Sesquiterpene Lactone in Nanostructured Parenteral Dosage Form Is Efficacious in Experimental Chagas Disease

Branquinho, Renata Tupinambá; Mosqueira, Vanessa Carla Furtado; Oliveira-Silva, Jaquelline Carla Valamiel de; Simões-Silva, Marianne Rocha; Saúde-Guimarães, Dênia Antunes; Lana, Marta de

doi:10.1128/aac.00617-13

Cited by 53 publications

(61 citation statements)

References 45 publications

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“…When LYC was administered intravenously as a solution (free LYC), parasitemia was reduced and the survival rate was increased compared to those of the untreated group at the acute phase of infection for mice, although no cure was observed (18). In con-trast, when LYC was encapsulated in polymeric nanocapsules [LYC-poly-ε-caprolactone nanocapsules (LYC-PCL-NC) and LYC-poly(D,L-lactide)-polyethylene glycol nanocapsules (LYC-PLA-PEG-NC)], a more pronounced parasitemia reduction and an increase of the survival rate were observed, as well as high percentages of cure in a murine model of infection with distinct T. cruzi strains (18).…”

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confidence: 99%

“…In con-trast, when LYC was encapsulated in polymeric nanocapsules [LYC-poly-ε-caprolactone nanocapsules (LYC-PCL-NC) and LYC-poly(D,L-lactide)-polyethylene glycol nanocapsules (LYC-PLA-PEG-NC)], a more pronounced parasitemia reduction and an increase of the survival rate were observed, as well as high percentages of cure in a murine model of infection with distinct T. cruzi strains (18). As previously reported, the LYC association with NC increased the substance efficacy and influenced LYC release in vitro (14).…”

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confidence: 99%

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Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Mello

Branquinho

Oliveira

et al. 2016

Antimicrob Agents Chemother

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The etiological treatment of Chagas disease remains neglected. The compounds available show several limitations, mainly during the chronic phase. Lychnopholide encapsulated in polymeric nanocapsules (LYC-NC) was efficacious in mice infected with Trypanosoma cruzi and treated by intravenous administration during the acute phase (AP). As the oral route is preferred for treatment of chronic infections, such as Chagas disease, this study evaluated the use of oral LYC-NC in the AP and also compared it with LYC-NC administered to mice by the oral and intravenous routes during the chronic phase (CP). The therapeutic efficacy was evaluated by fresh blood examination, hemoculture, PCR, and enzyme-linked immunosorbent assay (ELISA). The cure rates in the AP and CP were 62.5% and 55.6%, respectively, upon oral administration of LYC-poly(D,L-lactide)-polyethylene glycol nanocapsules (LYC-PLA-PEG-NC) and 57.0% and 30.0%, respectively, with LYC-poly--caprolactone nanocapsules (LYC-PCL-NC). These cure rates were significantly higher than that of free LYC, which did not cure any animals. LYC-NC formulations administered orally during the AP showed cure rates similar to that of benznidazole, but only LYC-NC cured mice in the CP. Similar results were achieved with intravenous treatment during the CP. The higher cure rates obtained with LYC loaded in PLA-PEG-NC may be due to the smaller particle size of these NC and the presence of PEG, which influence tissue diffusion and the controlled release of LYC. Furthermore, PLA-PEG-NC may improve the stability of the drug in the gastrointestinal tract. This work is the first report of cure of experimental Chagas disease via oral administration during the CP. These findings represent a new and important perspective for oral treatment of Chagas disease.

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confidence: 99%

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Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Mello

Branquinho

Oliveira

et al. 2016

Antimicrob Agents Chemother

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“…Here, we show that repeated-dose administration of free LYC can potentially promote severe cardiotoxicity in mice, as evidenced by alterations of both global heart function and intracellular Ca 2+ handling, with a critical effect on the RyR2 channel. However, a central finding of our study is that LYC encapsulated in biodegradable NC was safer with no adverse cardiac effects, indicating that this pharmaceutical formulation of LYC not only hold promise for curing CD 12,22 but also in terms of cardiac safety. Free LYC administered to C57BL/6 mice for 20 days (2.0 mg/kg/day) induced high mortality (50%), starting after 10 days of treatment, and severely altered cardiac function in the surviving animals.…”

Section: Discussionmentioning

confidence: 81%

“…Recently, we have documented the antitrypanosomal efficacy in vivo of a natural substance, lychnopholide (LYC), isolated from Lychnophora trichocarpha Spreng, a plant from Asteraceae family. In particular, a pharmaceutical formulation of LYC encapsulated in biodegradable polymeric nanocapsules (NC) and administered by intravenous route was more effective than benznidazole in curing Swiss mice infected experimentally with different T. cruzi strains 11,12 . The LYC associated to NC improved drastically the free LYC efficacy after intravenous administration.…”

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Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Farah¹,

Branquinho²,

Roy³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca 2+ handling, with spontaneous Ca 2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca 2+ handling alterations with abnormal RyR2-mediated diastolic Ca 2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. Chagas disease (CD) is an important neglected disease caused by an intracellular hemoflagellate protozoan parasite, Trypanosoma cruzi (T. cruzi).There are an estimated 6-7 million infected people worldwide, and the disease causes 12 500 deaths per year, mostly in Latin America (World Health Organization, Switzerland 2015). While CD is principally transmitted to humans by triatomine insects, other routes include blood transfusion or transplantation of contaminated organs, ingestion of contaminated food and congenital transmission from infected mothers to newborns. International migrations contribute to spread the disease in non-endemic areas such as North America, Europe and Western Pacific countries (World Health Organization, Switzerland 2015). CD evolves in different consecutive phases with a short acute period, characterized by patent parasitemia, followed by a chronic phase in which most infected individuals remain asymptomatic (indeterminate form). CD is also a common determinant of non-ischemic cardiomyopathy in addition to digestive complications and neurological disorders. Approximately 30% of patients infected with T. cruzi manifest cardiomyopathy characterized by severe myocarditis and multiple arrhythmias, and/or dilatation and physiological dysfunctions of hollow organs, mainly of the digestive tract, which develop progressively over the years or decades after infection [1][2][3][4] . The clinical course of CD shows great variability, and the mechanisms or determinants responsible for t...

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“…In addition, our group recently reported that nanostructured formulation is a strategy that can make a marked difference in vivo with improved efficacy and reduced toxicity of active compounds, including in the treatment of experimental Chagas disease by the oral route. [23][24][25] In this work, a RAV-SEDDS formulation for oral administration was developed and characterized. The safety of the formulation was evaluated in vivo in a 20-day treatment protocol in healthy mice and in T. cruzi-infected mice.…”

Section: Introductionmentioning

confidence: 99%

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

Spósito

Mazzeti

Faria

et al. 2017

IJN

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Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters <250 nm, zeta potential values in the range of −45 mV to −57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37°C showed a polydisperse profile for all blank and ravuconazole–SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol ® surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose-dependent Labrasol toxicity in healthy mice. Ravuconazole–SEDDS at low surfactant content (10%, v/v) in Trypanosoma cruzi -infected mice was safe during the 20-day treatment. The anti- T. cruzi activity of free ravuconazole, ravuconazole–SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC 50 and IC 90 ), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti- T. cruzi activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human T. cruzi infections.

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Sesquiterpene Lactone in Nanostructured Parenteral Dosage Form Is Efficacious in Experimental Chagas Disease

Cited by 53 publications

References 45 publications

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

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