Chemotherapy for the treatment of alveolar echinococcosis: Where are we?

Abstract

Alveolar echinococcosis (AE) is a severe liver disease due to infection with the Echinococcus multilocularis larval stage, called the metacestode. Management of AE is based on benzimidazole chemotherapy (albendazole or mebendazole), associated with surgery when possible. Benzimidazoles are the only compounds recommended for the treatment of AE; however, these are parasitostatic, which means that the parasite can resume growth when treatment is interrupted. Also, benzimidazoles can cause liver dysfunction which may prevent their use. Numerous drugs have been reported to have in vitro activity against E. multilocularis, but few had satisfactory in vivo activity, and none were clearly more effective than benzimidazoles. These drugs belong to various therapeutic categories including anti-infective agents (e.g. amphotericin B, mefloquine, pentamidine derivatives), anti-neoplastic compounds (e.g. imatinib, nilotinib, bortezomib), plant-extracted compounds (e.g. thymol, crocin, carvacrol) and others (e.g. metformin, verapamil, thiaclopride). These treatments are generally of limited interest due to their toxicity, their unfavorable pharmacokinetics, or the scarcity of studies involving humans. Apart from benzimidazoles, only amphotericin B, mefloquine and nitazoxanide have been reported to be used for human AE treatment, with unsatisfactory results. Few studies have aimed at developing innovative strategies for AE drug therapy, such as vectorization of drugs using nanoparticles. Altogether, this review emphasizes the urgent need for new therapeutic strategies in AE management, for which there is currently no curative chemotherapy.

Keywords: Alveolar echinococcosis; Benzimidazole; Chemotherapy; Echinococcus multilocularis; Nanoparticles.

Figure 1

In vitro methods for the evaluation of anti-Echinococcus multilocularis compounds. In vitro methods are based on the exposure of protoscoleces, metacestodes, or cultures of germinal cells to compounds. Different techniques are used for the assessment of drug activity, including morphology and/or exclusion tests, phosphoglucoisomerase (PGI) and the Echinococcus multilocularis Alkaline Phosphatase (EmAP) assays, Em14-3-3 RT-qPCR, the Alamar Blue assay, and ATP quantification. Except for the first one, all of them rely on automated quantification of a signal. However, correlation of these signals with parasite viability remains difficult to predict.