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Nifurtimox

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Nifurtimox.svg

Nifurtimox

Formula
C10H13N3O5S
CAS
23256-30-6
Mol weight
287.2923

FDA APPROVED, 2020/8/6, LAMPIT

Antiprotozoal
  Disease
Chagas disease

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
SYN
Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1
  • OriginatorBayer
  • ClassAntiprotozoals; Nitrofurans; Small molecules; Thiamorpholines; Thiazines
  • Mechanism of ActionDNA damage modulators
  • RegisteredChagas disease
  • 07 Aug 2020Registered for Chagas disease (In adolescents, In children, In infants) in USA (PO)
  • 31 Jan 2020Preregistration for Chagas disease (In infants, In children, In adolescents) in USA (PO)
  • 29 Jan 2020Bayer completes a phase I trial in Chagas disease in Argentina (PO) (NCT03334838)
Title: Nifurtimox
CAS Registry Number: 23256-30-6
CAS Name: 3-Methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholinamine 1,1-dioxide
Additional Names: 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide; tetrahydro-3-methyl-4-[(5-nitrofurfurylidene)amino]-2H-1,4-thiazine 1,1-dioxide; 1-[(5-nitrofurfurylidene)amino]-2-methyltetrahydro-1,4-thiazine 4,4-dioxide
Manufacturers’ Codes: Bay 2502
Trademarks: Lampit (Bayer)
Molecular Formula: C10H13N3O5S
Molecular Weight: 287.29
Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%
Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al., DE 1170957 corresp to US 3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch. 22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.
Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).
Melting point: mp 180-182°
Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)
Therap-Cat: Antiprotozoal (Trypanosoma).
Keywords: Antiprotozoal (Trypanosoma).

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness.[1][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.[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 these concerns have not be 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.[1] 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]

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

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.[2]

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]

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 catalaseglutathioneperoxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]

Manufacturing and availability

A bottle of nifurtimox

Nifurtimox is sold under the brand name Lampit by Bayer.[3] 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 was approved for medical use in the United States in August 2020.[3]

Research

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

SYN

Nifurtimox

Synthesis of Essential Drugs

2006, Pages 559-582

Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].

58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).

59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)

References

  1. Jump up to:a b c d e f “Nifurtimox (Systemic)”Drugs.com. 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
  2. Jump up to:a b “Lampit (nifurtimox) tablets, for oral use” (PDF)U.S. Food and Drug Administration(FDA). Bayer HealthCare Pharmaceuticals Inc. Retrieved 6 August 2020.
  3. Jump up to:a b c d “Lampit: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
  4. Jump up to:a b c 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. Jump up to:a b c d e f g h 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”JAMA298 (18): 2171–81. doi:10.1001/jama.298.18.2171ISSN 0098-7484PMID 18000201.
  6. ^ “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
  7. ^ Coura JR, de Castro SL (2002). “A critical review of Chagas disease chemotherapy”Mem Inst Oswaldo Cruz97 (1): 3–24. doi:10.1590/S0074-02762002000100001PMID 11992141.
  8. Jump up to:a b c d e f g h “Nifurtimox Drug Information, Professional”http://www.drugs.comArchivedfrom the original on 2016-11-08. Retrieved 2016-11-09.
  9. Jump up to: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 Diseases51 (10): e69–e75. doi:10.1086/656917ISSN 1058-4838PMID 20932171.
  10. ^ 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 Hyg83(4): 514–7. doi:10.1016/0035-9203(89)90270-8PMID 2694491.
  11. ^ 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 Dis195 (3): 322–329. doi:10.1086/510534PMID 17205469.
  12. ^ Pepin J (2007). “Combination Therapy for Sleeping Sickness: A Wake-Up Call”J Infect Dis195 (3): 311–13. doi:10.1086/510540PMID 17205466.
  13. ^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). “Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiensetrypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial”. Lancet374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-Xhdl:10144/72797PMID 19559476.
  14. ^ 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 9780124079014Archived from the original on 2017-09-08.
  15. Jump up to:a b “Nifurtimox use while Breastfeeding | Drugs.com”http://www.drugs.comArchived from the original on 2016-11-08. Retrieved 2016-11-07.
  16. Jump up to:a b c “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. Jump up to: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 Diseases63 (8): 1056–1062. doi:10.1093/cid/ciw477ISSN 1537-6591PMC 5036918PMID 27432838.
  18. ^ 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 Toxicology25 (8): 471–479. doi:10.1191/0960327106het653oaISSN 0960-3271PMID 16937919.
  19. Jump up to: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 Cruz94: 363–365. doi:10.1590/S0074-02761999000700070ISSN 0074-0276PMID 10677756.
  20. ^ “Chagas disease”World Health OrganizationArchived 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.

External links

  • “Nifurtimox”Drug Information Portal. U.S. National Library of Medicine.
Nifurtimox
Nifurtimox.svg
Nifurtimox 3D.png
Clinical data
Trade names Lampit[1]
Other names Bayer 2502[1]
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.377 Edit this at Wikidata
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)

///////////Nifurtimox, LAMPIT, 2020 APPROVALS, FDA 2020, ニフルチモックス, CHAGAS DISEASE, ANTI PROTOZOAL


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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