Mebendazole

Mebendazole
Names
Trade namesVermox,[1] others
IUPAC name
  • Methyl (5-benzoyl-1H-benzimidazol-2-yl)carbamate
Clinical data
Drug classAntihelminthic agent, benzimidazole[2]
Main usesPinworm, ascariasis, giardia[3]
Side effectsHeadache, vomiting, ringing in the ears[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use
    By mouth
    Defined daily dose200 mg[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa682315
    Legal
    Legal status
    Pharmacokinetics
    Bioavailability2–10%
    Protein binding95%
    MetabolismExtensive liver
    Elimination half-life3–6 hours
    ExcretionFaeces, urine (5–10%)
    Chemical and physical data
    FormulaC16H13N3O3
    Molar mass295.298 g·mol−1
    3D model (JSmol)
    Melting point288.5 °C (551.3 °F)
    SMILES
    • COC(=O)Nc3nc2ccc(C(=O)c1ccccc1)cc2[nH]3
    InChI
    • InChI=1S/C16H13N3O3/c1-22-16(21)19-15-17-12-8-7-11(9-13(12)18-15)14(20)10-5-3-2-4-6-10/h2-9H,1H3,(H2,17,18,19,21) checkY
    • Key:OPXLLQIJSORQAM-UHFFFAOYSA-N checkY

    Mebendazole (MBZ) is a medication used to treat a number of parasitic worm infestations.[2] This includes ascariasis, pinworm disease (threadworm), hookworm infections, guinea worm infections, hydatid disease, and giardia, among others.[3] It is taken by mouth.[2]

    It is usually well tolerated.[3] Common side effects include headache, vomiting, and ringing in the ears.[3] If used at large doses it may cause bone marrow suppression.[3] It is unclear if it is safe in pregnancy,[3] and generally not used in pregnancy or in children under the age of two.[2] Carbamazepine and phenytoin lower levels of mebendazole.[1]

    Mebendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.[2] After taking it by mouth, around 10% is absorbed, which is increased if taken with a fatty meal.[2] It is broken down quickly and excreted in bile and urine within 2 days.[2]

    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] The wholesale cost in the developing world is between USD 0.004 and 0.04 per dose.[9] In the United States a single dose is about USD 440 as of 2016, while in Australia and the UK it costs about USD 5.[10]

    Medical use

    Mebendazole is a highly effective, broad-spectrum antihelmintic indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, pinworm (threadworm), 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.[11] 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.[12] 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.[13]

    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.[11]

    Dosage

    It is taken by mouth; as a single dose for pinworm, and twice a day for three days for roundworm and hookworm.[2]

    The typical dose in people over the age of two is 100 mg by mouth twice a day for three days.[14] For pinworm a single 100 mg dose followed by a second one in two weeks may be used.[3] In trichinellosis 400 mg three times daily for 10 to 14 days maybe used.[3][15] In children over two the dose is 2.5 mg/kg twice per day.[15]

    The defined daily dose is 200 mg by mouth.[4]

    Side 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,[16][17] with a risk of agranulocytosis in rare cases.

    Pregnancy and breastfeeding

    Mebendazole is pregnancy category C, which means it 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. Whether it can be passed by breastfeeding is unknown.[16] It appears okay in breastfeeding.[15]

    Interactions

    Carbamazepine and phenytoin lower serum levels of mebendazole.[1] Cimetidine does not appreciably raise serum mebendazole (in contrast to the similar drug albendazole), consistent with its poor systemic absorption.[18][19]

    Stevens–Johnson syndrome and the more severe toxic epidermal necrolysis can occur when mebendazole is combined with high doses of metronidazole.[20]

    Mechanism

    Mebendazole works by selectively inhibiting the synthesis of microtubules via binding to colchicine binding site of β-tubulin, thereby blocking polymerisation of tubulin dimers in intestinal cells of parasites.[21] 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.[11]

    Poor absorption in digestive tract makes mebendazole an efficient drug for treating intestinal parasitic infections with limited adverse effects. However mebendazole has impact on mammalian cells mostly by inhibiting polymeration of tubulin dimers, thereby disrupting essential microtubule structures such as mitotic spindle.[22] Disassembly of mitotic spindle then leads to apoptosis mediated via dephosphorylation of Bcl-2 which allows pro-apoptotic protein Bax to dimerize and innitiate programmed cell death.[23]

    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.[24]

    Cost

    In the developing world the wholesale cost is between USD 0.004 and 0.04 per dose as of 2014.[9] In the United States a single dose was about US$18.00 in 2015.[3] In 2016 the price increased to US$440.00 per dose in the U.S. as Amedra Pharmaceuticals acquired the rights from Teva in 2013.[10]

    In 2010, Amedra also bought the U.S. marketing rights to the only other interchangeable anti-parasitic medication, albendazole, from GSK. The result of these acquisitions created a monopoly on these medications and the price increased dramatically.[25] In 2015 Amedra Pharmaceuticals became a subsidiary of Amneal Pharmaceuticals.

    In Australia 6 x 100mg costs approximately US$9 while in the UK this would cost around US$19.[10]

    Research

    Several studies show mebendazole exhibits potent antitumor properties. MBZ significantly inhibited cancer cell growth, migration, and metastatic formation of adrenocortical carcinoma, both in vitro and in vivo.[26] Treatment of lung cancer cell lines with MBZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release.[27] MBZ induced a dose- and time-dependent apoptotic response in human lung cancer cell lines,[28] and apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.[29] The anti-cancer effect of mebendazole comes from preclinical studies and case reports.[30]

    References

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    2. 1 2 3 4 5 6 7 8 Ritter, James M.; Flower, Rod; Henderson, Graeme; Loke, Yoon Kong; Rang, Humphrey P. (2020). "56. Antihelminthic drugs". Rang & Dale's Pharmacology. Elsevier. pp. 710–715. ISBN 978-0-7020-7448-6. Archived from the original on 2021-08-28. Retrieved 2021-10-12.
    3. 1 2 3 4 5 6 7 8 9 10 "Mebendazole". The American Society of Health-System Pharmacists. Archived from the original on 2015-09-07. Retrieved Aug 18, 2015.
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    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.
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    17. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Annals of Internal Medicine. 146 (9): 657–65. doi:10.7326/0003-4819-146-9-200705010-00009. PMID 17470834.
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    20. Chen KT, Twu SJ, Chang HJ, Lin RS (March 2003). "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. doi:10.2105/ajph.93.3.489. PMC 1447769. PMID 12604501.
    21. Lacey E (April 1990). "Mode of action of benzimidazoles". Parasitology Today. 6 (4): 112–5. doi:10.1016/0169-4758(90)90227-U. PMID 15463312.
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    23. Blagosklonny MV, Giannakakou P, el-Deiry WS, Kingston DG, Higgs PI, Neckers L, Fojo T (January 1997). "Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death". Cancer Research. 57 (1): 130–5. PMID 8988053. Archived from the original on 2019-02-10. Retrieved 2019-02-09.
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    27. Sasaki J, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay T (November 2002). "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. PMID 12479701.
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    29. Doudican N, Rodriguez A, Osman I, Orlow SJ (August 2008). "Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells". Molecular Cancer Research. 6 (8): 1308–15. doi:10.1158/1541-7786.MCR-07-2159. PMID 18667591.
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