title: Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin.
abstract: This study investigated the effects of oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine (MEF) and identified proteins that bind to MEF in parasite extracts and human cells by affinity chromatography. In a pilot experiment, MEF treatment was applied 5 days per week and was intensified by increasing the dosage stepwise from 12.5 mg/kg to 200 mg/kg during 4 weeks followed by treatments of 100 mg/kg during the last 7 weeks. This resulted in a highly significant reduction of parasite weight in MEF-treated mice compared with mock-treated mice, but the reduction was significantly less efficacious compared with the standard treatment regimen of albendazole (ABZ). In a second experiment, MEF was applied orally in three different treatment groups at dosages of 25, 50 or 100 mg/kg, but only twice a week, for a period of 12 weeks. Treatment at 100 mg/kg had a profound impact on the parasite, similar to ABZ treatment at 200 mg/kg/day (5 days/week for 12 weeks). No adverse side effects were noted. To identify proteins in E. multilocularis metacestodes that physically interact with MEF, affinity chromatography of metacestode extracts was performed on MEF coupled to epoxy-activated Sepharose(®), followed by SDS-PAGE and in-gel digestion LC-MS/MS. This resulted in the identification of E. multilocularis ferritin and cystatin as MEF-binding proteins. In contrast, when human cells were exposed to MEF affinity chromatography, nicotinamide phosphoribosyltransferase was identified as a MEF-binding protein. This indicates that MEF could potentially interact with different proteins in parasites and human cells.
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Küster
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Stadelmann
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Rufener
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland.
authors.forename: Corina
authors.initials: C
authors.lastname: Risch
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, CH-3012 Bern, Switzerland. Electronic address: andrew.hemphill@vetsuisse.unibe.ch.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage* / Q000009:adverse effects; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects; D018938:Caco-2 Cells; D002846:Chromatography, Affinity; D002853:Chromatography, Liquid; D015891:Cystatins / Q000378:metabolism; D004195:Disease Models, Animal; D058492:Drug Repositioning; D004443:Echinococcosis / Q000188:drug therapy* / Q000469:parasitology; D048210:Echinococcus multilocularis / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D015767:Mefloquine / Q000008:administration & dosage* / Q000009:adverse effects; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
chemical_list: D000871:Anthelmintics; D000962:Antimalarials; D015891:Cystatins; D005293:Ferritins; D015767:Mefloquine
keywords: Alveolar echinococcosis; Chemotherapy; Cystatin; Ferritin; Mefloquine; Nicotinamide phosphoribosyltransferase