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

Abstract

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.

Nematodicidal Activity of Flubendazole and Its Reduced Metabolite on a Murine Model of <b><i>Trichinella spiralis </i></b>Infection

“…It would be expected that worms were exposed to a higher amount of drug, explaining the high efficacy observed after the use of FLBZ and R-FLBZ as a CD-based solution. These results are consistent with previous studies where the use of an ABZ-CD [23,24,7] and FLBZ-CD solution [1,7] resulted in improved anthelmintic efficacy. …”

“…While H-FLBZ is an inactive metabolite, no data is available on the anthelmintic activity of the R-FLBZ, which is the main FLBZ metabolite systemically available in sheep [17] and mice [1]. Although some in vitro work on the effect on Fasciola hepatica egg hatching [18] and E. granulosus protoscolices [7] has been done, further information of the anthelmintic activity of the main FLBZ metabolite is needed. Since R-FLBZ may contribute to the final FLBZ anthelmintic effect, it would be relevant to assess the individual nematodicidal activity of this metabolite.…”

“…For BZD anthelmintics, dissolution is the rate-limiting step in the systemic availability of the active drug/metabolites [5]. It has been previously reported that the use of complexing agents such as cyclodextrins (CD) increases the water solubility of both FLBZ and ABZ [6] and their systemic drug exposure in mice [1,7]. After the oral administration of FLBZ as a solution or suspension, both formulations demonstrated a preventive chemoprophylactic effect in Echinococcus granulosus -infected mice [8].…”

Viability loss and ultrastructural changes on protoscolices of human hydatid cysts induced by retinoic acid

“…This was confirmed by morphological and ultrastructural deformities induced by the two effective atRA doses at different incubation periods. Such atRA-induced morphological and ultrastructural changes that included contraction in soma region, formation of blebs on the tegument, rosteller disorganization, loss of hooks, and destruction of microtriches were consistent with that observed with several established protoscolicidal compounds including praziquantel (Urrea-Parıis et al, 1999, 2000, benzimidazole (Pe´rez-Serrano et al, 2001), albendazole (Ceballos et al, 2011) and ivermectin (Casado et al, 1989;Elissondo et al, 2009).…”

Chemotherapy for Central Nervous System Hydatidosis

“…Chemotherapy for CNS hydatidosis became a reality with the introduction of the two benzimidazoles, MBZ andABZ, respectively, in 1976 andin 1982. Flubendazole (FBZ) was also shown to be effective for treatment of cystic echinococcosis (Ceballos et al 2011 ) but is less effi cacious than ABZ and is not used for the management of CNS hydatidosis. ABZ is most widely utilized, owing to its higher absorption in the gut and better gastrointestinal tolerability.…”