Increases in the Effects of Albendazole on Echinococcus multilocularis Metacestodes by the Dipeptide Methyl Ester (Phe-Phe-OMe)

Sarciron, Marie‐Elisabeth; Walchshofer, Nadia; Walbaum, S.; Arsac, C; Descotes, Jacques; Pétavy, A. F.; Pâris, J.

doi:10.4269/ajtmh.1997.56.226

Cited by 10 publications

(7 citation statements)

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“…There appeared to be a synergistic effect between albendazole and cimetidine, since the metabolism of albendazole was markedly altered and a greater therapeutic effect was observed. A more recent study provided evidence that the effect of albendazole in gerbils infected with E. multilocularis metacestodes can also be increased by administring the drug in combination with the dipeptide methyl ester Phe-Phe-OMe (36). Although all of these in vivo studies investigated either the ultrastructural characteristics of drug-treated parasites or the effects on parasite growth, they did not obtain information on drug uptake by the parasite or assess the metabolic changes occurring within the parasite.…”

Section: Discussionmentioning

confidence: 99%

Efficacies of Albendazole Sulfoxide and Albendazole Sulfone against In Vitro-Cultivated Echinococcus multilocularis Metacestodes

Ingold

Bigler²,

Thormann

et al. 1999

Antimicrob Agents Chemother

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The metacestode stage of Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a parasitic disease affecting the liver, with occasional metastasis into other organs. Benzimidazole carbamate derivatives such as mebendazole and albendazole are currently used for chemotherapeutic treatment of AE. Albendazole is poorly resorbed and is metabolically converted to its main metabolite albendazole sulfoxide, which is believed to be the active component, and further to albendazole sulfone. Chemotherapy with albendazole has been shown to have a parasitostatic rather than a parasitocidal effect; it is not effective in all cases, and the recurrence rate is rather high once chemotherapy is stopped. Thus, development of new means of chemotherapy of AE is needed. This could include modifications of benzimidazoles and elucidiation of the respective biological pathways. In this study we performed in vitro drug treatment of E. multilocularis metacestodes with albendazole sulfoxide and albendazole sulfone. High-performance liquid chromatography analysis of vesicle fluids showed that the drugs were taken up rapidly by the parasite. Transmission electron microscopic investigation of parasite tissues and nuclear magnetic resonance spectroscopy of vesicle fluids demonstrated that albendazole sulfoxide and albendazole sulfone had similar effects with respect to parasite ultrastructure and changes in metabolites in vesicle fluids. This study shows that the in vitro cultivation model presented here provides an ideal first-round test system for screening of antiparasite drugs.

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Section: Discussionmentioning

confidence: 99%

Efficacies of Albendazole Sulfoxide and Albendazole Sulfone against In Vitro-Cultivated Echinococcus multilocularis Metacestodes

Ingold

Bigler²,

Thormann

et al. 1999

Antimicrob Agents Chemother

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show abstract

“…Traditionally, assessment of the efficacy of drugs against E. multilocularis metacestodes has always relied on animal experimentation using mice or gerbils (6,23,24,27,28). Such investigations are usually associated with high costs and timeconsuming analyses.…”

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confidence: 99%

Echinococcus multilocularis Alkaline Phosphatase as a Marker for Metacestode Damage Induced by In Vitro Drug Treatment with Albendazole Sulfoxide and Albendazole Sulfone

Stettler

Siles-Lucas

Sarciron

et al. 2001

Antimicrob Agents Chemother

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Alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. The disease affects the human liver and occasionally other organs and is fatal if treatment is unsuccessful. The present chemotherapy of AE is based on the administration of benzimidazole carbamate derivatives, such as mebendazole and albendazole. Albendazole treatment has been found to be ineffective in some cases, parasitostatic rather than parasiticidal, and the recurrence rate is rather high. Therefore, chemotherapy usually involves the lifelong uptake of massive doses of albendazole and new treatment options are urgently needed. In order to avoid costly and time-consuming animal experimentation, a first step in searching for novel parasiticidal compounds could be the in vitro drug screening of novel compounds by employing metacestode cultivation. However, presently used techniques (e.g., transmission electron microscopy) for determination of parasite viability involve costly equipment and time-consuming preparation of rather large amounts of parasite material. We therefore searched for a parasite marker which can be easily traced and the presence or absence of which is indicative of parasite viability. In this study we show that the increase of E. multilocularis alkaline phosphatase activity in culture supernatants during in vitro drug treatment with albendazole derivatives correlates with the progressive degeneration and destruction of the metacestode tissue. The inexpensive and rapid assay presented here will serve as an ideal tool for performing first-round in vitro tests on the efficacy of a large number of antiparasitic compounds.

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“…Although more specialized techniques closely mimicking the in vivo behaviour of E. multilocularis were published recently (Emery et al, 1995;Gabrion et al, 1995;Hemphill & Gottstein, 1995;Jura et al, 1996), we used the simpler protoscoleces/vesicle in vitro maintenance with assessment of viability by eosin exclusion (Lorenzini & Ruggieri, 1990). However, many previous in vivo tests had been undertaken and positive efficacy of the tested substances had already been shown (Sarciron et al, 1991(Sarciron et al, , 1992(Sarciron et al, , 1993(Sarciron et al, , 1995(Sarciron et al, , 1997a. We wished to find out if a direct activity could be demonstrated and what parasite structures might be the targets of these chemicals.…”

Section: Discussionmentioning

confidence: 99%

In vitro effects of isoprinosine and a dipeptide methyl ester on Echinococcus multilocularis protoscoleces

Lawton¹,

Walchshofer²,

Sarciron³

2001

J. Helminthol.

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A protoscoleces/vesicles in vitro maintenance test with assessment of viability by eosin exclusion was used to evaluate the quantitative and qualitative activities of isoprinosine, its active component inosine and the dipeptide methylester L-Phe-Phe-OMe on isolated protoscoleces of Echinococcus multilocularis for 24 and 48 h. Isoprinosine and inosine showed dose- and time-dependent activity, the latter displaying a more rapid effect than the former. A high activity was shown with L-Phe-Phe-OMe, when compared to praziquantel. Ultrastructural alterations were much more striking with L-Phe-Phe-OMe, with an effect similar to that of praziquantel, whereas the chemotherapeutic activity of inosine and isoprinosine appeared to be directed against a metabolic target, with a lethal effect not immediately visible at the ultrastructural level. Thus, the previously reported in vivo activities of these drugs result largely from a direct effect on the parasite.

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Increases in the Effects of Albendazole on Echinococcus multilocularis Metacestodes by the Dipeptide Methyl Ester (Phe-Phe-OMe)

Cited by 10 publications

References 0 publications

Efficacies of Albendazole Sulfoxide and Albendazole Sulfone against In Vitro-Cultivated Echinococcus multilocularis Metacestodes

Efficacies of Albendazole Sulfoxide and Albendazole Sulfone against In Vitro-Cultivated Echinococcus multilocularis Metacestodes

Echinococcus multilocularis Alkaline Phosphatase as a Marker for Metacestode Damage Induced by In Vitro Drug Treatment with Albendazole Sulfoxide and Albendazole Sulfone

In vitro effects of isoprinosine and a dipeptide methyl ester on Echinococcus multilocularis protoscoleces

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