Navegando por Autor "Mello, Carlos Geraldo Campos de"
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Item Efficacy of Lychnopholide polymeric nanocapsules after oral and intravenous administration in murine experimental Chagas disease.(2016) Mello, Carlos Geraldo Campos de; Branquinho, Renata Tupinambá; Oliveira, Maykon Tavares de; Milagre, Matheus Marques; Guimarães, Dênia Antunes Saúde; Mosqueira, Vanessa Carla Furtado; Lana, Marta deThe 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.Item Eficácia do tratamento com licnofolida livre e em nanocápsulas em camundongos experimentalmente infectados com cepas de Trypanosoma cruzi de perfis distintos de resistência aos fármacos usuais.(2015) Mello, Carlos Geraldo Campos de; Lana, Marta de; Branquinho, Renata TupinambáA doença de Chagas (DCh) permanece negligenciada. O único fármaco disponível no Brasil para seu tratamento é o benznidazol (BZ), que provoca efeitos colaterais graves e baixa eficácia terapêutica na fase crônica (FC) da infecção. Já foi demonstrado que a licnofolida (LIC), isolada de Lychnophora trichocarpha apresenta atividade anti-T. cruzi in vitro e eficácia terapêutica nas fases aguda (FA) e FC da infecção in vivo. Sendo a LIC uma substância lipofílica com ação citotóxica, uma formulação farmacêutica para carreá-la, como nanocápsulas poliméricas (NC) é viável por permitir liberação controlada de substâncias, seletividade tecidual e redução da toxicidade. Sendo assim, os objetivos deste trabalho foram (I) determinar a eficácia terapêutica da LIC livre e de formulações de NC contendo LIC na FA e FC da infecção em modelo murino infectado com cepas de T. cruzi de distintos perfis de resistência ao BZ e (II) avaliar o real benefício das NC na evolução da infecção e eliminação tecidual do T. cruzi. Para tal, camundongos Swiss foram infectados com as cepas Y (parcialmente resistente ao BZ) e VL-10 (resistente ao BZ) tratados por 20 dias por via oral durante as FA e FC. Tratamentos: (I) Cepa Y – FA/FC: LIC-livre 5,0 mg/kg/dia, BZ 100,0 mg/kg/dia e controles; (II) Cepa VL-10 – FA/FC: LIC-livre 12,0 mg/kg/dia, BZ 100,0 mg/kg/dia, NC-PLAPEG-LIC (8,0 e 12,0 mg/kg/dia – FA) e controles. A avaliação da eficácia terapêutica foi realizada por exame de sangue a fresco (ESF -FA), hemocultura (HC), PCR e ELISA. (i) FA – Cepa Y: Não foi observada cura em nenhum animal tratado com LIC-livre e controles, mas 62,5% dos tratados com BZ foram curados. As taxas de sobrevida foram de 75,0%, 100,0% e 0% dos animais tratados com LIC-livre, BZ e controles, respectivamente, cujo tempo médio de sobrevida foi de somente19 dias. FC – Cepa Y: Ao avaliar os resultados dos exames parasitológicos e ELISA não foi observada cura em nenhum animal dos grupos tratados com LIC-livre, BZ e controles. As taxas de sobrevida foram semelhantes em todos os grupos: 70,0% nos tratados com LIC-livre e controles e 80,0 nos tratados com BZ. (ii) FA – Cepa VL-10: Houve cura em 75,0% e 37,5% dos animais tratados com NC-PLAPEG-LIC 12mg e NC-PLAPEG-LIC 8mg, enquanto nenhum animal tratado com LIC-livre, BZ e dos grupos controles foi curado. FC – Cepa VL-10-: Não foi revelada cura em nenhum animal tratado com LIC-livre. A sobrevida dos animais tratados com LIC-livre, BZ e controles foi de: 70,0%, 80,0% e 60,0% respectivamente. LIC-livre foi capaz de reduzir a parasitemia em animais infectados com as cepas Y e VL-10, mas não curou a infecção. NC-LIC promoveu cura de 75% dos animais infectados com a cepa VL-10 tratados na FA, e apresentou efeito dose x resposta. Os resultados da qPCR foram concordantes em sua maioria (97%) com os resultados obtidos com o controle de cura clássico (negatividade da HC, PCR convencional em sangue e ELISA). Esta técnica demonstrou eficiência > 97,0%, redução do parasitismo tecidual nos animais tratados com LIC-livre e NC-PCL-LIC, e ausência do T. cruzi no tecido cardíaco em 100% dos animais tratados com NC-PLAPEG-LIC, independentemente da cepa e fase da infecção em que o tratamento foi administrado.Item Lychnopholide in PLA-PEG nanocapsules cures infection by drug resistant Trypanosoma cruzi strain in acute and chronic phases.(2020) Branquinho, Renata Tupinambá; Mello, Carlos Geraldo Campos de; Oliveira, Maykon Tavares de; Reis, Levi Eduardo Soares; Vieira, Paula Melo de Abreu; Guimarães, Dênia Antunes Saúde; Mosqueira, Vanessa Carla Furtado; Lana, Marta deChagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(d,l-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti-Trypanosoma cruzi efficacy in mice infected with a partially drug-resistant strain. This study reports the efficacy of LYC-PLA-PEG-NC at higher doses in mice infected with a T. cruzi strain resistant to benznidazole (BZ) and nifurtimox (NF) treated at both the acute phase (AP) and the chronic phase (CP) of infection by the oral route. Mice infected with the T. cruzi VL-10 strain were treated by the oral route with free LYC (12 mg/kg of body weight/day), LYC-PLA-PEG-NC (8 or 12 mg/kg/day), or BZ at 100 mg/kg/day or were not treated (controls). Treatment efficacy was assessed by hemoculture (HC), PCR, enzyme-linked immunosorbent assay (ELISA), heart tissue quantitative PCR (qPCR), and histopathology. According to classical cure criteria, treatment with LYC-PLA-PEG-NC at 12 mg/kg/day cured 75% (AP) and 88% (CP) of the animals, while at a dose of 8 mg/kg/day, 43% (AP) and 43% (CP) were cured, showing dose-dependent efficacy. The negative qPCR results for heart tissue and the absence of inflammation/fibrosis agreed with the negative results obtained by HC and PCR. Thus, the mice treated with the highest dose could be considered 100% cured, in spite of a low ELISA reactivity in some animals. No cure was observed in animals treated with free LYC or BZ or the controls. These results are exceptional in terms of experimental Chagas disease chemotherapy and provide evidence of the outstanding contribution of nanotechnology in mice infected with a T. cruzi strain totally resistant to BZ and NF at both phases of infection. Therefore, LYC-PLA-PEG-NC has great potential as a new treatment for Chagas disease and deserves further investigations in clinical trials.Item Lychnopholide in Poly(D,L-Lactide)-block-polyethylene glycol nanocapsules cures infection with a drug-resistant Trypanosoma cruzi strain at acute and chronic phases.(2020) Branquinho, Renata Tupinambá; Mello, Carlos Geraldo Campos de; Oliveira, Maykon Tavares de; Reis, Levi Eduardo Soares; Vieira, Paula Melo de Abreu; Guimarães, Dênia Antunes Saúde; Mosqueira, Vanessa Carla Furtado; Lana, Marta deChagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti-Trypanosoma cruzi efficacy in mice infected with a partially drugresistant strain. This study reports the efficacy of LYC-PLA-PEG-NC at higher doses in mice infected with a T. cruzi strain resistant to benznidazole (BZ) and nifurtimox (NF) treated at both the acute phase (AP) and the chronic phase (CP) of infection by the oral route. Mice infected with the T. cruzi VL-10 strain were treated by the oral route with free LYC (12 mg/kg of body weight/day), LYC-PLA-PEG-NC (8 or 12 mg/kg/day), or BZ at 100 mg/kg/day or were not treated (controls). Treatment efficacy was assessed by hemoculture (HC), PCR, enzyme-linked immunosorbent assay (ELISA), heart tissue quantitative PCR (qPCR), and histopathology. According to classical cure criteria, treatment with LYC-PLA-PEG-NC at 12 mg/kg/day cured 75% (AP) and 88% (CP) of the animals, while at a dose of 8 mg/kg/day, 43% (AP) and 43% (CP) were cured, showing dose-dependent efficacy. The negative qPCR results for heart tissue and the absence of inflammation/fibrosis agreed with the negative results obtained by HC and PCR. Thus, the mice treated with the highest dose could be considered 100% cured, in spite of a low ELISA reactivity in some animals. No cure was observed in animals treated with free LYC or BZ or the controls. These results are exceptional in terms of experimental Chagas disease chemotherapy and provide evidence of the outstanding contribution of nanotechnology in mice infected with a T. cruzi strain totally resistant to BZ and NF at both phases of infection. Therefore, LYC-PLA-PEG-NC has great potential as a new treatment for Chagas disease and deserves further investigations in clinical trials.Item TcI, TcII and TcVI Trypanosoma cruzi samples from Chagas diseasepatients with distinct clinical forms and critical analysis of in vitro andin vivo behavior, response to treatment and infection evolution inmurine model.(2017) Oliveira, Maykon Tavares de; Branquinho, Renata Tupinambá; Alessio, Glaucia Diniz; Mello, Carlos Geraldo Campos de; Paiva, Nívia Carolina Nogueira de; Carneiro, Cláudia Martins; Toledo, Max Jean de Ornelas; Reis, Alexandre Barbosa; Martins Filho, Olindo Assis; Lana, Marta detThe clonal evolution of Trypanosoma cruzi sustains scientifically the hypothesis of association betweenparasite’s genetic, biological behavior and possibly the clinical aspects of Chagas disease in patientsfrom whom they were isolated. This study intended to characterize a range of biological properties ofTcI, TcII and TcVI T. cruzi samples in order to verify the existence of these associations. Several biologicalfeatures were evaluated, including in vitro epimastigote-growth, “Vero”cells infectivity and growth, alongwith in vivo studies of parasitemia, polymorphism of trypomastigotes, cardiac inflammation, fibrosis andresponse to treatment by nifurtimox during the acute and chronic murine infection. The global resultsshowed that the in vitro essays (acellular and cellular cultures) TcII parasites showed higher values for allparameters (growth and infectivity) than TcVI, followed by TcI. In vivo TcII parasites were more virulentand originated from patients with severe disease. Two TcII isolates from patients with severe pathologywere virulent in mice, while the isolate from a patient with the indeterminate form of the disease causedmild infection. The only TcVI sample, which displayed low values in all parameters evaluated, was alsooriginated of an indeterminate case of Chagas disease. Response to nifurtimox was not associated toparasite genetic and biology, as well as to clinical aspects of human disease. Although few number of T.cruzi samples have been analyzed, a discreet correlation between parasite genetics, biological behaviorin vitro and in vivo (murine model) and the clinical form of human disease from whom the samples wereisolated was verified.