nifurtimox and Acute-Disease

Chagas disease must be treated in all its stages: acute, indeterminate, chronic, and initial and middle determinant chronic, due to the fact that DNA of the parasite can be demonstrated by PCR in chronic cases, where optical microscopy does not detect parasites. Nifurtimox (NF) and benznidazole (BNZ) are the drugs accepted to treat humans based upon ethical considerations and efficiency. However, both the drugs produce secondary effects in 30% of the cases, and the treatment must be given for at least 30-60 days. Other useful drugs are itraconazole and posaconazole. The latter may be the drug to treat Chagas disease in the future when all the investigations related to it are finished. At present, there is no criterion of cure for chronic cases since in the majority, the serology remains positive, although it may decrease. In acute cases, 70% cure with NF and 75% with BNZ is achieved. In congenital cases, 100% cure is obtained if the treatment is performed during the first year of life. In chronic acquired cases, 20% cure and 50% improvement of the electrocardiographic changes are obtained with itraconazole.

Topics: Acute Disease; Animals; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Time Factors; Treatment Outcome; Trypanocidal Agents

There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.

Topics: Acute Disease; Animals; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Humans; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, an infection caused by a protozoan parasite and previously endemic to Mexico and Central and South America, is becoming more prevalent in the United States and Canada. Because nurses and physicians in health care settings may be the first to encounter undiagnosed cases of Chagas disease, it is essential that public health personnel and health care providers in general become more familiar with the disease, including its incidence and prevalence, clinical manifestations, diagnostic criteria, treatment options, and implications for nursing.

Topics: Acute Disease; Animals; Canada; Chagas Disease; Chronic Disease; Emigration and Immigration; Hispanic or Latino; Humans; Immunologic Tests; Incidence; Insect Control; Insect Vectors; Nifurtimox; Nitroimidazoles; Nurse's Role; Prevalence; Primary Prevention; Risk Factors; South America; Travel; Triatoma; Trypanocidal Agents; United States

As chronic Chagas disease does not have a definitive treatment, the development of alternative therapeutic protocols is a priority. Dipyridamole (DPY) is an alternative to counteract the pathophysiological phenomena involved in Chagas cardiomyopathy.. To evaluate the therapeutic efficacy of DPY associated with nifurtimox (Nfx) in epimastigote axenic cultures and in mice with acute Chagas disease.. NMRI adult male mice were divided into nine groups: three healthy and six Trypanosoma cruzi-infected groups. Mice received vehicle, Nfx or DPY, alone or combined. The doses assayed were Nfx 10 and 40 mg/kg and DPY 30 mg/kg. The treatment efficacy was evaluated by clinical, electrocardiographic, parasitological, biochemical and histopathological methods.. In vitro, DPY and Nfx had a trypanocidal effect with IC50 values of 372 ± 52 and 21.53 ± 2.13 µM, respectively; DPY potentiated the Nfx effect. In vivo, Nfx (40 mg/kg) with or without DPY had a therapeutic effect, which was reflected in the 84-92% survival rate and elimination of parasitaemia and heart tissue amastigotes. Nfx (10 mg/kg) had a subtherapeutic effect with no survival and persistence of amastigotes, inflammation and fibrosis in heart tissue; adding DPY increased the survival rate to 85%, and all tested parameters were significantly improved.. DPY has a trypanocidal effect in vitro and enhances the Nfx therapeutic effect in an in vivo murine model.

Topics: Acute Disease; Animals; Chagas Cardiomyopathy; Dipyridamole; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Male; Mice; Nifurtimox; Trypanocidal Agents

Outbreaks of acute Chagas disease associated with oral transmission are easily detected nowadays with trained health personnel in areas of low endemicity, or in which the vector transmission has been interrupted. Given the biological and genetic diversity of Trypanosoma cruzi, the high morbidity, mortality, and the observed therapeutic failure, new characteristics of these outbreaks need to be addressed at different levels, both in Trypanosoma cruzi as in patient response. The aim of this work was to evaluate the patient's features involved in six outbreaks of acute Chagas disease which occurred in Santander, Colombia, and the characteristics of Trypanosoma cruzi clones isolated from these patients, to establish the potential relationship between the etiologic agent features with host behavior.. The clinical, pathological and epidemiological aspects of outbreaks were analyzed. In addition, Trypanosoma cruzi clones were biologically characterized both in vitro and in vivo, and the susceptibility to the classical trypanocidal drugs nifurtimox and benznidazole was evaluated. Trypanosoma cruzi clones were genotyped by means of mini-exon intergenic spacer and cytochrome b genes sequencing.. All clones were DTU I, and based on the mini-exon intergenic spacer, belong to two genotypes: G2 related with sub-urban, and G11 with rural outbreaks. Girón outbreak clones with higher susceptibility to drugs presented G2 genotype and C/T transition in Cyt b. The outbreaks affected mainly young population (±25.9 years), and the mortality rate was 10 %. The cardiac tissue showed intense inflammatory infiltrate, myocardial necrosis and abundant amastigote nests. However, although the gastrointestinal tissue was congestive, no inflammation or parasites were observed.. Although all clones belong to DTU I, two intra-DTU genotypes were found with the sequencing of the mini-exon intergenic spacer, however there is no strict correlation between genetic groups, the cycles of the parasite or the clinical forms of the disease. Trypanosoma cruzi clones from Girón with higher sensitivity to nifurtimox presented a particular G2 genotype and C/T transition in Cyt b. When the diagnosis was early, the patients responded well to antichagasic treatment, which highlights the importance of diagnosis and treatment early to prevent fatal outcomes associated with these acute episodes.

Topics: Acute Disease; Animals; Base Sequence; Chagas Disease; Colombia; Disease Outbreaks; DNA, Protozoan; Exons; Female; Genetic Variation; Genotype; Humans; Male; Molecular Sequence Data; Nifurtimox; Nitroimidazoles; Sequence Analysis, DNA; Trypanocidal Agents; Trypanosoma cruzi

5-arylethenylbenzofuroxan derivatives with high in vitro anti-Trypanosoma cruzi activity were studied in vivo using acute murine models of Chagas' disease. The selected compounds, as pure isomeric forms, 1, 2, 3 and 4, or as equimolecular mixture of geometric isomers, 1:2, 3:4, 5:6 were studied against different T. cruzi strains. Consequently, Tulahuen 2 strain, Colombiana strain (resistant to Nifurtimox and Benznidazole), and two different wild strains, one isolated from the wild reservoir Didelphis marsupialis and another one from Uruguayan patients, were selected. No relevant signs of in vivo toxicity were observed with the benzofuroxans orally administered. Compound 1 and the mixture of isomers 1:2 were the best for treating infection against the four studied strains.

Topics: Acute Disease; Animals; Antibodies, Protozoan; Benzoxazoles; Chagas Disease; Disease Models, Animal; Female; Mice; Parasitemia; Treatment Outcome; Trypanosoma cruzi

L-buthionine (S,R)-sulfoximine (BSO) at a dose of 220 mg/kg of body weight/day showed an anti-Trypanosoma cruzi effect in infected mice, increasing their survival rate and decreasing the parasitemias and parasite burden in the hearts. Treatment with BSO plus nifurtimox caused an increase in the survival rate in comparison to the rates with treatment with each drug alone.

Topics: Acute Disease; Animals; Buthionine Sulfoximine; Chagas Disease; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Mice; Mice, Inbred BALB C; Nifurtimox; Survival Rate; Trypanocidal Agents; Trypanosoma cruzi

Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-benzimidazole 1,3-dioxides displayed remarkable in vitro activities against both parasites, with derivatives 28, 29, and 32 being the most potent (IC50 < 5 microM) against the epimastigote form of T. cruzi and 28, 33, and 35 the most potent against the promastigote form of Leishmania spp. Unspecific cytotoxicity was evaluated using murine macrophages, and derivative 33 was not toxic at a concentration 30 times that of its IC50 against T. cruzi that was completely toxic for Leishmania spp., implying that the series of 2H-benzimidazole 1,3-dioxides is selective toward both trypanosomatid parasites. Derivatives 33 and 35 were submitted to an in vivo assay using an acute model of Chagas' disease and a short-term treatment (30 mg/kg/day orally administrated as aqueous solution, during 10 days). While in the control (untreated) and Benznidazole (50 mg/kg/day) groups survival fraction was 60.0% and 87.5%, respectively, none of the animals treated with derivatives 33 and 35 died. From the preliminary structure-activity relationship studies reduction potential and electrophilicity were found relevant to anti-T. cruzi activity. Active compounds are better electrophiles and more easily reduced than inactive ones.

Topics: Acute Disease; Animals; Benzimidazoles; Cell Line; Chagas Disease; Cyclic N-Oxides; Leishmania; Macrophages; Mice; Mice, Inbred BALB C; Models, Molecular; Oxidation-Reduction; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

With the exception of assays for the detection of antibodies promoting complement-mediated lysis of Trypanosoma cruzi, serologic tests have generally failed to assess the effectiveness of chemotherapy for Chagas' disease. Conventional serology, although useful for the diagnosis of infection, is not capable of determining which patients have been cured. Here we demonstrate that a high proportion of antibodies detected by conventional serology (using fixed epimastigotes or trypomastigotes or crude extracts obtained therefrom) are directed against the carbohydrate residue galactosyl alpha 1- > 3 galactose (Gal alpha 1- > 3 Gal), a determinant also recognized by antibodies from noninfected healthy volunteers. In a study of 14 cured patients with long-term followup, we found that the persistently positive reactions detected using conventional serology were largely eliminated following immunoadsorption with melibiose. Because of their wide distribution among microorganisms of intestinal and pulmonary microflora, these carbohydrate determinants may keep stimulating lymphocytes previously primed by T. cruzi Gal alpha 1- > 3 Gal epitopes, thereby accounting for false-positive results in cured patients. Consistent with this proposition, enzyme-linked immunosorbent assays performed with two distinct T. cruzi antigen preparations that lack the Gal alpha 1- > 3 Gal epitope, namely purified GP57/51 and trypomastigote-shed antigens, were indeed capable of determining a cure after chemotherapy, albeit to a different degree. Collectively, the data indicate that conventional immunoassays prepared with highly specific T. cruzi antigens can be useful in the assessment of a cure after chemotherapy.

Topics: Acute Disease; Adsorption; Adult; Animals; Antibodies, Protozoan; Antibody Specificity; Antigens, Protozoan; Chagas Disease; Child; Chronic Disease; Cross Reactions; Cysteine Endopeptidases; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Follow-Up Studies; Glycoproteins; Humans; Middle Aged; Nifurtimox; Nitroimidazoles; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Topics: Acute Disease; Aged; Blood Donors; Bolivia; Chagas Disease; Child; Drug Therapy, Combination; Female; Hodgkin Disease; Humans; Interferon-gamma; Nifurtimox; Transfusion Reaction; United States

Topics: Acute Disease; Adult; Animals; Antibodies, Protozoan; Blood Donors; Chagas Disease; Female; Humans; Indians, North American; Manitoba; Nifurtimox; Paraguay; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transfusion Reaction; Trypanosoma cruzi

Topics: Acute Disease; Chagas Cardiomyopathy; Chagas Disease; Diet, Sodium-Restricted; Furosemide; Humans; Isosorbide Dinitrate; Male; Middle Aged; Nifurtimox