Chemistry:Mebendazole

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Short description: Medication for parasitic worm infestations
Mebendazole
Mebendazole.svg
Clinical data
Trade namesVermox,[1] Ovex, others
Other namesMBZ
AHFS/Drugs.comMonograph
MedlinePlusa682315
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine) / S5 and S6 for treatment of animals
  • CA: ℞-only / and OTC for treatment of animals[3]
  • UK: POM (Prescription only) / P[4]
  • US: ℞-only
Pharmacokinetic data
Bioavailability2–10%
Protein binding95%
MetabolismExtensive liver
Elimination half-life3–6 hours
ExcretionFeces, urine (5–10%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H13N3O3
Molar mass295.298 g·mol−1
3D model (JSmol)
Melting point288.5 °C (551.3 °F)
  (verify)

Mebendazole (MBZ), sold under the brand name Vermox among others, is a medication used to treat a number of parasitic worm infestations.[5] This includes ascariasis, pinworm infection, hookworm infections, guinea worm infections, hydatid disease, and giardia, among others.[5] It is taken by mouth.[5]

Mebendazole is usually well tolerated.[5] Common side effects include headache, vomiting, and ringing in the ears.[5] If used at large doses it may cause bone marrow suppression.[5] It is unclear if it is safe in pregnancy.[5][2] Mebendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.[5]

Mebendazole came into use in 1971, after it was developed by Janssen Pharmaceutica in Belgium.[6] It is on the World Health Organization's List of Essential Medicines.[7] Mebendazole is available as a generic medication.[8]

Medical use

Mebendazole is a highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm (pinworm), and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract. Other drugs are used to treat worm infections outside the digestive tract, as mebendazole is poorly absorbed into the bloodstream.[9] Mebendazole is used alone in those with mild to moderate infestations. It kills parasites relatively slowly, and in those with very heavy infestations, it can cause some parasites to migrate out of the digestive system, leading to appendicitis, bile duct problems, or intestinal perforation. To avoid this, heavily infested patients may be treated with piperazine, either before or instead of mebendazole. Piperazine paralyses the parasites, causing them to pass in the feces.[10] It is also used rarely in the treatment of cystic echinococcosis, also known as hydatid disease. Evidence for effectiveness for this disease, however, is poor.[11]

Mebendazole and other benzimidazole antithelmetics are active against both larval and adult stages of nematodes, and in the cases of roundworm and whipworm, kill the eggs, as well. Paralysis and death of the parasites occurs slowly, and elimination in the feces may require several days.[9]

Special populations

Mebendazole has been shown to cause ill effects in pregnancy in animal models, and no adequate studies of its effects in human pregnancy have been conducted.[2] Whether it can be passed by breastfeeding is unknown.[12][2]

Adverse effects

Mebendazole sometimes causes diarrhea, abdominal pain, and elevated liver enzymes. In rare cases, it has been associated with a dangerously low white blood cell count, low platelet count, and hair loss,[12][13] with a risk of agranulocytosis in rare cases.

Drug interactions

Carbamazepine and phenytoin lower serum levels of mebendazole. Cimetidine does not appreciably raise serum mebendazole (in contrast to the similar drug albendazole), consistent with its poor systemic absorption.[14][15]

Stevens–Johnson syndrome and the more severe toxic epidermal necrolysis can occur when mebendazole is combined with high doses of metronidazole.[16]

Mechanism

Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to the colchicine binding site of β-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites.[17] Disruption of cytoplasmic microtubules leads to blocking the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminths.[9]

Poor absorption in the digestive tract makes mebendazole an efficient drug for treating intestinal parasitic infections with limited adverse effects. However mebendazole has an impact on mammalian cells, mostly by inhibiting polymeration of tubulin dimers, thereby disrupting essential microtubule structures such as mitotic spindle.[18] Disassembly of the mitotic spindle then leads to apoptosis mediated via dephosphorylation of Bcl-2 which allows pro-apoptotic protein Bax to dimerize and initiate programmed cell death.[19]

Society and culture

Availability

Mebendazole is available as a generic medication.[8] Mebendazole is distributed in international markets by Johnson and Johnson and a number of generic manufacturers.[20]

Economics

In the United States, mebendazole is sometimes sold at about 200 times the price of the same medication in other countries.[21][22][23]

Research

Several studies show mebendazole exhibits potent antitumor properties. mebendazole significantly inhibited cancer cell growth, migration, and metastatic formation of adrenocortical carcinoma, both in vitro and in vivo.[24] Treatment of lung cancer cell lines with mebendazole caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release.[25] Mebendazole induced a dose- and time-dependent apoptotic response in human lung cancer cell lines,[26] and apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.[27] The anti-cancer effect of mebendazole comes from preclinical studies and case reports.[28]

References

  1. ↑ Ebadi, Manuchair (2008). Desk reference of clinical pharmacology (2nd ed.). Boca Raton: CRC Press. p. 403. ISBN 9781420047448. https://books.google.com/books?id=ihxyHbnj3qYC&pg=PA403. 
  2. ↑ 2.0 2.1 2.2 2.3 "Mebendazole Use During Pregnancy". 29 July 2020. https://www.drugs.com/pregnancy/mebendazole.html. 
  3. ↑ "Vermox Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=4743. 
  4. ↑ "Mebendazole". http://www.evidence.nhs.uk/formulary/bnf/current/5-infections/55-anthelmintics/551-drugs-for-threadworms/mebendazole. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "Mebendazole". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/mebendazole.html. 
  6. ↑ Mehlhorn, Heinz (2001). Encyclopedic reference of parasitology. 107 tables (2 ed.). Berlin [u.a.]: Springer. p. 259. ISBN 9783540668299. https://books.google.com/books?id=OBZbR4vpg0YC&pg=PA259. 
  7. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ 8.0 8.1 Hamilton, Richard J. (2012). Tarascon pocket pharmacopoeia (13 ed.). Burlington, Mass.: Jones & Bartlett Learning. p. 33. ISBN 9781449624286. https://books.google.com/books?id=BmKOS-b0s08C&pg=PA355. 
  9. ↑ 9.0 9.1 9.2 Petri WA in Brunton LL, Chabner BA, Knollmann BC, Ed. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed., Chapter 42. McGraw-Hill, 2011 New York.
  10. ↑ Martin AR in Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 8th edition, Doerge RF, ed. J.B. Lippincott, 1982, Chapter 4
  11. ↑ "Mebendazole". https://www.drugs.com/monograph/mebendazole.html. 
  12. ↑ 12.0 12.1 Finberg R, Fingeroth J in Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo, Ed. Harrison's Principles of Internal Medicine, 18th ed., McGraw-Hill, 2012, Chapter 217.
  13. ↑ "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Annals of Internal Medicine 146 (9): 657–65. May 2007. doi:10.7326/0003-4819-146-9-200705010-00009. PMID 17470834. 
  14. ↑ "Drug Interactions". Medicine chest. http://www.medicinechestonline.co.uk/static/professional2/drug_interactions.htm. 
  15. ↑ "Treatment of hydatid disease with high oral doses of mebendazole. Long-term follow-up of plasma mebendazole levels and drug interactions". European Journal of Clinical Pharmacology 31 (4): 443–8. 1986. doi:10.1007/bf00613522. PMID 3816925. 
  16. ↑ "Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan". American Journal of Public Health 93 (3): 489–92. March 2003. doi:10.2105/ajph.93.3.489. PMID 12604501. 
  17. ↑ "Mode of action of benzimidazoles". Parasitology Today 6 (4): 112–5. April 1990. doi:10.1016/0169-4758(90)90227-U. PMID 15463312. 
  18. ↑ "Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors". Molecular Medicine 23: 50–56. April 2017. doi:10.2119/molmed.2017.00011. PMID 28386621. 
  19. ↑ "Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death". Cancer Research 57 (1): 130–5. January 1997. PMID 8988053. http://cancerres.aacrjournals.org/content/57/1/130. Retrieved 9 February 2019. 
  20. ↑ Global Pharmaceutical Pricing and Reimbursement Database, zenRx Research, http://zenrx.org/, retrieved 12 June 2014 
  21. ↑ "US drugmaker charges 200 times UK price for common worm pill". 18 December 2016. https://www.ft.com/content/f0080fe4-c3ad-11e6-9bca-2b93a6856354. 
  22. ↑ "A Pinworm Medication Is Being Tested As A Potential Anti-Cancer Drug". https://www.npr.org/sections/health-shots/2017/01/30/512400204/a-pinworm-medication-is-being-tested-as-a-potential-anti-cancer-drug. 
  23. ↑ "Mebendazole and pyrantel pamoate as broad-spectrum anthelmintics". The Southeast Asian Journal of Tropical Medicine and Public Health (1): 81–84. March 1976. PMID 1027113. 
  24. ↑ "Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice". Cancer Chemotherapy and Pharmacology 61 (5): 809–17. April 2008. doi:10.1007/s00280-007-0538-0. PMID 17581752. 
  25. ↑ "The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells". Molecular Cancer Therapeutics 1 (13): 1201–9. November 2002. PMID 12479701. 
  26. ↑ "Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo". Clinical Cancer Research 8 (9): 2963–9. September 2002. PMID 12231542. 
  27. ↑ "Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells". Molecular Cancer Research 6 (8): 1308–15. August 2008. doi:10.1158/1541-7786.MCR-07-2159. PMID 18667591. 
  28. ↑ "Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent". ecancermedicalscience 8: 443. 2014. doi:10.3332/ecancer.2014.443. PMID 25075217. 

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