title: 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 μg · h/ml) and cysts (AUC = 0.3 μg · h/g) collected from treated infected animals. Conversely, ABZSO was the only active molecule measured in plasma (AUC = 4.4 μg·h/ml) and cysts (AUC = 1.5 μg·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.
authors.affiliation: Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario, 7000 Tandil, Argentina. ceballos@vet.unicen.edu.ar
authors.forename: Laura
authors.initials: L
authors.lastname: Ceballos
authors.forename: Celina
authors.initials: C
authors.lastname: Elissondo
authors.forename: Sergio
authors.initials: S
authors.lastname: Sánchez Bruni
authors.forename: Guillermo
authors.initials: G
authors.lastname: Denegri
authors.forename: Carlos
authors.initials: C
authors.lastname: Lanusse
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez
mesh_terms: D015766:Albendazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000923:Anticestodal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004443:Echinococcosis / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D048209:Echinococcus granulosus / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D008463:Mebendazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome
chemical_list: D000923:Anticestodal Agents; D008463:Mebendazole; D015766:Albendazole; C018945:flubendazole