Specific chemotherapy of Chagas disease: controversies and advances.

Parasite persistence in the aetiology of Chagas disease.

Chagas Disease Etiology: Autoimmunity or Parasite Persistence?

Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed.Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

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Experimental and Clinical Treatment of Chagas Disease: A Review.

BACKGROUND Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity. METHODS This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5). CONCLUSION Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced.

Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease

Eleven strains of Ttypanosoma cruzi were isolated from patients with Chagas disease in central Brazil by
xenodiagnosis and inoculation into newborn mice. Biological characterization and isoenzyme analysis
showed that 6 strains were type II (zymodeme 2) and 5 were type III (zymodeme 1). Patients were treated
with benznidazole or benznidazole plus nifurtimox. Mice infected with each isolated strain were treated for
comparison with the results obtained in the respective patient. Evaluation of cure of the patients was based
on the indirect immunofluorescence test, complement fixation reaction and xenodiagnosis. For the mice,
haemoculture, indirect immunofluorescence testing, xenodiagnosis and inoculation of blood into newborn
mice were used. Tests were performed 3-6 months after the end of treatment. The cure rate was 66-100% in
mice infected with type II strains and O-9% in those infected with type III strains. The correlation between
treatment results in patients and mice was 8 1.8% (9 of 11 cases). Type II strains were more susceptible to
treatment, in contrast to type III strains which yielded the majority of therapeutic failures.

https://www.arca.fiocruz.br/bitstream/icict/14625/2/Andrade%20SG%20Specific%20chemotherapy....pdf

Specific chemotherapy of Chagas disease: a comparison between the response in patients and experimental animals inoculated with the same strains

Ten patients with chronic Chagas' disease were treated with nifurtimox (8-9 mg/kg/day) associated with betamethasone (9 mg/day initially and then gradually reduced) during 60 days, with one exception. It was intended to combine the respective anti-parasitic and anti-inflammatory actions of these drugs. The expected stimulating effect of betamethasone on the infection could possibly enhance the anti-Trypanosoma cruzi action of nifurtimox. Long term persistence of negative xenodiagnosis, used to control the results, was observed in only one of the cases. Regaridng the other patients, post-treatment positivity of xenodiagnosis and serological testes attested the failure of this therapy. As this study has demonstrated, adequate and long term follow-up of treated cases is necessary to ensure correct conclusions.

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[Treatment of chronic Chagas' disease with an association of nifurtimox and corticoid].

Estudo biometrico de 10 amostras de Trypanosoma cruzi isoladas de casos humanos da doenca de CHAGAS, nove mantidas em camundongos brancos jovens e uma mantida em ratos brancos jovens, mostrou a existencia de grandes variacoes amostrais. Assim os valores do comprimento total medio das diferentes amostras variaram entre 16,3μ e 21,8μ., enquanto os valores do indice nuclear medio oscilaram entre 0,93 e 1,52. Estes resultados ampliam os limites de variacoes amostrais ate agora observadas no T. cruzi, especialmente os que se referem ao indice nuclear medio.

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Estudos sôbre reservatórios e vectores silvestres do Trypanosoma cruzi. XXIV. Variação dos dados biométricos obtidos em amostras do T. cruzi isolados de casos humanos da Doença de Chagas

Ratos inoculados previamente com a cepa Y do Trypanosoma cruzi (n = 15) e ratos-controles de mesma idade e sexo (n = 15) foram submetidos a estudo que consistiu no exame da mucosa gastrica apos a exposicao in vivo da mesma a solucao acidificada de um sal biliar, o taurocolato de sodio (TC). Em 10 animais de cada grupo procedeu-se tambem a contagem dos neuronios do plexo mienterico do estomago e ao exame histopatologico dos corpos neuronais, feito em microscopia optica convencional. Escores indicativos da gravidade das lesoes produzidas pelo TC foram significativamente maiores (P < 0,002) nos ratos chagasicos que nos controles. A area erosada da mucosa gastrica, em % da area total da regiao glandular do estomago, foi significativamente maior (P0,10) entre os ratos chagasicos (1683,6 ± 449,7 n = 10) e os controles (1732,8 ± 401,1 n = 10). Nao houve diferenca qualitativa ao exame histopatologico dos corpos neuronais. Estes resultados indicam que, na doenca de Chagas experimental cronica, a mucosa gastrica e mais sensivel a acao lesiva do TC, o que sugere reducao da citoprotecao natural do estomago. Esta anormalidade nao deve decorrer de alteracoes da inervacao intrinseca que impliquem reducao do numero de neuronios intramurais do estomago, mas pode ser o resultado de alteracoes qualitativas nao detectaveis a microscopia optica.

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Susceptibilidade da mucosa gástrica à ação lesiva de um sal biliar em ratos chagásicos crônicos

The Authors report two cases of chronic Chagas' heart disease. The children came from the States of Sao Paulo and Minas Gerais. The purposes of the report are to discuss the possibility of natural contamination in rural areas in those regions of the states from which the children came, and also to contribute to the knowledge of the Physiopathologic aspects of Chagas' heart disease. Both cases presented cardiac failure and did not respond to current therapeutic treatment and they died of uncontrolled cardiac failure. The Authors comment in a general way on the phisiopathology of the disease based on pertinent literature.

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Francisco Ferriolli Filho

Papers

Specific chemotherapy of Chagas disease: a comparison between the response in patients and experimental animals inoculated with the same strains

[Treatment of chronic Chagas' disease with an association of nifurtimox and corticoid].

Estudos sôbre reservatórios e vectores silvestres do Trypanosoma cruzi. XXIV. Variação dos dados biométricos obtidos em amostras do T. cruzi isolados de casos humanos da Doença de Chagas

Susceptibilidade da mucosa gástrica à ação lesiva de um sal biliar em ratos chagásicos crônicos

Cardiopatia chagásica em crianças: relato de dois casos