Alveolar and cystic echinococcosis: towards novel chemotherapeutical treatment options

Kriegel

Boykin

et al. 2013

c Alveolar echinococcosis (AE) is a disease predominantly affecting the liver, with metacestodes (larvae) of the tapeworm Echinococcus multilocularis proliferating and exhibiting tumor-like infiltrative growth. For many years, chemotherapeutical treatment against alveolar echinococcosis has relied on the benzimidazoles albendazole and mebendazole, which require long treatment durations and exhibit parasitostatic rather than parasiticidal efficacy. Although benzimidazoles have been and still are beneficial for the patients, there is clearly a demand for alternative and more efficient treatment options. Aromatic dications, more precisely a small panel of di-N-aryl-diguanidino compounds, were screened for efficacy against E. multilocularis metacestodes in vitro. Only those with a thiophene core group were active against metacestodes, while furans were not. The most active compound, DB1127, was further investigated in terms of in vivo efficacy in mice experimentally infected with E. multilocularis metacestodes. This diguanidino compound was effective against AE when administered intraperitoneally but not when applied orally. Thus, thiophene-diguanidino derivatives with improved bioavailability when administered orally could lead to treatment options against AE.

Section: T He Disease Alveolar Echinococcosis (Ae) Is Caused By Infecmentioning

confidence: 99%

In VitroandIn VivoActivities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

Kriegel

Boykin

et al. 2013

“…However, therapy using these drugs does not result in parasiticidal activity in vivo or in vitro, and treatment failures and/or the occurrence of adverse effects have been reported, leading to discontinuation of treatment or to progressive disease. Therefore, the search for novel drug candidates for the treatment of AE has to be pursued (7).…”

mentioning

confidence: 99%

In Vitro and In Vivo Efficacies of Mefloquine-Based Treatment against Alveolar Echinococcosis

Lundström‐Stadelmann

Hermann

et al. 2011

Alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis and causes severe disease in the human liver, and occasionally in other organs, that is fatal when treatment is unsuccessful. The present chemotherapy against AE is based on mebendazole and albendazole. Albendazole treatment has been found to be ineffective in some instances, is parasitostatic rather than parasiticidal, and usually involves the lifelong uptake of large doses of drugs. Thus, new treatment options are urgently needed. In this study we investigated the in vitro and in vivo efficacy of mefloquine against E. multilocularis metacestodes. Treatment using mefloquine (20 M) against in vitro cultures of metacestodes resulted in rapid and complete detachment of large parts of the germinal layer from the inner surface of the laminated layer within a few hours. The in vitro activity of mefloquine was dependent on the dosage. In vitro culture of metacestodes in the presence of 24 M mefloquine for a period of 10 days was parasiticidal, as determined by murine bioassays, while treatment with 12 M was not. Oral application of mefloquine (25 mg/kg of body weight administered twice a week for a period of 8 weeks) in E. multilocularis-infected mice was ineffective in achieving any reduction of parasite weight, whereas treatment with albendazole (200 mg/kg/day) was highly effective. However, when the same mefloquine dosage was applied intraperitoneally, the reduction in parasite weight was similar to the reduction seen with oral albendazole application. Combined application of both drugs did not increase the treatment efficacy. In conclusion, mefloquine represents an interesting drug candidate for the treatment of AE, and these results should be followed up in appropriate in vivo studies.In humans, infection with the larval stage of Echinococcus multilocularis causes alveolar echinococcosis (AE), a mainly hepatic disease, which is fatal if not treated appropriately. E. multilocularis metacestodes proliferate asexually by forming small daughter vesicles, leading to a parasite mass that exhibits tumor-like properties and progressively infiltrates the neighboring tissue (8). The treatment options for AE are surgery and/or chemotherapy. Surgery is, of course, an invasive procedure, and feasibility depends on the location of the metacestode tissue. In addition, care must be taken to remove the entire parasite mass (otherwise, recurrences are certain), and there is the risk of metastasis formation caused by accidental dissemination of small daughter vesicles or even parasitic cells. Surgery is always accompanied by pre-and postoperative chemotherapy. In cases where surgery is not possible, chemotherapy remains the only option. For chemotherapeutical treatment of AE, the only two drugs licensed to date are the benzimidazole carbamate derivatives albendazole and mebendazole (42). However, therapy using these drugs does not result in parasiticidal activity in vivo or in vitro, and treatment failures and/or the occu...

“…Failures in drug treatment and/or the occurrence of side effects has been reported, leading to discontinuation of treatment or to progressive disease. Due to this unsatisfactory situation, novel drug candidates for the treatment of AE need to be identified (17,18).…”

mentioning

confidence: 99%

In Vitro Efficacy of Dicationic Compounds and Mefloquine Enantiomers against Echinococcus multilocularis Metacestodes

Lundström‐Stadelmann

Scholl

et al. 2011

The current chemotherapy of alveolar echinococcosis (AE) is based on benzimidazoles such as albendazole and has been shown to be parasitostatic rather than parasiticidal, requiring lifelong duration. Thus, new and more efficient treatment options are urgently needed. By employing a recently validated assay based on the release of functional phosphoglucose isomerase (PGI) from dying parasites, the activities of 26 dicationic compounds and of the (؉)-and (؊)-erythro-enantiomers of mefloquine were investigated. Initial screening of compounds was performed at 40 M, and those compounds exhibiting considerable antiparasitic activities were also assessed at lower concentrations. Of the dicationic drugs, DB1127 (a diguanidino compound) with activities comparable to nitazoxanide was further studied. The activity of DB1127 was dose dependent and led to severe structural alterations, as visualized by electron microscopy. The (؉)-and (؊)-erythro-enantiomers of mefloquine showed similar dose-dependent effects, although higher concentrations of these compounds than of DB1127 were required for metacestode damage. In conclusion, of the drugs investigated here, the diguanidino compound DB1127 represents the most promising compound for further study in appropriate in vivo models for Echinococcus multilocularis infection.