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Identification
- Summary
Nifurtimox is an antiparasitic drug used for the treatment of Chagas disease (Trypanosoma cruzi infection).
- Brand Names
- Lampit
- Generic Name
- Nifurtimox
- DrugBank Accession Number
- DB11820
- Background
Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11
The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11
Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer's formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Nifurtimox (DB11820)
- Weight
- Average: 287.29
Monoisotopic: 287.057591705 - Chemical Formula
- C10H13N3O5S
- Synonyms
- Nifurtimox
- Nifurtimoxum
- External IDs
- BAY 2502
- BAY-2502
- BAY-A2502
- Bayer 2502
- BAYER-2502
- CCRIS 2201
- DNDI1613515
Pharmacology
- Indication
Nifurtimox is indicated in pediatric patients under 18 weighing at least 2.5 kg. Continued approval of this drug for this indication is dependent upon confirmatory clinical trial results.16
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Chagas disease •••••••••••• ••••••••• •••• •••••• •••• •• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Nifurtimox exerts trypanosomal activity against Trypanosoma cruzi, treating Chagas disease.6 One study reports that nifurtimox and other benzofuran derivatives reduce parasite dehydrogenase activity.4 Results of a recent phase III clinical trial13 have shown that a significant number of pediatric patients with acute or chronic Chagas disease treated with nifurtimox were immunoglobulin G (IgG) antibody negative and demonstrated at least a 20% decrease in optical density on two IgG antibody tests for T. cruzi antigens.10,14
- Mechanism of action
The mechanism of action of nifurtimox has not been fully elucidated, however, is believed to occur by the activation of nitroreductase enzymes that produce reactive metabolites with a series of deleterious effects on Trypanosoma cruzi, the parasite causing Chagas disease.6,10 The antiprotozoal actions of nifurtimox occur both intracellularly and extracellularly.10 Inhibition of parasite dehydrogenase activity is another purported mode of action of nifurtimox that warrants further research.4
Target Actions Organism UNitroreductases activatorTrypanosoma cruzi UGlyceraldehyde-3-phosphate dehydrogenase, glycosomal inhibitorTrypanosoma cruzi - Absorption
The average AUC of nifurtimox is estimated between 1676-2670 μg∙h/L.10 One pharmacokinetic study of healthy volunteers revealed an AUC of 5430 ng∙ml-1∙h.8 Cmax ranges between 425-568 μg/L (26–50%) after a single dose of 20 mg with food in adults. Tmax is 4 hours, ranging from 2 to 8 hours post-dose in the fed state.8,10 In a pharmacokinetic study of healthy volunteers, serum concentration was low, likely due to the first-pass effect.1
- Volume of distribution
Nifurtimox crosses the blood-brain barrier and the placenta.2,10
- Protein binding
The plasma protein binding of nifurtimox is approximately 42%.10 It is primarily bound to albumin.2
- Metabolism
Nifurtimox is largely metabolized via nitroreductase enzymes. Two major inactive metabolites have been identified: M-4 and M-6. The M-4 metabolite is a cysteine conjugate of nifurtimox, while M-6 is likely formed by hydrolytic cleavage of the hydrazone moiety of nifurtimox. Other minor metabolites have also been identified in human plasma.9,10
- Route of elimination
In the fed state, 44% of the dose was mainly recovered in the urine as metabolites. Fecal and biliary excretion of nifurtimox have not been studied.10
- Half-life
The elimination half-life of nifurtimox ranges from 2.4–3.6 hours.10 A pharmacokinetic study of healthy volunteers and patients with renal failure revealed respective mean half-lives of 2.95 h and 3.95 h.8
- Clearance
One pharmacokinetic study of nifurtimox revealed a clearance of 193.4 l∙h-1. In patients without renal failure; clearance was 99.7 l∙h-1.8
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
There is limited information in the literature regarding overdose with nifurtimox. Some symptoms of nifurtimox toxicity may include weight loss, anorexia, nausea, vomiting, vertigo, headache, nervous excitation, insomnia, convulsions, drowsiness, arthralgias, myalgias, disorientation, abdominal pain, mucosal edema, and skin manifestations. These symptoms are adverse effects of nifurtimox and are likely to be exaggerated with increased exposure.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Avoid alcohol. Alcohol use during nifurtimox treatment may increase undesirable adverse effects.
- Take with food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Lampit (Bayer)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Lampit Tablet, film coated 120 mg/1 Oral Bayer HealthCare Pharmaceuticals Inc. 2020-10-01 Not applicable US 
Lampit Tablet, film coated 30 mg/1 Oral Bayer HealthCare Pharmaceuticals Inc. 2020-10-01 Not applicable US
Categories
- ATC Codes
- P01CC01 — Nifurtimox
- Drug Categories
- Agents Against Leishmaniasis and Trypanosomiasis
- Anti-Infective Agents
- Antiparasitic Agents
- Antiparasitic Products, Insecticides and Repellents
- Antiprotozoals
- BCRP/ABCG2 Substrates
- Furans
- Nitro Compounds
- Nitrofuran Antiprotozoals
- Nitrofuran Derivatives
- Nitrofurans
- Sulfur Compounds
- Thiazines
- Trypanocidal Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as nitrofurans. These are compounds containing a furan ring which bears a nitro group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Furans
- Sub Class
- Nitrofurans
- Direct Parent
- Nitrofurans
- Alternative Parents
- Nitroaromatic compounds / Thiomorpholines / Sulfones / Heteroaromatic compounds / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Organic oxoazanium compounds / Hydrazones / Azacyclic compounds / Organopnictogen compounds show 3 more
- Substituents
- 1,4-thiazinane / 2-nitrofuran / Allyl-type 1,3-dipolar organic compound / Aromatic heteromonocyclic compound / Azacycle / C-nitro compound / Heteroaromatic compound / Hydrazone / Hydrocarbon derivative / Nitroaromatic compound show 12 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- nitrofuran antibiotic (CHEBI:7566)
- Affected organisms
- Trypanosoma cruzi
Chemical Identifiers
- UNII
- M84I3K7C2O
- CAS number
- 23256-30-6
- InChI Key
- ARFHIAQFJWUCFH-IZZDOVSWSA-N
- InChI
- InChI=1S/C10H13N3O5S/c1-8-7-19(16,17)5-4-12(8)11-6-9-2-3-10(18-9)13(14)15/h2-3,6,8H,4-5,7H2,1H3/b11-6+
- IUPAC Name
- 3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione
- SMILES
- CC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=O
References
- Synthesis Reference
Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1
- General References
- Paulos C, Paredes J, Vasquez I, Thambo S, Arancibia A, Gonzalez-Martin G: Pharmacokinetics of a nitrofuran compound, nifurtimox, in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1989 Sep;27(9):454-7. [Article]
- Jeganathan S, Sanderson L, Dogruel M, Rodgers J, Croft S, Thomas SA: The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. J Pharmacol Exp Ther. 2011 Feb;336(2):506-15. doi: 10.1124/jpet.110.172981. Epub 2010 Nov 5. [Article]
- Forsyth CJ, Hernandez S, Olmedo W, Abuhamidah A, Traina MI, Sanchez DR, Soverow J, Meymandi SK: Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States. Clin Infect Dis. 2016 Oct 15;63(8):1056-1062. doi: 10.1093/cid/ciw477. Epub 2016 Jul 17. [Article]
- Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [Article]
- Cerecetto H, Gonzalez M: Antiparasitic prodrug nifurtimox: revisiting its activation mechanism. Future Microbiol. 2011 Aug;6(8):847-50. doi: 10.2217/fmb.11.74. [Article]
- Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy. [Article]
- Castro JA, Diaz de Toranzo EG: Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas' disease). Biomed Environ Sci. 1988 Jun;1(1):19-33. [Article]
- Gonzalez-Martin G, Thambo S, Paulos C, Vasquez I, Paredes J: The pharmacokinetics of nifurtimox in chronic renal failure. Eur J Clin Pharmacol. 1992;42(6):671-3. doi: 10.1007/BF00265935. [Article]
- CA Pérez Montilla, S Moroni, N González, G Moscatelli, JM Altcheh, F García Bournissen: P38 Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS BMJ. [Article]
- FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]
- CDC: Chagas disease [Link]
- Bioworld: Bayer’s Lampit approved by FDA for treating Chagas disease [Link]
- Clinicaltrials.gov: History of Changes for Study: NCT02625974 Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease (CHICO) [Link]
- Clinicaltrials.gov, Results: Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease (CHICO) [Link]
- Cayman Chem MSDS: Nifurtimox [Link]
- FDA Approved Drug Products: LAMPIT (nifurtimox) tablets for oral use (February 2023) [Link]
- External Links
- KEGG Drug
- D00833
- KEGG Compound
- C08002
- PubChem Compound
- 6842999
- PubChem Substance
- 347828167
- ChemSpider
- 5246596
- BindingDB
- 50259708
- 7421
- ChEBI
- 7566
- ChEMBL
- CHEMBL290960
- Wikipedia
- Nifurtimox
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Chagas Disease 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Not Available Chagas Disease 1 somestatus stop reason just information to hide 4 Completed Treatment Human African Trypanosomiasis (HAT) 1 somestatus stop reason just information to hide 3 Completed Treatment Chagas Disease 1 somestatus stop reason just information to hide 3 Completed Treatment Trypanosoma Brucei Gambiense; Infection 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 120 mg/1 Tablet, film coated Oral 30 mg/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 177-183 https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx boiling point (°C) 550.3±50.0 https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx logP -0.27 https://deepblue.lib.umich.edu/bitstream/handle/2027.42/146268/bcp13650.pdf?sequence=1 logS 0.158 https://deepblue.lib.umich.edu/bitstream/handle/2027.42/146268/bcp13650.pdf?sequence=1 pKa -1.01±0.40 https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx - Predicted Properties
Property Value Source Water Solubility 0.285 mg/mL ALOGPS logP 0.25 ALOGPS logP -0.27 Chemaxon logS -3 ALOGPS pKa (Strongest Basic) 0.34 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 106.02 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 65.78 m3·mol-1 Chemaxon Polarizability 26.74 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-002f-9440000000-bb33e5f06115dd118316 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 153.36078 predictedDeepCCS 1.0 (2019) [M+H]+ 156.65587 predictedDeepCCS 1.0 (2019) [M+Na]+ 165.22116 predictedDeepCCS 1.0 (2019)
Targets
References
- Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy. [Article]
- Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [Article]
- FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]
- Kind
- Protein
- Organism
- Trypanosoma cruzi
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- This target action is supported by limited evidence in the literature.
- General Function
- Not Available
- Specific Function
- glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity
- Gene Name
- Not Available
- Uniprot ID
- P22513
- Uniprot Name
- Glyceraldehyde-3-phosphate dehydrogenase, glycosomal
- Molecular Weight
- 39060.3 Da
References
- Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [Article]
Enzymes
References
- Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy. [Article]
- Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [Article]
- FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Jeganathan S, Sanderson L, Dogruel M, Rodgers J, Croft S, Thomas SA: The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. J Pharmacol Exp Ther. 2011 Feb;336(2):506-15. doi: 10.1124/jpet.110.172981. Epub 2010 Nov 5. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- This transporter action is supported by data from an in vitro study. Limited evidence exists in the literature for this transporter action.
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Watson CP, Dogruel M, Mihoreanu L, Begley DJ, Weksler BB, Couraud PO, Romero IA, Thomas SA: The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein. Brain Res. 2012 Feb 3;1436:111-21. doi: 10.1016/j.brainres.2011.11.053. Epub 2011 Dec 4. [Article]
Drug created at October 20, 2016 20:50 / Updated at October 07, 2024 17:37