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Fexinidazole

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Fexinidazole
Clinical data
Other names
  • Fexinidazole Winthrop
  • HOE 239
ATC code
Identifiers
  • 1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.619 Edit this at Wikidata
Chemical and physical data
FormulaC12H13N3O3S
Molar mass279.31 g·mol−1
3D model (JSmol)
  • [O-][N+](=O)c1cnc(n1C)COc2ccc(SC)cc2

Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) cause by Trypanosoma brucei gambiense.[1] It is effective against both first and second stage disease.[1] Some evidence also supports its use in Chagas disease.[2] It is taken by mouth.[2]

Common side effects include nausea, vomiting, headache, and trouble sleeping.[3] Other side effects may include QT prolongation, psychosis, and low white blood cells.[4] It is unclear if use during pregnancy or breast feeding is safe.[4] Fexinidazole is in the antiparasitic and the nitroimidazole family of medications.[2] It is believed to work by turning on certain enzymes within the parasites that result in their death.[3]

Fexinidazole was first described in 1978.[5] It was given a positive opinion by the European Medicines Agency in 2018.[3] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] Development for sleeping sickness was funded by the Drugs for Neglected Diseases initiative in collaboration with Sanofi.[7]

Medical use

Sleeping sickness

A trial in Africa found fexinidazole to be 91% effective at treating sleeping sickness.[3][8] Though less effective than nifurtimox with eflornithine in severe disease, fexinidazole has the benefit that it can be taken by mouth.[3]

Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years.[9]

Other

It has activity against Trypanosoma cruzi, Tritrichomonas foetus, Trichomonas vaginalis, Entamoeba histolytica,[10] and Trypanosoma brucei.[11] It has not been found to be useful for visceral leishmaniasis.[2]

Mechanism of action

The biologically relevant active metabolites in vivo are the sulfoxide and sulfone.[12][13]

History

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s.[14]

Society and culture

Fexinidazole Winthrop, a Sanofi-Aventis product developed with the Drugs for Neglected Diseases Initiative (DNDi), received a positive endorsement from the European Medicines Agency in 2018, for use in non-European markets.[15][16] It was approved for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) in December 2018.[17]

References

  1. ^ a b DIMITROVA, Elena Kostadinova (22 January 2019). "Fexinidazole Winthrop H-W-2320". European Medicines Agency. Retrieved 12 November 2019.
  2. ^ a b c d Deeks, ED (February 2019). "Fexinidazole: First Global Approval". Drugs. 79 (2): 215–220. doi:10.1007/s40265-019-1051-6. PMID 30635838.
  3. ^ a b c d e "Fexinidazole Winthrop (fexinidazole)" (PDF). EMA. Retrieved 12 November 2019.
  4. ^ a b "Fexinidazole Winthrop" (PDF). EMA. Retrieved 12 November 2019.
  5. ^ Gil, Carmen; Rivas, Luis (2017). Drug Discovery for Leishmaniasis. Royal Society of Chemistry. p. 30. ISBN 9781788012584.
  6. ^ "World Health Organization model list of essential medicines: 21st list 2019" (Document). 2019. hdl:10665/325771. {{cite document}}: Cite document requires |publisher= (help)
  7. ^ "Fexinidazole – DNDi". www.dndi.org. Retrieved 12 November 2019.
  8. ^ Mesu VK, Kalonji WM, Bardonneau C, et al. (4 November 2017). "Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial". Lancet. 391 (10116): 144–154. doi:10.1016/s0140-6736(17)32758-7. ISSN 0140-6736. PMID 29113731.
  9. ^ Torreele, E; Bourdin Trunz, B; Tweats, D; Kaiser, M; Brun, R; Mazué, G; Bray, MA; Pécoul, B (2010). Boelaert, Marleen (ed.). "Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness". PLOS Neglected Tropical Diseases. 4 (12): e923. doi:10.1371/journal.pntd.0000923. PMC 3006138. PMID 21200426.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Raether, W; Seidenath, H (1983). "The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica". Annals of Tropical Medicine and Parasitology. 77 (1): 13–26. PMID 6411009.
  11. ^ Jennings, FW; Urquhart, GM (1983). "The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice". Zeitschrift für Parasitenkunde. 69 (5): 577–581. doi:10.1007/bf00926669. PMID 6636983.
  12. ^ Wyllie S, Patterson S, Stojanovski L, et al. (2012). "The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis". Science Translational Medicine. 4 (119): 119re1. doi:10.1126/scitranslmed.3003326. PMC 3457684. PMID 22301556.
  13. ^ Sokolova AY, Wyllie S, Patterson S, et al. (2010). "Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis". Antimicrobial Agents and Chemotherapy. 54 (7): 2893–900. doi:10.1128/AAC.00332-10. PMC 2897277. PMID 20439607.
  14. ^ McNeil, Jr., Donald (8 January 2008). "Jump-Start on Slow Trek to Treatment for a Disease". The New York Times.
  15. ^ "CHMP Summary of Opinion - Fexinidazole Winthrop" (PDF). Retrieved 19 November 2018.
  16. ^ McNeil, Jr., Donald (16 November 2018). "Rapid Cure Approved for Sleeping Sickness, a Horrific Illness". The New York Times. Retrieved 20 November 2018.
  17. ^ "Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo". Drugs for Neglected Diseases Initiative (DNDi). Retrieved 4 June 2019.
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