allopurinol and Chagas-Disease

From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day

Topics: Allopurinol; Chagas Disease; Drug Therapy, Combination; Humans; Nitroimidazoles; Randomized Controlled Trials as Topic; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Uncertainties regarding indications for the procedure, proper immunosuppressive regimen, and the fear of Trypanosoma cruzi infection reactivation are major concerns regarding heart transplantation (HTx) for patients with end-stage Chagas' heart disease.. To review indications for HTx, current immunosuppressive therapy, posttransplant morbidities, and outcome in Chagas' heart transplant recipients. Review of articles linking HTx and Chagas' disease at PubMed and Scielo database from 1966 onward. HTx can reasonably be indicated in patients with an annual probability of death of 70%. HTx has been associated with a similar incidence of rejection episodes in Chagas' and non-Chagas' heart transplant recipients. A lower incidence of infection episodes has been observed in Chagas' in comparison to non-Chagas' heart transplant recipients. T. cruzi infection reactivation is easily treated with either benznidazole or allopurinol and portends a very low mortality rate. Other posttransplant morbidities have a similar incidence in Chagas' and in non-Chagas' patients. Survival probability for Chagas' HTx recipients at 1 month, 1 year, 4 years, and 10 years follow-up is 83%, 71%, 57%, and 46%, respectively. Such an outcome is better than that seen in non-Chagas' heart transplant recipients.. HTx is safe and efficacious for patients with end-stage Chagas' heart disease.

Topics: Allopurinol; Chagas Disease; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Neoplasms; Nitroimidazoles; Perioperative Care; Postoperative Complications; Recurrence; Trypanocidal Agents

Pyrazolopyrimidines are purine analogues. These compounds are metabolized by the pathogenic hemoflagellates and other members of the family Trypanosomatidae as though they were purines. This metabolic sequence does not exist in man or other mammals. In the hemoflagellates, the pyrazolopyrimidine base, of which allopurinol is the paradigm, undergoes ribosylphosphorylation to the ribonucleotide. This ribonucleotide may remain as such or be aminated to the amino analogue and further converted to the aminopyrazolopyrimidine ribonucleoside triphosphate. The latter is incorporated into RNA. This metabolic sequence has been demonstrated in the genera Leishmania and Trypanosoma.

Topics: Allopurinol; Animals; Antiprotozoal Agents; Aotus trivirgatus; Chagas Disease; Humans; Leishmania; Leishmaniasis, Visceral; Polyribosomes; Protein Biosynthesis; Ribonucleosides; RNA; Thionucleosides; Trypanosoma; Trypanosoma cruzi; Trypanosomiasis; Trypanosomiasis, African

Even though the use of combined drugs has been proved to be effective in other chronic infections, assessment of combined treatment of antiparasitic drugs in human Chagas' disease has not been performed. Herein, a pilot study was conducted to evaluate the tolerance and side effects of a sequential combined treatment of two antiparasitic drugs, allopurinol and benznidazole, in the chronic phase of Trypanosoma cruzi infection.. Changes in total and T. cruzi-specific T and B cells were monitored during a median follow-up of 36 months. Allopurinol was administered for 3 months (600 mg/day) followed by 30 days of benznidazole (5 mg/kg/day) in 11 T. cruzi-infected subjects.. The combined sequential treatment of allopurinol and benznidazole was well tolerated. The levels of T. cruzi-specific antibodies significantly decreased after sequential combined treatment, as determined by conventional serology and by a multiplex assay using recombinant proteins. The frequency of T. cruzi-specific interferon-γ-producing T cells significantly increased after allopurinol treatment and decreased to background levels following benznidazole administration in a substantial proportion of subjects evaluated. The levels of total naive (CD45RA + CCR7 + CD62L+) CD4 + and CD8 + T cells were restored after allopurinol administration and maintained after completion of the combined drug protocol, along with a decrease in T cell activation in total peripheral CD4 + and CD8 + T cells.. This pilot study shows that the combination of allopurinol and benznidazole induces significant modifications in T and B cell responses indicative of a reduction in parasite burden, and sustains the feasibility of administration of two antiparasitic drugs in the chronic phase of Chagas' disease.

Topics: Adult; Allopurinol; Antiprotozoal Agents; B-Lymphocytes; Chagas Disease; Chronic Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitroimidazoles; Pilot Projects; T-Lymphocytes; Treatment Outcome; Trypanosoma cruzi

Thirty-five individuals from endemic areas of Central Brazil (age range, 18-64 years; 19 women) in the chronic phase of Chagas disease, with positive serology and presence of circulating parasites detected by one or more recent positive xenodiagnosis, were selected for this study. Allopurinol (900 mg/d) or placebo was administered in a double-blind clinical trial for 60 days. After codes were broken, 23 had been allocated to the intervention group and 12 to the placebo group. Side effects were observed in 11 patients in the intervention group and in 1 in the placebo group. Seventeen patients in the intervention group and 10 in the placebo group completed the trial. Follow-up was performed by monthly xenodiagnosis and serologic tests every 3 months during the first year and at the end of the trial. Xenodiagnosis remained positive in all 17 of the treated group and in all 10 of the placebo group. Serologic tests were persistently positive in both groups after treatment. We concluded that, at the doses used, allopurinol was not effective to clear, in our region, Trypanosoma cruzi from peripheral blood of infected individuals.

Topics: Adolescent; Adult; Allopurinol; Animals; Antiparasitic Agents; Chagas Disease; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Failure; Trypanosoma cruzi

At the present time the assessment of results of treatment of Chagas disease is mainly parasitological. Anti Trypanosoma cruzi IgGs remain positive practically lifelong and electrocardiographic tracings are not usually used as criteria of improvement.. To determine, in a long term follow up, if electrocardiographic evolution is associated with the persistence of the parasite in treated patients with chronic Chagas disease.. Thirty patients with chronic Chagas disease that participated in a randomized trial of treatment with itraconazole or allopurinol, were studied. Seven years after treatment, patients were classified in group I if they had a positive xenodiagnosis test, polymerase chain reaction and hybridization in blood or in group II if they had negative tests. A 12 lead electrocardiogram (EKG) was performed each year to all patients.. Seventeen patients were classified in group I and 13 in group II. At baseline 10 patients in group I and 8 in group II had a normal EKG. Six years after treatment 13 patients in group I and 10 in group II had a normal tracing. Of those with a normal tracing at baseline, only one patient in each group presented alterations after six years. A regression of abnormal tracings was observed in four and three patients of groups I and II respectively.. There is no association between the persistence of the parasite in treated patients with Chagas disease and the evolution of electrocardiographic tracings.

Topics: Adolescent; Adult; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Child; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Polymerase Chain Reaction; Retrospective Studies; Treatment Outcome; Trypanosoma cruzi; Xenodiagnosis

PCR and FC-ALTA were used to monitor parasite clearance in 54 chronic chagasic patients who had completed therapy with allopurinol (ALLO, n = 31) or itraconazole (ITRA, n = 23) ten years earlier. All patients maintained positive conventional serology. 25 of them showed positive XD (ALLO, n = 11 and ITRA, n = 14) and 29 negative XD (ALLO, n = 20 and ITRA, n = 9). 43 patients were positive by both techniques (ALLO, n = 23 and ITRA, n = 20). Seven of 54 patients were negative by PCR and positive by FC-ALTA and three of 54 were positive by PCR and negative by FC-ALTA. Only one case with both tests negative should be considered cured. Of 29 patients with negative XD, 14 treated ALLO (70 %) and nine with ITRA (77.8 %) showed positive PCR and FC-ALTA. These results do not show differences of efficacy among the drugs, and reinforce the relevance of using sensitive tools such as PCR and FC-ALTA for the follow-up of patients with chronic Chagas disease.

Topics: Adult; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Chile; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Humans; Itraconazole; Male; Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Trypanosoma cruzi

Several drugs are now known to have useful activity against Trypanosoma cruzi, the causative agent of human American trypanosomiasis (Chagas disease). However, the long-term effects of chemotherapy on the electrocardiographic (ECG) abnormalities associated with this disease have only been assessed for benznidiazole. In the present study, the ECG changes in 299 cases of chronic Chagas disease were followed for 9 years after treatment with itraconazole (N = 136) or allopurinol (N = 163). Among the 97 cases who were found to have ECG abnormalities immediately prior to their treatment, the two drugs appeared equally effective, such abnormalities being corrected in 23 (50%) of the 46 cardiopathy cases given itraconazole and 25 (49%) of the 51 given allopurinol (P > 0.05). Both of these 'cure rates' are much higher than the 8.1% frequency of abnormal-normal conversion observed among 198 'historical controls' (i.e. cases of chronic Chagas disease who had been left untreated; P < 0.05). Itraconazole appeared better than allopurinol at preventing the development of cardiopathy in the cases who appeared electrocardiographically normal at baseline. Among 202 such cases, only two (2.2%) of the 90 treated with itraconazole but 28 (25.0%) of the 112 given allopurinol were found to have developed ECG abnormalities during follow-up (P < 0.05). Therefore, although itraconazole and allopurinol are equally effective at reversing ECG alterations, itraconazole offers better protection against the development of new ECG abnormalities among those with chronic Chagas disease.

Topics: Adolescent; Adult; Allopurinol; Antiprotozoal Agents; Arrhythmias, Cardiac; Chagas Cardiomyopathy; Chagas Disease; Child; Double-Blind Method; Electrocardiography; Female; Heart Block; Humans; Itraconazole; Male; Middle Aged; Patient Compliance

Four hundred four patients with chronic Chagas' disease were treated with itraconazole (6 mg/kg of body weight/day for 120 days), allopurinol (8.5 mg/kg of body weight/day for 60 days), or with a placebo of pure starch. Patients were monitored over a period of four years by clinical examination, serology, xenodiagnosis, hemoculture, and electrocardiogram. Drug tolerance was good, with only four treatments discontinued due to side effects that subsided after suspension of treatment. Parasitologic cure was evident in 44% of the those treated with allopurinol and 53% of those treated with itraconazole, and the electrocardiographic evaluation showed normalization in 36.5% and 48.2%, respectively, of patients with chronic or recent cardiopathy.

Topics: Adolescent; Adult; Allopurinol; Animals; Antibodies, Protozoan; Antifungal Agents; Antimetabolites; Biological Assay; Chagas Cardiomyopathy; Chagas Disease; Child; Chronic Disease; Double-Blind Method; Electrocardiography; Follow-Up Studies; Humans; Insect Vectors; Itraconazole; Middle Aged; Nymph; Triatoma; Trypanosoma cruzi

The aim of this work was to assess the efficacy of itraconazole and allopurinol in chronic Chagas disease. Two hundred two subjects (137 infected, 59 with Chagas cardiopathy and 6 with non chagasic cardiopathy) were randomly assigned to be treated with itraconazole (87 subjects receiving 6 mg/kg/day for 120 days), allopurinol (68 subjects receiving 8.5 mg/kg/day for 60 days) or placebo (47 subjects during 60 days). Medications were well tolerated. Indirect hemagglutination test was modified in 5 subjects (3.2%) after treatment. Initially positive xenodiagnosis became negative in 34 of 36 subjects (94.4%) treated with itraconazole and 8 of 10 subjects (80%) treated with allopurinol. Initially normal EKG was not modified in 100% of patients receiving placebo, 84.9% receiving itraconazole and 86.7% receiving allopurinol. Initially abnormal EKG became normal in 10 of 31 subjects (32%) receiving itraconazole, 8 of 20 (40%) receiving allopurinol and none of 8 receiving placebo. It is concluded that xenodiagnosis and EKG improvements indicate that itraconazole and allopurinol have a role in the treatment of chronic Chagas disease. A 36 months follow up of these patients will help to confirm this conclusion.

Topics: Adolescent; Adult; Allopurinol; Chagas Disease; Child; Chronic Disease; Drug Resistance; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Prognosis; Time Factors

Laboratory and animal studies have demonstrated that pyrazolopyrimidines have significant activity against Trypanosoma cruzi. This clinical investigation was to ascertain the efficacy of allopurinol in the treatment of chronic Chagas' disease. Of 307 patients studied, 91 were untreated; the remaining 216 were divided into 4 treatment groups. These corresponded to 600 or 900 mg/day of allopurinol for 60 days and benznidazole or nifurtimox at conventional dosage regimens. Patients were evaluated clinically, serologically, and parasitologically. Allopurinol was found to be as efficacious as the conventional therapeutic modalities in eliminating the parasitemia and rendering patients seronegative. Adverse reactions occurred in 11% of patients who received allopurinol and in 30% of those receiving nitrofurans. Reactions with the conventional therapy were more frequent and of a more serious nature. Oral allopurinol is as effective as the nitrofurans, but has none of the side effects.

Topics: Adult; Allopurinol; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Allopurinol; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of

Topics: Animals; Chagas Disease; Drug Design; Drug Stability; Humans; Leishmania infantum; Male; Mice; Microsomes, Liver; Molecular Structure; Nucleosides; Pyrazoles; Pyrimidines; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

This study evaluated the effectiveness of low doses of benznidazole (BNZ) on continuous administration (BNZc), combined with allopurinol (ALO), in C57BL/6J and C3H/HeN mice infected with Trypanosoma cruzi Nicaragua strain and T. cruzi Sylvio-X10/4 clone. TcN-C57BL/6J was also treated with intermittent doses of BNZ (BNZit). The drug therapy started 3 months post infection (pi) in the chronic phase of mice with heart disease progression, followed-up at 6 months pi. TcN-C57BL/6J treated with BNZc was also monitored up to 12 months pi by serology and electrocardiogram. These mice showed severe electrical abnormalities, which were not observed after BNZc or BNZit. ALO only showed positive interaction with the lowest dose of BNZ. A clear parasitic effect, with significant reductions in antibody titres and parasitic loads, was achieved in all models with low doses of BNZ, and a 25% reduction of the conventional dose showed more efficacy to inhibit the development of the pathology. However, BNZ 75 showed partial efficacy in the TcSylvio-X10/4-C3H/HeN model. In our experimental designs, C57BL/6J allowed to clearly define a chronic phase, and through reproducible efficacy indicators, it can be considered a good preclinical model.

Topics: Allopurinol; Animals; Chagas Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Nitroimidazoles; Random Allocation; Specific Pathogen-Free Organisms; Trypanocidal Agents; Trypanosoma cruzi

Topics: Allopurinol; Animals; Cell Line; Chagas Disease; Humans; Mice; Mortality; Nifurtimox; Nitroimidazoles; Real-Time Polymerase Chain Reaction; Trypanosoma cruzi

Chagas disease is caused by Trypanosoma cruzi (T. cruzi) leading to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available using drugs such as benznidazole and nifurtimox. Here, C6-alkyl (2a-c) and N1-acyl (3a-c) derivatives of Allopurinol (Allop, compound with activity against T. cruzi) were synthesized in good yields and their structures were unambiguously characterized. Only 2a, 2b and 3c showed inhibitory activity against the proliferative stages of the parasite when tested at 1 μg mL(-1) with the 3c derivative exhibiting an IC50 value similar to that of Allop and not being toxic for mammalian cells. Relevant pharmaceutical physicochemical properties (pKa, stability, solubility, lipophilicity) were also determined as well by using Lipinski's rule, polar surface area and molecular rigidity. Taken together, the results demonstrated that the studied derivatives had optimal properties for bioavailability and oral absorption. For the stability studies, Micellar Liquid Chromatography was used as the analytical method which was fully validated according to the FDA guidelines and shown to be a suitable, sensitive and simple method for routine analysis of these Allop derivatives.

Topics: Allopurinol; Animals; Chagas Disease; Chemistry, Physical; Chlorocebus aethiops; Dose-Response Relationship, Drug; Humans; Molecular Structure; Parasitic Sensitivity Tests; Solubility; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

We evaluated the effect of chemotherapy with a sequential combined treatment of a low dose of benznidazole and allopurinol, in different schedules of administration, in experimental models of acute and chronic Trypanosoma cruzi infection. Mice were infected with Nicaragua T. cruzi isolate, a virulent parasite from an endemic area of Nicaragua, genotyped as TcI (Grosso et al. 2010). We assessed survival rate, IgG levels, histopathological studies and quantified parasitaemia. A 15% survival rate was recorded in untreated mice during the acute phase of T. cruzi infection. Allopurinol administered immediately after benznidazole treatment was able to reduce parasitaemia and attenuate tissue damage by reducing inflammation. Trypanosoma cruzi-specific antibodies also decreased in 40-50% of the treated mice. The addition of allopurinol during the chronic phase showed the highest beneficial effect, not only by reducing parasitaemia but also by lowering the degree of inflammation and fibrosis.

Topics: Allopurinol; Animals; Antibodies, Protozoan; Chagas Disease; Disease Models, Animal; Drug Therapy, Combination; Mice; Nicaragua; Nitroimidazoles; Survival Analysis; Treatment Outcome; Trypanosoma cruzi

In order to determine the in vivo activity against the protozoan Trypanosoma cruzi, two doses (50 and 75 mg/kg) of a chloroform extract of Carica papaya seeds were evaluated compared with a control group of allopurinol. The activity of a mixture of the three main compounds (oleic, palmitic and stearic acids in a proportion of 45.9% of oleic acid, 24.1% of palmitic and 8.52% of stearic acid previously identified in the crude extract of C. papaya was evaluated at doses of 100, 200 and 300 mg/kg. Both doses of the extracts were orally administered for 28 days. A significant reduction (p < 0.05) in the number of blood trypomastigotes was observed in animals treated with the evaluated doses of the C. papaya extract in comparison with the positive control group (allopurinol 8.5 mg/kg). Parasitemia in animals treated with the fatty acids mixture was also significantly reduced (p < 0.05), compared to negative control animals. These results demonstrate that the fatty acids identified in the seed extracts of C. papaya (from ripe fruit) are able to reduce the number of parasites from both parasite stages, blood trypomastigote and amastigote (intracellular stage).

Topics: Allopurinol; Animals; Carica; Chagas Disease; Drug Evaluation, Preclinical; Mice; Mice, Inbred BALB C; Myocarditis; Myocardium; Parasitemia; Plant Extracts; Seeds; Trypanocidal Agents; Trypanosoma cruzi

We describe some biological and molecular characteristics of a Trypanosoma cruzi isolate derived from a Triatomine captured in Nicaragua. PCR based typification showed that this isolate, named Nicaragua, belonged to the lineage Tc I. Nicaragua infected culture cells were treated with allopurinol, showing different behavior according to the cellular compartment, being cardiomyocyte primary cultures more resistant to this drug. The course of the infection in a mice experimental model and its susceptibility to benznidazole and allopurinol was analyzed. In benznidazole treatment, mice reverted the high lethal effect of parasites during the acute infection, however, a few parasites were detected in the heart of 88% of mice 1 year post-infection. Since T. cruzi is a heterogeneous species population it is important to study and characterize different parasites actually circulating in humans in endemic areas. In this work we show that T. cruzi Nicaragua isolate, is sensitive to early benznidazole treatment.

Topics: Allopurinol; Animals; Cell Line; Cells, Cultured; Chagas Disease; Endemic Diseases; Inhibitory Concentration 50; Insect Vectors; Mice; Mice, Inbred C3H; Muscle Cells; Muscles; Nicaragua; Nitroimidazoles; Phylogeny; Rats; Triatoma; Trypanocidal Agents; Trypanosoma cruzi

We have previously shown that clomipramine and allopurinol used separately are effective in preventing chronic chagasic cardiomyopathy. The aim of the present study was to evaluate the effect of the association of clomipramine (Clo--5 mg/kg/day/90 days) and allopurinol (Allo--5, 10, or 15 mg/kg/day/90 days) for the treatment of experimental Chagas disease in the acute stage. Treatment effectiveness was evaluated through parasitemia, survival, electrocardiography, serology, and cardiac histopathology. Groups treated showed no electrocardiographic abnormalities, in contrast to those untreated which presented 25% of mice with conduction alterations. The myocardium of treated mice (Clo, Allo10+Clo, and Allo15+Clo) presented no structural alterations. Cardiac b-receptor affinity was preserved in mice treated with Clo or Clo+Allo at the different doses; receptor density of the Clo and Allo15+Clo groups did not differ from the non-infected group. Anti-cruzipain antibody levels were similar in treated and untreated groups. Survival was significantly increased in the treated groups (p < 0.05), with Clo and all the Clo+Allo groups presenting the highest rates. These results show that the association of clomipramine + allopurinol is effective for Chagas disease treatment and has the same effect as clomipramine alone.

Topics: Allopurinol; Animals; Antibodies, Protozoan; Antigens, Protozoan; Antiprotozoal Agents; Chagas Disease; Clomipramine; Cysteine Endopeptidases; Disease Models, Animal; Drug Therapy, Combination; Electrocardiography; Male; Mice; Myocardium; Parasitemia; Protozoan Proteins; Survival Analysis; Treatment Outcome; Trypanosoma cruzi

Serum from asymptomatic or symptomatic (with cardiovascular manifestations) chagasic patients depleted of the complement system displayed an antiproliferative effect on Trypanosoma cruzi epimastigotes, RA strain, when added to the growth medium. This effect was also observed when patient's serum was depleted of specific antibodies. The antiproliferative effect was both time and concentration dependent. It was confined to the non-dialyzable, high molecular weight, fraction of the serum. This effect was abrogated by allopurinol and catalase, and enhanced by N-ethylmaleimide. Xanthine oxidoreductase and xanthine oxidase activities were increased in the chagasic sera, while catalase activity remained unchanged. Parasites exposed to chagasic sera showed a decrease in Fe/superoxide dismutase activity as well as an increase in membrane lipoperoxidation. Our data provides evidence to support the idea that the antiproliferative activity observed in sera from chagasic patients may be due, at least partially, to a direct effect of hydrogen peroxide on the epimastigotes of T. cruzi. The increase of hydrogen peroxide to antiproliferative levels might result from an increase in xanthine oxidase activity in the serum of patients infected with the parasite.

Topics: Adult; Animals; Antiprotozoal Agents; Chagas Disease; Humans; Hydrogen Peroxide; Serum; Trypanosoma cruzi; Xanthine Dehydrogenase; Xanthine Oxidase

In this study, we investigated whether inflammatory responses contribute to oxidative/nitrosative stress in patients with Chagas' disease. We used three tests (enzyme-linked immunosorbent assay, immuno-flow cytometry, and STAT-PAK immunochromatography) to screen human serum samples (n = 1,481) originating from Chiapas, Mexico, for Trypanosoma cruzi-specific antibodies. We identified 121 subjects who were seropositive for T. cruzi-specific antibodies, a finding indicative of an 8.5% seroprevalence in the rural population from Chiapas. Seropositive and seronegative subjects were examined for plasma levels of biomarkers of inflammation, i.e., myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and xanthine oxidase (XOD), as well as for oxidative (advanced oxidation protein products [AOPPs]) and nitrosative (3-nitrotyrosine [3NT]) biomarkers. The seropositive subjects exhibited a significant increase in MPO activity and protein level, the indicator of neutrophil activation. Subsequently, a corresponding increase in AOPP contents, formed by MPO-dependent hypochlorous acid and chloramine formation, was noted in seropositive subjects. The plasma level of 3NT was significantly increased in seropositive subjects, yet we observed no change in XOD activity (O(2)(-) source) and nitrate/nitrite contents (denotes iNOS activation and NO production), which implied that direct peroxynitrite formation does not contribute to increased nitrosative damage in chagasic subjects. Instead, a positive correlation between increased MPO activity and protein 3NT formation was observed, which suggested to us that MPO-dependent formation of nitrylchloride that occurs in the presence of physiological NO and O(2)(-) concentrations contributes to protein nitration. Overall, our data demonstrate that T. cruzi-induced neutrophil activation is pathological and contributes to MPO-mediated collateral protein oxidative and nitrosative damage in human patients with Chagas' disease. Therapies capable of suppressing MPO activity may be useful in controlling the inflammation and oxidative/nitrosative pathology in chagasic cardiomyopathy.

Topics: Animals; Antibodies, Protozoan; Chagas Disease; Humans; Mexico; Nitric Oxide Synthase Type II; Nitrosation; Oxidation-Reduction; Peroxidase; Prevalence; Proteins; Trypanosoma cruzi; Xanthine Oxidase

Topics: Adult; Allopurinol; Animals; Botulinum Toxins; Chagas Disease; Deglutition Disorders; Esophagoscopy; Female; Follow-Up Studies; Gastroscopy; Humans; Manometry; Risk Assessment; Travel; Treatment Outcome; Trypanosoma cruzi

As expert consensus has been arisen about universal antiparasitic treatment for all patients infected with Trypanosoma cruzi, most important drugs licensed for Chagas disease treatment are reviewed: nifurtimox and benznidazol, their mechanisms of action, doses, treatment schedules, adverse effects and contraindications. Two other drugs used for Chagas disease treatment, for which a Chilean experience may be exhibited, are allopurinol and itraconazole. Indications for treatment of Chagas disease in immunocompetent patients and immunocompromised hosts are detailed. This chapter refers besides to the evaluation and monitoring of antiparasitic therapy in immunocompromised patients, the availability of drugs and includes various forms facsimiles suggested to perform clinical and laboratory follow up of patients that undergo treatment, indicating the prescribed drug, adverse effects and time of follow up.

Topics: Allopurinol; Animals; Chagas Disease; Follow-Up Studies; Humans; Immunocompromised Host; Immunosuppressive Agents; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

There is a real need for new and less toxic drugs for the treatment of Chagas disease, as nifurtimox and benznidazole are effective but toxic and provoke unpleasant side effects, especially in adult patients. Allopurinol, commonly used to treat the hiperuricemia, is also used by the Trypanosoma cruzi's hypoxantine guanine fosforyltransferase as an alternative substrate incorporating it into the parasite's ribonucleic acid, provoking the death of the parasite. However, the results of using allopurinol as chemotherapy for Chagas disease are not clear. For that, we investigated the evolution of the T. cruzi infection in mice treated with allopurinol (5, 10 or 15 mg/kg for 90 days) obtaining a reduction in the parasitaemia (p<0.05), no electrocardiographic alterations (p<0.05) and a conserved myocardial and cardiac beta-receptors' affinity values with the highest dose of the drug, compared to those of the uninfected mice. Cruzipain immunoglobulin G levels remained high in all the groups as well as the survival (70%, 90 days post-infection). Allopurinol prevented the acute phase evolving into the chronic cardiac disease.

Topics: Allopurinol; Animals; Antibodies, Protozoan; Chagas Disease; Cysteine Endopeptidases; Electrocardiography; Male; Mice; Myocardium; Parasitemia; Protozoan Proteins; Survival Analysis; Trypanosoma cruzi

The aim of this work was to study the distribution of Trypanosoma cruzi clones after treatment failure with itraconazole or allopurinol in infected humans.. Blood samples from treated and untreated individuals were used to detect T. cruzi by PCR assays and were confirmed by hybridization tests using total kinetoplast DNA as a universal probe. Also, xenodiagnosis (XD) tests were performed with Triatoma infestans fed from the same group of patients. We performed Southern-blot analyses of PCR products from blood or XD samples using a panel of four genotype-specific probes: corresponding to T. cruzi clones TcI, TcIIb, TcIId and TcIIe. The membranes were hybridized with radiolabelled probes and exposed in a Personal Molecular Imager.. When comparing the presence of T. cruzi clones in the allopurinol-treated group with the non-treated group significant differences were only observed for XD samples. Clone TcI was present in 9/13 (69.2%) of the XD samples of the treated group, but only in 8/27 (29.6%) in the non-treated group (P = 0.0178). When the itraconazole-treated group and the control group were compared, significant differences were found in both the blood and XD samples. In blood, the clone TcIIb was detected in 6/17 (35.5%) of the treated group and in 18/27 (66.7%) of the non-treated group (P = 0.0207). When XD samples were analysed, the clone TcI was observed in 14/17 (82.3%) of the itraconazole-treated group but only in 8/27 (29.6%) of the control group (P = 0.0006), which suggests resistance of this clone to itraconazole.. We detected a dissimilar distribution of T. cruzi clones in treated and untreated groups of patients. The presence of TcI increased in patients treated with allopurinol and itraconazole, whereas the presence of TcIIb decreased in itraconazole-treated patients. The type of T. cruzi clone that prevails suggests that TcI is resistant to both drugs and that TcIIb is susceptible to itraconazole.

Topics: Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Humans; Itraconazole; Trypanosoma cruzi

Eleven years after they had been given itraconazole or allopurinol for the treatment of chronic American trypanosomiasis, 109 adult patients were checked for electrocardiographic abnormalities and evidence of Trypanosoma cruzi infection. The parasitological investigations included xenodiagnosis, in which the faeces of Triatoma infestans that had fed on the patients were checked under the microscope for flagellates. In addition, a PCR-based assay and a hybridization assay were used to test blood samples from the patients, and faeces from the Tri. infestans that had fed on the patients, for Try. cruzi DNA. For the data analysis, the patients were divided into four groups known as normal/normal, abnormal/normal, normal/abnormal and abnormal/abnormal, according to whether the patients had been found to have normal or abnormal electrocardiograms (ECG) shortly before the first treatment and to have normal or abnormal ECG when checked at the 11-year follow-up. The 51 normal/normal and 24 normal/abnormal patients were assumed to have been in the 'indeterminate' phase of the disease when they were treated, whereas the 16 abnormal/normal and 18 abnormal/abnormal patients all had evidence of chagasic cardiopathy at that time. When checked 11 years post-treatment, 40 (78.4%), 17 (70.8%), 14 (87.5%) and 17 (94.4%) of these patients, respectively, were each found positive for Try. cruzi in at least one of the parasitological tests. The hybridization assay, whether applied to human blood or bug faeces, appeared a significantly more sensitive test than the PCR-based assays or microscopically assessed xenodiagnosis (P<0.05). Only the 21 patients who appeared to be negative for Try. cruzi could be considered parasitologically cured (although all still appeared to have anti-Try. cruzi antibodies in their blood). Only 13 of these parasitologically cured patients (seven of those treated with itraconazole and six of those given allopurinol) had normal ECG at the 11-year follow-up. In Chile at least, itraconazole, which caused fewer adverse effects than the allopurinol while being no less effective at preventing cardiopathy, appears to be the drug of choice to treat chronic American trypanosomiasis in adults.

Topics: Adult; Allopurinol; Animals; Arrhythmias, Cardiac; Chagas Disease; Chronic Disease; DNA, Protozoan; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Polymerase Chain Reaction; Trypanosoma cruzi; Xenodiagnosis

The presence of Trypanosoma cruzi in chronic chagasic patients with negative xenodiagnosis (XD) after 6 years following completion of therapy with either itraconazole or allopurinol was assessed by polymerase chain reaction (PCR) and hybridization assays. A 330-bp DNA fragment amplified from the hypervariable regions of T. cruzi kinetoplastid minicircles was hybridized with total 32P-labeled kinetoplast DNA as probes. PCR alone enabled the identification of T. cruzi nucleotide sequences in 40% of the patients treated with itraconazole and in 60% of patients treated with allopurinol. PCR used in combination with hybridization detected parasite DNA in 60% and 53% of XD negative individuals treated with itraconazole or allopurinol, respectively. These results show that PCR and hybridization are more sensitive than conventional parasitological techniques in diagnosing patients that have undergone chemotherapy with itraconazole or allopurinol.

Topics: Adult; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Chronic Disease; Female; Humans; Itraconazole; Male; Nucleic Acid Hybridization; Polymerase Chain Reaction; Trypanosoma cruzi

In this study is presented the comparative therapeutical experience comparing the Allopurinol, Benznidazol y Nifurtimox, in a prospective following in a long term, considering the responses to the parasitemia, specific serology and evolution of the clinic manifestations and complementaries in the 535 chronic chagasic cases (44.5%), instead of 668 patients who did not get any treatment (1203 chagasic cases followed for more than 5 years average). This study was done between April 1984 and April 1994 in patients with and without cardiopathy, in the Córdoba Hospital and the Salud Estudiantil Direccion, Universidad Nacional de Córdoba (U.N.C.); from them, 309 patients were given Allopurinol, 130 were given Benznidazol, and 96 were given Nifurtimox, with usual doses of Benznidazol and Nifurtimox, but with Allopurinol it was made an study evaluating the answering-doses, with a following time of post-therapeutic average of 55.6 months (D.S. = + -57 m.) The comparative parameters were the starting clinic characteristics, the qualitative and quantitative for Chagas, the pre-treatment xerodiagnostic, the treatment fulfillment, the treatment duration, the adverse effects, the treatment abandon, the time of postreatment longitudinal following till the last clinic-complementary evaluation, the clinic characteristics at the end of the following period; quantitative and qualitative serology for Chagas after the treatment, and post-treatment xerodiagnostic. It was observe a prevalence of Electrocardiographic Changes in the ECG in rest, in the first complementary evaluation in 76 of the 535 "Treated" and in the 225 "No-treated" patients, being Electrocardiographic abnormality proportion much more in the "No-treated" patients (P = 0.000000). After the end of the following period it was thought to have been found Miocardic Damage Progression in 120 patients "No-treated" and in 31 "Treated" patients (17.9% and 5.8% respectively) (P = 0.0000000). The complications in the evolution course were proved in 113 of the "No-treated" and in 19 of the "Treated" patients (16.9% and 3.5%, being this a statistically significant difference (P = 0.0000000). The mortality along the evolution was proved in 37 of the "No-Treated:" patients and in 7 of the "Treated" patients (5.5% and 1.3%), being this a statistically significant difference (P = 0.00019). The most tolerated drug and the one with the least incidence of therapeutic abandons was the Allopurinol. The xerodiagnostic negativization

Topics: Adolescent; Adult; Aged; Allopurinol; Antiprotozoal Agents; Chagas Cardiomyopathy; Chagas Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Prospective Studies; Retrospective Studies; Time Factors; Treatment Outcome; Trypanocidal Agents

Chagas disease is endemic in Chile. Allopurinol and itraconazole have activity against Trypanosoma cruzi and are recommended for the treatment of chronic disease in adults.. To evaluate the chemotherapeutic effects of allopurinol and itraconazole using conventional and non conventional serologic tests.. Sera of 90 patients with chronic Chagas disease were studied before and after 9 to 11 months of treatment with allopurinol or itraconazole and after two months of treatment with placebo. Indirect immunofluorescence, ELISA and Western Blot analysis were the conventional serologic tests used and antibody dependent complement mediated lysis (CoML) the non conventional test.. There were no differences in ELISA and indirect immunofluorescence tests before and after therapy. Antigenic recognition profiles by Western Blot showed qualitative and quantitative differences in a small number of cases. CoML showed that the greater negativity was achieved in the Chagasic group treated with allopurinol or itraconazole that had a negative xenodiagnosis before drug treatment (35.8 and 61.6%, respectively).. There is a reversion of lytic activity in sera of patients with negative xenodiagnosis before treatment, suggesting the parasitemia could be an important parameter to be considered in the chemotherapy of Chagas disease.

Topics: Adolescent; Adult; Allopurinol; Antiprotozoal Agents; Chagas Disease; Child; Chronic Disease; Follow-Up Studies; Humans; Itraconazole; Middle Aged

We describe two patients who underwent cardiac transplantation for chronic cardiomyopathy of Chagas' disease, and in whom the disease was reactivated with the development of cutaneous lesions. In both cases, the skin lesions regressed completely after 2 months of therapy with allopurinol.

Topics: Adult; Allopurinol; Antiparasitic Agents; Chagas Cardiomyopathy; Chagas Disease; Female; Heart Transplantation; Humans; Male; Middle Aged; Recurrence; Skin Diseases, Parasitic; Trypanocidal Agents

Chagas' disease is a parasitic infection that provokes a severe form of dilated cardiomyopathy. In the initial experience with heart transplantation with Chagas' disease, a high rate of acute reactivation has been reported. Although benzinidazole and nifurtimox are effective in the treatment of reactivation or of the acute phase of the disease they are associated with important adverse effects. Allopurinol has substantial activity against Trypanosoma cruzi in vitro, in the experimental laboratory and in chronic human Chagas' disease; however, there is no information regarding its action in Chagas' reactivation after heart transplantation.. We describe two patients with Chagas' disease who underwent heart transplantation. The first one had asthenia, anorexia, and several painful subcutaneous nodules in the legs after transplantation; biopsy showed an inflammatory infiltrate with intracytoplasmatic nests of Trypanosoma cruzi, confirmed by immunohistochemical stains with monoclonal antibodies specific to parasitic antigens. Allopurinol (600 mg/day) produced complete regression of the symptoms and the nodules with a negative control biopsy within 2 weeks. Treatment was maintained for 2 months. Mild leukopenia developed which improved after azathioprine reduction, and no further side-effects were noted. The second patient had sudden heart failure months after transplantation; endomyocardial biopsy showed myocardial fibers infested with Trypanosoma, and a concomitantly performed right heart catheterization showed a low cardiac index and highfilling pressures. The patient received allopurinol at a daily dose of 900 mg and conventional treatment for heart failure. Echocardiogram showed improved wall motion and decreased left ventricular dimensions, and control biopsy showed no inflammatory activity; cardiac index and filling pressures normalized. Treatment was maintained for 2 months without side effects. The two patients have not had recurrences and were in New York Heart Association functional class I 12 and 3 months, respectively, after discontinuation of allopurinol.. Allopurinol seems to be safe and effective in treating Chagas' disease reactivation after heart transplantation. A larger number of case studies seems to be necessary to properly evaluate its role in the treatment of Chagas' disease reactivation.

Topics: Adult; Allopurinol; Chagas Cardiomyopathy; Chagas Disease; Heart Failure; Humans; Immunosuppression Therapy; Male; Middle Aged; Recurrence

The anti-Trypanosoma cruzi effect of allopurinol ribonucleoside and formycin B was examined against infections of the sensitive Y and Peru strains in inbred mice, strain DBA/1. Allopurinol ribonucleoside given in the drinking water at doses calculated to be 239, 511 and 929 mg/kg/day for 28 days, prevented the death of the mice but did not eradicate the infection. Formycin B given orally at 100 and 10 mg/kg/day X 5 days, showed a similar effect.

Topics: Allopurinol; Animals; Antibiotics, Antineoplastic; Chagas Disease; Formycins; Mice; Mice, Inbred DBA; Ribonucleosides; Trypanocidal Agents

Topics: Adult; Allopurinol; Chagas Disease; Female; Humans; Trypanocidal Agents

Strains of Trypanosoma cruzi differ in their susceptibilities to and metabolism of pyrazolopyrimidines. Allopurinol riboside can control but not eliminate infections with a sensitive strain in both tissue culture and mice. Formycin B, which proved to be greater than 10-fold more effective on a weight basis, showed a similar strain specificity but could eliminate an infection with a sensitive strain from tissue culture. However, this drug, unlike allopurinol riboside, was converted to toxic analogues of adenosine mono-, di-, and triphosphate by uninfected tissue culture cells. Thiopurinol and its riboside were effective against all strains unless culture was performed in purine-defined medium. Thus formycin B and allopurinol riboside appear to be good models for the design of antitrypanosomal agents. Suitable modification of the molecule may provide an effective chemotherapeutic agent.

Topics: Adenine; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Drug Resistance; Formycins; Inosine; Mice; Mice, Inbred DBA; Ribonucleosides; Thionucleosides; Trypanosoma cruzi

Allopurinol (4-hydroxypyrazolo [3,4-d]pyrimidine) is an effective agent in vitro against Trypanosoma cruzi. The important forms of this parasite, with respect to the pathogenesis of Chagas' disease in man, are the bloodstream (trypomastigote) and the intracellular forms. Experiments with radiolabeled allopurinol and analysis of the metabolic products of this compound by high-performance liquid chromatography showed that both the bloodstream and the intracellular forms of T. cruzi metabolize allopurinol in the same manner as has been shown for the epimastigotes in vitro. The metabolic pathways for pyrazolopyrimidines in the pathogenic forms were demonstrated with organisms isolated from infected animals and a tissue culture system infected with T. cruzi. Treatment of infected tissue culture with allopurinol eradicated the infection. This investigation implies that allopurinol may be useful in chemotherapy of T. cruzi infections, a supposition which has been borne out in one animal study.

Topics: Allopurinol; Animals; Cells, Cultured; Chagas Disease; Chinchilla; Culture Techniques; Erythrocytes; Spleen; Trypanosoma cruzi

Topics: Allopurinol; Animals; Chagas Disease; Liver; Male; Mice; Mice, Inbred C57BL; Spleen; Trypanosoma cruzi

Groups of mice were inoculated with six Trypanosoma cruzi strains and then treated with 32 mg/kg body weight allopurinol for 10 consecutive days. Effects of the drug on mortality rates were closely evaluated and repeated fresh blood examinations were done. Infected mice showed at least four parasitemia patterns with varied mortality rates and parasitemia levels. Evidence is provided that, independently of the parasitemia pattern or level and strain origin, there are marked differences in the sensitivity to allopurinol between the several T. cruzi strains studied. These differences in drug response seem to be related to biological characteristics of the strains and pose further challenges in the rational therapy of Chagas' disease.

Topics: Allopurinol; Animals; Chagas Disease; Mice; Mice, Inbred C57BL; Time Factors; Trypanosoma cruzi