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Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis.
Int J Parasitol Drugs Drug Resist. 2018 08; 8(2):331-340.IJ

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.

Authors+Show Affiliations

Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Division of Pharmacology and Toxicology, Vetsuisse Faculty, University of Bern, Länggassstrasse 124, 3012, Bern, Switzerland.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos - Far Manguinhos, 21041-250, Rio de Janeiro, Brazil.Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos - Far Manguinhos, 21041-250, Rio de Janeiro, Brazil.Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 266a, 8057 Zurich, Switzerland.Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.Institute of Animal Pathology COMPATH, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, Switzerland.Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos - Far Manguinhos, 21041-250, Rio de Janeiro, Brazil.Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos - Far Manguinhos, 21041-250, Rio de Janeiro, Brazil.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Division of Pharmacology and Toxicology, Vetsuisse Faculty, University of Bern, Länggassstrasse 124, 3012, Bern, Switzerland.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland. Electronic address: britta.lundstroem@vetsuisse.unibe.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29933218

Citation

Rufener, Reto, et al. "Activity of Mefloquine and Mefloquine Derivatives Against Echinococcus Multilocularis." International Journal for Parasitology. Drugs and Drug Resistance, vol. 8, no. 2, 2018, pp. 331-340.
Rufener R, Ritler D, Zielinski J, et al. Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. Int J Parasitol Drugs Drug Resist. 2018;8(2):331-340.
Rufener, R., Ritler, D., Zielinski, J., Dick, L., da Silva, E. T., da Silva Araujo, A., Joekel, D. E., Czock, D., Goepfert, C., Moraes, A. M., de Souza, M. V. N., Müller, J., Mevissen, M., Hemphill, A., & Lundström-Stadelmann, B. (2018). Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. International Journal for Parasitology. Drugs and Drug Resistance, 8(2), 331-340. https://doi.org/10.1016/j.ijpddr.2018.06.004
Rufener R, et al. Activity of Mefloquine and Mefloquine Derivatives Against Echinococcus Multilocularis. Int J Parasitol Drugs Drug Resist. 2018;8(2):331-340. PubMed PMID: 29933218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. AU - Rufener,Reto, AU - Ritler,Dominic, AU - Zielinski,Jana, AU - Dick,Luca, AU - da Silva,Emerson Teixeira, AU - da Silva Araujo,Adriele, AU - Joekel,Deborah Elisabeth, AU - Czock,David, AU - Goepfert,Christine, AU - Moraes,Adriana Marques, AU - de Souza,Marcus Vinicius Nora, AU - Müller,Joachim, AU - Mevissen,Meike, AU - Hemphill,Andrew, AU - Lundström-Stadelmann,Britta, Y1 - 2018/06/15/ PY - 2018/04/24/received PY - 2018/06/12/revised PY - 2018/06/14/accepted PY - 2018/6/23/pubmed PY - 2019/1/31/medline PY - 2018/6/23/entrez KW - Alveolar echinococcosis KW - Anti-malaria KW - Drug repurposing KW - HPLC KW - Structure activity relationship KW - Treatment SP - 331 EP - 340 JF - International journal for parasitology. Drugs and drug resistance JO - Int J Parasitol Drugs Drug Resist VL - 8 IS - 2 N2 - 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. SN - 2211-3207 UR - https://www.unboundmedicine.com/medline/citation/29933218/Activity_of_mefloquine_and_mefloquine_derivatives_against_Echinococcus_multilocularis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-3207(18)30061-7 DB - PRIME DP - Unbound Medicine ER -