MebenMed-50, 100 Tablets

MedbenMed-50:

Introduction

Mebendazole (MBZ), is a well-known anti-helminthic drug in wide clinical use, and has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types

MBZ has low toxicity, though patients may suffer from transient symptoms, such as abdominal pain and diarrhoea in cases of massive infection and excretion of parasites. Hypersensitivity reactions, such as rash, urticaria, and angioedema, have been observed on rare occasions. MBZ is contraindicated during pregnancy. Caution is also recommended in treating infants below the age of 2, primarily due to a lack of data in such cases.

Pharmacokinetic Properties

First-pass metabolism of MBZ ensures that only about 20% of the oral dose reaches systemic circulation, with maximum plasma concentration reached 2–4 h post-administration. After the first pass in the intestinal wall and liver, the metabolites are active against parasites in internal organs and tissues. MBZ is also extensively metabolized by the liver to amino and hydroxylated amino forms of the parent compound. However, P450 enzymes are also involved in the process due to the documented inhibition with cimetidine. The MBZ and its metabolites are excreted primarily in feces and about 2% in the urine.

Anti-Parasitic Applications

The anti-parasitic action of MBZ is due to its action as a microtubule-disrupting agent acting to prevent the polymerisation of tubulin in the gut of helminths, causing the parasites to die. MBZ induces the block of microtubule functions of parasites and mammalian cells through inhibition of polymerization of ß-tubulin into microtubules. The result is a loss of transport of secretory vesicles, a decrease in glucose uptake, and an increase in the use of stored glycogen.

Anti-Cancer Applications

Mebendazole has anticancer effects through microtubule polymerization, induction of apoptosis, cell cycle arrest (G2/M), anti-angiogenesis, blocking glucose and glutamine pathways. Apoptosis is induced by mitochondrial injury and mediated by p53 expression. Benzimidazoles also target CSCs and metastases and, thus, the chemoresistant (cisplatin) cancer cells. Mebendazole was more potent against gastric cancer cell lines than other well-known chemotherapeutic drugs (5-fluorouracil, oxaliplatin, gemcitabine, irinotecan, paclitaxel, cisplatin, etoposide and doxorubicin) in vitro. Whereas Mebendazole leads to significantly prolonged survival compared to standard chemotherapy (temozolomide) for glioblastoma multiforme in vivo.

In 2011, Dobrosotskaya et al. published the first clinical case report on MBZ as a cancer treatment in a human patient. He described a 35-year-old woman affected by metastatic adrenocortical carcinoma (right adrenal gland and multiple liver metastases) who showed tumor progression after repeated surgeries, radiation, and chemotherapy treatments. After administering MBZ 100 mg orally twice daily for 19 months, they observed prolonged tumor response, as the liver metastases initially regressed and remained stable for 19 months. In contrast to the morbidity observed with other treatments, MBZ was well tolerated and greatly improved the patient’s quality of life. This study also demonstrated reduced angiogenesis in the tumor treated with MBZ, which may result from diminished tumor growth.

Similar to its anti-parasitic action, tubulin formation is vital to cell division and is therefore a cancer target for several widely used chemotherapy drugs, including paclitaxel, colchicine, and vincristine. MBZ, as with the other benzimidazoles, binds to the colchicine-binding domain of tubulin.The inhibition of tubulin polymerisation by MBZ has been confirmed in vitro in a glioblastoma model and in a melanoma model. The latter work suggested that the apoptotic response to microtubule disruption is mediated by Bcl-2 phosphorylation. Subsequent work on melanoma confirmed this result, and also showed that MBZ decreased the levels of X-linked inhibitor of apoptosis (XIAP), but to date this has not been confirmed in non-melanoma cell lines.

One of the most relevant MBZ properties is that it exerts cancer cell-specific selectivity inducing minimal cytotoxicity in normal cells while inducing high cytotoxicity in tumor cells, showing a favorable therapeutic index for in vivo applications. Finally, MBZ can inhibit endothelial cells and tumor angiogenesis by inhibiting VEGF receptor 2. Many studies demonstrated the anti-angiogenic effect of MBZ in medulloblastoma preclinical mouse models and its encouraging impact on overall survival.

MBZ can also sensitize cancer cells to conventional therapy, such as chemotherapeutics and radiation, enhancing their combined antitumor potential, confirming that MBZ may be useful as an adjuvant therapeutic combined with traditional chemotherapy.

Diagnosis-specific activity was assessed using the NCI 60 z score data, which showed a high level of activity against leukaemia, colon cancer, CNS and melanoma panels of cell lines, with lesser activity in breast, ovarian, renal and NSCLC lines. It should be noted that the leukaemia panel had the highest level of sensitivity to MBZ, a finding that has not been further investigated to date. In the colon cancer panel, 80% of cells lines were sensitive to MBZ.

Other cancer types which have responded favourably to MBZ include:

1. a range of lung cancer cell lines
2. adrenocortical cancer
3. chemoresistant melanoma
4. glioblastoma multiforme
5. colon cancer

Some work on in vitro efficacy against a chemoresistant breast cancer cell line (SKBr-3) was performed by Coyne and colleagues in 2013. A range of benzimidazoles, including MBZ and albendazole, were tested and found to cause significant growth arrest and apoptosis, with flubendazole and MBZ showing the greatest level of cytotoxic activity. MBZ reduced cell survival by 63.1% at a dose of 0.5 μM.

MBZ is attractive as an anticancer therapy because it can cross the blood–brain barrier permeability with a low-toxicity profile. Toxicity is particularly low in children compared to other microtubule inhibitors such as vincristine and paclitaxel. Despite its poor oral bioavailability, available preclinical studies demonstrated that MBZ reaches plasmatic and tissue concentrations sufficient to activate antineoplastic activity in vitro. Additional clinical investigations will clarify this issue.

The greatest challenge facing any CNS-targeted drug discovery program is the effective penetration of the blood–brain barrier (BBB). The limited ability of cancer therapeutics to accumulate in the tumor is the major obstacle to improving brain cancer therapy. It is estimated that only ~2% of small-molecule drugs can effectively cross the BBB. MBZ’s small size (295 Daltons) and lipophilic property favor brain penetration.

Many research groups have investigated MBZ as a tubulin polymerization inhibitor and strongly recommend its clinical use as a replacement for vincristine for treating brain tumors. In addition, many studies demonstrated its capability in reducing angiogenesis, arresting the cell cycle, and targeting several key oncogenic signal transduction pathways. Therefore, MBZ’s ability to hit multiple targets can improve the efficacy of anticancer therapy and help overcome acquired resistance to conventional chemotherapy.

Dosage Guidelines

Mebendazole treatment (50 mg/kg daily for 9–18 months) was demonstrated to be without significant side effects. Patients receiving 1500 mg/day of Mebendazole for gliomas were also noted to be without toxicity from the drug. Patients with treatment refractory gastrointestinal cancer participating in a phase 2 study using individualized doses of Mebendazole, up to 4 g/day, experienced no severe adverse effects. A case of near-complete remission was reported in a patient with metastatic colon cancer after taking Mebendazole, following a failure of chemotherapeutic agents including Capecitabine, Oxaliplatin, Bevacizumab, Capecitabine and Irinotecan.

Low-grade cancers: Dose of 200 mg/day.

Intermediate-grade cancers: Dose of 400 mg/day.

High-grade cancers: Dose of 1,500 mg/day

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