Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.FAPESPCNP

Novel Derivatives of Kaurenoic Acid: Preparation and Evaluation of their Trypanocidal Activity

O ácido caurenóico, um diterpeno caurânico, mostrou-se ativo in vitro contra formas tripomastigotas do Trypanosoma cruzi. Uma ação lítica sobre os eritrócitos foi uma das limitações encontradas para esta atividade. A síntese de doze derivados deste ácido: quatro amidas, quatro aminas (e três cloridratos) e quatro oximas foi realizada, com o objetivo de se tentar diminuir ou eliminar esse efeito secundário e, se possível, aumentar a atividade em relação ao material de partida. Dentre esses compostos, um mostrou-se mais ativo que o ácido caurenóico, mas também apresentou lise discreta de eritrócitos; outro não apresentou este efeito, mas a atividade não foi aumentada em relação àquela apresentada pelo ácido caurenóico. Kaurenoic acid, a kauranic diterpenoid, presents in vitro activity against trypomastigote forms of Trypanosoma cruzi, showing, however, lytic activity on blood erythrocytes, as a side effect. The syntheses of twelve new derivatives of kaurenoic acid, four amides, four amines (and three hydroclorides) and four oximes, was carried out aiming at the improvement of the therapeutic activity and without the side effect. Among the derivatives prepared, one compound showed enhanced trypanocidal activity in vitro towards Trypanosoma cruzi trypomastigote erythrocytic forms, when compared to kaurenoic acid, but continued to show discrete lytic activity on erythrocytes; another compound showed a level of activity similar to that of kaurenoic acid, but without lysis

Trypanosoma cruzi high infectivity in vitro is related to cardiac lesions during long-term infection in Beagledogs

Trypanosoma cruzi is a hemoflagelate parasite associated with heart dysfunctions causing serious problems in Central and South America. Beagle dogs develop the symptoms of Chagas disease in humans, and could be an important experimental model for better understanding the immunopathogenic mechanisms involved in the chagasic infection. In the present study we investigated the relation among biological factors inherent to the parasite (trypomastigote polymorphism and in vitro infectivity) and immunoglobulin production, inflammation, and fibrosis in the heart of Beagle dogs infected with either T. cruzi Y or Berenice-78 strains. In vitro infectivity of Vero cells as well as the extension of cardiac lesions in infected Beagle was higher for Y strain when compared to Berenice-78 strain. These data suggested that in vitro infectivity assays may correlate with pathogenicity in vivo. In fact, animals infected with Y strain, which shows prevalence of slender forms and high infectivity in vitro, presented cardiomegaly, inflammation, and fibrosis in heart area. Concerning the immunoglobulin production, no statistically significant difference was observed for IgA, IgM or IgG levels among T. cruzi infected animals. However, IgA together IgM levels have shown to be a good marker for the acute phase of Chagas disease

Preparation and activity of diterpenoids against trypomastigotes of Trypanosoma cruzi

A systematic investigation on the trypanocidal effect of several natural products isolated from Brazilian plant species has been carried out. In this paper we report on the results obtained from the screening of 26 diterpenes from natural sources or of synthetic/microbial transformations origin (mainly derivatives of kaurenoic acid) against trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas'disease. In the in vitro assays, kaurenoic acid, kaurenol, acutifloric acid and stemodin showed a complete elimination of parasites from the blood. Therefore, such diterpenoids can be considered as starting materials for molecular modification in the search for lead compounds for clearance of infected blood to be used in transfusions. Blood previously treated with active compounds was submitted to an infectivity test. Samples proceeded from treatment with kaurenol and kaurenoic acid showed to be completly clean from T. cruzi as no infection was observed in mice inoculated with contaminated blood treated by these compounds

Asymptotic Behavior of the Solution to a Nonisentropic Hydrodynamic Model of Semiconductors

AbstractWe study the asymptotic behavior of the solution for a hydrodynamic model of semiconductors where the energy equation is included. We study the case where the flow is subsonic and the doping profile is close to a negative constant, depending on the spacial variablex. We shall show that a given steady state solution is asymptotically stable or unstable depending on whether or not the density of the initial data satisfiesP=0, wherePis defined in (3.5)