Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices

Leite, Elaine Amaral; Grabe‐Guimarães, Andrea; Guimarães, Homero Nogueira; Machado-Coelho, George Luiz Lins; Barratt, Gillian; Mosqueira, Vanessa Carla Furtado

doi:10.1016/j.lfs.2006.12.019

Cited by 68 publications

(48 citation statements)

References 29 publications

(48 reference statements)

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“…Minimal cardiac effects are then expected at these low released doses of LYC from NC inside blood. The reduction of cardiotoxicity may also reflect the ability of nanocarriers to modify the distribution of the entrapped drug in the body, as shown for halofantrine 52 , with a lower fraction of free drug available for interaction with cardiac tissue, in line with the lack of an effect of LYC in solution at subnanomolar concentrations on cardiomyocytes as shown here (Figs 4 and 5; 0.14 nM vs. 1.4 nM and 14 nM). This may be particularly interesting for repeated-dose oral treatment during chronic infection.…”

Section: Discussionsupporting

confidence: 65%

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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Section: Discussionsupporting

confidence: 65%

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Farah¹,

Branquinho²,

Roy³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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“…The NC formulations (LYC-PLA-PEG-NC and LYC-PCL-NC) presented a bluish milky aspect characteristic of colloidal suspensions. The experimental average particle diameters of the formulations, ranging from 106 to 190 nm, and a low polydispersity index (40) warrant safety by intravenous administration and a low risk of embolic events. LYC-PLA-PEG-NC showed reduced sizes compared to those of LYC-PCL-NC (18).…”

Section: Discussionmentioning

confidence: 99%

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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“…Polymeric NC are formed by an oil droplet surrounded by a polymeric membrane stabilized by surfactants (21) and have been used successfully for the following purposes: to increase the dispersibility of poorly water-soluble drugs, to protect drugs against inactivation (22), to reduce drug toxicity (23), to control drug release (13), and to prolong blood circulation time after intravenous (i.v.) administration (24).…”

mentioning

confidence: 99%

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

Branquinho

Mosqueira

Oliveira-Silva

et al. 2014

Antimicrob Agents Chemother

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dThe drugs available for Chagas disease treatment are toxic and ineffective. We studied the in vivo activity of a new drug, lychnopholide (LYC). LYC was loaded in nanocapsules (NC), and its effects were compared to free LYC and benznidazole against Trypanosoma cruzi. Infected mice were treated in the acute phase at 2.0 mg/kg/day with free LYC, LYC-poly--caprolactone NC (LYC-PCL), and LYC-poly(lactic acid)-co-polyethylene glycol NC (LYC-PLA-PEG) or at 50 mg/kg/day with benznidazole solution by the intravenous route. Animals infected with the CL strain, treated 24 h after infection for 10 days, evaluated by hemoculture, PCR, and enzyme-linked immunosorbent assay exhibited a 50% parasitological cure when treated with LYC-PCL NC and 100% cure when treated with benznidazole, but 100% of the animals treated during the prepatent period for 20 days with these formulations or LYC-PLA-PEG NC were cured. In animals with the Y strain treated 24 h after infection for 10 days, only mice treated by LYC-PCL NC were cured, but animals treated in the prepatent period for 20 days exhibited 100, 75, and 62.5% cure when treated with LYC-PLA-PEG NC, benznidazole, and LYC-PCL NC, respectively. Free LYC reduced the parasitemia and improved mice survival, but no mice were cured. LYC-loaded NC showed higher cure rates, reduced parasitemia, and increased survival when used in doses 2five times lower than those used for benznidazole. This study confirms that LYC is a potential new treatment for Chagas disease. Furthermore, the long-circulating property of PLA-PEG NC and its ability to improve LYC efficacy showed that this formulation is more effective in reaching the parasite in vivo.

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Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices

Cited by 68 publications

References 29 publications

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

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

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

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