Mebendazole

反应类型

甲苯达唑会发生各种化学反应，包括氧化、还原和取代反应。

常用试剂和条件

氧化： 可以使用过氧化氢或高锰酸钾等常见的氧化剂。

还原： 可以使用钯碳催化剂在氢气存在下等还原剂.

取代： 取代反应通常涉及使用卤化剂或亲核试剂。

主要产物

从这些反应中形成的主要产物取决于所用试剂和条件的具体情况。 例如，用钯碳催化剂还原 4-氨基-3-硝基苯甲酮得到 3,4-二氨基苯甲酮 .

Mebendazole works by inhibiting the polymerization of tubulin in parasites, disrupting microtubule formation and interfering with glucose uptake . This ultimately leads to the death of the parasite. The compound targets critical pathways involved in cell proliferation, apoptosis, and invasion/migration .

Mebendazole is a broad-spectrum anthelmintic drug primarily used to treat parasitic infections. However, recent studies have unveiled its potential in oncology, particularly its biological activity against various cancer types. This article delves into the biological mechanisms, pharmacokinetics, and clinical applications of this compound, supported by data tables and case studies.

Antiparasitic Activity
this compound works by inhibiting the polymerization of tubulin, which is essential for microtubule formation in parasites. This disruption leads to impaired glucose uptake and energy depletion in the parasites, ultimately resulting in their death.

Antitumor Activity
Recent research highlights this compound's potential as an anticancer agent. It has been shown to induce apoptosis in cancer cells through several mechanisms:

• Bcl-2 Inactivation : this compound induces apoptosis in melanoma cells by phosphorylating Bcl-2, which prevents its interaction with the pro-apoptotic protein Bax, thus promoting cell death .
• Cell Cycle Arrest : It has been observed to cause cell cycle arrest in various cancer cell lines, including ovarian and colorectal cancers .
• Inhibition of Tumor Angiogenesis : this compound reduces angiogenesis by inhibiting VEGFR2 kinase activity, leading to decreased microvessel density in tumors .

Table 1: Biological Activities of this compound

Pharmacokinetics

This compound exhibits variable pharmacokinetic properties influenced by dosage and formulation. Studies indicate that plasma levels increase with higher doses, and the drug achieves a maximum concentration within hours post-administration.

Table 2: Pharmacokinetic Parameters of this compound

Case Study: this compound in Glioblastoma Treatment

A phase II clinical trial investigated the combination of this compound with temozolomide in patients with newly diagnosed high-grade glioma. The study enrolled 24 patients, revealing promising results regarding safety and overall survival:

• Median Overall Survival (OS) : 21 months.
• Progression-Free Survival (PFS) : 13.1 months for patients receiving more than one month of treatment .

Table 3: Clinical Outcomes from Glioblastoma Study

Case Study: this compound for COVID-19

A recent randomized controlled trial indicated that this compound therapy improved innate immunity and reduced inflammation markers in COVID-19 outpatients compared to a placebo group. Significant reductions in C-reactive protein (CRP) levels were noted within three days of treatment .

Basic Research Question: What experimental design considerations are critical for evaluating mebendazole’s pharmacokinetics in heterogeneous populations?

Methodological Answer:
To assess pharmacokinetics (PK) in diverse populations, researchers should:

• Define subpopulations (e.g., neonates, immunocompromised individuals) based on metabolic or physiological differences .
• Use population PK modeling to account for variability in drug absorption, distribution, and clearance. For example, sparse sampling in pediatric cohorts can reduce ethical and logistical challenges .
• Validate assays (e.g., HPLC, differential pulse polarography) to ensure sensitivity in detecting low plasma concentrations .
• Data sharing protocols must comply with ethical standards, including anonymization and controlled access to sensitive datasets .

Advanced Research Question: How can conflicting efficacy data for this compound in repurposed oncology studies be reconciled?

Methodological Answer:
Conflicting results often arise from:

• Variability in experimental models : Compare outcomes across cell lines (e.g., LNCaP vs. DU145 prostate cancer cells) and in vivo models (e.g., xenografts vs. genetically engineered mice) .
• Dose-response discordance : Use dose-ranging studies to identify therapeutic thresholds. For example, this compound’s anti-cancer effects in PDE4D7-knockdown LNCaPs occur at lower doses than in wild-type cells .
• Mechanistic heterogeneity : Conduct transcriptomic or proteomic analyses to map pathways (e.g., cAMP dynamics, microtubule disruption) influenced by tumor microenvironment factors .
• Meta-analysis frameworks : Apply PRISMA guidelines to aggregate preclinical data and identify bias sources (e.g., publication bias, model selection) .

Basic Research Question: What validated analytical methods are recommended for quantifying this compound in pharmaceutical formulations?

Methodological Answer:

• Electrochemical techniques : Differential pulse polarography (DPP) offers sensitivity at µg/mL levels, validated in pH 7.4 buffers to mimic physiological conditions .
• Chromatography : HPLC with UV detection (λ = 254 nm) provides reproducibility, but requires column optimization to separate this compound from excipients .
• Quality control : Cross-validate results with mass spectrometry (LC-MS) to confirm specificity, especially in complex matrices like serum .

Advanced Research Question: What strategies address this compound’s solubility limitations in preclinical testing?

Methodological Answer:

• Co-solvent systems : Test biocompatible solvents (e.g., PEG-400) to enhance aqueous solubility while monitoring cytotoxicity in vitro .
• Nanoformulation : Develop liposomal or polymeric nanoparticles to improve bioavailability. Characterize particle size (DLS) and encapsulation efficiency (UV-Vis) .
• In silico modeling : Use tools like COSMO-RS to predict solubility in simulated biological fluids and guide formulation design .

Basic Research Question: How should researchers design studies to evaluate this compound resistance in helminthic parasites?

Methodological Answer:

• Longitudinal sampling : Collect parasite isolates pre- and post-treatment to track β-tubulin mutations linked to resistance .
• Phenotypic assays : Measure IC50 shifts in larval motility or egg hatching inhibition assays across multiple generations .
• Genomic sequencing : Identify SNPs in β-tubulin isotype-1 genes and correlate with clinical failure rates .

Advanced Research Question: What methodologies optimize this compound combination therapies for synergistic anti-helminthic effects?

Methodological Answer:

• Checkerboard assays : Determine fractional inhibitory concentration indices (FICI) for this compound paired with albendazole or ivermectin .
• Mechanistic synergy : Use RNAi or CRISPR to validate target pathways (e.g., dual β-tubulin and glutamate-gated chloride channel disruption) .
• In vivo validation : Employ factorial design experiments in rodent models to assess efficacy-toxicity trade-offs .

Basic Research Question: How to ensure reproducibility in this compound’s in vitro cytotoxicity assays?

Methodological Answer:

• Standardize cell lines : Use authenticated stocks (e.g., ATCC-certified DU145) and control for passage number .
• Culture conditions : Maintain consistent O2 levels (5% CO2) and serum concentrations (10% FBS) to minimize batch effects .
• Endpoint validation : Combine MTT assays with live-cell imaging to confirm apoptosis vs. necrosis .

Advanced Research Question: How can computational models predict this compound’s off-target effects in repurposing studies?

Methodological Answer:

• Docking simulations : Use AutoDock Vina to screen this compound against human kinases or GPCRs implicated in side effects .
• Network pharmacology : Construct protein-protein interaction networks to identify secondary targets (e.g., PDE4D7 in prostate cancer) .
• Toxicogenomics : Apply LINCS database queries to predict gene expression changes in non-target tissues .