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Nifurtimox
Nifurtimox
Formula |
C10H13N3O5S
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CAS |
23256-30-6
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Mol weight |
287.2923
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FDA APPROVED, 2020/8/6, LAMPIT
Antiprotozoal
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|
Disease |
Chagas disease
|
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IUPAC Name
SMILES
melting point (°C) | 177-183 | https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx |
- 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)
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 catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]
Manufacturing and availability
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
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
- ^ 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.
- ^ 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.
- ^ Jump up to:a b c d “Lampit: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
- ^ 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.
- ^ 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”. JAMA. 298 (18): 2171–81. doi:10.1001/jama.298.18.2171. ISSN 0098-7484. PMID 18000201.
- ^ “Trypanosomiasis, human African (sleeping sickness)”. World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
- ^ 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.
- ^ Jump up to:a b c d e f g h “Nifurtimox Drug Information, Professional”. http://www.drugs.com. Archivedfrom the original on 2016-11-08. Retrieved 2016-11-09.
- ^ 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 Diseases. 51 (10): e69–e75. doi:10.1086/656917. ISSN 1058-4838. PMID 20932171.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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”. Lancet. 374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-X. hdl:10144/72797. PMID 19559476.
- ^ 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. Archived from the original on 2017-09-08.
- ^ Jump up to:a b “Nifurtimox use while Breastfeeding | Drugs.com”. http://www.drugs.com. Archived from the original on 2016-11-08. Retrieved 2016-11-07.
- ^ 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.
- ^ 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 Diseases. 63 (8): 1056–1062. doi:10.1093/cid/ciw477. ISSN 1537-6591. PMC 5036918. PMID 27432838.
- ^ 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. doi:10.1191/0960327106het653oa. ISSN 0960-3271. PMID 16937919.
- ^ 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 Cruz. 94: 363–365. doi:10.1590/S0074-02761999000700070. ISSN 0074-0276. PMID 10677756.
- ^ “Chagas disease”. World Health Organization. Archived from the original on 2014-02-27. Retrieved 2016-11-08.
- ^ 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.
Clinical data | |
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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 |
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
FDA approves first U.S. treatment benznidazole for Chagas disease
The U.S. Food and Drug Administration today granted accelerated approval to benznidazole for use in children ages 2 to 12 years old with Chagas disease. It is the first treatment approved in the United States for the treatment of Chagas disease.
Chagas disease, or American trypanosomiasis, is a parasitic infection caused by Trypanosoma cruzi and can be transmitted through different routes, including contact with the feces of a certain insect, blood transfusions, or from a mother to her child during pregnancy. After years of infection, the disease can cause serious heart illness, and it also can affect swallowing and digestion. While Chagas disease primarily affects people living in rural parts of Latin America, recent estimates are that there may be approximately 300,000 persons in the United States with Chagas disease.
“The FDA is committed to making available safe and effective therapeutic options to treat tropical diseases,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
The safety and efficacy of benznidazole were established in two placebo-controlled clinical trials in pediatric patients 6 to 12 years old. In the first trial, approximately 60 percent of children treated with benznidazole had an antibody test change from positive to negative compared with approximately 14 percent of children who received a placebo. Results in the second trial were similar: Approximately 55 percent of children treated with benznidazole had an antibody test change from positive to negative compared with 5 percent who received a placebo. An additional study of the safety and pharmacokinetics (how the body absorbs, distributes and clears the drug) of benznidazole in pediatric patients 2 to 12 years of age provided information for dosing recommendations down to 2 years of age.
The most common adverse reactions in patients taking benznidazole were stomach pain, rash, decreased weight, headache, nausea, vomiting, abnormal white blood cell count, urticaria (hives), pruritus (itching) and decreased appetite. Benznidazole is associated with serious risks including serious skin reactions, nervous system effects and bone marrow depression. Based on findings from animal studies, benznidazole could cause fetal harm when administered to a pregnant woman.
Benznidazole was approved using the Accelerated Approval pathway. The Accelerated Approval pathway allows the FDA to approve drugs for serious conditions where there is unmet medical need and adequate and well-controlled trials establish that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe the anticipated clinical benefit of benznidazole.
The FDA granted benznidazole priority review and orphan product designation. These designations were granted because Chagas disease is a rare disease, and until now, there were no approved drugs for Chagas disease in the United States.
With this approval, benznidazole’s manufacturer, Chemo Research, S. L., is awarded a Tropical Disease Priority Review Voucher in accordance with a provision included in the Food and Drug Administration Amendments Act of 2007 that aims to encourage development of new drugs and biological products for the prevention and treatment of certain tropical diseases.
Clinical data | |
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Trade names | Rochagan, Radanil[1] |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
Routes of administration |
by mouth |
ATC code | |
Pharmacokinetic data | |
Bioavailability | High |
Metabolism | Liver |
Biological half-life | 12 hours |
Excretion | Kidney and fecal |
Identifiers | |
CAS Number | |
PubChem CID | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
ECHA InfoCard | 100.153.448 |
Chemical and physical data | |
Formula | C12H12N4O3 |
Molar mass | 260.249 g/mol |
3D model (JSmol) | |
Melting point | 188.5 to 190 °C (371.3 to 374.0 °F) |
Benznidazole is an antiparasitic medication used in the treatment of Chagas disease.[2] While it is highly effective in early disease this decreases in those who have long term infection.[3] It is the first line treatment given its moderate side effects compared to nifurtimox.[1] It is taken by mouth.[2]
Side effects are fairly common. They include rash, numbness, fever, muscle pain, loss of appetite, and trouble sleeping.[4][5] Rare side effects include bone marrow suppression which can lead to low blood cell levels.[1][5] It is not recommended during pregnancy or in people with severe liver or kidney disease.[4][3]Benznidazole is in the nitroimidazole family of medication and works by the production of free radicals.[5][6]
Benznidazole came into medical use in 1971.[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] It is not commercially available in the United States, but can be obtained from the Centers of Disease Control.[2] As of 2012 Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer.[8]
Medical uses
Benznidazole has a significant activity during the acute phase of Chagas disease, with a therapeutical success rate up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of T. cruzi from the body) in pediatric and young patients during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%.[6]
However, some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure, because it reduces electrocardiographic changes and a delays worsening of the clinical condition of the patient.[6]
Benznidazole has proven to be effective in the treatment of reactivated T. cruzi infections caused by immunosuppression, such as in people with AIDS or in those under immunosuppressive therapy related to organ transplants.[6]
Children
Benznidazole can be used in children and infants, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections.[9] Children are found to be at a lower risk of adverse events compared to adults, possibly due to increased hepatic clearance of the drug. The most prevalent adverse effects in children were found to be gastrointestinal, dermatologic, and neurologic in nature. However, the incidence of severe dermatologic and neurologic adverse events is lower in the pediatric population compared to adults.[10]
Pregnant women
Studies in animals have shown that benznidazole can cross the placenta.[11] Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended.[9]
Side effects
Side effects tend to be common and occur more frequently with increased age.[12] The most common adverse reactions associated with benznidazole are allergic dermatitis and peripheral neuropathy.[1] It is reported that up to 30% of people will experience dermatitis when starting treatment.[11][13] Benznidazole may cause photosensitization of the skin, resulting in rashes.[1] Rashes usually appear within the first 2 weeks of treatment and resolve over time.[13] In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever.[13] Peripheral neuropathy may occur later on in the treatment course and is dose dependent.[1] It is not permanent, but takes time to resolve.[13]
Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysguesia, and bone marrow suppression.[1] Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time.[13] Bone marrow suppression has been linked to the cumulative dose exposure.[13]
Contraindications
Benznidazole should not be used in people with severe liver and/or kidney disease.[12] Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity.[11]
Pharmacology
Mechanism of action
Benznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypanosoma cruzi, commonly referred to as Chagas disease.[11] Like other nitroimidazoles, benznidazole’s main mechanism of action is to generate radical species which can damage the parasite’s DNA or cellular machinery.[14] The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present.[15] This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.[16]
Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species.[14] The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead.[15] The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates.[14] In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form.[14] This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).[15]
In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as “futile cycling“.[14] In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species.[15] The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells’ ability to detoxify superoxide radicals and other reactive oxygen species.[15] In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited direct toxicity to human cells.[15] In Trypanosoma species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasite’s cellular machinery.[15]
Pharmacokinetics
Oral benznidazole has a bioavailability of 92%, with a peak concentration time of 3–4 hours after administration.[17] 5% of the parent drug is excreted unchanged in the urine, which implies that clearance of benznidazole is mainly through metabolism by the liver.[18] Its elimination half-life is 10.5-13.6 hours.[17]
Interactions
Benznidazole and other nitroimidazoles have been shown to decrease the rate of clearance of 5-fluorouracil (including 5-fluorouracil produced from its prodrugs capecitabine, doxifluridine, and tegafur).[19]While co-administration of any of these drugs with benznidazole is not contraindicated, monitoring for 5-fluorouracil toxicity is recommended in the event they are used together.[20]
The GLP-1 receptor agonist lixisenatide may slow down the absorption and activity of benznidazole, presumably due to delayed gastric emptying.[21]
Because nitroimidazoles can kill Vibrio cholerae cells, use is not recommended within 14 days of receiving a live cholera vaccine.[22]
Alcohol consumption can cause a disulfiram like reaction with benznidazole.[1]
References
- ^ 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: A Systematic Review”. JAMA. 298 (18): 2171–81. ISSN 0098-7484. PMID 18000201. doi:10.1001/jama.298.18.2171.
- ^ Jump up to:a b c d “Our Formulary | Infectious Diseases Laboratories | CDC”. http://www.cdc.gov. 22 September 2016. Retrieved 7 December2016.
- ^ Jump up to:a b “Chagas disease”. World Health Organization. March 2016. Retrieved 7 December 2016.
- ^ Jump up to:a b Prevention, CDC – Centers for Disease Control and. “CDC – Chagas Disease – Resources for Health Professionals – Antiparasitic Treatment”. http://www.cdc.gov. Retrieved 2016-11-05.
- ^ Jump up to:a b c 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. doi:10.1191/0960327106het653oa.
- ^ Jump up to:a b c d Urbina, Julio A. “Nuevas drogas para el tratamiento etiológico de la Enfermedad de Chagas” (in Spanish). Retrieved March 24, 2012.
- Jump up^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
- Jump up^ “Treatment for Chagas: Enter Supplier Number Two | End the Neglect”. endtheneglect.org. 21 March 2012. Retrieved 7 December 2016.
- ^ Jump up to:a b Carlier, Yves; Torrico, Faustino; Sosa-Estani, Sergio; Russomando, Graciela; Luquetti, Alejandro; Freilij, Hector; Vinas, Pedro Albajar (2011-10-25). “Congenital Chagas Disease: Recommendations for Diagnosis, Treatment and Control of Newborns, Siblings and Pregnant Women”. PLOS Negl Trop Dis. 5 (10): e1250. ISSN 1935-2735. PMC 3201907 . PMID 22039554. doi:10.1371/journal.pntd.0001250.
- Jump up^ Altcheh, Jaime; Moscatelli, Guillermo; Moroni, Samanta; Garcia-Bournissen, Facundo; Freilij, Hector (2011-01-01). “Adverse Events After the Use of Benznidazole in Infants and Children With Chagas Disease”. Pediatrics. 127 (1): e212–e218. ISSN 0031-4005. PMID 21173000. doi:10.1542/peds.2010-1172.
- ^ Jump up to:a b c d Pérez-Molina, José A.; Pérez-Ayala, Ana; Moreno, Santiago; Fernández-González, M. Carmen; Zamora, Javier; López-Velez, Rogelio (2009-12-01). “Use of benznidazole to treat chronic Chagas’ disease: a systematic review with a meta-analysis”. Journal of Antimicrobial Chemotherapy. 64 (6): 1139–1147. ISSN 0305-7453. PMID 19819909. doi:10.1093/jac/dkp357.
- ^ Jump up to:a b Prevention, CDC – Centers for Disease Control and. “CDC – Chagas Disease – Resources for Health Professionals – Antiparasitic Treatment”. http://www.cdc.gov. Retrieved 2016-11-07.
- ^ Jump up to:a b c d e f Grayson, M. Lindsay; Crowe, Suzanne M.; McCarthy, James S.; Mills, John; Mouton, Johan W.; Norrby, S. Ragnar; Paterson, David L.; Pfaller, Michael A. (2010-10-29). Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. CRC Press. ISBN 9781444147520.
- ^ Jump up to:a b c d e Edwards, David I (1993). “Nitroimidazole drugs – action and resistance mechanisms. I. Mechanism of action”. Journal of Antimicrobial Chemotherapy. 31: 9–20. doi:10.1093/jac/31.1.9.
- ^ Jump up to:a b c d e f g Eller, Gernot. “Synthetic Nitroimidazoles: Biological Activities and Mutagenicity Relationships”. Scientia Pharmaceutica. 77: 497–520. doi:10.3797/scipharm.0907-14.
- Jump up^ Cheng, Thomas C. (1986). General Parasitology. Orlando, Florida: Academic Press. p. 140. ISBN 0-12-170755-5.
- ^ Jump up to:a b Raaflaub, J; Ziegler, WH (1979). “Single-dose pharmacokinetics of the trypanosomicide benznidazole in man”. Arzneimittelforschung. 29 (10): 1611–1614.
- Jump up^ Workman, P.; White, R. A.; Walton, M. I.; Owen, L. N.; Twentyman, P. R. (1984-09-01). “Preclinical pharmacokinetics of benznidazole.”. British Journal of Cancer. 50 (3): 291–303. ISSN 0007-0920. PMC 1976805 . PMID 6466543. doi:10.1038/bjc.1984.176.
- Jump up^ Product Information: Teysuno oral capsules, tegafur gimeracil oteracil oral capsules. Nordic Group BV (per EMA), Hoofddorp, The Netherlands, 2012.
- Jump up^ Product Information: TINDAMAX(R) oral tablets, tinidazole oral tablets. Mission Pharmacal Company, San Antonio, TX, 2007.
- Jump up^ Product Information: ADLYXIN(TM) subcutaneous injection, lixisenatide subcutaneous injection. sanofi-aventis US LLC (per manufacturer), Bridgewater, NJ, 2016.
- Jump up^ Product Information: VAXCHORA(TM) oral suspension, cholera vaccine live oral suspension. PaxVax Inc (per manufacturer), Redwood City, CA, 2016.
External links
- “Rochagan [Patient Information]” (PDF) (in Portuguese). Hoffmann-La Roche. Retrieved 2006-11-27.
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