With an IC50 value of 0.24 μM, mebendazole (1 nM-0.1 mM; 72 h) inhibits GL261 tumor neural cells [1]. 0.1 μM and 1 μM mebendazole for 24 hours causes 060919 pleomorphic astrocyte disruption. Mebendazole (10 nM–10 μM; 48 h) suppresses microtubule polymerization and microtubule structure in tumor (GBM) cells, inhibits Hh signaling, and reduces downstream Hh protein expression. It also regulates Hh protein expression by lowering Gli1 in tumor tissues [1]. Gli1 expression is inhibited by metronidazole, with an IC50 value of 516 nM[2]. Human medulloblastoma tumor cells with constitutive Hh activation exhibit reduced expression and blocked primary cilia development when exposed to mebendazole (10 nM-10 μM; 48 h). Additive suppression of normal Hh signaling is achieved when mebendazole and vismodegib are combined [2]. In a therapeutic environment, mebendazole has been demonstrated to be successful in treating severe cases of CNS echinococcosis. fluorescent imaging [1]

Mebendazole (50 mg/kg; oral; once daily for the first 20 days, five days a week, two days off; 45 days) was administered to both the human pleomorphic blastoma (GBM) xenograft 060919 and the syngeneic GL261 mouse model.

Immunofluorescence [1]
Cell Types: Glioblastoma multiforme (GBM) 060919 Cell
Tested Concentrations: 1 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: The microtubule structure is destroyed. System penetration characteristics [3].

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Immunofluorescence [2]
Cell Types: DAOY and hTERT-RPE1 Cell
Tested Concentrations: 0, 0.1, 0.5, 0.75 and 1 μM
Incubation Duration: 12 hrs (hours)
Experimental Results: GLI1 protein levels diminished and caspase-3 protein levels increased cleavage.

Animal/Disease Models: C57BL/6 mice (5-6 weeks old) implanted with GL261 glioma cells and 060919 human glioblastoma multiforme (GBM) [1]
Doses: 50 mg/kg; Inhibition in mouse model Intracranial tumor growth [1]. Use 50% (v/v) sesame oil and PBS[2]
Route of Administration: po (oral gavage); starting 5 days after tumor implantation, daily dose of 50 mg/kg for the first 20 days of treatment, then changing to 50 mg/kg, Lasts 5 days, with 2 days off per week.
Experimental Results: In the syngeneic GL261 mouse model, mean survival increased to 49 days compared with 30 days in controls. Mean survival was extended to 65 days compared with 48 days of controls in the 060919 human glioblastoma multiforme (GBM) xenograft mouse model.

Absorption, Distribution and Excretion
Poorly absorbed (approximately 5 to 10%) from gastrointestinal tract. Fatty food increases absorption.
In man, approximately 2% of administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or a primary metabolite.
Elimination: Fecal: Approximately 95% excreted unchanged or as the primary metabolite (2-amino derivative) in feces. Renal: Approximately 2 to 5% excreted unchanged or as the primary metabolite in urine.
Peak serum concentration: Following a dose of 100 mg twice a day for 3 days: Mebendazole: Not more than 0.03 ug/mL. 2-Amino metabolite: Not more than 0.09 ug/mL. Serum concentrations up to 0.5 ug/mL have been reported in chronic, high-dose therapy.
Time to peak serum concentration: 2 to 5 hours (range: 0.5 to 7 hours).
Mebendazole is highly bound to plasma proteins. It is not known if mebendazole is distributed into milk.
For more Absorption, Distribution and Excretion (Complete) data for MEBENDAZOLE (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Primarily hepatic. Primary metabolite is 2-amino-5-benzoylbenzimidazole, but also metabolized to inactive hydroxy and hydroxyamino metabolites. All metabolites are devoid of anthelmintic activity.
Primarily hepatic; metabolized in inactive amino, hydroxy, and hydroxyamino metabolites; primary metabolite is 2-amino-5-benzoylbenzimidazole.
Although the exact metabolic fate of mebendazole has not been fully determined, the drug is metabolized via decarboxylation to 2-amino-5(6)-benzimidazolyl phenylketone; this metabolite does not have anthelmintic activity.
Mebendazole ... is extensively metabolized. Two major metabolites, methyl-5-(alpha-5-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5-benzoylbenzimidazole, have lower rates of clearance than does mebendazole itself. Mebendazole, rather than its metabolites, appears to be the active drug form. Conjugates of mebendazole and its metabolites have been found in bile, but little unchanged mebendazole appears in the urine.

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Biological Half-Life
2.5 to 5.5 hours (range 2.5 to 9 hours) in patients with normal hepatic function. Approximately 35 hours in patients with impaired hepatic function (cholestasis).
Normal hepatic function: 2.5 to 5.5 hours (range: 2.5 to 9 hours). Impaired hepatic function (cholestasis): Approximately 35 hours.
The elimination half-life of mebendazole has been reported to be about 2.8-9 hours.

Hepatotoxicity
Mebendazole when given in typical doses has not been associated with serum enzyme elevations, although the duration of therapy is usually short and monitoring for enzyme elevations has rarely been reported. With high dose therapy (which is now rarely used with the availability of albendazole), elevations in serum aminotransferase levels (2 to 10 times normal) can occur, but are usually well tolerated. There have been rare reports of acute liver injury due to mebenazole, particularly when it is given repeatedly or in higher doses. The onset is usually with fever and malaise within days of starting or restarting therapy. The pattern of serum enzyme elevations is typically hepatocellular, and jaundice is uncommon. The abnormalities usually resolve rapidly with stopping therapy. Signs of hypersensitivity (rash, fever and eosinophilia) are typical and liver biopsy may show granulomas.
Likelihood score: D (possible cause of clinically apparent liver injury with extended therapy).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Mebendazole is poorly excreted into breastmilk and poorly absorbed orally. Reports on the use of mebendazole during breastfeeding have found no adverse reactions in breastfed infants. There are rare case reports of a decrease in milk supply following use of mebendazole, but no convincing evidence that these were caused by the drug. No special precautions are required.
◉ Effects in Breastfed Infants
A case series reported 45 nursing mothers who took mebendazole in doses ranging from 100 mg once to 200 mg twice daily for 3 days. About half took 100 mg repeated once after 7 to 14 days. Thirty-three of the infants were exclusively breastfed with ages ranging from 1 to 30 weeks of age. Eight of the 12 partially breastfed infants were over 20 weeks of age. None of the infants were reported by their mothers to have had any adverse reactions.
A cohort of 33 infants who were breastfed (extent not stated) by hospitalized mothers taking nifurtimox was followed in the Democratic Republic of the Congo. Thirty mothers took a full course of 30 doses of oral nifurtimox 15 mg/kg daily and all received 14 doses of intravenous eflornithine 400 mg/kg daily for 7 days for human African trypanosomiasis. (sleeping sickness). Seventeen nursing mothers also took mebendazole. No serious adverse events were reported in any of the breastfed infants.
◉ Effects on Lactation and Breastmilk
A nursing mother who was 13 weeks postpartum was taking oral metronidazole 250 mg three times daily. Milk production seemed to be unaffected. On the eighth day of therapy she passed a roundworm. Metronidazole was discontinued and oral mebendazole 100 mg twice daily was started. The patient was "tense" for a few days after passing the worm. On the second day of mebendazole treatment, milk production dropped markedly and she began supplementation with formula. By day 7, milk production had ceased. The authors suggested that mebendazole might have caused the drop in milk production, but offered no further evidence other than the temporal relationship.
Four patients were treated with oral mebendazole 100 mg twice daily for 3 days beginning the first day postpartum. Two had pinworm (Enterobius), 1 had roundworm (Ascaris) and 1 had hookworm (Ancyclostomia) infestations. All breastfed successfully.
One author reported information received by personal communication from the manufacturer stating that no inhibition of lactation was noted after a single 100 mg oral dose of mebendazole to a nursing mother (time postpartum not stated).
In a case series reported 45 nursing mothers who took mebendazole in doses ranging from 100 mg once to 200 mg twice daily for 3 days, one mother reported a slight decrease in milk production.

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Protein Binding
90-95%

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Interactions
Preliminary evidence suggests that cimetidine inhibits mebendazole metabolism and may result in increased plasma concentrations of the drug.
Limited data suggest that both carbamazepine and phenytoin may enhance the metabolism of mebendazole, probably by inducing hepatic microsomal enzymes, resulting in decreased plasma mebendazole concentrations.This interaction is unlikely to be clinically important in patients receiving mebendazole for the management of intestinal helminth infections; however, use of carbamazepine or phenytoin may prevent an adequate therapeutic response in patients receiving the anthelmintic for the management of extraintestinal infections (e.g., hydatid disease). Pending further accumulation of data, use of alternative anticonvulsant agents (e.g., valproic acid) should be considered in patients receiving mebendazole for extraintestinal infections.

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Non-Human Toxicity Values
LD50 Sheep orally greater than 80 mg/kg

[1]. Bai RY, et al. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. 2011 Sep;13(9):974-82.
[2]. Larsen AR, et al. Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Mol Cancer Ther. 2015 Jan;14(1):3-13.
[3]. Erdinçler P, et al. The role of mebendazole in the surgical treatment of central nervous system hydatid disease. Br J Neurosurg. 1997 Apr;11(2):116-20.

Therapeutic Uses
Mesh Heading: Antinematodal agents
Mebendazole is indicated as a primary agent for tichuriasis caused by Trichuris trichiura (whipworm). /Included in US product labeling/
Mebendazole is indicated in the treatment of multiple intestinal roundworm infections. /Included in US product labeling/
Mebendazole is indicated a a primary agent for enterobiasis caused by Enterobius vermicularis (pinworm). /Included in US product labeling/
For more Therapeutic Uses (Complete) data for MEBENDAZOLE (19 total), please visit the HSDB record page.

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Drug Warnings
Organ system function (including hematopoietic and hepatic) should be assessed periodically during prolonged mebendazole therapy.
Other adverse effects reported rarely in patients receiving mebendazole include alopecia, rash, pruritus, urticaria, angioedema, flushing, hiccups, cough, weakness,drowsiness, chills, hypotension, seizures, transient abnormalities in liver function tests (e.g., increased serum concentrations of aminotransferases, alkaline phosphatase, and/or bilirubin), hepatitis, increased BUN, decreased hemoglobin concentration and/or hematocrit, leukopenia, thrombocytopenia, eosinophilia, hematuria, and cylindruria.Migration of roundworms through the mouth and nose also has been reported.
Myelosuppression manifested as neutropenia (including agranulocytosis) and/or thrombocytopenia also has been reported in patients receiving high-dose (e.g., 30-50 mg/kg daily) mebendazole therapy for extraintestinal infections; while the myelosuppression usually was reversible following discontinuance of the drug, death has occurred rarely.
At usual recommended dosages (i.e., 100-200 mg daily), mebendazole appears to cause minimal adverse effects. Adverse effects appear to occur more frequently when higher dosages (e.g., those used in the treatment of extraintestinal infections such as hydatid disease) are used, and may be related to effects resulting from drug-induced killing of the parasites in some cases. Transient diarrhea and abdominal pain have occurred occasionally during mebendazole treatment, but usually have been associated with massive infections and expulsion of the helminths. Nausea, vomiting, headache, tinnitus, numbness, and dizziness also have been reported occasionally during mebendazole therapy. Fever has occurred in some patients, particularly in those receiving high-dose therapy for extraintestinal infections.
For more Drug Warnings (Complete) data for MEBENDAZOLE (9 total), please visit the HSDB record page.

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Pharmacodynamics
Mebendazole is a (synthetic) broad-spectrum anthelmintic. The principal mode of action for Mebendazole is by its inhibitory effect on tubulin polymerization which results in the loss of cytoplasmic microtubules.

C16H13N3O3

295.3

295.095

31431-39-7

Mebendazole-d3;1173021-87-8

4030

Off-white amorphous powder
Crystals from acetic acid and methanol

1.4±0.1 g/cm3

288.5°C

1.703

2.83

2

4

4

22

423

0

O=C(OC)NC1=NC2=CC=C(C(C3=CC=CC=C3)=O)C=C2N1

OPXLLQIJSORQAM-UHFFFAOYSA-N InChi Code

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)

methyl N-(6-benzoyl-1H-benzimidazol-2-yl)carbamate

Mebendazole Vermox Telmin Pantelmin Mebenvet Telmin Vermicol Vermidil Vermin Vermox Wormkuur

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~4.17 mg/mL (~14.12 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 0.42 mg/mL (1.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 4.2 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.42 mg/mL (1.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 4.2 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.42 mg/mL (1.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 4.2 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)