Benznidazole

Last updated
Benznidazole
Benznidazole.svg
Clinical data
Trade names Rochagan, Radanil [1]
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability High
Metabolism Liver
Elimination half-life 12 hours
Excretion Kidney and fecal
Identifiers
  • N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.153.448 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H12N4O3
Molar mass 260.253 g·mol−1
3D model (JSmol)
Melting point 188.5 to 190 °C (371.3 to 374.0 °F)
  • O=[N+]([O-])c1nccn1CC(=O)NCc2ccccc2
  • InChI=1S/C12H12N4O3/c17-11(14-8-10-4-2-1-3-5-10)9-15-7-6-13-12(15)16(18)19/h1-7H,8-9H2,(H,14,17) Yes check.svgY
  • Key:CULUWZNBISUWAS-UHFFFAOYSA-N Yes check.svgY
   (verify)

Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. [2] While it is highly effective in early disease, the effectiveness 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]

Contents

Side effects are fairly common. [4] 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. [7] As of 2012, Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer. [8] [ needs update ]

Medical uses

Benznidazole has a significant activity during the acute phase of Chagas disease, with a success rate of 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 children during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%. [6]

Some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure because it reduces electrocardiographic changes and 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, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections. [9] A formulation for children up to two years of age is available. [10] It was added to the WHO Essential Medicines List for Children in 2013. [11] 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. [12] It use for Chagas in children was approved by the FDA in the US in 2017. [13]

Pregnant women

Studies in animals have shown that benznidazole can cross the placenta. [14] Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended. [9]

Side effects

Reaction to benznidazole 0037-8682-rsbmt-50-01-00145-gf1.jpg
Reaction to benznidazole

Side effects tend to be common and occur more frequently with increased age. [4] 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. [14] [16] 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. [16] In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever. [16] Peripheral neuropathy may occur later on in the treatment course and is dose dependent. [1] It is not permanent, but takes time to resolve. [16]

Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysgeusia, and bone marrow suppression. [1] Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time. [16] Bone marrow suppression has been linked to the cumulative dose exposure. [16]

Contraindications

Benznidazole should not be used in people with severe liver and/or kidney disease. [4] Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity. [14]

Pharmacology

Mechanism of action

Benznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypanosoma cruzi, commonly referred to as Chagas disease. [14] Like other nitroimidazoles, benznidazole's main mechanism of action is to generate radical species which can damage the parasite's DNA or cellular machinery. [17] The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present. [18] This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes. [19]

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. [17] The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead. [18] The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates. [17] 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. [17] 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). [18]

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". [17] In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species. [18] The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells' ability to detoxify superoxide radicals and other reactive oxygen species. [18] In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited direct toxicity to human cells. [18] In Trypanosoma species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasite's cellular machinery. [18]

Pharmacokinetics

Oral benznidazole has a bioavailability of 92%, with a peak concentration time of 3–4 hours after administration. [20] 5% of the parent drug is excreted unchanged in the urine, which implies that clearance of benznidazole is mainly through metabolism by the liver. [21] Its elimination half-life is 10.5-13.6 hours. [20]

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). [22] 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. [23]

The GLP-1 receptor agonist lixisenatide may slow down the absorption and activity of benznidazole, presumably due to delayed gastric emptying. [24]

Because nitroimidazoles can kill Vibrio cholerae cells, use is not recommended within 14 days of receiving a live cholera vaccine. [25]

Alcohol consumption can cause a disulfiram like reaction with benznidazole. [1]

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">Metronidazole</span> Antibiotic and antiprotozoal medication

Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis. It is an option for a first episode of mild-to-moderate Clostridioides difficile colitis if vancomycin or fidaxomicin is unavailable. Metronidazole is available orally, as a cream or gel, and by slow intravenous infusion.

<span class="mw-page-title-main">Chronic granulomatous disease</span> Hereditary disease group

Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.

<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 Sarcomastigophora. 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.

Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and urticaria caused by plants such as poison ivy or stinging nettle. It can also be caused by chronic kidney disease and related conditions.

<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.

Fluorouracil, sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

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

Megacolon is an abnormal dilation of the colon. This leads to hypertrophy of the colon. The dilation is often accompanied by a paralysis of the peristaltic movements of the bowel. In more extreme cases, the feces consolidate into hard masses inside the colon, called fecalomas, which can require surgery to be removed.

<i>Trypanosoma cruzi</i> Species of parasitic euglenoids (protozoans)

Trypanosoma cruzi is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood of disease that varies with the organism: Chagas disease in humans, dourine and surra in horses, and a brucellosis-like disease in cattle. Parasites need a host body and the haematophagous insect triatomine is the major vector in accord with a mechanism of infection. The triatomine likes the nests of vertebrate animals for shelter, where it bites and sucks blood for food. Individual triatomines infected with protozoa from other contact with animals transmit trypanosomes when the triatomine deposits its faeces on the host's skin surface and then bites. Penetration of the infected faeces is further facilitated by the scratching of the bite area by the human or animal host.

Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic agents of the infections by destroying them or inhibiting their growth; they are usually effective against a limited number of parasites within a particular class. Antiparasitics are one of the antimicrobial drugs which include antibiotics that target bacteria, and antifungals that target fungi. They may be administered orally, intravenously or topically. Overuse or misuse of antiparasitics can lead to the development of antimicrobial resistance.

<span class="mw-page-title-main">Nifurtimox</span> Anti-parasitic medical drug

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

<span class="mw-page-title-main">Nitazoxanide</span> Broad-spectrum antiparasitic and antiviral medication

Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; evidence as of 2014 suggested that it possesses efficacy in treating a number of viral infections as well.

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

Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. It has been isolated from a variety of plant sources and is being studied for its variety of pharmacological properties.

<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.

Cruzipain is a cysteine protease expressed by Trypanosoma cruzi.

<span class="mw-page-title-main">Chagas: Time to Treat campaign</span>

The Chagas: Time to Treat Campaign is an international campaign started by the Drugs for Neglected Diseases initiative to advocate for increased research and development of treatments for Chagas disease. Chagas is a potentially fatal neglected disease that affects between 8 and 13 million people worldwide. DNDi's Time to Treat campaign is pushing for increased political interest in new treatments for Chagas disease, increased public awareness of the disease and treatment limitations and increased public and private investment in R&D.

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.

Additive effect in pharmacology describes the situation when the combining effects of two drugs equal the sum of the effects of the two drugs acting independently. The concept of additive effect is derived from the concept of synergy. It was introduced by the scientists in pharmacology and biochemistry fields in the process of understanding the synergistic interaction between drugs and chemicals over the century.

References

  1. 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. Archived from the original on 2016-11-07.
  2. 1 2 3 4 "Benznidazole tablet". DailyMed. 12 November 2019. Retrieved 13 October 2020.
  3. 1 2 "Chagas disease". World Health Organization. March 2016. Archived from the original on 27 February 2014. Retrieved 7 December 2016.
  4. 1 2 3 4 5 "Antiparasitic Treatment". Centers for Disease Control and Prevention (CDC). Archived from the original on 2016-11-06. Retrieved 2016-11-05.
  5. 1 2 3 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.
  6. 1 2 3 4 Urbina JA. "Nuevas drogas para el tratamiento etiológico de la Enfermedad de Chagas" (in Spanish). Archived from the original on May 8, 2012. Retrieved March 24, 2012.
  7. ↑ 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.
  8. ↑ "Treatment for Chagas: Enter Supplier Number Two | End the Neglect". endtheneglect.org. 21 March 2012. Archived from the original on 6 November 2016. Retrieved 7 December 2016.
  9. 1 2 Carlier Y, Torrico F, Sosa-Estani S, Russomando G, Luquetti A, Freilij H, et al. (October 2011). "Congenital Chagas disease: recommendations for diagnosis, treatment and control of newborns, siblings and pregnant women". PLOS Neglected Tropical Diseases. 5 (10): e1250. doi: 10.1371/journal.pntd.0001250 . PMC   3201907 . PMID   22039554.
  10. ↑ "Paediatric Benznidazole – DNDi". www.dndi.org. January 2008. Retrieved 2020-02-13.
  11. ↑ WHO Model List of Essential Medicines for Children 4th list (April 2013) https://apps.who.int/iris/bitstream/handle/10665/93143/EMLc_4_eng.pdf;jsessionid=E14AB3B91001367EBF107EB43C039A0C?sequence=1 retrieved 13 February 2020
  12. ↑ Altcheh J, Moscatelli G, Moroni S, Garcia-Bournissen F, Freilij H (January 2011). "Adverse events after the use of benznidazole in infants and children with Chagas disease". Pediatrics. 127 (1): e212–e218. doi:10.1542/peds.2010-1172. PMID   21173000. S2CID   22258852. Archived from the original on 2016-02-20.
  13. ↑ "FDA approves first U.S. treatment for Chagas disease". U.S. Food and Drug Administration (FDA) (Press release). 29 August 2017. Archived from the original on 3 September 2017. Retrieved 31 August 2017.
  14. 1 2 3 4 Pérez-Molina JA, Pérez-Ayala A, Moreno S, Fernández-González MC, Zamora J, López-Velez R (December 2009). "Use of benznidazole to treat chronic Chagas' disease: a systematic review with a meta-analysis". The Journal of Antimicrobial Chemotherapy. 64 (6): 1139–1147. doi: 10.1093/jac/dkp357 . PMID   19819909.
  15. ↑ Coronel MV, Frutos LO, Muñoz EC, Valle DK, Rojas DH (February 2017). "Adverse systemic reaction to benznidazole". Revista da Sociedade Brasileira de Medicina Tropical. 50 (1): 145–147. doi: 10.1590/0037-8682-0071-2016 . PMID   28327820.
  16. 1 2 3 4 5 6 Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, et al. (2010-10-29). Kucers' The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs (Sixth ed.). CRC Press. ISBN   9781444147520. Archived from the original on 2017-09-10.
  17. 1 2 3 4 5 Edwards DI (January 1993). "Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action". The Journal of Antimicrobial Chemotherapy. 31 (1): 9–20. doi:10.1093/jac/31.1.9. PMID   8444678.
  18. 1 2 3 4 5 6 7 Eller G (2009). "Synthetic Nitroimidazoles: Biological Activities and Mutagenicity Relationships". Scientia Pharmaceutica. 77 (3): 497–520. doi: 10.3797/scipharm.0907-14 . Archived from the original on 2016-11-06.
  19. ↑ Cheng TC (1986). General Parasitology. Orlando, Florida: Academic Press. p. 140. ISBN   0-12-170755-5.
  20. 1 2 Raaflaub J, Ziegler WH (1979). "Single-dose pharmacokinetics of the trypanosomicide benznidazole in man". Arzneimittel-Forschung. 29 (10): 1611–1614. PMID   583230.
  21. ↑ Workman P, White RA, Walton MI, Owen LN, Twentyman PR (September 1984). "Preclinical pharmacokinetics of benznidazole". British Journal of Cancer. 50 (3): 291–303. doi:10.1038/bjc.1984.176. PMC   1976805 . PMID   6466543.
  22. ↑ Product Information: Teysuno oral capsules, tegafur gimeracil oteracil oral capsules. Nordic Group BV (per EMA), Hoofddorp, The Netherlands, 2012.
  23. ↑ Product Information: TINDAMAX(R) oral tablets, tinidazole oral tablets. Mission Pharmacal Company, San Antonio, TX, 2007.
  24. ↑ Product Information: ADLYXIN(TM) subcutaneous injection, lixisenatide subcutaneous injection. sanofi-aventis US LLC (per manufacturer), Bridgewater, NJ, 2016.
  25. ↑ Product Information: VAXCHORA(TM) oral suspension, cholera vaccine live oral suspension. PaxVax Inc (per manufacturer), Redwood City, CA, 2016.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.