Combined Flubendazole-Nitazoxanide treatment of cystic echinococcosis: pharmacokinetic and efficacy assessment in mice

CEBALLOS, L; ELISSONDO, C; SANCHEZ BRUNI, S; DENEGRI, G; LANUSSE, C

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2015

0001-706X

The current chemotherapy of cystic echinococcosis (CE) is mainly based on the use of albendazole, and 3 the results have been shown to be highly variable. Thus, new and more efficient treatment options are 4 urgently needed. The goals of the current study were: a) to compare the ex vivo activity of flubendazole 5 (FLBZ) and nitazoxanide (NTZ), given either separately or co-administered, against Echinococcus 6 granulosus protoscoleces and cysts, b) to characterize the plasma disposition kinetics of FLBZ 7 administered alone or combined with NTZ in mice; c) to compare the in vivo activity of FLBZ and NTZ 8 (either each alone or as a combined treatment) against secondary CE developed in mice. Ex vivo drug 9 activity study: E. granulosus protoscoleces and cysts were incubated either with FLBZ, NTZ, or the 10 FLBZ-NTZ combination. Protoscoleces and cyst viability was monitored by the methylene blue 11 exclusion test and scanning electron microscopy (SEM). Pharmacokinetic study: Balb/C mice received 12 FLBZ (5 mg/kg) orally either alone or co-administered with NTZ (100 mg/kg). Blood samples were 13 collected up to 12 h post treatment and plasma analyzed for FLBZ/metabolites by HPLC. 14 Clinical Efficacy study: following secondary infection, meaning i.p. injection of 1500 E. granulosus 15 protoscoleces/animal (n=40), the both drugs were administered by intragastric inoculation on a daily 16 basis for a period of 25 days. Balb/C mice received FLBZ (5 mg/kg, twice a day) alone, NTZ (100 17 mg/kg, once daily) alone or a combination of both molecules (FLBZ, 5 mg/kg twice a day and NTZ, 100 18 mg/kg, once daily). Ten untreated animals were used as a control. All animals were killed and the 19 weight of the cysts collected from each animal was recorded. The presence of NTZ did not markedly 20 affect the FLBZ kinetic parameters in mice. FLBZ alone or combined with NTZ induced a reduction 21 (P