scholarly journals Chemotherapy with Benznidazole and Itraconazole for Mice Infected with Different Trypanosoma cruzi Clonal Genotypes

2003 ◽  
Vol 47 (1) ◽  
pp. 223-230 ◽  
Author(s):  
Max Jean de Ornelas Toledo ◽  
Maria Terezinha Bahia ◽  
Cláudia M. Carneiro ◽  
Olindo Assis Martins-Filho ◽  
Michel Tibayrenc ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Drug Susceptibility ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
Biological Behavior ◽  
Resistance Pattern ◽  
Standard Set ◽  
Phylogenetic Divergence

ABSTRACT The 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.

scholarly journals Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Solange L. de Castro ◽  
Denise G. J. Batista ◽  
Marcos M. Batista ◽  
Wanderson Batista ◽  
Anissa Daliry ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Public Health Problem ◽  
Term Therapy ◽  
High Morbidity ◽  
Synthetic Compounds ◽  
Natural And Synthetic

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

scholarly journals A rapid method for testing in vivo the susceptibility of different strains of Trypanosoma cruzi to active chemotherapeutic agents

1984 ◽  
Vol 79 (2) ◽  
pp. 221-225 ◽  
Author(s):  
Leny S. Filardi ◽  
Zigman Brener
Keyword(s):  
Trypanosoma Cruzi ◽  
Rapid Method ◽  
Chemotherapeutic Agents ◽  
Prolonged Treatment ◽  
Long Term Study ◽  
Short Period ◽  
Different Strains ◽  
Method Show

A method is described which permits to determine in vivo an in a short period of time (4-6 hours) the sensitivity of T. cruzo strains to known active chemotherapeutic agents. By using resistant- and sensitive T. cruzi stains a fairly good correlation was observed between the results obtained with this rapid method (which detects activity against the circulating blood forms) and those obtained with long-term schedules which involve drug adminstration for at least 20 consecutive days and a prolonged period of assessment. This method may be used to characterize susceptibility to active drugs used clinically, provide infomation on the specific action against circulating trypomastigotes and screen active compounds. Differences in the natural susceptibility of Trypanosoma cruzi strains to active drugs have been already reported using different criteria, mostly demanding long-term study of the animal (Hauschka, 1949; Bock, Gonnert & Haberkorn, 1969; Brener, Costa & Chiari, 1976; Andrade & Figueira, 1977; Schlemper, 1982). In this paper we report a method which detects in 4-6 hours the effect of drugs on bloodstream forms in mice with established T. cruzi infections. The results obtained with this method show a fairly good correlation with those obtained by prolonged treatment schedules used to assess the action of drugs in experimental Chagas' disease and may be used to study the sensitivity of T. cruzi strains to active drugs.

scholarly journals Prediction of in Vivo Cytotoxicity of Chemotherapeutic Agents by Their Effect on Malignant Leukocytes in Vitro

Blood ◽  
1967 ◽  
Vol 30 (2) ◽  
pp. 176-188 ◽  
Author(s):  
MARTIN J. CLINE
Keyword(s):  
Test System ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
In Vitro Test ◽  
Malignant Cells ◽  
Vitro Test ◽  
In Vitro Effects ◽  
In Vivo Cytotoxicity

Abstract In order to develop a test system for predicting the response to chemotherapeutic agents, leukocytes from patients with leukemia and leukolymphosarcoma were cultured in vitro and the effect of several drugs on the incorporation of H3-uridine into ribonucleic acid was measured. Cortisol, vincristine and cytosine arabinoside at concentrations near the therapeutic range produced inhibition of H3-uridine incorporation in sensitive leukocytes. The in vitro effects of 6-mercaptopurine and methotrexate were variable. In 39 trials on 25 patients with leukemia or lymphosarcoma, the in vitro test was used successfully to predict the response to treatment with prednisone and vincristine. It was concluded that the in vitro test system can predict the in vivo cytotoxicity of certain drugs for malignant cells, although it cannot be used to predict the likelihood of the induction of remissions with these drugs.

Are phylogenetic position, virulence, drug susceptibility and in vivo response to treatment in mycobacteria interrelated?

2012 ◽  
Vol 12 (4) ◽  
pp. 832-837 ◽  
Author(s):  
Jakko van Ingen ◽  
Martin J. Boeree ◽  
Dick van Soolingen ◽  
Michael D. Iseman ◽  
Leonid B. Heifets ◽  
...  
Keyword(s):  
Drug Susceptibility ◽  
Response To Treatment ◽  
Phylogenetic Position

scholarly journals Influence of age and ways of treatment in the parasitemia in mice infected with Trypanosoma cruzi treated with high potency biotherapy

2021 ◽  
Vol 10 (36) ◽  
pp. 138-141
Author(s):  
Denise Lessa Aleixo ◽  
Paula Fernanda Massini ◽  
Caroline Felicio Braga ◽  
Neide Martins Moreira ◽  
Camila Fernanda Brustolin ◽  
...  
Keyword(s):  
Single Dose ◽  
Trypanosoma Cruzi ◽  
Controlled Trial ◽  
Biological Behavior ◽  
Control Group ◽  
High Potency ◽  
Different Ages ◽  
Microbiological Testing ◽  
Old Mice

Introduction: The infection of mice by Trypanosoma cruzi is well known, making this a good model for understanding the effect of highly diluted medications. Mice of different ages show different responses to biotherapic T. cruzi [1]. Other data from our laboratory using biotherapic treatment at low potencies show that long lasting treatment has a better effect in mice infected with T. cruzi. However, the use of high potency biotherapics in mice of different ages infected with T. cruzi has not been analysed yet. Aim: To evaluate the effect of different ways of treatment using biotherapic 200 DH T. cruzi in the evolution of the curve of parasitemia of mice of different ages infected with T. cruzi. Materials and methods: A blind randomized controlled trial was performed using 107 swiss male mice, aged 28, 35 and 56 days, divided into groups: CONTROL(C) – mice aged 28(C28), 38(C38) and 56(C56) days, treated with 7% water-alcohol solution diluted with water (1mL/100mL); ONE DAY(OD) – mice aged 28(OD28), 38(OD38) and 56(OD56) days, treated with highly diluted medication 200 DH T. cruzi in a single dose, diluted in water (10mL/100mL); EVERY DAY(ED) – mice aged 28(ED28), 38(ED38) and 56(ED56) days, treated with highly diluted medication 200DH T.cruzi until the end of the experiment, diluted in water(1mL/100mL). Amber bottle was used and the water was changed every two days. The groups were infected with strain Y-T. cruzi, intraperitoneal,1400 blood trypomastigotes. Medicines were handled according to the Brazilian Homeopathic Pharmacopoeia [2], with microbiological testing according to RDC n° 67 and in vivo biological risk. We compared the parasitemia curve and total parasitemia, determined daily counting of the parasites [3], obtained using the tests Kruskal-Wallis and Wald-Wolfowitz, Statistica 8.0, 5% significance. Approved by the Ethics Committee for Animal Experimentation/ UEM - 030/2008. Results: The animal age and the ways of treatment used influenced the evolution of the parasitemia curve. This evolution was different among different ages, and the youngest mice of the control group had higher averages of parasitemia ( C28=1.4x106/mL; C38= 1.3 x106/mL and C56=1.0x106/mL ) (fig1). This evolution was not observed in the groups treated daily, in which 56 day-old mice presented a higher parasitemia compared to the other groups ( ED28= 1.3x106/mL; ED38=0.9x106/mL and ED56=1.2x106/mL )(fig1b). For animals treated with a single dose, the energetic stimulus provided by biotherapic caused homogeneity of biological behavior, with significant elevation of parasitemia ( OD28=1.8x106/mL; OD38=1.3x106/mL and OD56=1.5 x106/mL) (fig1c). Likewise, the single dose treatment invariably resulted in an increase of parasitemia when compared to other treatments within the same age group (fig1d-f). The treatment performed daily in animals aged 28 and 38 days showed a decrease in parasitemia (fig1d-f). For 56 day-old mice this fall was not observed (fig1f). The meaning of this finding should be better explored considering the physiological maturity versus the vital energy of mice of different ages. Conclusion: The age and the ways of treatment used are important factors to be considered when using a highly diluted medication. The clinical use of these results in humans, should take into consideration the allometric system of medication dosage which takes into account the metabolic rate of each organism.

scholarly journals Trypanosoma cruzi: chemotherapy with benznidazole in mice inoculated with strains from Paraná State and from different endemic areas of Brazil

1997 ◽  
Vol 39 (5) ◽  
pp. 283-290 ◽  
Author(s):  
Max Jean de Ornelas TOLEDO ◽  
Ana Lúcia Falavigna GUILHERME ◽  
José Carlos da SILVA ◽  
Marco Venício de GASPERI ◽  
Andréa Pereira MENDES ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Drug Susceptibility ◽  
The Other ◽  
Inflammatory Lesions ◽  
Triatoma Sordida ◽  
Northwestern Region ◽  
Endemic Areas ◽  
Different Levels ◽  
Trypanocidal Drugs

Strains of Trypanosoma cruzi from different geographical areas have shown different levels of susceptibility to trypanocidal drugs. The susceptibility in vivo to benznidazole was investigated in eighteen strains of T. cruzi. Twelve were isolated from chronic chagasic patients from different Chagas’ disease endemic areas. The other six strains were isolated from the northwestern region of Paraná state; two of them from patients three from triatomines (Triatoma sordida) and one from wild reservoir (Didelphis sp.). To test drug the infected mice were divided into two groups of twenty. One group was treated with benznidazole for twenty consecutive days and the other group was used as untreated control. The treatment began after detection of the infection by direct blood examination or haemoculture. The control of cure was done through haemoculture and indirect immunofluorescence test. The drug eliminated the inflammatory lesions of the skeletal muscle of mice considered cured and from the heart of most of them. Moreover, the inflammatory lesions were reduced in treated but not cured animals. The T. cruzi strains studied showed a gradient of drug susceptibility that varied from 0% to 100%. Ten strains were considered sensitive to the treatment (61 to 100% of cure), one strain was partially sensitive (50% of cure) and seven strains were considered resistant to the treatment (0 to 40% of cure). This variation was observed both in strains of T. cruzi isolated from domestic and sylvatic cycles

scholarly journals Old Yellow Enzyme from Trypanosoma cruzi Exhibits In Vivo Prostaglandin F2α Synthase Activity and Has a Key Role in Parasite Infection and Drug Susceptibility

2018 ◽  
Vol 9 ◽  
Author(s):  
Florencia Díaz-Viraqué ◽  
María Laura Chiribao ◽  
Andrea Trochine ◽  
Fabiola González-Herrera ◽  
Christian Castillo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Prostaglandin F2α ◽  
Drug Susceptibility ◽  
Parasite Infection ◽  
Old Yellow Enzyme

scholarly journals Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Nadjania Saraiva de Lira Silva ◽  
Cristina Mary Orikaza ◽  
Fabiana Rodrigues de Santana ◽  
Luana Aguiar dos Santos ◽  
Bruno Ramos Salu ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Experimental Infection ◽  
Cardiac Fibrosis ◽  
Tissue Injury ◽  
Chronic Phase ◽  
Protective Role

Chagas’ disease is a parasitosis caused by Trypanosoma cruzi, which affects approximately 8 million people worldwide. The balance between pro- and anti-inflammatory cytokines produced during immunological responses contributes to disease prognosis and progression. Parasite tissue persistence can induce chronic inflammatory stimuli, which can cause long-term tissue injury and fibrosis. Chronic Chagas’ patients exhibit increased levels of interleukin (IL)-9, an important cytokine in the regulation of inflammatory and fibrogenic processes. Data on the role of IL-9 in other pathologies are sometimes contradictory, and few studies have explored this cytokine’s influence in Chagas’ disease pathology. Hence, the aim of this study was to evaluate the role of IL-9 in the progression of T. cruzi infection in vivo and in vitro. In vitro infection demonstrated that IL-9 reduced the number of infected cells and decreased the multiplication of intracellular amastigotes in both C2C12 myoblasts and bone marrow-derived macrophages. In myoblasts, the increased production of nitric oxide (NO) was essential for reduced parasite multiplication, whereas macrophage responses resulted in increased IL-6 and reduced TGF-β levels, indicating that parasite growth restriction mechanisms induced by IL-9 were cell-type specific. Experimental infection of BALB/c mice with T. cruzi trypomastigotes of the Y strain implicated a major role of IL-9 during the chronic phase, as increased Th9 and Tc9 cells were detected among splenocytes; higher levels of IL-9 in these cell populations and increased cardiac IL-9 levels were detected compared to those of uninfected mice. Moreover, rIL9 treatment decreased serum IL-12, IL-6, and IL-10 levels and cardiac TNF-α levels, possibly attempting to control the inflammatory response. IL-9 neutralization increased cardiac fibrosis, synthesis of collagens I and III, and mastocyte recruitment in BALB/c heart tissue during the chronic phase. In conclusion, our data showed that IL-9 reduced the invasion and multiplication of T. cruzi in vitro, in both myoblasts and macrophages, favoring disease control through cell-specific mechanisms. In vivo, IL-9 was elevated during experimental chronic infection in BALB/c mice, and this cytokine played a protective role in the immunopathological response during this phase by controlling cardiac fibrosis and proinflammatory cytokine production.

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