Nifurtimox
{{Short description|Anti-parasitic medical drug}}
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{{Infobox drug
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| image = Nifurtimox.svg
| image_class = skin-invert-image
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| image2 = Nifurtimox 3D.png
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| chirality = Racemic mixture
| caption =
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| Drugs.com = {{drugs.com|mmx|nifurtimox}}
{{drugs.com|parent|Lampit}}
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| DailyMedID = Nifurtimox
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| routes_of_administration = By mouth
| class =
| ATCvet =
| ATC_prefix = P01
| ATC_suffix = CC01
| ATC_supplemental = {{ATCvet|P51|AC01}}
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| legal_US = Rx-only
| legal_UN =
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| legal_status = Rx-only
| bioavailability = Low
| protein_bound =
| metabolism = Liver (Cytochrome P450 oxidase (CYP) involved)
| metabolites =
| onset =
| elimination_half-life = 2.95 ± 1.19 hours
| duration_of_action =
| excretion = Kidney, very low
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 23256-30-6
| CAS_supplemental =
| PubChem = 6842999
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| DrugBank = DB11820
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| UNII = M84I3K7C2O
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| KEGG = D00833
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = C08002
| ChEBI_Ref =
| ChEBI = 7566
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 290960
| NIAID_ChemDB =
| PDB_ligand =
| IUPAC_name = N-(3-Methyl-1,1-dioxido-4-thiomorpholinyl)-1-(5-nitro-2-furyl)methanimine
| C=10 | H=13 | N=3 | O=5 | S=1
| SMILES = CC1CS(=O)(=O)CCN1N=CC2=CC=C(O2)[N+](=O)[O-]
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
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| melting_point = 180
| melting_high = 182
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Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease it is a second-line option to benznidazole. It is given by mouth.
Common side effects include abdominal pain, headache, nausea, and weight loss. There are concerns from animal studies that it may increase the risk of cancer but these concerns have not been found in human trials. Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems. It is a type of nitrofuran.
Nifurtimox came into medication use in 1965.{{cite journal | vauthors = Bern C, Montgomery SP, Herwaldt BL, Rassi A, Marin-Neto JA, Dantas RO, Maguire JH, Acquatella H, Morillo C, Kirchhoff LV, Gilman RH, Reyes PA, Salvatella R, Moore AC | display-authors = 6 | title = Evaluation and treatment of chagas disease in the United States: a systematic review | journal = JAMA | volume = 298 | issue = 18 | pages = 2171–2181 | date = November 2007 | pmid = 18000201 | doi = 10.1001/jama.298.18.2171 | doi-access = free }} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} It is not available commercially in Canada.{{cite web|title=Nifurtimox (Systemic)|url=https://www.drugs.com/cons/nifurtimox.html|date=1995|website=Drugs.com|access-date=3 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220042503/https://www.drugs.com/cons/nifurtimox.html|archive-date=20 December 2016}} It was approved for medical use in the United States in August 2020.{{cite web | title=Lampit: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213464 | archive-url=https://web.archive.org/web/20201020014224/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213464 | url-status=dead | archive-date=October 20, 2020 | access-date=6 August 2020}} In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO).{{cite web|title=Trypanosomiasis, human African (sleeping sickness)|url=https://www.who.int/mediacentre/factsheets/fs259/en/|website=World Health Organization|access-date=7 December 2016|date=February 2016|url-status=live|archive-url=https://web.archive.org/web/20161204153318/http://www.who.int/mediacentre/factsheets/fs259/en/|archive-date=4 December 2016}}
Medical uses
Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.{{cite journal | vauthors = Rodriques Coura J, de Castro SL | title = A critical review on Chagas disease chemotherapy | journal = Memórias do Instituto Oswaldo Cruz | volume = 97 | issue = 1 | pages = 3–24 | date = January 2002 | pmid = 11992141 | doi = 10.1590/S0074-02762002000100001 | doi-access = free }}{{Cite web|url=https://www.drugs.com/mmx/nifurtimox.html|title=Nifurtimox Drug Information, Professional|website=www.drugs.com|access-date=2016-11-09|url-status=live|archive-url=https://web.archive.org/web/20161108140805/https://www.drugs.com/mmx/nifurtimox.html|archive-date=2016-11-08}} However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.{{cite journal | vauthors = Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F | title = Tolerance and safety of nifurtimox in patients with chronic chagas disease | journal = Clinical Infectious Diseases | volume = 51 | issue = 10 | pages = e69–e75 | date = November 2010 | pmid = 20932171 | doi = 10.1086/656917 | doi-access = free }} Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.
In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least {{convert|2.5|kg|lb}} for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.{{cite web | title=Lampit- nifurtimox tablet, film coated | website=DailyMed | date=27 January 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90d09714-a8b1-4696-8ada-f99dc54d0721 | access-date=23 February 2023}}
Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,{{cite journal | vauthors = Pepin J, Milord F, Mpia B, Meurice F, Ethier L, DeGroof D, Bruneel H | title = An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 83 | issue = 4 | pages = 514–517 | year = 1989 | pmid = 2694491 | doi = 10.1016/0035-9203(89)90270-8 }} but the combination of melarsoprol with nifurtimox appears to be efficacious.{{cite journal | vauthors = Bisser S, N'Siesi FX, Lejon V, Preux PM, Van Nieuwenhove S, Miaka Mia Bilenge C, Būscher P | title = Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness | journal = The Journal of Infectious Diseases | volume = 195 | issue = 3 | pages = 322–329 | date = February 2007 | pmid = 17205469 | doi = 10.1086/510534 | doi-access = free }} Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.{{cite journal | vauthors = Pepin J | title = Combination therapy for sleeping sickness: a wake-up call | journal = The Journal of Infectious Diseases | volume = 195 | issue = 3 | pages = 311–313 | date = February 2007 | pmid = 17205466 | doi = 10.1086/510540 | doi-access = free }}
Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.{{cite journal | vauthors = Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, Ghabri S, Baudin E, Buard V, Kazadi-Kyanza S, Ilunga M, Mutangala W, Pohlig G, Schmid C, Karunakara U, Torreele E, Kande V | display-authors = 6 | title = Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial | journal = Lancet | volume = 374 | issue = 9683 | pages = 56–64 | date = July 2009 | pmid = 19559476 | doi = 10.1016/S0140-6736(09)61117-X | hdl-access = free | s2cid = 32757305 | hdl = 10144/72797 }}
= Pregnancy and breastfeeding =
Use of nifurtimox should be avoided in pregnant women due to limited use.{{Cite book | vauthors = Padberg S | chapter = Anti-infective agents: Nitrofurans and drugs for urinary infection | chapter-url= https://books.google.com/books?id=L2NzAwAAQBAJ&q=Nifurtimox+pregnancy&pg=PA124 |title=Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment| veditors = Schaefer C, Peters PW, Miller RK |date=2014-09-17|publisher=Academic Press|isbn=9780124079014|url-status=live|archive-url=https://web.archive.org/web/20170908221306/https://books.google.com/books?id=L2NzAwAAQBAJ&pg=PA124&lpg=PA124&dq=Nifurtimox+pregnancy&source=bl&ots=XzIcQyHD_0&sig=_2ucLo3S4ng_MtnTsjGknCbCXtM&hl=en&sa=X&ved=0ahUKEwiR486g5ZfQAhVkslQKHUVFCysQ6AEIVTAI#v=onepage&q=Nifurtimox%20pregnancy&f=false|archive-date=2017-09-08}} There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.{{Cite web|url=https://www.drugs.com/breastfeeding/nifurtimox.html|title=Nifurtimox use while Breastfeeding |website=Drugs.com|access-date=2016-11-07|url-status=live|archive-url=https://web.archive.org/web/20161108140741/https://www.drugs.com/breastfeeding/nifurtimox.html|archive-date=2016-11-08}} Other authors do not consider breastfeeding a contraindication during nifurtimox use.
Side effects
Side effects occur following chronic administration, particularly in elderly people.
Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.
Most common side effects{{cite web|url=https://www.cdc.gov/parasites/chagas/health_professionals/tx.html | title=Parasites - American Trypanosomiasis (also known as Chagas Disease) |website=U.S. Centers for Disease Control and Prevention (CDC) | access-date=2016-11-09 | url-status=live | archive-url=https://web.archive.org/web/20161106123343/http://www.cdc.gov/parasites/chagas/health_professionals/tx.html | archive-date=2016-11-06}}{{cite journal | vauthors = Forsyth CJ, Hernandez S, Olmedo W, Abuhamidah A, Traina MI, Sanchez DR, Soverow J, Meymandi SK | display-authors = 6 | title = Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States | journal = Clinical Infectious Diseases | volume = 63 | issue = 8 | pages = 1056–1062 | date = October 2016 | pmid = 27432838 | pmc = 5036918 | doi = 10.1093/cid/ciw477 }}{{cite journal | vauthors = Castro JA, de Mecca MM, Bartel LC | title = Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis) | journal = Human & Experimental Toxicology | volume = 25 | issue = 8 | pages = 471–479 | date = August 2006 | pmid = 16937919 | doi = 10.1191/0960327106het653oa | bibcode = 2006HETox..25..471C | hdl-access = free | s2cid = 8980212 | hdl = 11336/82805 }}{{cite journal | vauthors = Sosa Estani S, Segura EL | title = Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina | journal = Memórias do Instituto Oswaldo Cruz | volume = 94 | pages = 363–365 | date = 1999-09-01 | issue = Suppl 1 | pmid = 10677756 | doi = 10.1590/S0074-02761999000700070 | doi-access = free }}
- anorexia
- weight loss
- nausea
- vomiting
- headache
- dizziness
- amnesia
- rash
- depression
- anxiety
- confusion
- fever
- sore throat
- chills
- seizures
- impotence
- tremors
- muscle weakness
- numbness of hands or feet
= Contraindications =
Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.{{Cite web|url=https://www.who.int/mediacentre/factsheets/fs340/en/|title=Chagas disease|website=World Health Organization|access-date=2016-11-08|url-status=live|archive-url=https://web.archive.org/web/20140227181940/http://www.who.int/mediacentre/factsheets/fs340/en/|archive-date=2014-02-27}}
Mechanism of action
Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA. Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.
Society and culture
{{update-section|date=August 2020}}
= Legal status =
= Names =
Research
Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.{{ClinicalTrialsGov|NCT00601003|Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma}}. Retrieved on July 10, 2009.
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References
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External links
- {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/nifurtimox | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Nifurtimox }}
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Category:Drugs developed by Bayer
Category:World Health Organization essential medicines