Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. Issue 2 (August 2018)

• Record Type: Journal Article
• Authors: Rufener, Reto; Ritler, Dominic; Zielinski, Jana; Dick, Luca; da Silva, Emerson Teixeira; da Silva Araujo, Adriele; Joekel, Deborah Elisabeth; Czock, David; Goepfert, Christine; Moraes, Adriana Marques; de Souza, Marcus Vinicius Nora; Müller, Joachim; Mevissen, Meike; Hemphill, Andrew; Lundström-Stadelmann, Britta
• Is Part Of: International journal for parasitology. Volume 8:Issue 2(2018)
• Page Start: 331
• Page End: 340
• Publication Date: 2018-08
• Subjects: Alveolar echinococcosis -- Treatment -- Anti-malaria -- HPLC -- Drug repurposing -- Structure activity relationship; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2018.06.004
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria. Graphical abstract: Image 1 Highlights: Tested anti-malarial mefloquine against mice infected orally with E. multilocularis . Reduced liver lesion numbers upon bi-weekly treatment with 100 mg/kg mefloquine. Similar mefloquine levels reached in mice as in human malaria prophylaxis. Efficacy of mefloquine is dependent on two molecular residues.