EFAR - Escola de Farmácia

URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/451

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O curso de Farmácia em Ouro Preto foi criado em 1839, sendo a mais antiga Escola de Farmácia da América Latina.

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Agora exibindo 1 - 10 de 78

Benznidazole, itraconazole and their combination in the treatment of acute experimental chagas disease in dogs.
(2019) Cunha, Eleonora Lima Alves; Torchelsen, Fernanda Karoline Vieira da Silva; Cunha, Lucas Maciel; Oliveira, Maykon Tavares de; Fonseca, Kátia da Silva; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins; Lana, Marta de
Chagas disease (CD) is a serious public health problem in Latin America and its treatment remains neglected. Benznidazole (BZ), the only drug available in Brazil, presents serious side effects and low therapeutic efficacy, especially at the chronic phase. The last clinical trials demonstrated that the first generation of azole compounds were less successful than BZ in CD chemotherapy, which stimulated studies of these compounds associated to BZ and nifurtimox (NF). This study evaluated the therapeutic efficacy of BZ, itraconazole (ITZ) and their combination (BZ + ITZ) in dogs infected with the VL-10 T. cruzi strain in the acute phase of the disease. Twenty young mongrel dogs were inoculated with 2.0 × 103 blood trypomastigotes/kg and divided into four groups: treated with BZ, ITZ and BZ + ITZ for 60 days, and control group (INT). The parasitemia of the BZ + ITZ and BZ groups were similar and showed significant reduction compared to the INT group. The group treated with ITZ also showed significant parasitemia reduction compared to the INT group. The global analysis of hemoculture (HC), blood PCR, conventional serology (CS-ELISA), heart qPCR and histopathology techniques, used in the post-treatment evaluation, revealed that BZ + ITZ combination lead to a more reduction of parasitemia during the acute phase and heart qPCR positivity, less cardiac damage (inflammation and fibrosis in the left ventricle) and total survival. According to the classical cure criteria one animal treated with BZ + ITZ can be considered cured in its final evaluation and two other dogs, one of this group and one treated with ITZ were in process of cure. At least for BZ-resistant T. cruzi strains such as VL-10, BZ + ITZ was not effective to induce parasitological cure or a profound and sustained reduction of the parasite burden in blood and infected organs.
Increased body exposure to new anti-trypanosomal through nanoencapsulation.
(2017) Branquinho, Renata Tupinambá; Lana, Gwenaelle Elza Nathalie Pound; Milagre, Matheus Marques; Guimarães, Dênia Antunes Saúde; Vilela, José Mário Carneiro; Andrade, Margareth Spangler; Lana, Marta de; Mosqueira, Vanessa Carla Furtado
Lychnopholide, a lipophilic sesquiterpene lactone, is efficacious in mice at the acute and chronic phases of Chagas disease. Conventional poly-ε-caprolactone (PCL) and long-circulating poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules containing lychnopholide were developed and characterized. Lychnopholide presented high association efficiency (>90%) with the nanocapsules. A new, fast and simple HPLC-UV-based bioanalytical method was developed, validated in mouse plasma and applied to lychnopholide quantification in in vitro release kinetics and pharmacokinetics. The nanocapsules had mean hydrodynamic diameters in the range of 100–250 nm, negative zeta potentials (−30 mV to −57 mV), with good physical stability under storage. Atomic force microscopy morphological analysis revealed spherical monodispersed particles and the absence of lychnopholide crystallization or aggregation. Association of lychnopholide to PLA-PEG nanocapsules resulted in a 16-fold increase in body exposure, a 26-fold increase in plasma half-life and a dramatic reduction of the lychnopholide plasma clearance (17-fold) in comparison with free lychnopholide. The improved pharmacokinetic profile of lychnopholide in long-circulating nanocapsules is in agreement with the previously reported improved efficacy observed in Trypanosoma cruzi-infected mice. The present lychnopholide intravenous dosage form showed great potential for further pre-clinical and clinical studies in Chagas disease and cancer therapies.
Differential expression of proteins in genetically distinct Trypanosoma cruzi samples (TcI and TcII DTUs) isolated from chronic Chagas disease cardiac patients.
(2018) Oliveira, Maykon Tavares de; Rúbio, Karina Taciana Santos; Neves, Leandro Xavier; Toledo, Max Jean de Ornelas; Borges, William de Castro; Lana, Marta de
Background Trypanosoma cruzi, a hemoflagellate protozoan parasite and the etiological agent of Chagas disease (CD), exhibits great genetic and biological diversity. Infected individuals may present clinical manifestations with different levels of severity. Several hypotheses have been proposed to attempt to correlate the diversity of clinical signs and symptoms to the genetic variability of T. cruzi. This work aimed to investigate the differential expression of proteins from two distinct genetic groups of T. cruzi (discrete typing units TcI and TcII), isolated from chronically infected individuals displaying the cardiac form of CD. For this purpose, epimastigote forms of the two isolates were cultured in vitro and the cells recovered for protein extraction. Comparative two-dimensional (2D) gel electrophoreses were performed and differentially expressed spots selected for identification by mass spectrometry, followed by database searching and protein categorization. Results The 2D electrophoretic profiles revealed the complex composition of the T. cruzi extracted proteome. Protein spots were distributed along the entire pH and molecular mass ranges attesting for the integrity of the protein preparations. In total, 46 differentially expressed proteins were identified present in 40 distinct spots found in the comparative gel analyses. Of these, 16 displayed upregulation in the gel from TcI-typed parasites and 24 appeared overexpressed in the gel from TcII-typed parasites. Functional characterization of differentially expressed proteins revealed major alterations associated with stress response, lipid and amino acid metabolism in parasites of the TcII isolate, whilst those proteins upregulated in the TcI sample were primarily linked to central metabolic pathways. Conclusions The comparative 2D-gel electrophoresis allowed detection of major differences in protein expression between two T. cruzi isolates, belonging to the TcI and TcII genotypes. Our findings suggest that patients displaying the cardiac form of the disease harbor parasites capable of exhibiting distinct proteomic profiles. This should be of relevance to disease prognosis and treatment.
Synthesis, in vitro and in vivo anti-Trypanosoma cruzi and toxicological activities of nitroaromatic Schiff bases.
(2018) Almeida, Tamires Cunha; Ribeiro, Luis Henrique Gonzaga; Santos, Luiza Braga Ferreira dos; Silva, Cleiton Moreira da; Branquinho, Renata Tupinambá; Lana, Marta de; Gadelha, Fernanda Ramos; Fátima, Angelo de
Chagas disease is a major health problem not only in Latin America but also in Europe and North America due to the spread of this disease into nonendemic areas. In terms of global burden, this major tropical infection is considered to be one of the most neglected diseases, and there are currently only two available chemotherapies: benznidazole and nifurtimox. Unfortunately, although these chemotherapies are beneficial in the acute phase of the disease, benznidazole and nifurtimox lead to significant side effects, including hepatitis and neurotoxicity. Therefore, the search for and development of more effective, safe and inexpensive anti-Trypanosoma cruzi drugs are required. In this work, a series of 10 nitroaromatic Schiff bases bearing different (nitro) aromatic rings-was synthesized. Subsequently, the in vitro and in vivo anti-T. cruzi activities of the Schiff bases were investigated, as well as the in vivo toxicity and the biological effects. The basic structure of the most promising in vivo Schiff base, 10 would be useful in the synthesis of new compounds for Chagas disease treatment.
Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection : a systematic review and meta-analysis of individual participant data.
(2018) Sguassero, Yanina; Roberts, Karen N.; Harvey, Guillermina B.; Comandé, Daniel; Cuesta, Cristina B.; Aguiar, Camila; Castro, Ana M. de; Danesi, Emmaría; Andrade, Ana L. de; Lana, Marta de; Escribà, Josep M.; Fabbro, Diana L.; Fernandes, Cloé Duarte; Flores Chávez, María; Hasslocher Moreno, Alejandro Marcel; Jackson, Yves Laurent; Assis, Girley Francisco Machado de; Maldonado, Marisel; Meira, Wendell Sérgio Ferreira; Molina, Israel; Monje Rumi, María Mercedes; Muñoz San Martín, Catalina; Murcia, Laura; Castro, Cleudson Nery de; Negrette, Olga Sánchez; Segovia, Manuel; Silveira, Celeste Aída Nogueira; Solari, Aldo; Steindel, Mário; Streiger, Mirtha Leonor; Bilbao, Ninfa Vera de; Zulantay, Inés; Sosa Estani, Sergio
Objective To determine the course of serological tests in subjects with chronic Trypanosoma cruzi infection treated with anti-trypanosomal drugs. Methods A systematic review and meta-analysis was conducted using individual participant data. Survival analysis and the Cox proportional hazards regression model with random effects to adjust for covariates were applied. The protocol was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO; CRD42012002162). Results A total of 27 studies (1296 subjects) conducted in eight countries were included. The risk of bias was low for all domains in 17 studies (63.0%). Nine hundred and thirteen subjects were assessed (149 seroreversion events, 83.7% censored data) for enzyme-linked immunosorbent assay (ELISA), 670 subjects (134 events, 80.0% censored) for indirect immunofluorescence assay (IIF), and 548 subjects (99 events, 82.0% censored) for indirect hemagglutination assay (IHA). A higher probability of seroreversion was observed within a shorter time span in subjects aged 1–19 years compared to adults. The chance of seroreversion also varied according to the country where the infection might have been acquired. For instance, the pooled adjusted hazard ratio between children/adolescents and adults for the IIF test was 1.54 (95% confidence interval 0.64–3.71) for certain countries of South America (Argentina, Bolivia, Chile, and Paraguay) and 9.37 (95% confidence interval 3.44–25.50) for Brazil. Conclusions The disappearance of anti-T. cruzi antibodies was demonstrated along the course of follow-up. An interaction between age at treatment and country setting was found.
Evaluation of parasite and host genetics in two generations of a family with Chagas disease.
(2018) Lima, Ana Paula Braga; Oliveira, Maykon Tavares de; Silva, Rafael Rodrigues; Torres, Rosália Morais; Veloso, Vanja Maria; Lana, Marta de; Silva, Glenda Nicioli da
Chagas disease, caused by the protozoan Trypanosoma cruzi, is considered to be a multifactorial disease associated with host and parasite genetics, which influence clinical aspects of the disease and other host conditions. In order to understand better the evolution of the disease, this study intended to evaluation of parasite and host genetics in two generations of a family with Chagas disease from the Alto Paranaiba region, Minas Gerais, Brazil, comprising a mother and her five daughters. Several features were evaluated, including the characterization of T. cruzi directly from the blood of patients, host polymorphisms of genes related to cardiomyopathy (TNF, WISP1, CCR5, and TGF-β1) and clinical aspects of the patients. To verify the intraspecific variability of the parasite, the characterization was done directly from human blood using the PCR-LSSP technique and analyzed based on Dice coefficient and unweighted pair group analysis (UPGMA). The host polymorphism was evaluated by PCR-RFLP. The global results showed low variability of the parasites characterized from blood of patients, through Shannon index (0.492) and mean heterozygosity value per locus (0.322). All six patients presented the same genetic polymorphism profile for TNF, WISP1, and TGF-β1, and only one patient was homozygous to CCR5, which suggests that there is no association between the clinical aspects of the patients and their genetic profiles. In conclusion, the findings confirm that the understanding of the clinical evolution of Chagas disease goes beyond the genetic aspects of the parasite and the host.
Accomplishing the genotype-specific serodiagnosis of single and dual Trypanosoma cruzi infections by flow cytometry Chagas- Flow ATE-IgG2a.
(2018) Alessio, Glaucia Diniz; Araújo, Fernanda Fortes de; Sales Júnior, Policarpo Ademar; Gomes, Matheus de Souza; Amaral, Laurence Rodrigues do; Xavier, Marcelo Antônio Pascoal; Carvalho, Andréa Teixeira de; Lana, Marta de; Martins Filho, Olindo Assis
The methods currently available for genotype-specific diagnosis of T. cruzi infection still present relevant limitations, especially to identify mixed infection. In the present investigation, we have evaluated the performance of Chagas-Flow ATE-IgG2a test for early and late differential diagnosis of single and dual genotype-specific T. cruzi infections. Serum samples from Swiss mice at early and late stages of T. cruzi infection were assayed in parallel batches for genotype-specific diagnosis of single (TcI, TcVI or TcII) and dual (TcI+TcVI, TcVI+TcII or TcII+TcI) infections. The intrinsic reactivity to TcI, TcVI and TcII target antigens, including amastigote (AI/AVI/AII), trypomastigote-(TI/TVI/TII) and epimastigote (EI/ EVI/EII), at specific reverse of serum dilutions (500 to 64,000), was employed to provide reliable decision-trees for ªearlyº vs ªlateº, ªsingle vs ªdualº and ªgenotype-specificº serology. The results demonstrated that selective set of attributes ªEII 500/EI 2,000/AII 500º were able to provide high-quality accuracy (81%) to segregate early and late stages of T. cruzi infection. The sets ªTI 2,000/AI 1,000/EII 1,000º and ªTI 8,000/AII 32,000º presented expressive scores to discriminate single from dual T. cruzi infections at early (85%) and late stages (84%), respectively. Moreover, the attributes ªTI 4,000/TVI 500/TII 1,000º, ªTI 16,000/EI 2,000/EII 2,000/AI 500/TVI 500º showed good performance for genotype-specific diagnosis at early stage of single (72%) and dual (80%) T. cruzi infections, respectively. In addition, the attributes ªTI 4,000/AII 1,000/EVI 1,000º, ªTI 64,000/AVI 500/AI 2,000/AII 1,000/EII 4,000º showed moderate performance for genotype-specific diagnosis at late stage of single (69%) and dual (76%) T. cruzi infections, respectively. The sets of decision-trees were assembled to construct a sequential algorithm with expressive accuracy (81%) for serological diagnosis of T. cruzi infection. These findings engender new perspectives for the application of Chagas-Flow ATE-IgG2a method for genotype-specific diagnosis in humans, with relevant contributions for epidemiological surveys as well as clinical and post-therapeutic monitoring of Chagas disease.
Benznidazole treatment during early indeterminate Chagas' disease shifted the cytokine expression by innate and adaptive immunity cells toward a type-1 modulated immune profile.
(2006) Avelar, Renato Sathler; Avelar, Danielle Marchetti Vitelli; Massara, Rodrigo Lima; Lana, Marta de; Carvalho, Andréa Teixeira de; Dias, João Carlos Pinto; Santos, Silvana Maria Elói; Martins Filho, Olindo Assis
Trypanosoma cruzi-infected children was treated with benznidazole (Bz) duringthe early-indeterminate disease (E-IND) and the cytokine pattern of innate andadaptive immune compartments were evaluated prior to the treatment and1 year after it. At first, we observed that the ex vivo cytokine profile of circula-ting leukocytes from E-IND (n ¼ 6) resembled the one observed for healthyschoolchildren (n ¼ 7). Additionally, in vitro stimulation with T. cruzi anti-gens drove the E-IND cytokine pattern toward a mixed immune profile withhigher levels of IFN-c+, TNF-a+and IL-4+NK cells, increased numbers ofIFN-c+, TNF-a+and IL-10+CD4+T cells in addition to enhanced frequencyof TNF-a+/IL-4+CD19+lymphocytes. Interestingly, upon T. cruzi antigen invitro stimulation, E-IND CD8+lymphocytes displayed a selective enhancementof IFN-c expression, accounting for a global type 1-modulated cytokine micro-environment. A shift toward a type 1-modulated profile was also the hallmarkof Bz-treated children (E-INDT). In this context, despite the mixed overall exvivo cytokine profile observed for NK and CD8+T cells, incr eased ability ofthese leukocytes to produce IFN-c in respons e to T. cruzi antigens was repor-ted. Most noteworthy was the IL-10 production evidenced at T lymphocytes,mainly CD4+cells, as well as B lymphocytes, both ex vivo and upon antigenstimulation. Toget her, these findings gave evidence that NK cells and CD8+T lymphocytes are the major sources of IFN-c, a pivotal cytokine for successfultherapeutic response in human Chagas’ disease. Moreover, our data have alsobrought additional information, pointing out IL-10 production by CD4+cellsand B lymphocytes, as the putative key element for parasite clearance in theabsence of deleterious tissue damage.
Advances in Chagas disease chemotherapy.
(2006) Guedes, Paulo Marcos da Matta; Fietto, Juliana Lopes Rangel; Lana, Marta de; Bahia, Maria Terezinha
Chagas disease is endemic from Mexico to Argentina, where it is estimated that 16 to 18 million people are infected with its causative agent, Trypanosoma cruzi, and 100 million remain at risk of infection, emphasizing the necessity to sustain and extend control measures and strategies to combat this disease. Specific chemotherapy with benznidazole or nifurtimox has been recommended for treatment of recent and congenital infection. However, clinical trials with nifurtimox and benznidazole have shown that these compounds have very low activity in preventing the development of chronic Chagas disease. Moreover, the drugs induce a number of toxic side effects. The discovery of new active, non-toxic compounds would probably expand treatment, including those patients in which clinical manifestations are absent or can only be disclosed by more elaborate medical procedures. Recent developments in the study of basic biochemical aspects of T. cruzi have allowed for the identification of new targets for chemotherapy. Like many fungi, T. cruzi has a strict requirement for specific endogenous sterol synthesis for cell viability and growth and is extremely susceptible to sterol biosynthesis inhibitors (SBI). An intensive investigation of the potential trypanocidal effect of specific SBI has been performed, and it was demonstrated that some of these compounds exhibited suppressive and curative activity in murine and dog models of acute and chronic Chagas disease. Other potential targets for anti-T. cruzi chemotherapy that include the antiproliferative lysophospholipid analogs (evaluated in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine protease inhibitors and compounds that interfere with purine salvage and inositol metabolism are also discussed.
Preclinical monitoring of drug association in experimental chemotherapy of Chagas’ disease by a new HPLC-UV method.
(2012) Silva, Ricardo Moreira da; Oliveira, Líliam Teixeira; Barcellos, Neila Marcia Silva; Souza, Jacqueline de; Lana, Marta de
A combination of drugs in experimental chemotherapy of Chagas’ disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (Cmax) and an increase of 2.66-fold in the volume of distribution (V) and 7.5-fold in the elimination half-life (t1/2 ) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC0-t), area under the curve extrapolated to infinity (AUC0- ), time to maximum concentration of drug in serum (Tmax), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against Trypanosoma cruzi in vivo.

EFAR - Escola de Farmácia

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