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1.
PLoS One ; 10(6): e0128707, 2015.
Article in English | MEDLINE | ID: mdl-26076455

ABSTRACT

The nitroheterocyclic drugs nifurtimox and benznidazole are first-line drugs available to treat Chagas disease; however, they have limitations, including long treatment courses and toxicity. Strategies to overcome these limitations include the identification of new drugs with specific target profiles, re-dosing regimens for the current drugs, drug repositioning and combination therapy. In this work, we evaluated combination therapy as an approach for optimization of the current therapeutic regimen for Chagas disease. The curative action of benznidazole/itraconazole combinations was explored in an established infection of the mice model with the T. cruzi Y strain. The activities of the benznidazole/itraconazole combinations were compared with the results from those receiving the same dosage of each individual drug. The administration of benznidazole/itraconazole in combination eliminated parasites from the blood more efficiently than each drug alone. Here, there was a significant reduction of the number of treatment days (number of doses) necessary to induce parasitemia suppression with the benznidazole/itraconazole combination, as compared to each compound administered alone. These results clearly indicate the enhanced effects of these drugs in combination, particularly at the dose of 75 mg/kg, as the effects observed with the drug combinations were four times more effective than those of each drug used alone. Moreover, benznidazole/itraconazole treatment was shown to prevent or decrease the typical lesions associated with chronic experimental Chagas disease, as illustrated by similar levels of inflammatory cells and fibrosis in the cardiac muscle tissue of healthy and treated mice. These results emphasize the importance of exploring the potential of combination treatments with currently available compounds to specifically treat Chagas disease.


Subject(s)
Chagas Disease/parasitology , Itraconazole/pharmacology , Nitroimidazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Antibodies, Protozoan/immunology , Chagas Disease/drug therapy , Chagas Disease/immunology , Chagas Disease/pathology , Disease Models, Animal , Drug Therapy, Combination , Female , Immunoglobulin G/immunology , Itraconazole/administration & dosage , Mice , Myocardium/pathology , Nitroimidazoles/administration & dosage , Parasite Load , Trypanocidal Agents/administration & dosage , Trypanosoma cruzi/immunology
2.
Trop Med Int Health ; 18(1): 75-84, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23107306

ABSTRACT

OBJECTIVES: The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. METHODS: Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. RESULTS: All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen/74931 µm(2) in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen/74931 µm(2) in infected by AAS and 6294.40 ± 896.04 collagen/74931 µm(2) in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen/74931 µm(2) ) and Bz-resistant AAS strains (4024 ± 1272.44 collagen/74931 µm(2) ), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen/74931 µm(2) ) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. CONCLUSIONS: These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated.


Subject(s)
Chagas Disease/drug therapy , Cicatrix/prevention & control , Collagen/metabolism , Heart Atria/drug effects , Myocardium/pathology , Nitroimidazoles/therapeutic use , Trypanosoma cruzi , Animals , Atrioventricular Block , Chagas Disease/pathology , Chagas Disease/physiopathology , Chagas Disease/veterinary , Chronic Disease , Dogs , Drug Resistance/drug effects , Electrocardiography , Fibrosis/prevention & control , Heart Atria/physiopathology , Nitroimidazoles/pharmacology , Prospective Studies , Treatment Outcome , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use
3.
Am J Trop Med Hyg ; 84(2): 325-31, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21292909

ABSTRACT

Chagas cardiomyopathy remodeling is based on the presence of Trypanosoma cruzi in heart tissue and on the complex inflammatory response leading to a myocardium fibrosis and alterations in conductive and functional heart parameters. This study aims to evaluate Simvastatin on the inflammatory response and heart functionality using dogs infected with Y strain of T. cruzi. Animals were treated daily with Simvastatin (20 mg) for 6 months and submitted to clinical and immunopathological evaluations. Simvastatin reduced heart expression and serum levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) but not interleukin-10 (IL-10), possibly favoring blood parasitism but reducing inflammation and fibrosis in the left ventricle and right atrium. Simvastatin also ameliorated ejection fraction, diastolic diameter, and mass index of the left ventricle 6 months after infection. This study suggests that more investigation should be performed on the use of statins as a prophylactic therapy against cardiac remodeling because of their effects on modifying immune response and benefiting functional parameters in dogs with T. cruzi-induced ventricular dysfunctions.


Subject(s)
Chagas Cardiomyopathy/veterinary , Dog Diseases/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Simvastatin/therapeutic use , Animals , Chagas Cardiomyopathy/drug therapy , Dog Diseases/parasitology , Dogs , Female , Heart/drug effects , Heart/parasitology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Interferon-gamma/blood , Interleukin-10/blood , Male , Myocardium/metabolism , Polymerase Chain Reaction/veterinary , Simvastatin/administration & dosage , Stroke Volume/drug effects , Trypanosoma cruzi , Tumor Necrosis Factor-alpha/blood
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