In vitro and in vivo efficacies of novel carbazole aminoalcohols in the treatment of cystic echinococcosis.

OBJECTIVES

Cystic echinococcosis (CE), caused by the cestode Echinococcus granulosus, is a worldwide chronic zoonosis. Current chemotherapeutic options are limited to albendazole and mebendazole, which only exert parasitostatic effects and have to be administered at high dosages for long periods. In an effort to find alternative treatment options, the in vitro and in vivo efficacies of novel carbazole aminoalcohols were evaluated.

METHODS

Carbazole aminoalcohols were tested against E. granulosus protoscoleces in vitro and metacestodes ex vivo. The in vivo chemotherapeutic effect of representative compounds was assessed in experimentally infected mice. Oral and intravenous pharmacokinetic profiles were determined in mice.

RESULTS

The carbazole aminoalcohols exhibited potent protoscolicidal activity with LC50 values ranging from 18.2 to 34.3 μM. Among them, compounds 2 and 24 killed all ex vivo cultured metacestodes at concentrations of 34.3 and 30.6 μM. In vivo studies showed that oral administration of compounds 2 and 24 (25 mg/kg/day) for 30 days led to reductions of 68.4% and 54.3% in parasite weight compared with the untreated group (both groups: P < 0.001). Compound 2 (25 mg/kg/day) and compound 24 (50 mg/kg/day) induced significantly higher cyst mortality rates in comparison with that of the albendazole group (both groups: P < 0.01). Analysis of cysts collected from compound 2- or 24-treated mice by transmission electron microscopy revealed a drug-induced structural destruction. The structural integrity of the germinal layer was lost, and the majority of the microtriches disappeared. Pharmacokinetic profiling of compounds 2 and 24 revealed low clearance and decent oral bioavailability (>70%).

CONCLUSIONS

Our study identifies carbazole aminoalcohols as a class of novel anti-CE agents. Compounds 2 and 24 represent promising drug candidates in anti-CE chemotherapy.