Combined flubendazole-nitazoxanide treatment of cysticechinococcosis: Pharmacokinetic and efficacy assessment in mice.

CEBALLOS, LAURA; ELISSONDO, CELINA; SANCHEZ BRUNI, SERGIO; DENEGRI, GUILLERMO; LANUSSE, CARLOS; ALVAREZ, LUIS

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2015 vol. 148 p. 89 - 96

0001-706X

tThe current chemotherapy of cystic echinococcosis (CE) is mainly based on the use of albendazole, andthe results have been shown to be highly variable. Thus, new and more efficient treatment options areurgently needed. The goals of the current study were: a) to compare the ex vivo activity of flubendazole(FLBZ) and nitazoxanide (NTZ), given either separately or co-administered, against Echinococcus granulo-sus protoscoleces and cysts, b) to characterize the plasma disposition kinetics of FLBZ administered aloneor combined with NTZ in mice; (c) to compare the in vivo activity of FLBZ and NTZ (either each alone or asa combined treatment) against secondary CE developed in mice. Ex vivo drug activity study: E. granulosusprotoscoleces and cysts were incubated either with FLBZ, NTZ, or the FLBZ-NTZ combination. Proto-scoleces and cyst viability was monitored by the methylene blue exclusion test and scanning electronmicroscopy (SEM). Pharmacokinetic study: Balb/C mice received FLBZ (5 mg/kg) orally either alone or co-administered with NTZ (100 mg/kg). Blood samples were collected up to 12 h post treatment and plasmaanalyzed for FLBZ/metabolites by HPLC. Clinical Efficacy study: following secondary infection, meaningi.p. injection of 1500 E. granulosus protoscoleces/animal (n = 40), the both drugs were administered byintragastric inoculation on a daily basis for a period of 25 days. Balb/C mice received FLBZ (5 mg/kg, twicea day) alone, NTZ (100 mg/kg, once daily) alone or a combination of both molecules (FLBZ, 5 mg/kg twicea day and NTZ, 100 mg/kg, once daily). Ten untreated animals were used as a control. All animals werekilled and the weight of the cysts collected from each animal was recorded. The presence of NTZ didnot markedly affect the FLBZ kinetic parameters in mice. FLBZ alone or combined with NTZ induced areduction (P < 0.05) of cyst weight in comparison to the untreated control and NTZ-treated treated mice.The data obtained here indicate that NTZ did not affect hydatid cyst development in mice. Conversely,FLBZ shows an excellent efficacy against CE.