Nifurtimox

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Nifurtimox
Nifurtimox.svg
Nifurtimox 3D.png
Clinical data
Trade names Lampit [1]
Other namesBayer 2502 [2]
AHFS/Drugs.com Drugs.com archive
Lampit
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low
Metabolism Liver (Cytochrome P450 oxidase (CYP) involved)
Elimination half-life 2.95 ± 1.19 hours
Excretion Kidney, very low
Identifiers
  • N-(3-Methyl-1,1-dioxido-4-thiomorpholinyl)-1-(5-nitro-2-furyl)methanimine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.377 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H13N3O5S
Molar mass 287.29 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 180 to 182 °C (356 to 360 °F)
  • CC1CS(=O)(=O)CCN1N=CC2=CC=C(O2)[N+](=O)[O-]
  • 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 Yes check.svgY
  • Key:ARFHIAQFJWUCFH-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. [2] [4] For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. [4] In Chagas disease it is a second-line option to benznidazole. [5] It is given by mouth. [2]

Contents

Common side effects include abdominal pain, headache, nausea, and weight loss. [2] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not been found in human trials. [5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems. [5] It is a type of nitrofuran. [5]

Nifurtimox came into medication use in 1965. [5] It is on the World Health Organization's List of Essential Medicines. [4] It is not available commercially in Canada. [2] It was approved for medical use in the United States in August 2020. [3] In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO). [6]

Medical uses

Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days. [7] [8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects. [8] [9] 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. [5] [9]

In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi. [1]

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, [10] but the combination of melarsoprol with nifurtimox appears to be efficacious. [11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness. [12]

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. [13]

Pregnancy and breastfeeding

Use of nifurtimox should be avoided in pregnant women due to limited use. [5] [8] [14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants. [15] Other authors do not consider breastfeeding a contraindication during nifurtimox use. [15]

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. [8]

Most common side effects [16] [8] [17] [18] [19]

Less common effects [16] [8] [17] [19]

Contraindications

Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders. [5] [16] [20]

Mechanism of action

Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA. [8] 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. [8]

Society and culture

A bottle of nifurtimox NECT treatment (cropped).jpg
A bottle of nifurtimox

Nifurtimox is licensed for use in Argentina, the United States, Turkey and Germany amongst others.[ citation needed ] It was approved for medical use in the United States in August 2020. [3]

Names

Research

Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma. [21]

Related Research Articles

<span class="mw-page-title-main">Chagas disease</span> Mammal parasitic disease

Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by Trypanosoma cruzi. It is spread mostly by insects in the subfamily Triatominae, known as "kissing bugs". The symptoms change over the course of the infection. In the early stage, symptoms are typically either not present or mild, and may include fever, swollen lymph nodes, headaches, or swelling at the site of the bite. After four to eight weeks, untreated individuals enter the chronic phase of disease, which in most cases does not result in further symptoms. Up to 45% of people with chronic infections develop heart disease 10–30 years after the initial illness, which can lead to heart failure. Digestive complications, including an enlarged esophagus or an enlarged colon, may also occur in up to 21% of people, and up to 10% of people may experience nerve damage.

<span class="mw-page-title-main">African trypanosomiasis</span> Parasitic disease also known as sleeping sickness

African trypanosomiasis is an insect-borne parasitic infection of humans and other animals.

<span class="mw-page-title-main">Trypanosomatida</span> Group of single-celled parasitic organisms

Trypanosomatida is a group of kinetoplastid unicellular organisms distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Some trypanosomatida are intracellular parasites, with the important exception of Trypanosoma brucei.

<span class="mw-page-title-main">Pentamidine</span> Medical antimicrobial drug

Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin. It is an option for both visceral leishmaniasis and cutaneous leishmaniasis. Pentamidine can be given by injection into a vein or muscle or by inhalation.

<span class="mw-page-title-main">Trypanosomiasis</span> Medical condition

Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and Chagas disease. A number of other diseases occur in other animals.

<span class="mw-page-title-main">Suramin</span> Medical drug

Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.

<i>Trypanosoma</i> Genus of parasitic flagellate protist in the Kinetoplastea class

Trypanosoma is a genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Euglenozoa. The name is derived from the Greek trypano- (borer) and soma (body) because of their corkscrew-like motion. Most trypanosomes are heteroxenous and most are transmitted via a vector. The majority of species are transmitted by blood-feeding invertebrates, but there are different mechanisms among the varying species. Trypanosoma equiperdum is spread between horses and other equine species by sexual contact. They are generally found in the intestine of their invertebrate host, but normally occupy the bloodstream or an intracellular environment in the vertebrate host.

<span class="mw-page-title-main">Carlos Chagas</span> Brazilian doctor and scientist (1879–1934)

Carlos Justiniano Ribeiro Chagas, or Carlos Chagas, was a Brazilian sanitary physician, scientist, and microbiologist who worked as a clinician and researcher. Most well known for the discovery of an eponymous protozoal infection called Chagas disease, also called American trypanosomiasis, he also discovered the causative fungi of the pneumocystis pneumonia. He described the two pathogens in 1909, while he was working at the Oswaldo Cruz Institute in Rio de Janeiro, and named the former Trypanosoma cruzi to honour his friend Oswaldo Cruz.

<span class="mw-page-title-main">Melarsoprol</span> Medication used to treat sleeping sickness

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness. It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred. It is effective in about 95% of people. It is given by injection into a vein.

<span class="mw-page-title-main">Eflornithine</span> Chemical compound

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the second stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously or topically. It is an ornithine decarboxylase inhibitor.

<i>Trypanosoma brucei</i> Species of protozoan parasite

Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases: African trypanosomiasis or sleeping sickness in humans, and animal trypanosomiasis or nagana in cattle and horses. It is a species complex grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. The first is a parasite of non-human mammals and causes nagana, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.

<span class="mw-page-title-main">Winterbottom's sign</span> Medical condition

Winterbottom's sign is a swelling of lymph nodes (lymphadenopathy) along the posterior cervical lymph node chain, associated with the early phase of African trypanosomiasis, a disease caused by the parasites Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It may be suggestive of cerebral infection. Winterbottom reported about the slave traders who, apparently aware of the ominous sign of swollen cervical lymph glands, used to palpate the necks of the slaves before buying them.

<span class="mw-page-title-main">Drugs for Neglected Diseases Initiative</span> Non-profit organization

The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness, Chagas disease, malaria, filarial diseases, mycetoma, paediatric HIV, cryptococcal meningitis, hepatitis C, and dengue. DNDi's malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.

<span class="mw-page-title-main">Benznidazole</span> Chemical compound

Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. While it is highly effective in early disease, the effectiveness decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to nifurtimox. It is taken by mouth.

<span class="mw-page-title-main">Protozoan infection</span> Parasitic disease caused by a protozoan

Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. These organisms are now classified in the supergroups Excavata, Amoebozoa, Harosa, and Archaeplastida. They are usually contracted by either an insect vector or by contact with an infected substance or surface.

Fexinidazole is a medication used to treat African trypanosomiasis caused by Trypanosoma brucei gambiense. It is effective against both first and second stage disease. Also a potential new treatment for Chagas disease, a neglected tropical disease that affects millions of people worldwide. It is taken by mouth.

<span class="mw-page-title-main">VNI (molecule)</span> Chemical compound

VNI is an experimental drug for treating Chagas disease currently being studied at Vanderbilt University. The molecule acts by inhibiting Trypanosoma cruzi sterol 14α-desmethylase activity in vitro. It exhibits no toxicity in mouse cells and, unlike the related compounds posaconazole and fluconazole, increasing the dose is not required to maintain anti-parasitic activity.

<span class="mw-page-title-main">Acoziborole</span> Antiprotozoal drug to treat sleeping sickness

Acoziborole (SCYX-7158) is an antiprotozoal drug invented by Anacor Pharmaceuticals in 2009, and now under development by the Drugs for Neglected Diseases Initiative for the treatment of African trypanosomiasis.

Nifurtimox/eflornithine is a combination of two antiparasitic drugs, nifurtimox and eflornithine, used in the treatment of African trypanosomiasis. It is included in the World Health Organization's Model List of Essential Medicines.

Victor Kande Betu Kumeso is a Congolese physician who is an expert in African trypanosomiasis. He works at the Programme National de Lutte contre la Trypanosomiase Humaine Africaine at the University of Kinshasa.

References

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  2. 1 2 3 4 5 "Nifurtimox (Systemic)". Drugs.com. 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
  3. 1 2 3 "Lampit: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
  4. 1 2 3 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. 1 2 3 4 5 6 7 8 Bern C, Montgomery SP, Herwaldt BL, Rassi A, Marin-Neto JA, Dantas RO, et al. (November 2007). "Evaluation and treatment of chagas disease in the United States: a systematic review". JAMA. 298 (18): 2171–2181. doi: 10.1001/jama.298.18.2171 . PMID   18000201.
  6. ↑ "Trypanosomiasis, human African (sleeping sickness)". World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
  7. ↑ Rodriques Coura J, de Castro SL (January 2002). "A critical review on Chagas disease chemotherapy". Memórias do Instituto Oswaldo Cruz. 97 (1): 3–24. doi: 10.1590/S0074-02762002000100001 . PMID   11992141.
  8. 1 2 3 4 5 6 7 8 "Nifurtimox Drug Information, Professional". www.drugs.com. Archived from the original on 2016-11-08. Retrieved 2016-11-09.
  9. 1 2 Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F (November 2010). "Tolerance and safety of nifurtimox in patients with chronic chagas disease". Clinical Infectious Diseases. 51 (10): e69–e75. doi: 10.1086/656917 . PMID   20932171.
  10. ↑ Pepin J, Milord F, Mpia B, Meurice F, Ethier L, DeGroof D, Bruneel H (1989). "An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire". Transactions of the Royal Society of Tropical Medicine and Hygiene. 83 (4): 514–517. doi:10.1016/0035-9203(89)90270-8. PMID   2694491.
  11. ↑ Bisser S, N'Siesi FX, Lejon V, Preux PM, Van Nieuwenhove S, Miaka Mia Bilenge C, Būscher P (February 2007). "Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness". The Journal of Infectious Diseases. 195 (3): 322–329. doi: 10.1086/510534 . PMID   17205469.
  12. ↑ Pepin J (February 2007). "Combination therapy for sleeping sickness: a wake-up call". The Journal of Infectious Diseases. 195 (3): 311–313. doi: 10.1086/510540 . PMID   17205466.
  13. ↑ Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, 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. hdl: 10144/72797 . PMID   19559476. S2CID   32757305.
  14. ↑ Padberg S (2014-09-17). "Anti-infective agents: Nitrofurans and drugs for urinary infection". In Schaefer C, Peters PW, Miller RK (eds.). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN   9780124079014. Archived from the original on 2017-09-08.
  15. 1 2 "Nifurtimox use while Breastfeeding". Drugs.com. Archived from the original on 2016-11-08. Retrieved 2016-11-07.
  16. 1 2 3 "Parasites - American Trypanosomiasis (also known as Chagas Disease)". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 2016-11-06. Retrieved 2016-11-09.
  17. 1 2 Forsyth CJ, Hernandez S, Olmedo W, Abuhamidah A, Traina MI, Sanchez DR, et al. (October 2016). "Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States". Clinical Infectious Diseases. 63 (8): 1056–1062. doi:10.1093/cid/ciw477. PMC   5036918 . PMID   27432838.
  18. ↑ Castro JA, de Mecca MM, Bartel LC (August 2006). "Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis)". Human & Experimental Toxicology. 25 (8): 471–479. Bibcode:2006HETox..25..471C. doi:10.1191/0960327106het653oa. hdl: 11336/82805 . PMID   16937919. S2CID   8980212.
  19. 1 2 Sosa Estani S, Segura EL (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 (Suppl 1): 363–365. doi: 10.1590/S0074-02761999000700070 . PMID   10677756.
  20. ↑ "Chagas disease". World Health Organization. Archived from the original on 2014-02-27. Retrieved 2016-11-08.
  21. ↑ Clinical trial number NCT00601003 for "Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma" at ClinicalTrials.gov. Retrieved on July 10, 2009.
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