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The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis.
Food Waterborne Parasitol. 2019 Jun; 15:e00040.FW

Abstract

The lethal disease alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical treatment of AE relies on albendazole and mebendazole, with the caveat that these compounds are not parasiticidal. Drugs have to be taken for a prolonged period of time, often life-long, which can cause adverse effects and reduces the patients' quality of life. In some individuals, benzimidazoles are inactive or cause toxicity, leading to treatment discontinuation. Alternatives to benzimidazoles are urgently needed. Over the recent years, in vivo and in vitro models for low-to-medium throughput drug discovery against AE have been set in place. In vitro drug tests include the phosphoglucose-isomerase (PGI) assay to measure physical damage induced to metacestodes, and viability assays to assess parasiticidal activity against metacestodes and stem cells. In vitro models are also employed for studies on mechanisms of action. In vivo models are thus far based on rodents, mainly mice, and benefits could be gained in future by comparative approaches in naturally infected dogs or captive monkeys. For the identification of novel drugs against AE, a rare disease with a low expected market return, drug-repurposing is the most promising strategy. A variety of chemically synthesized compounds as well as natural products have been analyzed with respect to in vitro and/or in vivo activities against AE. We here review and discuss the most active of these compounds including anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B, itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine, kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and taxanes). Taking into account the efficacy as well as the potential availability for patients, the most promising candidates are new formulations of benzimidazoles and mefloquine. Future drug-repurposing approaches should also target the energy metabolism of E. multilocularis, in particular the understudied malate dismutation pathway, as this offers an essential target in the parasite, which is not present in mammals.

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.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.Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32095613

Citation

Lundström-Stadelmann, Britta, et al. "The Importance of Being Parasiticidal… an Update On Drug Development for the Treatment of Alveolar Echinococcosis." Food and Waterborne Parasitology, vol. 15, 2019, pp. e00040.
Lundström-Stadelmann B, Rufener R, Ritler D, et al. The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food Waterborne Parasitol. 2019;15:e00040.
Lundström-Stadelmann, B., Rufener, R., Ritler, D., Zurbriggen, R., & Hemphill, A. (2019). The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food and Waterborne Parasitology, 15, e00040. https://doi.org/10.1016/j.fawpar.2019.e00040
Lundström-Stadelmann B, et al. The Importance of Being Parasiticidal… an Update On Drug Development for the Treatment of Alveolar Echinococcosis. Food Waterborne Parasitol. 2019;15:e00040. PubMed PMID: 32095613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. AU - Lundström-Stadelmann,Britta, AU - Rufener,Reto, AU - Ritler,Dominic, AU - Zurbriggen,Raphael, AU - Hemphill,Andrew, Y1 - 2019/03/14/ PY - 2018/12/18/received PY - 2019/02/06/revised PY - 2019/02/12/accepted PY - 2020/2/26/entrez PY - 2020/2/26/pubmed PY - 2020/2/26/medline KW - 2-ME, 2-methoxyestradiol KW - ABZ, albendazole KW - AE, alveolar echinococcosis KW - Albendazole KW - Chemotherapy KW - Drug treatment KW - Echinococcus multilocularis KW - MAPK, mitogen activated protein kinases KW - MBZ, mebendazole KW - MMV, Medicines for Malaria Venture KW - Malate dismutation KW - Mefloquine KW - PGI, phosphoglucose isomerase KW - SPEMs, small particles of Echinococcus multilocularis SP - e00040 EP - e00040 JF - Food and waterborne parasitology JO - Food Waterborne Parasitol VL - 15 N2 - The lethal disease alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical treatment of AE relies on albendazole and mebendazole, with the caveat that these compounds are not parasiticidal. Drugs have to be taken for a prolonged period of time, often life-long, which can cause adverse effects and reduces the patients' quality of life. In some individuals, benzimidazoles are inactive or cause toxicity, leading to treatment discontinuation. Alternatives to benzimidazoles are urgently needed. Over the recent years, in vivo and in vitro models for low-to-medium throughput drug discovery against AE have been set in place. In vitro drug tests include the phosphoglucose-isomerase (PGI) assay to measure physical damage induced to metacestodes, and viability assays to assess parasiticidal activity against metacestodes and stem cells. In vitro models are also employed for studies on mechanisms of action. In vivo models are thus far based on rodents, mainly mice, and benefits could be gained in future by comparative approaches in naturally infected dogs or captive monkeys. For the identification of novel drugs against AE, a rare disease with a low expected market return, drug-repurposing is the most promising strategy. A variety of chemically synthesized compounds as well as natural products have been analyzed with respect to in vitro and/or in vivo activities against AE. We here review and discuss the most active of these compounds including anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B, itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine, kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and taxanes). Taking into account the efficacy as well as the potential availability for patients, the most promising candidates are new formulations of benzimidazoles and mefloquine. Future drug-repurposing approaches should also target the energy metabolism of E. multilocularis, in particular the understudied malate dismutation pathway, as this offers an essential target in the parasite, which is not present in mammals. SN - 2405-6766 UR - https://www.unboundmedicine.com/medline/citation/32095613/The_importance_of_being_parasiticidal…_an_update_on_drug_development_for_the_treatment_of_alveolar_echinococcosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2405-6766(18)30045-3 DB - PRIME DP - Unbound Medicine ER -
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