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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Item 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 AssisTrypanosoma 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.Item Advances in Chagas disease chemotherapy.(2006) Guedes, Paulo Marcos da Matta; Fietto, Juliana Lopes Rangel; Lana, Marta de; Bahia, Maria TerezinhaChagas 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.Item Heart autonomic innervation during the acute phase of the experimental American trypanosomiasis in the dog.(1998) Machado, Conceição Ribeiro da Silva; Caliari, Marcelo Vidigal; Lana, Marta de; Tafuri, Washington LuizHeart autonomic innervation was studied in dogs during the acute phase of the experimental infection with the Berenice-78 strain of Trypanosoma cruzi. A glyoxylic acid–induced fluorescence method for catecholamines and a thiocholine method for demonstrating acetylcholinesterase activity showed the sympathetic and the parasympathetic nerve fibers, respectively. At day 34 of infection, moderate-to-intense rarefaction of both cholinergic and noradrenergic nerve fibers occurred in the atria of all animals coincident with moderate to intense myocarditis. In the ventricles, sympathetic denervation was clearly present only when the inflammatory processes were moderate to intense. Preliminary results on the chronic phase indicate that normal autonomic innervation coexists with an incipient chronic fibrosing myocarditis.Item Compared vectorial transmissibility of pure and mixed clonal genotypes of Trypanosoma cruzi in Triatoma infestans.(1998) Pinto, Artur da Silveira; Lana, Marta de; Bastrenta, Brigitte; Barnabé, Christian; Quesney, Virginie; Noel, Sébastien; Tibayrenc, MichelA total of 15 mixtures involving 9 di erent stocks attributed to the 19/20, 32 and 39 major clonal genotypes of Trypanosoma cruzi were used to infect third-instar nymphs of Triatoma infestans via an arti®- cial feeding device. Three biological parameters were considered: (1) the percentage of infected insects (%II), (2) the number of ¯agellates per insect (NFI), and (3) the percentage of trypomastigotes per insect (%DIF). Ge- netic characterization by both multilocus enzyme elec- trophoresis (MLEE) and random ampli®cation of polymorphic DNA (RAPD) indicated that in almost all cases (87%), mixtures remained present after completion of the whole cycle in the insect vector. Two lines of comparison were performed: (1) pure clonal genotypes versus corresponding mixed clonal genotypes and (2) the actual behavior of mixed clonal genotypes versus the expected behavior of the theoretical mixture (i.e. the arithmetic mean of the results observed for each of the two clonal genotypes taken separately). Statistical analyses of the variables were made di cult because of the presence of large standard deviations. Nevertheless, in several cases, mixtures di ered signi®cantly from pure clonal genotypes, and in one case the actual mixture di ered signi®cantly from the theoretical mixture. In some cases, interaction (either potentialization or re- ciprocal inhibition) could be suspected.Item Characterization of two isolates of Trypanosoma cruzi obtained from the patient Berenice, the first human case of Chagas disease.(1996) Lana, Marta de; Chiari, Cléa de Andrade; Chiari, Egler; Morel, Carlos Medicis; Gonçalves, Antônio M.; Romanha, Alvaro JoséTwo isolates of Trypanosoma cruzi were obtained from the patient Berenice, the first human case of Chagas’ disease (Chagas 1909), when she was 55 and 71 years old, respectively. The isolates were characterized on the basis of their epimastigote-trypomastigote differentiation in liquid media and of the electrophoretic pattern of EcoR1 digestion products of kinetoplast DNA (k- DNA) minicircles (schizodeme) and isoenzyme patterns (zymodeme). Clear differences were found between the isolates, suggesting the occurrence of a heterogeneous population of T. cruzi in the infection of this patient.Item Are increased frequency of macrophage-like and natural killer (NK) cells, together with high levels of NK T and CD4+CD25high T cells balancing activated CD8+ T cells, the key to control Chagas'disease morbidity?.(2006) Avelar, Danielle Marchetti Vitelli; Avelar, Renato Sathler; Massara, Rodrigo Lima; Borges, Jaila Dias; Lage, Paula Souza; Lana, Marta de; Carvalho, Andréa Teixeira de; Dias, João Carlos Pinto; Santos, Silvana Maria Elói; Martins Filho, Olindo AssisThe immunological response during early human Trypanosoma cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Herein we report the results of a descriptive flow cytometric immunophenotyping investigation of major and minor peripheral blood leucocyte subpopulations in T. cruzi - infected children, characterizing the early stages of the indeterminate clinical form of Chagas’ disease. Our results indicated significant alterations by comparison with uninfected children, including increased values of pre-natural killer (NK)-cells (CD3 – CD16 + CD56 – ), and higher values of proinflammatory monocytes (CD14 + CD16 + HLA-DR ++ ). The higher values of activated B lymphocytes (CD19 + CD23 + ) contrasted with impaired T cell activation, indicated by lower values of CD4 + CD38 + and CD4 + HLA-DR + lymphocytes, a lower frequency of CD8 + CD38 + and CD8 + HLA-DR + cells; a decreased frequency of CD4 + CD25 HIGH regulatory T cells was also observed. These findings reinforce the hypothesis that simultaneous activation of innate and adaptive immunity mechanisms in addition to suppression of adaptive cellular immune response occur during early events of Chagas’ disease. Comparative cross-sectional analysis of these immunophenotypes with those exhibited by patients with late chronic indeterminate and cardiac forms of disease suggested that a shift toward high values of macrophage-like cells extended to basal levels of proinflammatory monocytes as well as high values of mature NK cells, NKT and regulatory T cells, may account for limited tissue damage during chronic infection favouring the establishment/maintenance of a lifelong indeterminate clinical form of the disease. On the other hand, development of an adaptive cell-mediated inflammatory immunoprofile characterized by high levels of activated CD8 + cells and basal levels of mature NK cells, NKT and CD4 + CD25 HIGH cells might lead to late chronic pathologies associated with chagasic heart disease.Item Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts.(2004) Guedes, Paulo Marcos da Matta; Urbina, Julio Alberto; Lana, Marta de; Afonso, Luís Carlos Crocco; Veloso, Vanja Maria; Tafuri, Washington Luiz; Coelho, George Luiz Lins Machado; Chiari, Egler; Bahia, Maria TerezinhaAlbaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas’ disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas’ disease.Item Variation in susceptibility to benznidazole in isolates derived from Trypanosoma cruzi parental strains.(2001) Veloso, Vanja Maria; Toledo, Max Jean de Ornelas; Lana, Marta de; Chiari, Egler; Tafuri, Washington Luiz; Bahia, Maria TerezinhaIn this work, the susceptibility to benznidazole of two parental Trypanosoma cruzi strains, Colombian and Berenice-78, was compared to isolates obtained from dogs infected with these strains for several years. In order to evaluate the susceptibility to benznidazole two groups of mice were infected with one of five distinct populations isolated from dogs as well as the two parental strains of T. cruzi. The first group was treated with benznidazole during the acute phase and the second remained untreated controls. The animals were considered cured when parasitological and serological tests remained persistently negative. Mice infected with the Colombian strain and its isolates Colombian (A and B) did not cure after treatment. On the other hand, all animals infected with Berenice-78 were cured by benznidazole treatment. However, 100%, 50% and 70% of cure rates were observed in animals infected with the isolates Berenice-78 B, C and D, respectively. No significant differences were observed in serological profile of infected control groups, with all animals presenting high antibody levels. However, the ELISA test showed differences in serological patterns between mice inoculated with the different T. cruzi isolates and treated with benznidazole. This variability was dependent on the T. cruzi population used and seemed to be associated with the level of resistance to benznidazole.Item Immunohistochemical studies in acute and chronic canine chagasic cardiomyopathy.(2002) Caliari, Marcelo Vidigal; Lana, Marta de; Cajá, Rosângela Aparecida França; Carneiro, Cláudia Martins; Bahia, Maria Terezinha; Santos, César Augusto Bueno dos; Magalhães, Gustavo Albergaria; Sampaio, Ivan Barbosa Machado; Tafuri, Washington LuizA major characteristic of Chagas’ disease is a myocarditis constituted primarily of mononuclear cells, both during the acute and chronic phases of the disease. Using monoclonal antibodies and image analyses we have quantified canine CD8+ T cells (caCD8+ T cells), canine CD4+ T cells (caCD4+ T cells) and neutrophils in canine chagasic myocardiopathy induced by two strains isolated from the first human clinical case of Chagas’ disease. We also evaluated the influence of tissue parasitism in the genesis of chronic myocarditis through immunohistochemistry. As in human myocarditis, there was a predominance of T lymphocytes in the inflammatory infiltrate in all animals studied. In the dogs inoculated with strain Berenice 78 (Be78) and necropsied during the acute phase of infection, we found 58% caCD8+ and 42% caCD4+ T cells. In chronically infected animals, 53% of T cells were represented by caCD8+ and 47% were caCD4+ T cells. Since normal canine lymphoid organs are constituted by 70–80% caCD4+ T cells and 20–30% caCD8+ T cells our results indicate a higher proliferation of caCD8+ T cells in dogs inoculated with the Be78 strain. In chronic myocarditis induced by the Berenice 62 (Be62) strain, caCD8+ cells constituted 33% of the T cells and 67% were caCD4+ T cells, a proportion similar to that found in normal canine lymphoid organs. Since the Be78 strain induces greater loss of myocardiocytes than strain Be62, we believe that the caCD8+ T cells, among other factors, can be important in the genesis of these lesions. Amastigote nests and immunohistochemically labelled Trypanosoma cruzi antigen were not found in dogs necropsied during the chronic phase. The absence of the parasite in the myocardium suggests the involvement of otherItem Chemotherapy with Benznidazole and Itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes.(2003) Toledo, Max Jean de Ornelas; Bahia, Maria Terezinha; Carneiro, Cláudia Martins; Martins Filho, Olindo Assis; Tibayrenc, Michel; Barnabé, Christian; Tafuri, Washington Luiz; Lana, Marta deThe benznidazole (BZ) and itraconazole (ITC) susceptibilities of a standard set of Trypanosoma cruzi natural stocks were evaluated during the acute phase and the chronic phase of experimental chagasic infection in BALB/c mice. Twenty laboratory-cloned stocks representative of the total phylogenetic diversity of T. cruzi, including genotypes 20 and 19 (T. cruzi I) and genotypes 39 and 32 (T. cruzi II), were analyzed. Our results demonstrate important differences among stocks that could be pointed out as markers of biological behavior. Members of the T. cruzi I group were highly resistant to both BZ and ITC, whereas members of the T. cruzi II group were partially resistant to both drugs, despite their susceptibilities to ITC during the chronic phase of infection. The resistance to BZ observed for T. cruzi I was mainly triggered by genotype 20 isolates, whereas resistance to ITC was due to both genotype 20 and 19 isolates. Two polar patterns of response to BZ observed for genotype 39 isolates had a major impact on the partial resistance pattern observed for members of the T. cruzi II group. Genotype 32 isolates showed a typical profile of susceptibility. The correlation between the response to treatment and phylogenetic classification of T. cruzi stocks was clearer for ITC than for BZ. In conclusion, the data presented show a correlation between phylogenetic divergence among T. cruzi stocks and their susceptibilities to chemotherapeutic agents in vivo. Our results warn of the necessity to take into account the lesser genetic subdivisions of T. cruzi stocks since the upper subdivisions (T. cruzi I and II) show a great deal of heterogeneity for in vivo drug susceptibility.