<i>In Vitro</i>
            Efficacy of Dicationic Compounds and Mefloquine Enantiomers against Echinococcus multilocularis Metacestodes

SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

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“…2012), Besnoitia besnoiti (Cortes et al . 2011) and Echinococcus multilocularis (Stadelmann et al . 2011).…”

Section: Design and Synthesisunclassified

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

et al. 2013

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“…The in vivo effects of DB1127 were investigated and compared to those of standard oral albendazole treatments. Two experiments were performed, one assessing the intraperitoneal (21) and one the oral (30) delivery route. DB1127 was prepared as a stock solution in DMSO and diluted 1,000 times with 1% carboxymethyl cellulose (CMC) in saline solution.…”

Section: Methodsmentioning

confidence: 99%

“…PGI is abundant in metacestode vesicle fluid and released into the metacestode culture supernatant by dying parasites, while intact, viable metacestodes do not release this enzyme (26). Recently, we demonstrated that DB1127, a dicationic thiophene derivative (di-Naryl-diguanidino compound), triggered the release of high levels of PGI activity from metacestodes in a dose-dependent manner, was substantially active at concentrations as low as 1 M, and induced structural damage upon E. multilocularis metacestodes (21).…”

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

confidence: 99%

“…These include other benzimidazole derivatives, broad-spectrum anti-infective agents, and anticancer drugs (reviewed in references [18][19][20]. However, none of the compounds investigated has been translated into clinical application, either due to low efficacy, high toxicity, or simply because the pharmaceutical industry has not been prepared to invest in a disease without a meaningful market return (21).…”

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

confidence: 99%

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In VitroandIn VivoActivities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

Küster

Kriegel

Boykin

et al. 2013

Antimicrob Agents Chemother

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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.

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“…All but one of the drugs tested, imatinib, have been proposed to have anticestode activity in other in vitro or in vivo assays (13,(19)(20)(21). Nitazoxanide and artesunate showed effects on the release of both enzymes, which reinforces the utility of these assays for drug screening.…”

Section: Discussionmentioning

confidence: 78%

Quantitative Screening for Anticestode Drugs Based on Changes in Baseline Enzyme Secretion by Taenia crassiceps

Mahanty

Madrid²,

Nash

2013

Antimicrob Agents Chemother

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Neurocysticercosis (NCC), an infection of the brain with the larval stage of the Taenia solium tapeworm, is responsible for an estimated one-third of adult-onset epilepsy cases in regions of the world where it is endemic. Currently, anthelmintic drugs used for treatment of NCC are only partially effective, and there is, therefore, a pressing need for new therapeutic agents. Discovery of new anthelmintics with activity against T. solium has been limited by the lack of suitable sensitive assays that allow highthroughput screening. Using an in vitro culture system with Taenia crassiceps metacestodes, we demonstrate that changes in secretion of parasite-associated alkaline phosphatase (AP) and phosphoglucose isomerase (PGI) can be used to detect and quantify anthelmintic effects of praziquantel (PZQ), a drug with activity against T. solium. We applied two enzyme release assays to screen for anti-T. crassiceps activity in nonconventional antiparasitic drugs and demonstrate that nitazoxanide and artesunate induced release of both AP and PGI in differing time-and dose-related patterns. Furthermore, imatinib, a tyrosine kinase inhibitor previously reported to have parasiticidal activity against Schistosoma mansoni, also induced release of both AP and PGI in a dose-dependent manner, similar in pattern to that observed with the other anthelmintics. We also evaluated release of ATP into cyst supernatants as an indicator of drug effects but did not see any differences between treated and untreated cysts. These data provide the basis for rapid and quantitative screening assays for testing for anthelmintic activity in candidate anticestode agents.

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

Cited by 36 publications

References 49 publications

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

In VitroandIn VivoActivities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

Quantitative Screening for Anticestode Drugs Based on Changes in Baseline Enzyme Secretion by Taenia crassiceps

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