title: In vitro efficacy of dicationic compounds and mefloquine enantiomers against Echinococcus multilocularis metacestodes.
abstract: The current chemotherapy of alveolar echinococcosis (AE) is based on benzimidazoles such as albendazole and has been shown to be parasitostatic rather than parasiticidal, requiring lifelong duration. Thus, new and more efficient treatment options are urgently needed. By employing a recently validated assay based on the release of functional phosphoglucose isomerase (PGI) from dying parasites, the activities of 26 dicationic compounds and of the (+)- and (-)-erythro-enantiomers of mefloquine were investigated. Initial screening of compounds was performed at 40 μM, and those compounds exhibiting considerable antiparasitic activities were also assessed at lower concentrations. Of the dicationic drugs, DB1127 (a diguanidino compound) with activities comparable to nitazoxanide was further studied. The activity of DB1127 was dose dependent and led to severe structural alterations, as visualized by electron microscopy. The (+)- and (-)-erythro-enantiomers of mefloquine showed similar dose-dependent effects, although higher concentrations of these compounds than of DB1127 were required for metacestode damage. In conclusion, of the drugs investigated here, the diguanidino compound DB1127 represents the most promising compound for further study in appropriate in vivo models for Echinococcus multilocularis infection.
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Langgass-Strasse 122, CH-3012 Berne, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Stadelmann
authors.forename: Tatiana
authors.initials: T
authors.lastname: Küster
authors.forename: Sabrina
authors.initials: S
authors.lastname: Scholl
authors.forename: Fabienne
authors.initials: F
authors.lastname: Barna
authors.forename: Christian
authors.initials: C
authors.lastname: Kropf
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000818:Animals; D000923:Anticestodal Agents / Q000494:pharmacology*; D048210:Echinococcus multilocularis / Q000187:drug effects* / Q000648:ultrastructure; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D015767:Mefloquine / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013237:Stereoisomerism; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000923:Anticestodal Agents; C570443:DB1127; D006146:Guanidines; D013876:Thiophenes; D005956:Glucose-6-Phosphate Isomerase; D015767:Mefloquine