Synergistic effects of in vitro combinations of piplartine, epiisopiloturine and praziquantel against Schistosoma mansoni

Campelo, Yuri Dias Mâcedo; Mafud, Ana Carolina; Véras, Leiz Maria Costa; Guimarães, Maria Adelaide; Yamaguchi, Lydia F.; Lima, David Fernandes; Arcanjo, Daniel Dias Rufino; Kato, Massuo Jorge; Mendonça, Ronaldo Zucatelli; Pintó, Pedro; Mascarenhas, Yvonne P.; Silva, Marcos P.N.; Moraes, Josué de; Eaton, Peter; Leite, José de Souza de Almeida Roberto

doi:10.1016/j.biopha.2016.12.057

Cited by 24 publications

(11 citation statements)

References 55 publications

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“…All data from the in vitro antischistosomal assay are presented as means ± SD of at least three independent experiments. IC 50 values were calculated using sigmoid dose-response curves [32,33]. For in vivo experimental analysis, a parametric Dunnett's multiple-comparison test was applied to compare the vehicle group versus the treated group.…”

Section: Methodsmentioning

confidence: 99%

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

et al. 2019

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Background: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for povertyassociated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties. Methods: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato-and splenomegaly. Findings: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato-and splenomegaly. Interpretation: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent antischistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

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Section: Methodsmentioning

confidence: 99%

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

et al. 2019

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“…Therefore, additional concentrations of selected drugs were tested (25, 12.5, 6.25, and 3.12 M). The halfmaximum lethal concentrations (i.e., the LC 50 s) for active compounds were calculated with GraphPad Prism software using sigmoid dose-response curves and the 95% confidence intervals as previously described (33,34). Each concentration was tested in triplicate, and experiments were performed at least three times.…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Guerra

Silva

et al. 2019

Antimicrob Agents Chemother

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Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

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“…EPI was identified in the 1970s [ 18 ] and its subsequent isolation and chemical characterization revealed strong pharmacological potency against S . mansoni [ 17 , 19 , 20 – 21 ]. Other biological functions have been described, including anti-inflammatory, anti-contraceptive [ 22 ], and gastro-protective effects [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Computational quantum chemistry, molecular docking, and ADMET predictions of imidazole alkaloids of Pilocarpus microphyllus with schistosomicidal properties

et al. 2018

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Schistosomiasis affects million people and its control is widely dependent on a single drug, praziquantel. Computational chemistry has led to the development of new tools that predict molecular properties related to pharmacological potential. We conducted a theoretical study of the imizadole alkaloids of Pilocarpus microphyllus (Rutaceae) with schistosomicidal properties. The molecules of epiisopiloturine, epiisopilosine, isopilosine, pilosine, and macaubine were evaluated using theory models (B3lyp/SDD, B3lyp/6-31+G(d,p), B3lyp/6-311++G(d,p)). Absorption, distribution, metabolization, excretion, and toxicity (ADMET) predictions were used to determine the pharmacokinetic and pharmacodynamic properties of the alkaloids. After optimization, the molecules were submitted to molecular docking calculations with the purine nucleoside phosphorylase, thioredoxin glutathione reductase, methylthioadenosine phosphorylase, arginase, uridine phosphorylase, Cathepsin B1 and histone deacetylase 8 enzymes, which are possible targets of Schistosoma mansoni. The results showed that B3lyp/6-311++G(d,p) was the optimal model to describe the properties studied. Thermodynamic analysis showed that epiisopiloturine and epiisopilosine were the most stable isomers; however, the epiisopilosine ligand achieved a superior interaction with the enzymes studied in the molecular docking experiments, which corroborated the results of previous experimental studies on schistosomiasis.

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Synergistic effects of in vitro combinations of piplartine, epiisopiloturine and praziquantel against Schistosoma mansoni

Cited by 24 publications

References 55 publications

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Computational quantum chemistry, molecular docking, and ADMET predictions of imidazole alkaloids of Pilocarpus microphyllus with schistosomicidal properties

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