor0.6339
CYP450 2C9 inhibitorInhibitor0.6655
CYP450 2D6 inhibitorNon-inhibitor0.9027
CYP450 2C19 inhibitorNon-inhibitor0.6341
CYP450 3A4 inhibitorInhibitor0.6669
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5635
Ames testAMES toxic0.8322
CarcinogenicityNon-carcinogens0.7746
BiodegradationReady biodegradable0.5458
Rat acute toxicity1.7902 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9283
hERG inhibition (predictor II)Non-inhibitor0.9295
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01b9-1950000000-3d1aca26d9cbdaaab410

Taxonomy

Description
This compound belongs to the class of organic compounds known as acylsalicylamides. These are o-acylated derivatives of salicylamide.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Acylsalicylamides
Alternative Parents
Phenol esters / Benzamides / Phenoxy compounds / Benzoyl derivatives / Nitroaromatic compounds / Nitrothiazoles / 2,5-disubstituted thiazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Carboxylic acid esters
show 10 more
Substituents
Acylsalicylamide / Phenol ester / Benzamide / Phenoxy compound / Nitroaromatic compound / Benzoyl / Nitrothiazole / 2,5-disubstituted 1,3-thiazole / Azole / Thiazole
show 24 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Desulfovibrio africanus
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
General Function
Thiamine pyrophosphate binding
Specific Function
Catalyzes the ferredoxin-dependent oxidative decarboxylation of pyruvate. Required for the transfer of electrons from pyruvate to ferredoxin (PubMed:9294422, PubMed:7612653). Ferredoxin I and ferre...
Gene Name
por
Uniprot ID
P94692
Uniprot Name
Pyruvate synthase
Molecular Weight
133679.405 Da
References
  1. Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG: Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob Agents Chemother. 2007 Mar;51(3):868-76. Epub 2006 Dec 11. [PubMed:17158936]
  2. Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Hoffman PS, Macdonald TL: Biological activity of modified and exchanged 2-amino-5-nitrothiazole amide analogues of nitazoxanide. Bioorg Med Chem Lett. 2010 Jun 15;20(12):3537-9. doi: 10.1016/j.bmcl.2010.04.126. Epub 2010 May 18. [PubMed:20488706]

Enzymes

Kind
Protein
Organism
Desulfovibrio africanus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thiamine pyrophosphate binding
Specific Function
Catalyzes the ferredoxin-dependent oxidative decarboxylation of pyruvate. Required for the transfer of electrons from pyruvate to ferredoxin (PubMed:9294422, PubMed:7612653). Ferredoxin I and ferre...
Gene Name
por
Uniprot ID
P94692
Uniprot Name
Pyruvate synthase
Molecular Weight
133679.405 Da
References
  1. Anderson VR, Curran MP: Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs. 2007;67(13):1947-67. [PubMed:17722965]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Reduced folate carrier activity
Specific Function
Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely th...
Gene Name
SLC19A1
Uniprot ID
P41440
Uniprot Name
Folate transporter 1
Molecular Weight
64867.62 Da
References
  1. Balamurugan K, Said HM: Role of reduced folate carrier in intestinal folate uptake. Am J Physiol Cell Physiol. 2006 Jul;291(1):C189-93. doi: 10.1152/ajpcell.00594.2005. Epub 2006 Feb 22. [PubMed:16495369]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 04:22