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Nifurtimox

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Nifurtimox
Clinical data
Trade namesLampit[1]
Other namesBayer 2502[1]
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • Undetermined
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityLow
MetabolismLiver (CYP involved)
Elimination half-life2.95 ± 1.19 hours
ExcretionKidney, very low
Identifiers
  • N-(3-Methyl-1,1-dioxido-4-thiomorpholinyl)-1-(5-nitro-2-furyl)methanimine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.377 Edit this at Wikidata
Chemical and physical data
FormulaC10H13N3O5S
Molar mass287.293 g/mol g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point180 to 182 °C (356 to 360 °F)
  • O=S2(=O)CC(N(N=Cc1oc([N+]([O-])=O)cc1)CC2)C
  • 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 checkY
  • Key:ARFHIAQFJWUCFH-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Nifurtimox is a medication used to Chagas disease and sleeping sickness.[1][2] For sleeping sickness it is used together with eflornithine.[2] In Chagas disease it is a second line option to benznidazole.[3] It is given by mouth.[1]

Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but this concerns have not be 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.[3]

Nifurtimox came into medication use in 1965.[3] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2] It is not avaliable commercially in Canada or the United States.[1] In the United States the medication can be gotten from the Center for Disease Control.[4] It cost about 20 USD for a course of treatment as of 2013.[5]

Medical uses

Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[6][7] However, long term use of Nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[7][8] 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.[8][3]

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,[9] but the combination of melarsoprol with nifurtimox appears to be efficacious.[10] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[11]

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.[12]

Pregnancy and breastfeeding

Use of nifurtimox should be avoided in pregnant women due to limited use.[7][3][13] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[14] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[14]

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.[7]

Most common side effects[7][4][15][16][17]

  • anorexia
  • weight loss
  • nausea
  • vomiting
  • headache
  • dizziness
  • amnesia

Less common effects[7][4][17][15]

  • 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.[3][18][4]

Mechanism of action

Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant break down of DNA.[7] Its mechanism is similar to that proposed for the antibacterial action of nitrofuran agents. 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.[7]

Manufacturing and availability

Nifurtimox is sold as Lampit by Bayer. It was previously known as Bayer 2502.

Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It is not commercially available in the United States, but can be distributed to qualifying healthcare professionals by the Centers for Disease Control and Prevention Drug Service.[7][19][4]

Research

Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.[20]

References

  1. ^ a b c d e f "Nifurtimox (Systemic)". Drugs.com. 1995. Retrieved 3 December 2016.
  2. ^ a b c "WHO Model List of EssentialMedicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved December 2016. {{cite web}}: Check date values in: |accessdate= (help)
  3. ^ a b c d e f Bern, Caryn; Montgomery, Susan P.; Herwaldt, Barbara L.; Rassi, Anis; Marin-Neto, Jose Antonio; Dantas, Roberto O.; Maguire, James H.; Acquatella, Harry; Morillo, Carlos (2007-11-14). "Evaluation and Treatment of Chagas Disease in the United States". JAMA. 298 (18). doi:10.1001/jama.298.18.2171. ISSN 0098-7484. PMID 18000201.
  4. ^ a b c d e Prevention, CDC - Centers for Disease Control and. "CDC - Chagas Disease - Resources for Health Professionals - Antiparasitic Treatment". www.cdc.gov. Retrieved 2016-11-09.
  5. ^ Dumas, Michel; Bouteille, Bernard; Buguet, Alain (2013). Progress in Human African Trypanosomiasis, Sleeping Sickness. Springer Science & Business Media. p. 268. ISBN 9782817808574.
  6. ^ Coura JR, de Castro SL (2002). "A critical review of Chagas disease chemotherapy". Mem Inst Oswaldo Cruz. 97 (1): 3–24. doi:10.1590/S0074-02762002000100001. PMID 11992141.
  7. ^ a b c d e f g h i "Nifurtimox Drug Information, Professional". www.drugs.com. Retrieved 2016-11-09.
  8. ^ a b Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François (2010-11-15). "Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease". Clinical Infectious Diseases. 51 (10): e69–e75. doi:10.1086/656917. ISSN 1058-4838. PMID 20932171.
  9. ^ Pepin J, Milord F, Mpia B, et al. (1989). "An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire". Trans R Soc Trop Med Hyg. 83 (4): 514–7. doi:10.1016/0035-9203(89)90270-8. PMID 2694491.
  10. ^ Bisser S, N'Siesi FX, Lejon V, et al. (2007). "Equivalence Trial of Melarsoprol and Nifurtimox Monotherapy and Combination Therapy for the Treatment of Second-Stage Trypanosoma brucei gambiense Sleeping Sickness". J Infect Dis. 195 (3): 322–329. doi:10.1086/510534. PMID 17205469.
  11. ^ Pepin J (2007). "Combination Therapy for Sleeping Sickness: A Wake-Up Call". J Infect Dis. 195 (3): 311–13. doi:10.1086/510540. PMID 17205466.
  12. ^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). "Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial". Lancet. 374 (9683): 56–64. doi:10.1016/S0140-6736(09)61117-X. PMID 19559476.
  13. ^ Schaefer, Christof; Peters, Paul W. J.; Miller, Richard K. (2014-09-17). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN 9780124079014.
  14. ^ a b "Nifurtimox use while Breastfeeding | Drugs.com". www.drugs.com. Retrieved 2016-11-07.
  15. ^ a b Forsyth, Colin J.; Hernandez, Salvador; Olmedo, Wilman; Abuhamidah, Adieb; Traina, Mahmoud I.; Sanchez, Daniel R.; Soverow, Jonathan; Meymandi, Sheba K. (2016-10-15). "Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States". Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 63 (8): 1056–1062. doi:10.1093/cid/ciw477. ISSN 1537-6591. PMC 5036918. PMID 27432838.
  16. ^ Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). "Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis)". Human & Experimental Toxicology. 25 (8): 471–479. ISSN 0960-3271. PMID 16937919.
  17. ^ a b Estani, Sergio Sosa; Segura, Elsa Leonor (1999-09-01). "Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina". Memórias do Instituto Oswaldo Cruz. 94: 363–365. doi:10.1590/S0074-02761999000700070. ISSN 0074-0276.
  18. ^ "Chagas disease". World Health Organization. Retrieved 2016-11-08.
  19. ^ "Our Formulary | Infectious Diseases Laboratories | CDC". www.cdc.gov. Retrieved 2016-11-08.
  20. ^ Clinical trial number NCT00601003 at ClinicalTrials.gov. Retrieved on July 10, 2009.
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