Flubendazole in cystic echinococcosis therapy: Pharmaco-parasitological evaluation in mice

Ceballos, Laura; Elissondo, Marı́a Celina; Bruni, Sergio Fabian Sanchez; Denegri, Guillermo M.; Álvarez, Luis Ignacio Ortega; Lanusse, Carlos

doi:10.1016/j.parint.2009.07.006

Cited by 48 publications

(77 citation statements)

References 24 publications

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“…4). The mean cyst weight was reduced by 90% in the FLBZ-treated mice, which agrees with previously reported results (8). On the contrary, under our experimental conditions, ABZ treatment did not result in significant changes in cyst weight compared to that of the unmedicated mice (14% reduction; P Ͼ 0.05).…”

supporting

confidence: 92%

“…Furthermore, current observations show similar behavior after ABZ administration as a CD-based solution in mice compared to that obtained after the administration of ABZ as a conventional suspension (7). CDs increased FLBZ and ABZ water solubility (6), which accounted for enhanced absorption and bioavailability in mice compared with results for the conventional suspension formulation (8). After oral administration of FLBZ to mice, FLBZ and R-FLBZ were the main analytes recovered in plasma.…”

supporting

confidence: 65%

“…Small differences in drug solubility may have a major influence on their absorption and resultant pharmacokinetic behavior (21). It has been previously reported that the use of complexing agents, such as hydroxypropyl-␤-cyclodextrins (CDs), increases both the water solubility of the BZ methylcarbamates flubendazole (FLBZ) and albendazole (ABZ) (6) and their systemic drug exposure in different species (8,13). ABZ formulated as either a suspension or capsules is the drug most frequently used to treat CE in humans.…”

mentioning

confidence: 99%

“…FLBZ, an alternative BZ methylcarbamate compound, failed to affect E. granulosus cysts in humans after its oral administration as a suspension or tablets (9,29). However, the improved kinetic behavior of FLBZ administered as a CD-based solution resulted in enhanced FLBZ clinical efficacy against CE developed in mice (8), showing that the increased FLBZ bioavailability induced by CDs would impact the amount of drug reaching the hydatid cysts and its overall antiparasitic effect.…”

mentioning

confidence: 99%

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Comparative Performances of Flubendazole and Albendazole in Cystic Echinococcosis: Ex Vivo Activity, Plasma/Cyst Disposition, and Efficacy in Infected Mice

Ceballos

Elissondo

Bruni

et al. 2011

Antimicrob Agents Chemother

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The need to identify improved therapy against cystic echinococcosis (CE) has motivated pharmacology-based research. The comparative pharmacological performances of the benzimidazole compounds flubendazole (FLBZ) and albendazole (ABZ) were addressed here. The goals of the work were as follows: (i) to evaluate the ex vivo activities of FLBZ, ABZ, and their respective metabolites against Echinococcus granulosus protoscoleces, (ii) to compare the plasma and cyst disposition kinetics for the two drugs in infected mice, and (iii) to compare the clinical efficacies of FLBZ and ABZ against CE in mice. For the ex vivo study, E. granulosus protoscoleces were incubated with FLBZ, reduced FLBZ (R-FLBZ), ABZ, and ABZ-sulfoxide (ABZSO) (10 nmol/ml). Protoscolex viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). For the pharmacokinetic study, BALB/c mice with CE were allocated to two different groups and orally treated with either FLBZ or ABZ (5 mg/kg of body weight), both formulated as a cyclodextrin-based solution. Blood and cyst samples were taken up to 12 h posttreatment and analyzed by high-performance liquid chromatography (HPLC). For the efficacy study, CE-infected BALB/c mice were divided into three groups: the unmedicated control group and the FLBZ-and ABZ-treated groups. Oral treatments were performed twice a day during 25 days. After treatment, all animals were killed and the weight of the cysts was recorded. Loss of protoscolex viability was observed after drug incubation. FLBZ was detected in plasma (area under the concentration-versus-time curve [AUC] ‫؍‬ 1.8 g ⅐ h/ml) and cysts (AUC ‫؍‬ 0.3 g ⅐ h/g) collected from treated infected animals. Conversely, ABZSO was the only active molecule measured in plasma (AUC ‫؍‬ 4.4 g ⅐ h/ml) and cysts (AUC ‫؍‬ 1.5 g ⅐ h/g) after ABZ treatment. FLBZ induced a 90% reduction in cyst weight in comparison to those collected from untreated control mice (P < 0.05). However, no differences in cyst weight were observed between the ABZ-treated (8.2 g) and unmedicated control (10.5 g) groups. Due to these results, we consider flubendazole to have great potential to become a drug of choice in the treatment of cystic echinococcosis.

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supporting

confidence: 92%

supporting

confidence: 65%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Comparative Performances of Flubendazole and Albendazole in Cystic Echinococcosis: Ex Vivo Activity, Plasma/Cyst Disposition, and Efficacy in Infected Mice

Ceballos

Elissondo

Bruni

et al. 2011

Antimicrob Agents Chemother

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“…Another study has found that the maximum concentration (C max ) of flubendazole observed after its administration is significantly higher when solution is used instead of suspension. Moreover it was demonstrated that hydroxypropyl-β-cyclodextrin significantly increases aqueous solubility of flubendazole, which resulted in the higher plasma C max and enhanced its absorption and bioavailability in treated mice (17). Hydroxypropyl-β-cyclodextrin is commonly-used reagent for enhancing bioavail-ability of lipophilic drugs and can be used in both liquid and solid dosage forms (4).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Anthelmintic Flubendazole and Its Potential Use in Anticancer Therapy

Čáňová¹,

Rozkydalova²,

Rudolf³

2017

Acta Med. (Hradec Kralove, Czech Repub.)

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A B ST R AC T Flubendazole is a widely used anthelmintic drug belonging to benzimidazole group. The molecular mechanism of action of flubendazole is based on its specific binding to tubulin, which results in disruption of microtubule structure and function, and in the interference with the microtubule-mediated transport of secretory vesicles in absorptive tissues of helminths. The microtubule-disrupting properties of benzimidazole derivatives raised recently interest in these compounds as possible anti-cancer agents. In this minireview flubendazole effects towards selected human malignant cells including myeloma, leukemia, neuroblastoma, breast cancer, colorectal cancer and melanoma are discussed along with basic data on its pharmacokinetics, metabolism and toxicity.

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Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Kim

et al. 2018

Intl Journal of Cancer

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Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24 /CD44 , CD24 /CD49f subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.

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Flubendazole in cystic echinococcosis therapy: Pharmaco-parasitological evaluation in mice

Cited by 48 publications

References 24 publications

Comparative Performances of Flubendazole and Albendazole in Cystic Echinococcosis: Ex Vivo Activity, Plasma/Cyst Disposition, and Efficacy in Infected Mice

Comparative Performances of Flubendazole and Albendazole in Cystic Echinococcosis: Ex Vivo Activity, Plasma/Cyst Disposition, and Efficacy in Infected Mice

Anthelmintic Flubendazole and Its Potential Use in Anticancer Therapy

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

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