Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis

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.

Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis

“…Consistent with these findings, the drug was also active against E. multilocularis metacestodes at 10 μM, but not at 1 μM. Mefloquine (MMV000016), originally developed and used against Plasmodium , has recently been found to be active against E. multilocularis both in vitro , as well as in vivo ( Stadelmann et al, 2011 ; Küster et al, 2011 , 2015 ; Rufener et al, 2018 ). Mefloquine has a rather high IC 50 value against this parasite in vitro (>30 μM), but nevertheless it was identified in our screening at 10 μM.…”

Echinococcosis: Advances in the 21st Century

“…Lists of those drugs that were tested in vitro and found not suitable for use in humans after being tested in vivo in experimental animals are available in morespecialized reviews (182,213). There is some hope from in vivo experiments with mefloquine (214)(215)(216)(217)(218) and artemisinin (219,220) derivatives, and very recently, derivatives of carbazole aminoalcohols have been shown effective against cysts of E. granulosus both in vitro and in vivo (221). However, none of these compounds have, as yet, been subjected to pilot clinical trials.…”

Medical Treatment of Cystic Echinococcosis

“…• Mefloquine (MMV000016) is an antiparasitic drug used in malaria, active on Plasmodium spp., which has proven to be effective against Echinococcus multilocularis metacestodes in vitro and in vivo [51][52][53][54]. In a study conducted by Küster (2011), oral administration of mefloquine (25 mg/kg of body weight administered twice a week for a period of 8 weeks) was compared with albendazole (200 mg/kg/day) or mefloquine intraperitoneally compared with albendazole.…”