Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis

Rufener, Reto; Ritler, Dominic; Zielinski, Jana; Dick, Luca; da Silva, Emerson Teixeira; da Silva Araujo, Adriele; Joekel, Deborah Elisabeth; Czock, David; Göpfert, Christine; Moraes, Adriana Marques; de Souza, Marcus Vinicius Nora; Müller, Joachim; Mevissen, Meike; Hemphill, Andrew; Lundström-Stadelmann, Britta (2018). Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. International journal for parasitology. Drugs and drug resistance, 8(2), pp. 331-340. Elsevier 10.1016/j.ijpddr.2018.06.004

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Pharmacology and Toxicology

UniBE Contributor:

Rufener, Reto; Ritler, Dominic; Zielinski, Jana; Dick, Luca Julian; Göpfert, Christine; Müller, Joachim; Mevissen, Meike; Hemphill, Andrew and Lundström Stadelmann, Britta

Subjects:

600 Technology > 630 Agriculture

ISSN:

2211-3207

Publisher:

Elsevier

Language:

English

Submitter:

Britta Lundström Stadelmann

Date Deposited:

07 Nov 2018 12:10

Last Modified:

17 Dec 2018 08:51

Publisher DOI:

10.1016/j.ijpddr.2018.06.004

PubMed ID:

29933218

BORIS DOI:

10.7892/boris.120970

URI:

https://boris.unibe.ch/id/eprint/120970

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