Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes

Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestodeEchinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore thein vitroandin vivoeffects of tamoxifen (TAM) againstE. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival ofE. granulosusprotoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment.

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confidence: 99%

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

Nicolao

Elissondo

Denegri

et al. 2014

“…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.…”

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confidence: 99%

“…As a consequence, it is more sensible to search for effective compounds or compound classes that are at an advanced stage of development or, even more realistically, are present in already marketed drugs. In the case of echinococcosis, these potentially interesting compounds are either broad-spectrum antiinfective drugs (8) or compounds that have been developed for cancer treatment (18,22,32).…”

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confidence: 99%

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

Küster

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...

“…Traditionally, the effects of drugs on taeniid cysts have been assessed by visual examination of cysts for morphological and histopathological changes on light or electron microscopy suggesting damage (16,17). Although these approaches have demonstrated effects of the commonly used anthelmintics for treatment of T. solium (17) and other cestodes (7,11), the techniques require experienced personnel and equipment and are time-consuming for routine use and analysis. We were interested in investigating alternative, potentially more sensitive methods for detection of damage to parasites that had the potential for testing new drugs rapidly and inexpensively.…”

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confidence: 99%

Sensitive In Vitro System To Assess Morphological and Biochemical Effects of Praziquantel and Albendazole on Taenia solium Cysts

Mahanty

Paredes

Marzal

et al. 2011

Neurocysticercosis resulting from Taenia solium infections is a major cause of adult-acquired seizures worldwide. Disease is caused by larval cysts, and treatment consists of the anthelmintic drugs albendazole or praziquantel. There are no standard methods to assess drug activity to T. solium cysts in vitro. Morphological, functional, and biochemical changes that might reflect damaging (inhibiting, cytotoxic) drug effects were analyzed after exposure of cysts to albendazole sulfoxide (ABZ-SO), the major active metabolite of the drug in vivo, praziquantel (PZQ), or combinations of both. PZQ exposure led to a decrease in cyst size and inhibition of evagination, whereas ABZ-SO exposure resulted in minimal changes. Alkaline phosphatase (AP) is normally secreted by cysts, and both drugs inhibited AP secretion at concentrations of 5 and 50 ng/ml for PZQ and ABZ-SO, respectively. Some combinations of both drugs resulted in additive and/or synergistic activities. Parasite-specific antigen, detected in the cerebrospinal fluid and blood of infected patients, is also normally secreted by T. solium cysts. Antigen secretion was similarly inhibited by ABZ-SO and PZQ and a combination of both drugs, suggesting that inhibition of secretion is a common downstream consequence of the activities of both drugs. These studies establish quantitative methods to measure in vitro anthelmintic activity and suggest combination therapy with ABZ-SO and PZQ may have clinical benefit. Neurocysticercosis (NCC), the most common cause of adult acquired seizures worldwide, results from infection of the brain by the cystic larval stage of Taenia solium. The adult tapeworm resides in the human intestines. It consists of a head with a scolex, which is an attachment organ, a neck, and increasingly maturing segments containing infectious ova. These are excreted as segments in the feces and, when ingested by freeroaming pigs, hatch and are carried to the brain, muscles, and other organs, where they develop into viable cysts in about 2 to 3 months. After ingestion and exposure to bile and other factors in the gastrointestinal tract milieu, the cysts evaginate and develop into tapeworms. Humans develop NCC after accidental ingestion of infectious ova sometimes originating from their own tapeworm or one residing in a family member or coinhabitant.The clinical manifestations of NCC are due to growth, degeneration, and inflammation associated with the host response to the cyst. Treatment consists of the anthelmintic agents albendazole or praziquantel (PZQ) (4, 5, 15), as well as corticosteroids or other anti-inflammatory agents (4,14), that are commonly used to control treatment-induced inflammation. However, cure rates are relatively low with currently available regimens, and more effective agents are needed.T. solium larval cysts (metacestodes) can only be obtained from infected pigs. Studies using T. solium cysts are difficult because many infected pigs are required, harvesting cysts individually is laborious and time-consuming, and culturing and maintain...