nifurtimox and Chagas-Disease

Chagas disease (American Trypanosomiasis) is classified by the World Health Organization (WHO) as one of the seventeen neglected tropical diseases (NTD), affecting, mainly, several regions of Latin America.. However, immigration has expanded the range of this disease to other continents. Thousands of patients with Chagas disease die annually, yet no new therapeutics for Chagas disease have been approved, with only nifurtimox and benznidazole available. Treatment with these drugs presents several challenges, including protozoan resistance, toxicity, and low efficacy. Natural products, including the secondary metabolites found in plants, offer a myriad of complex structures that can be sourced directly or optimized for drug discovery.. Therefore, this review aims to assess the literature from the last 10 years (2012-2021) and present the anti-T. cruzi compounds isolated from plants in this period, as well as briefly discuss computational approaches and challenges in natural product drug discovery. Using this approach, more than 350 different metabolites were divided based on their biosynthetic pathway alkaloids, terpenoids, flavonoids, polyketides, and phenylpropanoids which displayed activity against different forms of this parasite epimastigote, trypomastigote and more important, the intracellular form, amastigote.. In this aspect, there are several compounds with high potential which could be considered as a scaffold for the development of new drugs for the treatment of Chagas disease-for this, more advanced studies must be performed including pharmacokinetics (PK) and pharmacodynamics (PD) analysis as well as conduction of in vivo assays, these being important limitations in the discovery of new anti-T. cruzi compounds.

Topics: Chagas Disease; Drug Discovery; Humans; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi

Topics: Chagas Disease; Emigrants and Immigrants; Humans; Nifurtimox; Organ Transplantation; Trypanosoma cruzi; United States

Nifurtimox is a nitroheterocyclic drug employed for treatment of trypanosomiases (Chagas disease and West African sleeping sickness); its use for certain cancers has also been assessed. Despite having been in the market for over 50 years, knowledge of nifurtimox is still fragmentary and incomplete. Relevant aspects of the chemistry and biology of nifurtimox are reviewed to summarize the current knowledge of this drug. These comprise its chemical synthesis and the preparation of some analogues, as well as its chemical degradation. Selected physical data and physicochemical properties are also listed, along with different approaches toward the analytical characterization of the drug, including electrochemical (polarography, cyclic voltammetry), spectroscopic (ultraviolet-visible, nuclear magnetic resonance, electron spin resonance), and single crystal X-ray diffractometry. The array of polarographic, ultraviolet-visible spectroscopic, and chromatographic methods available for the analytical determination of nifurtimox (in bulk drug, pharmaceutical formulations, and biological samples), are also presented and discussed, along with chiral chromatographic and electrophoretic alternatives for the separation of the enantiomers of the drug. Aspects of the drug likeliness of nifurtimox, its classification in the Biopharmaceutical Classification System, and available pharmaceutical formulations are detailed, whereas pharmacological, chemical, and biological aspects of its metabolism and disposition are discussed.

Topics: Chagas Disease; Humans; Nifurtimox; Pharmaceutical Preparations; Pharmacy

Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment: benznidazole (BZN) and nifurtimox (NF). Treating CD-infected patients, especially children and women of reproductive age, is vital in order to prevent long-term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Early diagnosis and treatment of CD, especially in paediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drug development.

Topics: Biomarkers; Chagas Disease; Child; Female; Humans; Nifurtimox; Treatment Outcome; Trypanosoma cruzi

Chagas disease is a neglected parasitosis caused by the protozoan parasite Trypanosoma cruzi. This infection is present in most Latin American countries, although, due to migratory movements, it is a growing cause for concern in non-endemic countries. The only two drugs currently available for its treatment-benznidazole and nifurtimox-were marketed 50 years ago. While they are very effective for acute and recent infection, and for the prevention of maternofoetal transmission, their efficacy declines in people who have chronic infection, especially those older than 18 years of age. In the presence of visceral involvement, parasiticidal treatment is of little or no value. The safety profile of both drugs is far from ideal, with frequent adverse events and high rates of drug discontinuation, mainly in adults. So far, new drugs and new strategies have not been shown to improve the results of the current nitroimidazoles, although the results are promising. In this review, we focus on the aspects that allow clinicians to make the best use of currently available drugs. In addition, we discuss new therapeutic options and ongoing research in the field.

Topics: Adult; Antiparasitic Agents; Chagas Disease; Humans; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by the protozoan Trypanosoma cruzi is a neglected tropical disease with high prevalence (5.7 million in Latin America, WHO 2015), significant burden, and significant morbimortality mostly due to severe heart disorders during the chronic phase of infection. Chagas disease is endemic in Latin America, and medical care for the disease is the major expense for Brazil's Universal Healthcare System (Sistema Único de Saúde (SUS). The efficacy of the available drugs benznidazole and nifurtimox are low for the chronic phase of Chagas disease, the phase in which most patients are diagnosed, and there are frequent side effects, and drug resistance occurs. The rapid deployment of new drug regimens that are effective for the chronic phase treatment is low-cost and less toxic than the currently available therapy, which is a global priority. Repurposing drugs already in clinical use with other combinations would be the fastest and safest strategy for treating Chagas disease patients. We hypothesize that the combined treatment using repurposing drugs with benznidazole will be more efficacious than benznidazole alone. This needs to be tested further both in vitro and in animal models to understand the efficacy of the treatment before performing human clinical trials. We further hypothesize that producing nanoparticle formulation of the drugs can reduce their toxicity and improve therapeutic use.

Topics: Animals; Chagas Disease; Drug Repositioning; Humans; Neglected Diseases; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is a vector-borne neglected tropical disease caused by Trypanosoma cruzi. It is a systemic and chronic parasitic infection which is endemic in 21 countries with 10 million cases worldwide and 12,000 annual deaths. Around 70 million people in the Americas are at risk of contracting this disease, and less than 1% of infected people are treated due to low disease awareness and limited access to treatment. The current treatment for Chagas disease consists of benznidazole and nifurtimox under the World Health Organization (WHO) authorization protocol. The current treatment has limitations in terms of efficacy against the chronic phase of infection and side effects associated with prolonged therapy. This review provides an update on nifurtimox progress over the years and its recent approval by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of Chagas disease in pediatric patients under 18 years of age.

Topics: Adolescent; Chagas Disease; Child; Humans; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi; United States; United States Food and Drug Administration

Chagas disease, caused by Trypanosoma cruzi, is treated with only two drugs; benznidazole and nifurtimox. These drugs have some disadvantages, including their efficacy only in the acute or early infection phases, adverse effects during their use, and the resistance that the parasite has developed to their activity. Therefore, it is necessary to identify new, safe and effective therapeutic alternatives to treat Chagas disease, though governments and the pharmaceutical industry have shown a lack of interest in contributing to this solution. Institutions and research groups on the other hand have worked on some strategies that can help to address the problem. Some of these include the modification of conventional drug dosages, drug repurposing, and combined therapy. Plants and derived compounds with antiparasitic effects have also been studied, taking advantage of traditional medicinal knowledge. Others have studied the parasite to identify essential genes that can be used as therapeutic targets to design new, targeted drugs. Some of these studies have generated promising results, but few reach clinical phase studies. Institutions and research groups should be encouraged to unify efforts and cover all aspects of drug development according to resources and knowledge availability. In the end, this exchange of knowledge would lead to the development of new therapeutic alternatives to treat Chagas disease and benefit the populations it affects.

Topics: Animals; Chagas Disease; Drug Development; Drug Resistance; Humans; Medicine, Traditional; Molecular Targeted Therapy; Nifurtimox; Nitroimidazoles; Plant Preparations; Trypanocidal Agents; Trypanosoma cruzi

Despite more than 100 years since it was firstly described Chagas disease, only two drugs are available to treat Chagas disease: Nifurtimox launched by Bayer in 1965 and benznidazole launched by Roche in 1971. Drug discovery initiatives have been looking for new compounds as an alternative to these old drugs. Although new platforms have been used with the latest technologies, a critical step on that process still relies on the in vivo model. Unfortunately, to date, available animal models have limited predictive value and there is no standardization. With the aim to better understand the role of benznidazole, the current standard of care of Chagas disease, we performed this review. We intend to analyze the influence of the experimental design of the most used animal model, the murine model, in the assessment of the efficacy endpoint.

Topics: Animals; Chagas Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is an infectious tropical disease included within the group of neglected tropical diseases. Though historically endemic to Latin America, it has lately spread to high-income countries due to human migration. At present, there are only two available drugs, nifurtimox and benznidazole, approved for this treatment, both with considerable side-effects (which often result in treatment interruption) and limited efficacy in the chronic stage of the disease in adults. Drug repositioning involves finding novel therapeutic indications for known drugs, including approved, withdrawn, abandoned and investigational drugs. It is today a broadly applied approach to develop innovative medications, since indication shifts are built on existing safety, ADME and manufacturing information, thus greatly shortening development timeframes. Drug repositioning has been signaled as a particularly interesting strategy to search for new therapeutic solutions for neglected and rare conditions, which traditionally present limited commercial interest and are mostly covered by the public sector and not-for-profit initiatives and organizations. Here, we review the applications of computer-aided technologies as systematic approaches to drug repositioning in the field of Chagas disease. In silico screening represents the most explored approach, whereas other rational methods such as network-based and signature-based approximations have still not been applied.

Topics: Chagas Disease; Drug Repositioning; Humans; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could bette

Topics: Adult; Cardiomyopathies; Chagas Disease; Databases, Factual; Humans; Nifurtimox; Nitroimidazoles; Patient Safety; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles; Trypanosoma cruzi

People with Chagas disease may develop progressive and lethal heart conditions. Drugs to eliminate the parasite Trypanosoma cruzi (T cruzi) currently carry limited therapeutic value and are used in the early stages of the disease. Extending the use of these drugs to treat chronic chagasic cardiomyopathy (CCC) has also been proposed.. To assess the benefits and harms of nitrofurans and trypanocidal drugs for treating late-stage, symptomatic Chagas disease and CCC in terms of blood parasite reduction or clearance, mortality, adverse effects, and quality of life.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS databases on 12 November 2019. We also searched two clinical trials registers, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), on 3 December 2019.. We included randomised controlled trials (RCTs) assessing trypanocidal drugs versus placebo or no treatment for late-stage, symptomatic Chagas disease and CCC.. We conducted the reporting of the review according the standard Cochrane methods. Two review authors independently retrieved articles, performed data extraction, and assessed risk of bias. Any disagreements were resolved by a third review author. We contacted study authors for additional information.. We included two studies in this review update. One RCT randomly assigned 26 participants to benznidazole 5 mg/kg/day; 27 participants to nifurtimox 5 mg/kg/day; and 24 participants to placebo for 30 days. The second RCT, newly included in this update, randomised 1431 participants to benznidazole 300 mg/day for 40 to 80 days and 1423 participants to placebo. We also identified one ongoing study. Benznidazole compared to placebo At five-year follow-up, low quality of the evidence suggests that there may be a benefit of benznidazole when compared to placebo for clearance or reduction of antibody titres (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.14 to 1.37; 1 trial; 1896 participants). We are uncertain about the effects of benznidazole for the clearance of parasitaemia demonstrated by negative xenodiagnosis, blood culture, and/or molecular assays due to very limited evidence. Low quality of the evidence suggests that when compared to placebo, benznidazole may make little to no difference in the risk of heart failure (RR 0.89, 95% CI 0.69 to 1.14; 1 trial; 2854 participants) and ventricular tachycardia (RR 0.80, 95% CI 0.51 to 1.26; 1 trial; 2854 participants). We found moderate quality of the evidence that adverse events increase with benznidazole when compared to placebo (RR 2.52, 95% CI 2.09 to 3.03; 1 trial; 2854 participants). Adverse effects were observed in 23.9% of patients in the benznidazole group compared to 9.5% in the placebo group. The most frequent adverse effects were: cutaneous rash, gastrointestinal symptoms, and peripheral polyneuropathy. No data were available for the outcomes of pathological demonstration of tissue parasites and quality of life. Nifurtimox compared to placebo Data were only available for this comparison for the outcome clearance or reduction of antibody titres, and we are uncertain about the effect due to very limited evidence. Regarding adverse events, one RCT mentioned in a general manner that nifurtimox caused intense adverse events, without any quantification.. There is insufficient evidence to support the efficacy of the trypanocidal drugs benznidazole and nifurtimox for late-stage, symptomatic Chagas disease and CCC.

Topics: Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Placebos; Randomized Controlled Trials as Topic; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by infection with the parasite Trypanosoma cruzi, represents a huge public health problem in the Americas, where millions of people are affected. Despite the availability of two drugs against the infection (benznidazole and nifurtimox), multiple factors impede their effective usage: (1) gaps in patient and healthcare provider awareness; (2) lack of access to diagnosis; (3) drug toxicity and absence of treatment algorithms to address adverse effects; (4) failures in drug supply and distribution; and (5) inconsistent drug efficacy against the symptomatic chronic stage. Areas covered: We review new approaches and technologies to enhance access to diagnosis and treatment to reduce the disease burden. We also provide an updated picture of recently published and ongoing anti-T. cruzi drug clinical trials. Although there has been progress improving the research and development (R&D) landscape, it is unclear whether any new treatments will emerge soon. Literature search methodologies included multiple queries to public databases and the use of own-built libraries. Expert opinion: Besides R&D, there is a major need to continue awareness and advocacy efforts by patient associations, local and national governments, and international agencies. Overall, health systems strengthening is essential to ensure vector control commitments, as well as patient access to diagnosis and treatment.

Topics: Chagas Disease; Health Services Accessibility; Humans; Latin America; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Neglected tropical diseases (NTDs) constitute a group of infectious diseases prevalent in countries with tropical and subtropical climate that affect the poorest individuals and produce high chronic disability associated with serious problems for the health system and socioeconomic development. Chagas disease or American trypanosomiasis is included on the NTDs list. However, even though this disease affects more than 10 million people, mostly in Latin America, causing the death of over 10,000 people every year, only two drugs are approved for its treatment, benznidazole and nifurtimox. These antiparasitic agents were developed almost half a century ago and present several biopharmaceutical disadvantages such as low aqueous solubility and permeability limiting their bioavailability. In addition, both therapeutic agents are available only as tablets and a liquid pediatric formulation is still lacking. Therefore, novel pharmaceutical strategies to optimize the pharmacotherapy of Chagas disease are urgently required. In this regard, nanotechnological approaches may be a crucial alternative for the delivery of both drugs ensuring an effective pharmacotherapy although the successful bench-to-bedside translation remains a major challenge. The present work reviews in detail the formulation and in-vitro/in-vivo analysis of different nanoformulations of nifurtimox and benznidazole in order to enhance their solubility, dissolution, bioavailability and trypanocidal activity.

Topics: Chagas Disease; Dosage Forms; Humans; Nanostructures; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It is a significant public health problem, affecting millions of people worldwide. And although it was described 110 years ago, only two old nitroheterocyclic drugs, benznidazole and nifurtimox, are currently available for the treatment of Chagas disease and both have several limitations. Besides the clear unmet medical need, many challenges preclude the development of new treatments, some of them related to a lack of understanding of the pathophysiology of the disease and parasite-host interactions. New knowledge and tools are becoming available, but the number of new chemical entities progressing through the preclinical pipeline is inadequate. Therefore, it is still uncertain whether safe, effective and accessible new drugs will be available in the near future. The Chagas disease research community must commit to even greater collaboration to ensure that patients eventually benefit from better treatments.

Topics: Chagas Disease; Drug Discovery; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease has become a global health problem due to migration of infected people out of Latin America to non-endemic countries. For more than 40 years, only the nitroimidazole compounds Benznidazole and Nifurtimox, have been used for specific treatment of Trypanosoma cruzi infection with disappointing results, specially due to the long duration of treatment and adverse events in the chronic phase. In the last years, ergosterol inhibitors have been also proposed for specific treatment. Different randomized clinical trials were performed for evaluating their treatment efficacy and safety. One of the greatest concerns in clinical trials is to provide an early surrogate biomarker of response to trypanocidal chemotherapy. Serological response is slow and the classical parasitological tests have poor sensitivity and are time-consuming. Nowadays, PCR is the most helpful tool for assessing treatment response in a short period of time. Different protocols of PCR have been developed, being quantitative real time PCR based on amplification of repetitive satellite or minicircle DNA sequences plus an internal amplification standard, the mostly employed strategies in clinical trials. Standardized protocols and the use of an external quality assessment ensure adequate technical procedures and reliable data. Clinical trials have shown a significant reduction in parasite loads, reaching undetectable DNA levels in bloodstream after specific treatment, however events of treatment failure have also been reported. Treatment failure could be due to inadequate penetrance of the drugs into the affected tissues, to the presence of primary or secondary drug resistance of the infecting strains as well as to the existence of dormant parasite variants reluctant to drug action. The early diagnosis of drug resistance would improve clinical management of Chagas disease patients, allowing dictating alternative therapies with a combination of existing drugs or new anti-T. cruzi agents. The aim of this review was to describe the usefulness of detecting T.cruzi DNA by means of real time PCR assays, as surrogate biomarker in clinical trials for evaluating new drugs for CD or new regimens of available drugs and the possibility to detect treatment failure.

Topics: Biomarkers; Chagas Disease; Chronic Disease; Drug Resistance; Humans; Nifurtimox; Nitroimidazoles; Nucleic Acids; Parasite Load; Real-Time Polymerase Chain Reaction; Treatment Failure; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

The genetic diversity of Trypanosoma cruzi, the protozoan agent of Chagas disease, is widely recognized. At present, T. cruzi is partitioned into seven discrete typing units (DTUs), TcI-TcVI and Tcbat. This article reviews the present knowledge on the parasite population structure, the evolutionary relationships among DTUs and their distinct, but not exclusive ecological and epidemiological associations. Different models for the origin of hybrid DTUs are examined, which agree that genetic exchange among T. cruzi populations is frequent and has contributed to the present parasite population structure. The geographic distribution of the prevalent DTUs in humans from the southern United States to Argentina is here presented and the circumstantial evidence of a possible association between T. cruzi genotype and Chagas disease manifestations is discussed. The available information suggests that parasite strains detected in patients, regardless of the clinical presentation, reflect the principal DTU circulating in the domestic transmission cycles of a particular region. In contrast, in several orally transmitted outbreaks, sylvatic strains are implicated. As a consequence of the genotypic and phenotypic differences of T. cruzi strains and the differential geographic distribution of DTUs in humans, regional variations in the sensitivity of the serological tests are verified. The natural resistance to benznidazole and nifurtimox, verified in vivo and in vitro for some parasite stocks, is not associated with any particular DTU, and does not explain the marked difference in the anti-parasitic efficacy of both drugs in the acute and chronic phases of Chagas disease. Throughout this review, it is emphasized that the interplay between parasite and host genetics should have an important role in the definition of Chagas disease pathogenesis, anti-T. cruzi immune response and chemotherapy outcome and should be considered in future investigations.

Topics: Animals; Argentina; Biological Evolution; Chagas Disease; Drug Resistance; Genetic Variation; Genotype; Humans; Nifurtimox; Nitroimidazoles; Serologic Tests; Trypanosoma cruzi

Chagas disease is caused by the parasite Trypanosoma cruzi and is regularly found among particular people living in Central and South America. Paediatric Chagas disease occurs in 1-10% of infants of infected mothers. The major important point considered in the treatment of congenital Chagas disease focuses on killing the parasite in acute infection and managing signs and symptoms in later stages. Nowadays, two drugs benznidazole and nifurtimox are currently available in the market for the treatment of paediatric Chagas disease.

Topics: Antiparasitic Agents; Chagas Disease; Drug Discovery; Humans; Nifurtimox; Nitroimidazoles; Parasitic Sensitivity Tests; Trypanosoma cruzi

Chagas disease (CD) is caused by the protozoan parasite

Topics: Animals; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Disease Models, Animal; Drug Compounding; Humans; Incidence; Latin America; Nanoparticles; Nifurtimox; Nitroimidazoles; Observational Studies as Topic; Randomized Controlled Trials as Topic; Tissue Distribution; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease or American trypanosomiasis is a major parasitic disease in Latin America with restricted available treatment: nifurtimox and benznidazole. These two drugs are ineffective in the chronic phase of the disease; therefore, there is a need for the development of new, efficient and safe drugs for the treatment of this pathology. With this goal, one of the promising targets is trypanothione reductase (TR), a key enzyme in the metabolism of Trypanosoma cruzi.. In this review, we analyse the importance of TR as a drug target, as well as the well-known and new inhibitors reported in the last decade as potential therapeutic agents for Chagas disease.

Topics: Animals; Chagas Disease; Drug Delivery Systems; Enzyme Inhibitors; Humans; Molecular Structure; NADH, NADPH Oxidoreductases; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi

One of the most significant health problems in the American continent in terms of human health, and socioeconomic impact is Chagas disease, caused by the protozoan parasite Trypanosoma cruzi. Infection was originally transmitted by reduviid insects, congenitally from mother to fetus, and by oral ingestion in sylvatic/rural environments, but blood transfusions, organ transplants, laboratory accidents, and sharing of contaminated syringes also contribute to modern day transmission. Likewise, Chagas disease used to be endemic from Northern Mexico to Argentina, but migrations have earned it global. The parasite has a complex life cycle, infecting different species, and invading a variety of cells - including muscle and nerve cells of the heart and gastrointestinal tract - in the mammalian host. Human infection outcome is a potentially fatal cardiomyopathy, and gastrointestinal tract lesions. In absence of a vaccine, vector control and treatment of patients are the only tools to control the disease. Unfortunately, the only drugs now available for Chagas' disease, Nifurtimox and Benznidazole, are relatively toxic for adult patients, and require prolonged administration. Benznidazole is the first choice for Chagas disease treatment due to its lower side effects than Nifurtimox. However, different strategies are being sought to overcome Benznidazole's toxicity including shorter or intermittent administration schedules-either alone or in combination with other drugs. In addition, a long list of compounds has shown trypanocidal activity, ranging from natural products to specially designed molecules, re-purposing drugs commercialized to treat other maladies, and homeopathy. In the present review, we will briefly summarize the upturns of current treatment of Chagas disease, discuss the increment on research and scientific publications about this topic, and give an overview of the state-of-the-art research aiming to produce an alternative medication to treat T. cruzi infection.

Topics: Americas; Chagas Disease; Humans; Life Cycle Stages; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

A conservative estimation indicates that more than 400 000 Latin American immigrants are living in Italy. Several studies have shown that among these, the prevalence of Chagas disease is between 3.9% and 17%, so it is not unlikely to find a patient with this disease during a cardiology visit. How many patients from Latin America are diagnosed with heart failure in Italy and no one has ever thought about a possible Chagas disease? This brief review describes the situation of the disease in Italy, its characteristics, the etiology of this disease and its treatment. The latter aspect will be discussed considering the recent published results of the BENEFIT study, where it was found that treatment with benznidazole in patients with Chagas' cardiomyopathy is able to reduce significantly the detection of parasites in the blood, but it is not able to prevent clinical deterioration during 5 years of follow-up. The possible implications of these results will be discussed.

Topics: Chagas Cardiomyopathy; Chagas Disease; Emigrants and Immigrants; Humans; Italy; Neglected Diseases; Nifurtimox; Nitroimidazoles; Prevalence; South America; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process.

Topics: Chagas Disease; Clinical Trials as Topic; Drug Discovery; Humans; Nifurtimox; Nitroimidazoles; Real-Time Polymerase Chain Reaction; RNA, Protozoan; Trypanocidal Agents; Trypanosoma cruzi

BACKGROUND Chagas disease is a chronic parasitosis transmitted by the inoculation of infected triatomine feces into wounds or conjunctival sac, transfusion, congenitally, organ transplantation, and ingestion of contaminated food. The disease is classified into an acute and chronic phase; the latter is a life-long infection that can be asymptomatic or progress to cardiac or digestive complications. CASE REPORT We report a case of acute-phase Chagas disease, transmitted by the splash of gut content from an infected triatomine into the conjunctival mucosa. CONCLUSIONS The diagnosis of Chagas disease is made by the direct visualization of the parasite in blood smears during the acute phase of the disease; during the chronic phase of the disease the diagnosis is made by the detection of IgG antibodies. Parasitological cure can be achieved in up to 80% of the cases in acute phase of the disease, in contrast with less than 30% during the chronic phase.

Topics: Adult; Animals; Chagas Disease; Edema; Fever; Headache; Humans; Male; Neglected Diseases; Nifurtimox; Treatment Outcome; Triatominae; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). It is endemic in Latin American countries outside the Caribbean. The current criterion for cure in the chronic phase of the disease is the negativization of at least two serological tests such as enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IIF) and indirect hemagglutination assay (IHA). The serological evolution of treated subjects with chronic T. cruzi infection is variable. Treatment failure is indicated by a positive parasitological and/or molecular test (persistence of parasitemia).. To summarize the pattern of response to treatment of parasitological, molecular and serological tests performed during the follow-up of subjects with chronic T. cruzi infection.. Electronic searches in relevant databases and screening of citations of potentially eligible articles were accomplished. Organizations focusing on neglected infectious diseases were asked for help in identifying relevant studies. Included studies were randomized controlled trials (RCTs), quasi-RCTs, and cohort studies involving adults and children with chronic infection who received trypanocidal treatment (benznidazole or nifurtimox) and were followed over time. The assessment of risk of bias was performed separately for each study design. The Cochrane Collaboration's tool and the guidelines developed by Hayden et al. were used. Two reviewers extracted all data independently. A third review author was consulted in case of discordant opinion. Additional analyses were defined in ad-hoc basis. Scatter plots for percentage of positive parasitological and molecular tests and for negative serological tests were developed by using the lowess curve technique. Heterogeneity was measured by I2. The protocol was registered in PROSPERO, an international prospective register of systematic review protocols (Registration Number CRD42012002162).. Out of 2,136 citations screened, 54 studies (six RCTs and 48 cohort studies) were included. The smoothed curves for positive xenodiagnosis and positive polymerase chain reaction (PCR) were characterized by a sharp decrease at twelve month posttreatment. Afterwards, they reached 10-20% and 40% for xenodiagnosis and PCR, respectively. The smoothed curves for negative conventional serological tests increased up to 10% after 48 months of treatment. In the long-term, the rate of negativization was between 20% and 45%. The main sources of bias identified across cohort studies were the lack of control for confounding and attrition bias. In general, RCTs were judged as low risk of bias in all domains. The level of heterogeneity across included studies was moderate to high. Additional analysis were incomplete because of the limited availability of data. In this regard, the country of origin of study participants might affect the results of parasitological and molecular tests, while the level of risk of bias might affect serological outcomes. Subgroup analysis suggested that seronegativization occurs earlier in children compared to adults.. We acknowledge that there is a dynamic pattern of response based on parasitological, molecular and serological tests in subjects chronically infected with T. cruzi after treatment. Our findings suggest a trypanocidal effect in the long-term follow-up. Further research is needed to explore potential sources of heterogeneity and to conduct reliable subgroup analysis.

Topics: Adult; Antibodies, Protozoan; Chagas Disease; Child; Chronic Disease; Cohort Studies; Disease Progression; DNA, Protozoan; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Hemagglutination Tests; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Randomized Controlled Trials as Topic; Treatment Failure; Trypanocidal Agents; Trypanosoma cruzi; Xenodiagnosis

In the last decades, increasing international migration and travel from Latin America to Europe have favoured the emergence of tropical diseases outside their "historical" boundaries. Chagas disease, a zoonosis endemic in rural areas of Central and South America represents a clear example of this phenomenon. In the absence of the vector, one of the potential modes of transmission of Chagas disease in non-endemic regions is through blood and blood products. As most patients with Chagas disease are asymptomatic and unaware of their condition, in case of blood donation they can inadvertently represent a serious threat to the safety of the blood supply in non-endemic areas. Since the first cases of transfusion-transmitted Chagas disease were described in the last years, non-endemic countries began to develop ad hoc strategies to prevent and control the spread of the infection. United States, Spain, United Kingdom and France first recognised the need for Trypanosoma cruzi screening in at-risk blood donors. In this review, we trace an up-to-date perspective on Chagas disease, describing its peculiar features, from epidemiological, pathological, clinical and diagnostic points of view. Moreover, we describe the possible transmission of Chagas disease through blood or blood products and the current strategies for its control, focusing on non-endemic areas.

Topics: Adult; Blood Donors; Blood Safety; Chagas Disease; Donor Selection; Emigration and Immigration; Enzyme-Linked Immunosorbent Assay; Europe; Female; Global Health; Health Services Needs and Demand; Humans; Infant, Newborn; Latin America; Male; Mass Screening; Nifurtimox; Nitroimidazoles; North America; Parasitemia; Pregnancy; Pregnancy Complications, Infectious; Transfusion Reaction; Travel; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is the highest impact parasitic disease in the Americas but often goes untreated due to the shortcomings of currently available therapeutics. Thus there is an urgent need for new treatment options and growing interest in drug development for the infection. This review summarizes some of the recent advances and failures in this realm, with particular emphasis on recently published studies and unpublished results presented at a recent Chagas Drug Discovery Consortium meeting.

Topics: Chagas Disease; Clinical Trials as Topic; Drug Discovery; Drug Therapy, Combination; Humans; Nifurtimox; Nitroimidazoles; Sterols; Trypanocidal Agents; Trypanosoma cruzi

For years, Chagas disease treatment has been limited to only two drugs of highly questionable and controversial use (Nifurtimox(®) and Benznidazole(®)). In the search of effective drugs, many efforts have been made, but only a few structures have emerged as actual candidates. Heading into this, the multitarget-directed approach appears as the best choice. In this framework, indazoles were shown to be potent Trypanosoma cruzi growth inhibitors, being able to lead both the formation of reactive oxygen species and the inhibition of trypanothione reductase. Herein, we discuss the main structural factors that rule the anti-T. cruzi properties of indazoles, and how they would be involved in the biological properties as well as in the action mechanisms, attempting to make parallels between the old paradigms and current evidences in order to outline what could be the next steps to follow in regard to the future drug design for Chagas disease treatment.

Topics: Chagas Disease; Drug Design; Humans; Indazoles; NADH, NADPH Oxidoreductases; Nifurtimox; Nitroimidazoles; Protozoan Proteins; Reactive Oxygen Species; Trypanocidal Agents; Trypanosoma cruzi

Immunosuppression, which has become an increasingly relevant clinical condition in the last 50 years, modifies the natural history of Trypanosoma cruzi infection in most patients with Chagas disease. The main goal in this setting is to prevent the consequences of reactivation of T. cruzi infection by close monitoring. We analyze the relationship between Chagas disease and three immunosuppressant conditions, including a description of clinical cases seen at our center, a brief review of the literature, and recommendations for the management of these patients based on our experience and on the data in the literature. T. cruzi infection is considered an opportunistic parasitic infection indicative of AIDS, and clinical manifestations of reactivation are more severe than in acute Chagas disease. Parasitemia is the most important defining feature of reactivation. Treatment with benznidazole and/or nifurtimox is strongly recommended in such cases. It seems reasonable to administer trypanocidal treatment only to asymptomatic immunosuppressed patients with detectable parasitemia, and/or patients with clinically defined reactivation. Specific treatment for Chagas disease does not appear to be related to a higher incidence of neoplasms, and a direct role of T. cruzi in the etiology of neoplastic disease has not been confirmed. Systemic immunosuppressive diseases or immunosuppressants can modify the natural course of T. cruzi infection. Immunosuppressive doses of corticosteroids have not been associated with higher rates of reactivation of Chagas disease. Despite a lack of evidence-based data, treatment with benznidazole or nifurtimox should be initiated before immunosuppression where possible to reduce the risk of reactivation. Timely antiparasitic treatment with benznidazole and nifurtimox (or with posaconazole in cases of therapeutic failure) has proven to be highly effective in preventing Chagas disease reactivation, even if such treatment has not been formally incorporated into management protocols for immunosuppressed patients. International consensus guidelines based on expert opinion would greatly contribute to standardizing the management of immunosuppressed patients with Chagas disease.

Topics: Adult; Antiprotozoal Agents; Chagas Disease; Female; Humans; Immunocompromised Host; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Opportunistic Infections; Triazoles; Trypanosoma cruzi

Hundred years after the discovery of Chagas' disease, there is a lack of effective treatment to control this neglected disease caused by the parasite Trypanosoma cruzi. The transmission is primarily through vector-borne blood transfusion or during pregnancy, producing high mortality and morbidity among poor people in many countries of Latin America. In the last decades, the efforts have been focused mainly on the elimination of vectors. At the same time, screening of blood donors in order to avoid transfusional transmission has been improved all over the world. However, Chagas' disease is still a major public health problem, with estimates of nearly 90 million people at risk of infection and more than eight million infected in 18 endemic countries. Despite the high incidence in endemic regions and the dissemination of neglected diseases in North America and Europe, to date, there are only two drugs developed and prescribed for the treatment of Chagas' disease, nifurtimox (tablets of 120 mg) and benzonidazole (tablets of 100 mg). In this review, different approaches carried out in the last decades for developing novel pharmaceutical formulations for the delivery of nifurtimox and benznidazole are discussed.

Topics: Animals; Chagas Disease; Drug Delivery Systems; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Most Chagas patients belong to the chronic indeterminate stage, in which pharmacological treatment has an inconclusive outcome.. To evaluate the efficacy of nifurtimox treatment in chronic asymptomatic Trypanosoma cruzi infection.. We performed a systematic review and meta-analysis of electronically published literature, with no language, type of study, age or gender restrictions, until September 2010. Studies of chronic asymptomatic Chagas disease patients treated exclusively with nifurtimox were included in the analysis. Treatment efficacy was evaluated using parasitological or serological parameters.. Of 463 identified studies, 7 were finally selected: 6 observational studies and 1 randomized clinical trial; 4 of the studies were in adults, 3 in children < 14 years. In 6 studies, outcomes were defined by serological techniques. Summary estimate (log odds) was 0.37 (CI9 -1.32 - 2.07).. The analyzed studies gave discordant results. Those might be explained by differences in the populations studied, follow-up periods, diagnostic techniques, and sample size. More studies are necessary to obtain conclusive results about treatment efficacy of nifurtimox in this clinical phase of T. cruzi infection.

Topics: Adult; Chagas Disease; Child; Chronic Disease; Humans; Nifurtimox; Treatment Outcome; Trypanocidal Agents

Chagas disease, also known as American trypanosomiasis, is a chronic infection caused by Trypanosoma cruzi, a protozoan parasite. It is transmitted to human beings mainly through the feces of infected triatomine bugs. The disease affects an estimated 8 to 10 million people in the Americas, putting them at risk of developing life-threatening cardiac and gastrointestinal complications. This article provides a brief update on the epidemiology, clinical manifestations, diagnosis, and treatment of Chagas disease.

Topics: Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.

Topics: Adult; Animals; Chagas Disease; Child; Clinical Trials as Topic; Drug Administration Schedule; Humans; Latin America; Mice; Myocarditis; Nifurtimox; Nitroimidazoles; Survival Analysis; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease and African sleeping sickness are trypanosomal infections that represent important public health problems in Latin America and Africa, respectively. The restriction of these diseases to the poorer parts of the world has meant that they have been largely neglected and limited progress has been made in their treatment. The nitroheterocyclic prodrugs nifurtimox and benznidazole, in use against Chagas disease for >40 years, remain the only agents available for this infection. In the case of African sleeping sickness, nifurtimox has recently been added to the arsenal of medicines, with the nitroheterocycle fexinidazole currently under evaluation. For a long time, the cytotoxic mechanism of these drugs was poorly understood: nifurtimox was thought to act via production of superoxide anions and nitro radicals, while the mode of benznidazole action was more obscure. The trypanocidal activity of nitroheterocyclic drugs is now known to depend on a parasite type I nitroreductase (NTR). This enzyme is absent from mammalian cells, a difference that forms the basis for the drug selectivity. The role of this enzyme in drug activation has been genetically and biochemically validated. It catalyses the 2-electron reduction of nitroheterocyclic compounds within the parasite, producing toxic metabolites without significant generation of superoxide. Recognition that this enzyme is responsible for activation of nitroheterocyclic prodrugs has allowed screening for compounds that preferentially target the parasite. This approach has led to the identification of two new classes of anti-trypanosomal agents, nitrobenzylphosphoramide mustards and aziridinyl nitrobenzamides, and promises to yield new, safer, more effective drugs.

Topics: Africa; Animals; Benzamides; Chagas Disease; Humans; Insect Vectors; Latin America; Nifurtimox; Nitro Compounds; Nitroimidazoles; Nitroreductases; Phosphoramide Mustards; Prodrugs; Protozoan Proteins; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis, African

Topics: Adult; Animals; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Disease Progression; Electrocardiography; Female; Humans; Life Cycle Stages; Nifurtimox; Nitroimidazoles; Practice Guidelines as Topic; Trypanocidal Agents; Trypanosoma cruzi

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 is a neglected parasitic disease endemic in the Americas. It mainly affects impoverished populations and the acute phase of the infection mostly affects children. Many cases have also been detected in nonendemic countries as a result of recent migratory trends. The chronic phase is relatively asymptomatic, but 30% of patients with chronic infection eventually develop cardiac and digestive complications that commonly lead to death or disability. Only two drugs are available for the treatment of Chagas disease, benznidazole and nifurtimox. These drugs have been shown to be effective in the treatment of both acute and early chronic phases in children, but the pharmacokinetics of these drugs have never been studied in this population. We have set out to conduct a pharmacokinetics study of benznidazole in a pediatric population with Chagas disease. The results of this study are expected to allow better estimation of the optimal doses and schedule of pharmacotherapy for Chagas disease in children.

Topics: Argentina; Chagas Cardiomyopathy; Chagas Disease; Child; Drug Administration Schedule; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

It is estimated that over 300,000 people with Chagas disease are living in the USA, with more than 30,000 cases of Chagas cardiomyopathy expected per year. The epidemiology of Chagas disease in Central and South America differs from that of the USA, where particular attention must focus on blood bank screening, organ donation and vertical transmission. It is essential that healthcare practitioners have heightened awareness of Chagas disease in the differential diagnosis of certain patients and are aware of recommendations for the management of these patients in the USA. Ongoing attention must focus on trials that determine whether all patients will benefit from treatment as well as studies of new agents for therapy.

Topics: Chagas Disease; Guidelines as Topic; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi; United States

Chagas disease is a significant public health problem in the Americas, despite efforts to decrease the number of new cases since 1990. Etiologic treatment of the disease's chronic phase is still controversial.. We reviewed the strongest studies to evaluate the drugs used in the acute and chronic disease phases, with emphasis on benznidazole.. A Medline search using the keywords 'Chagas disease' and 'treatment,' with no date limitations, was performed.. Study methods in completed trials varied greatly, with none being a randomized, double-blind, placebo-controlled study. The only trial using these methods is still ongoing. The treatment in acute phase is the major indication, but during chronic phase doubts still remain.. Only patients in the acute phase of Chagas disease (whatever their age; including children and adolescents) who are treated have good outcomes, although the criteria defining 'cure' remain controversial.

Topics: Adolescent; Adult; Chagas Disease; Child; Humans; Middle Aged; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Current knowledge of the biochemistry of Trypanosoma cruzi has led to the development of new drugs and the understanding of their mode of action. Some trypanocidal drugs such as nifurtimox and benznidazole act through free radical generation during their metabolism. T. cruzi is very susceptible to the cell damage induced by these metabolites because enzymes scavenging free radicals are absent or have very low activities in the parasite. Another potential target is the biosynthetic pathway of glutathione and trypanothione, the low molecular weight thiol found exclusively in trypanosomatids. These thiols scavenge free radicals and participate in the conjugation and detoxication of numerous drugs. Inhibition of this key pathway could render the parasite much more susceptible to the toxic action of drugs such as nifurtimox and benznidazole without affecting the host significantly. Other drugs such as allopurinol and purine analogs inhibit purine transport in T. cruzi, which cannot synthesize purines de novo. Nitroimidazole derivatives such as itraconazole inhibit sterol metabolism. The parasite's respiratory chain is another potential therapeutic target because of its many differences with the host enzyme complexes. The pharmacological modulation of the host's immune response against T. cruzi infection as a possible chemotherapeutic target is discussed. A large set of chemicals of plant origin and a few animal metabolites active against T. cruzi are enumerated and their likely modes of action are briefly discussed.

Topics: Acute-Phase Reaction; Animals; Chagas Disease; Ergosterol; Host-Parasite Interactions; Humans; Immunologic Factors; Mammals; Nifurtimox; Nitric Oxide; Nitroimidazoles; Purines; Sulfhydryl Compounds; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease (American trypanosomiasis) is endemic in 21 countries of the Americas, where control is largely focused on elimination of the domestic insect vectors (Triatominae) coupled with measures to extend and improve the screening of blood donors in order to avoid tranfusional transmission. Through national programmes and multinational initiatives coordinated by WHO-PAHO, much has been accomplished in these domains in terms of reducing transmission. Attention now turns to consolidating the successes in interrupting transmission, and improved treatment for those already infected and those who may become affected in the future. This article, based on technical discussions at the "Epidemiological and Sociological Determinants of Chagas Disease, Basic Information to Establish a Surveillance and Control Policy " meeting in Rio de Janeiro, is designed to open the debate on appropriate strategies for continuation of the successful initiatives against Chagas disease.

Topics: Chagas Disease; Health Services Accessibility; Humans; International Cooperation; Nifurtimox; Nitroimidazoles; Pan American Health Organization; Trypanocidal Agents

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

Chagas' disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: (1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; (2) via blood transfusion or congenital transmission, accounting for 0.5-8% of transmission; (3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild nonspecific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas' disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and it

Topics: Animals; Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

People with Chagas disease (American Trypanosomiasis) may develop progressive and potentially lethal heart conditions. Drugs to eliminate the causative parasite, Trypanosoma cruzi, currently in use have limited therapeutic value and are used in early stages of the disease. Extending the use of these drugs to treat symptomatic chronic parasitism with chronic Chagasic cardiopathy (CCC) and progressive dilated cardiomyopathy has been proposed.. To assess the effects (harms and benefits) of nitrofurans and imidazolic trypanocidal drugs for treating late stage chronic Chagas disease and CCC.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3, 2004), MEDLINE (1985-2004), EMBASE (1985-2004), BIREME (1985-2004), LILACS (1985-2004), ARTEMISA (1985-2004), SCIELO (1985-2004). Indexing terms in English and Spanish were used. References obtained were assessed for relevance by two reviewers independently.. We included randomized controlled clinical trials (RCTs), single or double blind using trypanocidal drugs versus placebo or no treatment in CCC.. All articles retrieved were assessed using a predefined check list to determine if they met the inclusion criteria. Two independent reviewers collected data using a pre-designed form piloted on three articles before the review process started. Disagreements were resolved by a third reviewer. If the information was unavailable the articles were excluded. We planned a quantitative analysis of reduction of parasite load whether recorded as a categorical variable or the reduction of specific antibody titers. However insufficient data were available for quantitative analysis. We prepared a qualitative description of data identified.. We found only one randomized double blind placebo controlled trial. We also found six uncontrolled or non-randomized studies which were of some relevance and were therefore described. We found insufficient evidence to define the effects of drug treatment for people with CCC.. There is insufficient evidence to support the efficacy of nitrofurans or imidazolic drugs as recommended treatment in CCC and chronic T.cruzi infections, specifically if overt heart disease is present. A well designed randomized controlled trial is necessary to establish if new drugs are suitable for treatment of cardiac patients with CCC.

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

Chagas' disease is a major parasitic problem in developing countries in Central and South America. Chemotherapy for such disease is still insufficient and not effective in its chronic part. Many efforts have been made in recent years to know more about possible new biochemical targets to design new selective drugs. This paper reviews old therapeutic approaches -Nifurtimox, Benznidazole and related compounds- and the latest rationally developed drugs that prove to be active against different parasitic forms.

Topics: Animals; Chagas Disease; Drug Design; Enzyme Inhibitors; Humans; Nifurtimox; Nitroimidazoles; Phosphoenolpyruvate Carboxykinase (ATP); Reducing Agents; Trypanocidal Agents; Trypanosoma cruzi

In this "Critical Review" we made a historical introduction of drugs assayed against Chagas disease beginning in 1912 with the works of Mayer and Rocha Lima up to the experimental use of nitrofurazone. In the beginning of the 70s, nifurtimox and benznidazole were introduced for clinical treatment, but results showed a great variability and there is still a controversy about their use for chronic cases. After the introduction of these nitroheterocycles only a few compounds were assayed in chagasic patients. The great advances in vector control in the South Cone countries, and the demonstration of parasite in chronic patients indicated the urgency to discuss the etiologic treatment during this phase, reinforcing the need to find drugs with more efficacy and less toxicity. We also review potential targets in the parasite and present a survey about new classes of synthetic and natural compounds studied after 1992/1993, with which we intend to give to the reader a general view about experimental studies in the area of the chemotherapy of Chagas disease, complementing the previous papers of Brener (1979) and De Castro (1993).

Topics: Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Animals; Chagas Disease; Gentian Violet; Humans; Insect Vectors; Nifurtimox; Nitroimidazoles; Toxicology; Trypanocidal Agents

An effective treatment for Trypanosoma cruzi infection has been investigated, since the 30s. The goals of the specific treatment against T. cruzi infection are, at the individual level, to eliminate the parasite, and to reduce the probability of developing Chagas disease. At the end of the 60s and at the beginning of the 70s, two compounds were clinically investigated in Argentina: Nifurtimox and Benznidazole. After the approval by the Ministry of Health, in 1983 the first guidelines for the treatment of T. cruzi infection were proposed and approved. These guidelines recommended the treatment of cases in the acute phase. Due to the publication of new information in support of the utility of these drugs for treating cases in the indeterminate phase of Chagas disease, in 1997 the original guidelines were revised and new procedures were approved. At present, the treatment is recommended for: 1) all patients undergoing the acute phase; 2) children and young people undergoing the indeterminate phase; 3) adult patients undergoing the indeterminate phase or with incipient heart lesions; 4) laboratory accidents and during surgery, and 5) organ transplant recipients or donors. The general clinical laboratory control is needed for the intra-treatment monitoring of the patient. Titration of specific antibodies with monospecific antigens has been shown to be an adequate marker of therapeutic efficacy.

Topics: Adult; Argentina; Chagas Disease; Child; Drug Administration Schedule; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Argentina; Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

The chemotherapy of Chagas' disease remains an unsolved problem, and the search for alternative drugs continues. Only two nitroheterocyclic drugs are in clinical use at the present time, and these have severely restricted applicability for chronic patients, as well as being highly toxic. This review covers drugs tested in the last 12 years. A large number of different compounds have been assayed in a variety of ways, most commonly in terms of their capacity to inhibit epimastigote proliferation. Allopurinol has emerged for the treatment of chronic cases. However, only with greater knowledge of the biochemistry of the parasite and in particular of its peculiarities, will it be possible to shift the emphasis of drug research away from random screenings onto a more rational footing. This is exemplified by recent studies carried out using purine derivatives and trypanothione reductase inhibitors.

Topics: Animals; Anti-Bacterial Agents; Azoles; Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by the protozoan parasite, Trypanosoma cruzi, is a major source of morbidity and death in Latin America. Many infected immigrants from that region now reside in the United States, posing a risk of transfusion-associated transmission of the organism. Serologic testing is the cornerstone of diagnosing chronic T. cruzi infections, and improved assays are needed. Drug treatment is problematic because the two available drugs can have severe side effects and lack efficacy. T. cruzi infection can be particularly severe in immunosuppressed patients.

Topics: Animals; Chagas Disease; Heart; Humans; Immunocompromised Host; Interferon-gamma; Laboratory Infection; Mice; Nifurtimox; Nitroimidazoles; Recombinant Proteins; Trypanocidal Agents; Trypanosoma cruzi; United States

American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million persons in Latin America. Two drugs are currently being used for treatment of the acute phase of Chagas' disease: 4-[(5-nitrofurfurylidene)amino-3-methylthiomorpholine-1,1-di oxide] (Nifurtimox; Nfx) and (N-benzl-2-nitro-1-imidazole acetamide) (Benznidazole; Bz). Nfx and Bz have serious undesirable effects, which have been reported during their clinical use, including anorexia and weight loss, nausea and vomiting, nervous excitation, insomnia, psyche depressions, convulsions, vertigo, headache, sleepiness, myalgias, arthralgias, loss of balance, disorientation, forgetfulness, paresthesias, adynamia, acoustic phenomena, peripheral neuropathies, gastralgia, mucosal edema, hepatic intolerance, skin manifestations, and intolerance to drinking alcohol. Effects in the central and peripheral nervous system of Nfx were also reproduced in animals. Signs of testicular and ovarian injury were reported for both Nfx and Bz, the effects of Bz being in general less intense than those of Nfx. Both drugs evidenced mutagenicity. In light of the present knowledge about the toxicity of Nfx and Bz, further studies on the mutagenic, teratogenic, carcinogenic, and reproductive effects of both drugs are recommended. Lack of information is particularly serious for Bz. Studies on Nfx and Bz biotransformation, activation to reactive metabolites, and potential mechanisms for their toxic effects were analyzed. Risk-benefit considerations of the use of Nfx and Bz were made and an analysis of the need for research on Chagas' disease chemotherapy was also performed.

Topics: Chagas Disease; Humans; Latin America; Nifurtimox; Nitrofurans; Nitroimidazoles

Topics: Chagas Disease; Gentian Violet; Humans; Melarsoprol; Nifurtimox; Nitroimidazoles; Pentamidine; Suramin; Trypanocidal Agents; Trypanosomiasis, African

Nifurtimox is recommended for the treatment of Chagas disease; however, long-term follow-up data are scarce. This prolonged follow-up phase of the prospective, historically controlled, CHICO clinical trial evaluated seronegative conversion in pediatric patients aged <18 years with Chagas disease who were followed for 4 years after nifurtimox treatment. Patients were randomly assigned 2:1 to nifurtimox 60-day or 30-day regimens comprising 10 to 20 mg/kg/day for patients aged <12 years and body weight <40 kg, and 8 to 10 mg/kg/day for those aged ≥12 years and body weight ≥40 kg. Anti-Trypanosoma cruzi antibodies decreased during the study period, achieving seronegative conversion in 16 (8.12%) and 8 (8.16%) patients in the 60-day and 30-day nifurtimox regimens, respectively, with corresponding incidence rates per 100 patients/year of seronegative conversion of 2.12 (95% confidence interval [CI]: 1.21 to 3.45) and 2.11 (95% CI: 0.91 to 4.16). Superiority of the 60-day nifurtimox regimen was confirmed by the lower limit of the 95% CI being higher than that (0%) in a historical placebo control group. Children aged <2 years at baseline were more likely to reach seronegative conversion during the 4-year follow-up than older children. At any annual follow-up visit, >90% of evaluable patients had persistently negative quantitative PCR results for T. cruzi DNA. No adverse events potentially related to treatment or caused by protocol-required procedures were documented for either treatment regimen. This study confirms the effectiveness and safety of a pediatric formulation of nifurtimox administered in an age- and weight-adjusted regimen for 60 days to treat children with Chagas disease.

Topics: Adolescent; Body Weight; Chagas Disease; Child; Follow-Up Studies; Historically Controlled Study; Humans; Nifurtimox; Nitroimidazoles; Prospective Studies; Treatment Outcome; Trypanocidal Agents

Measurement of the success of antitrypanosomal treatment for Chagas disease is difficult, particularly in the chronic phase of the disease, because anti-Trypanosoma cruzi antibodies persist in serum for prolonged periods. We studied the effects of nifurtimox administered by two different treatment regimens on the T. cruzi calcium-binding flagellar protein F29 in children diagnosed with Chagas disease measured using an enzyme-linked immunosorbent assay (ELISA) technique (ELISA F29).. In a phase 3, randomized, double-blind, parallel-group, historically controlled study (ClinicalTrials.gov NCT02625974), blood samples obtained from children diagnosed with Chagas disease and treated with nifurtimox for either 60 days or 30 days were analyzed using an ELISA with an F29 recombinant protein as the antigen, as well as conventional serological tests (recombinant ELISA and indirect hemagglutination assay). In an exploratory approach, serological response to nifurtimox treatment was evaluated for 4 years post-treatment. In both treatment groups, the number of patients with negative ELISA F29 values increased over the period of observation. The incidence rate of negative seroconversion using ELISA F29 was 22.94% (95% CI: 19.65%, 26.63%) in the 60-day treatment group and 21.64% (95% CI: 17.21%, 26.86%) in the 30-day treatment group. In the subpopulation of patients who tested seropositive for F29 before nifurtimox treatment, 88 patients (67.7%) in the 60-day regimen and 39 patients (59.1%) in the 30-day regimen were F29 seronegative at 4 years post-treatment. All patients who had a positive ELISA F29 test at baseline and seroconverted to negative measured by conventional serology reached seronegativity in ELISA F29 earlier than in conventional serology.. The results demonstrate a serological response to treatment with nifurtimox measured by the ELISA F29 test in children diagnosed with Chagas disease. The F29-based ELISA can be considered a potential early marker of response to antitrypanosomal therapy for Chagas disease.. ClinicalTrials.gov NCT02625974.

Topics: Antibodies, Protozoan; Biomarkers; Chagas Disease; Child; Enzyme-Linked Immunosorbent Assay; Humans; Nifurtimox; Trypanocidal Agents

Treatment of Chagas disease with nifurtimox requires age- and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease. One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC

Topics: Adult; Area Under Curve; Biological Availability; Chagas Disease; Cross-Over Studies; Fasting; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Nifurtimox; Tablets; Therapeutic Equivalency; Trypanocidal Agents; Young Adult

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016-July 2018, 330 patients aged <18 years from 25 medical centres across three South American countries were randomised 2:1 to nifurtimox 10-20 mg/kg/day (aged <12 years) or 8-10 mg/kg/day (aged ≥12 years) for 60 days (n = 219), or for 30 days plus placebo for 30 days (n = 111) (ClinicalTrials.gov NCT02625974). The primary outcome was anti-Trypanosoma cruzi serological response (negative seroconversion or seroreduction ≥20% in mean optical density from baseline determined by two conventional enzyme-linked immunosorbent assays) at 12 months in the 60-day treatment group versus historical placebo controls. Nifurtimox for 60 days achieved negative seroconversion (n = 10) and seroreduction (n = 62) in 72 patients (serological response 32.9%; 95% confidence interval [CI] 26.4%, 39.3%, of all treated patients), confirming superiority relative to the upper 95% CI of 16% for controls. In patients aged <8 months, 10/12 treated for 60 days (83.3%) and 5/7 treated for 30 days (71.4%) achieved negative seroconversion. Overall serological response was lower for 30-day than for 60-day nifurtimox (between-treatment difference 14.0% [95% CI 3.7%, 24.2%]). The frequency of T. cruzi-positive quantitative polymerase chain reactions decreased substantially from baseline levels (60-day regimen 53.4% versus 1.4%; 30-day regimen 51.4% versus 4.5%). Study drug-related treatment-emergent adverse events (TEAEs), which were observed in 62 patients (28.3%) treated for 60 days and 29 patients (26.1%) treated for 30 days, were generally mild or moderate and resolved without sequelae; 4.2% of all TEAEs led to nifurtimox discontinuation. Age- and weight-adjusted nifurtimox for 60 days achieved a serological response at 12 months post-treatment that was superior to historical placebo, was well tolerated and had a favourable safety profile in children with Chagas disease. Although, at 1 year serological follow-up, efficacy of the shorter nifurtimox treatment was not comparable to the 60-day treatment regimen for the overall study population, further long-term follow-up of the patients will provide important information about the progress of serological conversion in childre

Topics: Adolescent; Chagas Disease; Child; Child, Preschool; Female; Historically Controlled Study; Humans; Infant; Infant, Newborn; Male; Nifurtimox; Prospective Studies; South America; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Treatment with nifurtimox (NF) for Chagas disease is discouraged during breast-feeding because no information on NF transfer into breast milk is available. NF is safe and effective for paediatric and adult Chagas disease. We evaluated the degree of NF transfer into breast milk in lactating women with Chagas disease.. Prospective study of a cohort of lactating women with Chagas disease. Patients were treated with NF for 1 month. NF was measured in plasma and milk by high performance liquid chromatography (HPLC). Breastfed infants were evaluated at admission, 7th and 30th day of treatment (and monthly thereafter, for 6 months).. Lactating women with chronic Chagas disease (N = 10) were enrolled (median age 28 years, range 17-36). Median NF dose was 9.75 mg/kg/day three times a day (TID). Six mothers had mild adverse drug reactions (ADRs), but no ADRs were observed in any of the breastfed infants. No interruption of breastfeeding was observed. Median NF concentrations were 2.15 mg/L (Inter quartil range (IQR) 1.32-4.55) in milk and 0.30 mg/L (IQR 0.20-0.95) in plasma. Median NF milk/plasma ratio was 16 (range 8.75-30.25). Median relative infant NF dose (assuming a daily breastmilk intake of 150 mL/kg/day) was 6.7% of the maternal dose/kg/day (IQR 2.35-7.19%).. The low concentrations of NF in breast milk and the normal clinical evaluation of the breastfed babies imply that maternal NF treatment for Chagas disease during breastfeeding is unlikely to lead to clinically relevant exposures in the breastfed infants.. Clinical trial registry name and registration number: ClinicalTrials.gov NCT01744405.

Topics: Adolescent; Adult; Chagas Disease; Chromatography, High Pressure Liquid; Female; Humans; Infant; Male; Milk, Human; Nifurtimox; Plasma; Prospective Studies; Trypanocidal Agents; Young Adult

Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America.. The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20-65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12-18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60-80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80-90% power; one-sided alpha level 1%).. The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents.. ClinicalTrials.gov, NCT02369978 . Registered on 24 February 2015.

Topics: Adult; Aged; Asymptomatic Diseases; Chagas Disease; Colombia; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Nifurtimox; Nitroimidazoles; Randomized Controlled Trials as Topic; Therapeutic Equivalency; Time Factors; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

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: Animals; Cats; Chagas Disease; Clinical Trials as Topic; Cricetinae; Dogs; Guinea Pigs; Humans; Mice; Nifurtimox; Nitrofurans; Nitroimidazoles; Rats; Trypanocidal Agents; Trypanosoma cruzi

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

Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis. The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC

Topics: Chagas Disease; Computer Simulation; Humans; Nifurtimox; Oxidation-Reduction; Quinones; Trypanocidal Agents; Trypanosoma cruzi

A drawback in the treatment of chronic Chagas disease (American trypanosomiasis) is the long time required to achieve complete loss of serological reactivity, the standard for determining treatment efficacy.. Antibody-secreting cells and memory B cells specific for Trypanosoma cruzi and their degree of differentiation were evaluated in adult and pediatric study participants with chronic Chagas disease before and after etiological treatment.. T. cruzi-specific antibody-secreting cells disappeared from the circulation in benznidazole or nifurtimox-treated participants with declining parasite-specific antibody levels after treatment, whereas B cells in most participants with unaltered antibody levels were low before treatment and did not change after treatment. The timing of the decay in parasite-specific antibody-secreting B cells was similar to that in parasite-specific antibodies, as measured by a Luminex-based assay, but preceded the decay in antibody levels detected by conventional serology. The phenotype of total B cells returned to a noninfection profile after successful treatment.. T. cruzi-specific antibodies in the circulation of chronically T. cruzi-infected study participants likely derive from both antigen-driven plasmablasts, which disappear after successful treatment, and long-lived plasma cells, which persist and account for the low frequency and long course to complete seronegative conversion in successfully treated participants.

Topics: B-Lymphocytes; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Persistent Infection; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited.. This study aimed to better understand the fate of oral nifurtimox. We investigated the exposure and excretion pathways of [. In rats, orally administered nifurtimox was rapidly absorbed (t. This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.

Topics: Administration, Oral; Animals; Biotransformation; Chagas Disease; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Nifurtimox; Rats

Topics: Animals; Chagas Disease; Macrophages; Mammals; Nifurtimox; Peroxiredoxins; Trypanosoma cruzi

Chagas disease (CD) has become an emerging global health problem in association with the immigration of individuals from endemic areas (in LatinAmerica) to other countries.Spain is the country in Europe with the highest number of CD cases. Concerning pediatric CD, treatment is not only better tolerated by younger children but also has greater cure possibilities. The aim of this study was to describe clinical and epidemiological aspects of CD in a pediatric population diagnosed of 10 hospitals in the Community of Madrid during the 2004-2018 period, as well as the safety and efficacy of CD treatment on this population.. A multicenter, retrospective, descriptive study was conducted. The studied population included all identified children under the age of 18 with a diagnosis of CD. Diagnosis was performed with a positive parasitological test (with subsequent confirmation) or confirmed persistence of positive serology beyond 9 months, for children younger than one year-old, and with two different positive serological tests, for children older than one. Fifty-one children were included (59% male; 50.9% born in Spain). All mothers were from Latin America. The median age at diagnosis was 0.7 months for those under one year of age, and 11.08 years for those older than one year-old. Only one case presented a symptomatic course (hydrops faetalis, haemodynamic instability at birth, ascites, anaemia). For 94% treatment was completed. Considering patients who received benznidazole (47), AE were recorded in 48,9%. Among the 32 patients older than one year-old treated with benznidazole, 18 (56.25%) had adverse events whereas in the 15 under one year, 5(33,3%) did. Eigtheen (78.2%) of the patients with benznidazole AE were older than one year-old(median age 11.4 years). Of the patients treated with nifurtimox (9), AE were reported in 3 cases (33,3%). Cure was confirmed in 80% of the children under one year-old vs 4.3% in those older (p<0.001). Loss to follow- up occurred in 35.3% of patients.. Screening programs of CD since birth allow early diagnosis and treatment, with a significantly higher cure rate in children treated before one year of age, with lower incidence of adverse events. The high proportion of patients lost to follow-up in this vulnerable population is of concern.

Topics: Chagas Disease; Child; Emigration and Immigration; Female; Humans; Infant; Infant, Newborn; Male; Nifurtimox; Retrospective Studies; Trypanosoma cruzi

Chagas disease, or American trypanosomiasis, is caused by the parasite Trypanosoma cruzi. Chagas disease is endemic in rural areas of Latin America, but T. cruzi, triatomine vectors, infected mammalian reservoir hosts, and rare cases of autochthonous vector borne transmission have been reported in the United States (1). Possible modes of transmission include the following: vector borne via skin or mucosal contact with feces of infected triatomine bugs, congenital, blood transfusion, organ transplantation, or laboratory accident. Chagas disease can be treated with benznidazole (commercially available since May 14, 2018) or nifurtimox (2). Before January 25, 2021, nifurtimox (Lampit) had been exclusively available through CDC under an Institutional Review Board-approved Investigational New Drug (IND) treatment protocol, at which time it became reasonably accessible to health care providers outside of the program. This report summarizes CDC Drug Service reports for selected characteristics of and adverse events reported by 336 patients for whom nifurtimox was requested under the CDC IND program during January 1, 2001-January 25, 2021. Of the 336 patients, 34.2% resided in California. Median age of patients was 37 years (range = 1-78 years). Most patients were aged ≥18 (91.8%; 305 of 332) and Hispanic (93.2%; 290 of 311). Among the patients with available information, 91.4% (222 of 243) reported an adverse event. Among those with information about the severity of their adverse events, 20.5% reported a severe event. On August 7, 2020, the Food and Drug Administration (FDA) announced approval of a nifurtimox product, Lampit (Bayer), for treatment of Chagas disease in patients aged <18 years weighing ≥5.5 lbs (≥2.5 kg). Lampit became commercially available during October 2020. Physicians should take frequency of adverse events into consideration when prescribing nifurtimox and counseling patients.

Topics: Adolescent; Adult; Aged; Centers for Disease Control and Prevention, U.S.; Chagas Disease; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Drugs, Investigational; Female; Humans; Infant; Male; Middle Aged; Nifurtimox; Patients; Trypanocidal Agents; United States

Chagas disease (ChD), caused by Trypanosoma cruzi, has a global prevalence due to patient migration. However, despite its worldwide distribution, long-term follow-up efficacy studies with nifurtimox (NF) are scarce and have been conducted with only small numbers of patients. A retrospective study of a large cohort of ChD treated children and adults with NF. Treatment response was evaluated by clinical, parasitological, and serological after-treatment evaluation. A total of 289 patients were enrolled, of which 199 were children and 90 adults. At diagnosis, 89.6% of patients were asymptomatic. Overall, all symptomatic patients showed clinical improvement. At baseline, parasitemia was positive in 130 of 260 (50%) patients. All but one adult patient had cleared their parasitemia by the end of treatment. That patient was considered a treatment failure. Median follow-up time for children was 37.7 months, with an interquartile range of (IQR

Topics: Adult; Antibodies, Protozoan; Chagas Disease; Child; Cohort Studies; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose-equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast- vs slow-dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8-20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.

Topics: Adult; Body Weight; Chagas Disease; Child; Humans; Nifurtimox; Tablets

American trypanosomiasis is a neglected tropical disease and an endemic problem in 21 Latin American countries, whose treatment relies on only two US FDA-approved drugs: benznidazole and nifurtimox. Patent literature reveals vital information on new trends in therapies for various diseases, including Chagas disease. The authors used the patent databases of the world's major patent offices to generate an overview of patent trends related to the treatment of Chagas disease. A total of 50 patent families were collected and grouped as 'small molecules', 'pharmaceutical compositions of known compounds' and vaccines. From the results and interpretation, it can be concluded that the treatment of Chagas disease receives little attention in the field of patents and that the upward trend is minimal.

Topics: Chagas Disease; Humans; Neglected Diseases; Nifurtimox; Pharmaceutical Preparations; Trypanocidal Agents

The antiparasitic drug nifurtimox was approved in the USA in 2020 for the treatment of patients with Chagas disease aged less than 18 years and weighing at least 2.5 kg, based on outcomes from the phase 3 CHICO study. Accordingly, pediatric patients with Chagas disease take nifurtimox thrice daily with food at one of two body weight-adjusted dose ranges. We investigated possible relationships between pharmacokinetic (PK) data, and pharmacodynamic efficacy and safety data collected in an analysis population of 111 participants in CHICO, using a published population PK model to estimate nifurtimox exposure at the patient level. Pediatric exposure to nifurtimox was benchmarked against levels of nifurtimox exposure known to be effective in adults with Chagas disease. Given the complex dosing regimen for nifurtimox, we also modeled nifurtimox exposure associated with simpler dosing strategies. We found no relationship between exposure to nifurtimox and efficacy measures (e.g., serological response to treatment), or between exposure and safety outcomes (including typical adverse events, e.g., headache, decreased appetite, nausea/vomiting). The analysis population appeared to represent the overall CHICO population based on the similarity of their baseline characteristics and the profiles of adverse events in the two groups. Modeled exposure based on the dosing regimen in CHICO was within the reference range derived from phase 1 data in adults. The relationship between nifurtimox exposure and cure is complex; a simplified pediatric dosing regimen is unlikely to be beneficial.

Topics: Chagas Disease; Child; Clinical Trials, Phase III as Topic; Humans; Nifurtimox

The objective of this study was to molecularly characterize Mexican isolates of T. cruzi obtained from infected triatomine bugs (the vectors of T. cruzi) and to evaluate their susceptibility to Nifurtimox (NFX).. Three isolates obtained from Triatoma dimidiata (collected in the State of Veracruz) and one isolate obtained from Triatoma bassolsae (collected in the State of Puebla) were molecularly characterized and the expression of genes associated with natural resistance to NFX was analyzed by qPCR.. Molecular characterization by PCR showed that isolates Zn3, Zn5, and SRB1 belong to the DTU TcI, while isolate Sum3 belongs to TcIV. The latter was also confirmed by sequencing of mitochondrial genes. Isolate Zn5 was the most sensitive to treatment with NFX (IC50, 6.8 μM), isolates SRB1 and Zn3 were partially resistant (IC50, 12.8 μM and 12.7 μM) and isolate Sum3 showed a high degree of resistance to NFX (IC50, 21.4 µM). We also found an association between decreased NTR1 or OYE gene expression with NFX resistance.. Our results also evidenced a high variability in the susceptibility to NFX of these T. cruzi isolates Central and Southeastern Mexico, suggesting the presence of naturally resistant isolates circulating in the country. These results have important implications for defining treatment policies for patients with Chagas disease.

Topics: Animals; Chagas Disease; Genotype; Humans; Insect Vectors; Mexico; Nifurtimox; Triatoma; Trypanosoma cruzi

Due to its severe burden and geographic distribution, Chagas disease (CD) has a significant social and economic impact on low-income countries. Benznidazole and nifurtimox are currently the only drugs available for CD. These are prodrugs activated by reducing the nitro group, a reaction catalyzed by nitroreductase type I enzyme from Trypanosoma cruzi (TcNTR), with no homolog in the human host. The three-dimensional structure of TcNTR, and the molecular and chemical bases of the selective activation of nitro drugs, are still unknown. To understand the role of TcNTR in the basic parasite biology, investigate its potential as a drug target, and contribute to the fight against neglected tropical diseases, a combined approach using multiple biophysical and biochemical methods together with in silico studies was employed in the characterization of TcNTR. For the first time, the interaction of TcNTR with membranes was demonstrated, with a preference for those containing cardiolipin, a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane in eukaryotic cells. Prediction of TcNTR's 3D structure suggests that a 23-residue long insertion (199 to 222), absent in the homologous bacterial protein and identified as conserved in protozoan sequences, mediates enzyme specificity, and is involved in protein-membrane interaction.

Topics: Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Nitroreductases; Prodrugs; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a serious chronic parasitic disease, currently treated with Nifurtimox (NFX) and Benznidazole (BZ). In addition to high toxicity, these drugs have low healing efficacy, especially in the chronic phase of the disease. The existence of drug-resistant T. cruzi strains and the occurrence of cross-resistance between BZ and NFX have also been described. In this context, it is urgent to study the metabolism of these drugs in T. cruzi, to better understand the mechanisms of resistance. Prostaglandin F2α synthase (PGFS) is an enzyme that has been correlated with parasite resistance to BZ, but the mechanism by which resistance occurs is still unclear. Our results show that the genome of the CL Brener clone of T. cruzi, contains five PGFS sequences and three potential pseudogenes. Using CRISPR/Cas9 we generated knockout cell lines in which all PGFS sequences were disrupted, as shown by PCR and western blotting analyses. The PGFS deletion did not alter the growth of the parasites or their susceptibility to BZ and NFX when compared to wild-type (WT) parasites. Interestingly, NTR-1 transcripts were shown to be upregulated in ΔPGFS mutants. Furthermore, the ΔPGFS parasites were 1.6 to 1.7-fold less tolerant to oxidative stress generated by menadione, presented lower levels of lipid bodies than the control parasites during the stationary phase, and were less infective than control parasites.

Topics: Chagas Disease; Dinoprost; Humans; Nifurtimox; Oxidative Stress; Trypanocidal Agents; Trypanosoma cruzi; Vitamin K 3

Parasite persistence after acute infection with Trypanosoma cruzi is an important factor in the development of Chagas disease (CD) cardiomyopathy. Few studies have investigated the clinical effectiveness of CD treatment through the evaluation of cardiological events by long term follow-up of treated children. Cardiological evaluation in children is challenging since features that would be diagnosed as abnormal in an adult's ECG may be normal, age-related findings in a pediatric ECG trace. The objective was to evaluate cardiac involvement in patients with Chagas disease with a minimum follow-up of 6 years post-treatment.. A descriptive study of a cohort of pediatric patients with CD treated with benznidazole (Bz) or nifurtimox (Nf) was conducted. Children (N = 234) with at least 6 years post CD treatment followed at the Parasitology and Chagas Service, Buenos Aires Children's Hospital (Argentina) were enrolled. By convenience sampling, children who attended a clinical visit between August 2015 and November 2019 were also invited to participate for additional cardiovascular studies like 24-hour Holter monitoring and speckle-tracking 2D echocardiogram (STE). Benznidazole was prescribed in 171 patients and nifurtimox in 63 patients. Baseline parasitemia data was available for 168/234 patients. During the follow-up period, alterations in routine ECG were observed in 11/234 (4.7%, 95% CI [2-7.4%]) patients. In only four patients, with complete right bundle branch block (cRBBB) and left anterior fascicular block (LAFB), ECG alterations were considered probably related to CD. During follow-up, 129/130 (99%) treated patients achieved persistent negative parasitemia by qPCR. Also decrease in T.cruzi antibodies titers was observed in all patients and negative seroconversion occurred in 123/234 (52%) patients.. A low incidence of cardiological lesions related to CD was observed in patients treated early for pediatric CD. This suggests a protective effect of parasiticidal treatment on the development of cardiological lesions and highlights the importance of early treatment of infected children.. ClinicalTrials.gov NCT04090489.

Topics: Adult; Cardiology; Chagas Cardiomyopathy; Chagas Disease; Child; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by

Topics: Animals; Chagas Disease; Isoenzymes; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas Disease is a pathology caused by the parasite Trypanosoma cruzi. It is considered a public health issue, especially its congenital transmission, not only in endemic countries but also in non endemic ones, being the main form of transmission in Chile. Objectives: To describe a congenital Chagas Disease case and to report about the usefulness of prenatal screening for Chagas Disease. Cli nical Case: A 29-week preterm newborn of a multiparous mother with Chagas Disease detected in the perinatal screening of current pregnancy. Due to history of Trypanosoma cruzi, PCR was performed on the 4th day of life resulting undetectable. At the 6th and the 8th week of life, a macular erythema tous rash and fever and respiratory distress were observed, respectively, both self-limited. At the 8th week of life, as a routine prematurity follow-up, a fundus examination was performed which showed bilateral retinal granulation, therefore, a TORCH study was performed with a negative result. Also, in this same week, a second Trypanosoma cruzi PCR was performed, with a positive result. Lab tests reported visualization of trypomastigotes, confirming the Congenital Chagas Disease diagnosis. The patient was treated with Nifurtimox, presenting an adverse reaction at 35 days of treatment with neu tropenia, vomiting, and poor weight gain. The treating drug was replaced by Benznidazole, achieving 60 days of treatment. At 22 months of chronologic age, the patient has remained asymptomatic. Con clusions: It is necessary to increase efforts in prevention, early detection, and study of direct relatives. This report is an example of the usefulness of Chagas disease prenatal screening for the detection and early treatment of new cases.

Topics: Chagas Disease; Chile; Female; Humans; Infant, Newborn; Nifurtimox; Pregnancy; Prenatal Diagnosis; Trypanosoma cruzi

This study aimed to describe the electrocardiographic and echocardiographic status of chronic Chagas disease (cChD) patients treated with nifurtimox.. An observational study was performed in 146 cChD patients followed over a mean of 7.9 years.. Of the 146 patients, 41 (28.1%) with normal electrocardiogram (ECG) at baseline maintained this condition, 34 (23.3%) with altered ECG at baseline normalised the alterations, and 46 (31.5%) with ECG abnormalities at baseline maintained this condition [23 (15.8%) with small alterations]. Finally, 25 cases (17.1%) in indeterminate phase altered the ECG. Differences before and after follow-up (P < 0.001) were found. The percentage of beneficial treatment was different than expected by chance (Z = 4.8; P < 0.001) and the annual percentage of cases that developed ECG alterations was lower than that of a historical cohort of untreated patients (P < 0.001). An echocardiogram was performed in 68 patients with baseline ECG alterations. The ejection fraction (EF) was normal in 57 (83.8%) and abnormal in 11 (16.2%). In 38 patients with ECG abnormalities that did not progress after treatment, EF and segmental motility (SM) were normal in 31 (81.6%) and 26 (68.4%), respectively. In 17 patients with ECG abnormalities, EF and SM were normal in 15 (88.2%) and 14 (82.4%) cases, respectively.. Less progression to cardiomyopathy compared with a historical untreated cohort as well as the EF/SM results in patients with abnormal ECG that did not progress and in indeterminate cChD that altered the ECG suggests a beneficial effect of nifurtimox.

Topics: Chagas Cardiomyopathy; Chagas Disease; Chile; Echocardiography; Electrocardiography; Follow-Up Studies; Humans; Nifurtimox

Nifurtimox is indicated in Chagas disease but determining its effectiveness in chronic disease is hindered by the length of time needed to demonstrate negative serological conversion. We manually reviewed long-term follow-up data from hospital records of patients with chronic Chagas disease (N = 1,497) in Argentina diagnosed during 1967-1980. All patients were aged ≥18 years at diagnosis and were either treated with nifurtimox (n = 968) or received no antitrypanosomal treatment (n = 529). The primary endpoint was negative seroconversion (the "event"), defined as a change from positive to negative in the serological or parasitological laboratory test used at diagnosis. Time to event was from baseline visit to date of endpoint event or censoring. The effectiveness of nifurtimox versus no treatment was estimated with Cox proportional hazard regression using propensity scores with overlap weights to calculate the hazard ratio and 95% confidence interval. The nifurtimox group was younger than the untreated group (mean, 32.4 vs. 40.3 years), with proportionally fewer females (47.9% vs. 60.1%), and proportionally more of the nifurtimox group than the untreated group had clinical signs and symptoms of Chagas disease at diagnosis (28.9% vs. 14.0%). Median maximum daily dose of nifurtimox was 8.0 mg/kg/day (interquartile range [IQR]: 8.0-9.0) and median treatment duration was 44 days (IQR: 1-90). Median time to event was 2.1 years (IQR: 1.0-4.5) for nifurtimox-treated and 2.4 years (IQR: 1.0-4.2) for untreated patients. Accounting for potential confounders, the estimated hazard ratio (95% confidence interval) for negative seroconversion was 2.22 (1.61-3.07) favoring nifurtimox. Variable treatment regimens and follow-up duration, and an uncommonly high rate of spontaneous negative seroconversion, complicate interpretation of this epidemiological study, but with the longest follow-up and largest cohort analyzed to date it lends weight to the benefit of nifurtimox in adults with chronic Chagas disease. Trial registration: The study protocol was registered at ClinicalTrials.gov: NCT03784391.

Topics: Adult; Antibodies, Protozoan; Argentina; Chagas Disease; Chronic Disease; Female; Humans; Male; Middle Aged; Nifurtimox; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Chagas disease remains a significant public health problem in Latin America. There are only two chemotherapy drugs, nifurtimox and benznidazole, and both may have severe side effects. After complete chemotherapy of acute cases, seropositive diagnosis may revert to negative. However, there are no definitive parasitological or serological biomarkers of cure.. Following a pilot study with seven Bolivian migrants to Spain, we tested 71 serum samples from chronic patients (mean age 12.6 years) inhabiting the Argentine Chaco region. Benznidazole chemotherapy (5-8 mg/kg day, twice daily for 60 days) was administered during 2011-2016. Subsequently, pre-and post-chemotherapy serum samples were analysed in pairs by IgG1 and IgG ELISA using two different antigens and Chagas Sero K-SeT rapid diagnostic tests (RDT). Molecular diagnosis by kDNA-PCR was applied to post-treatment samples.. Pilot data demonstrated IgG1 antibody decline in three of seven patients from Bolivia 1 year post-treatment. All Argentine patients in 2017 (averaging 5 years post-treatment), except one, were positive by conventional serology. All were kDNA-PCR-negative. Most (91.5%) pre-treatment samples were positive by the Chagas Sero K-SeT RDT, confirming the predominance of TcII/V/VI. IgG1 and IgG of Argentine patients showed significant decline in antibody titres post-chemotherapy, with either lysate (IgG, P = 0.0001, IgG1, P = 0.0001) or TcII/V/VI peptide antigen (IgG, P = 0.0001, IgG1, P = 0.0001). IgG1 decline was more discriminative than IgG. Antibody decline after treatment was also detected by the RDT. Incomplete treatment was associated with high IgG1 post-treatment titres against lysate (P = 0.013), as were IgG post-treatment titres to TcII/V/VI peptide (P = 0.0001). High pre-treatment IgG1 with lysate was associated with Qom ethnicity (P = 0.045). No associations were found between gender, age, body mass index and pre- or post-treatment antibody titres.. We show that following chemotherapy of early chronic Chagas disease, significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure. We show that following chemotherapy of early chronic Chagas disease, a significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure.

Topics: Adolescent; Antibodies, Protozoan; Chagas Disease; Chronic Disease; Cohort Studies; Female; Humans; Immunoglobulin G; Immunologic Tests; Male; Molecular Diagnostic Techniques; Nifurtimox; Nitroimidazoles; Pilot Projects; Time Factors; Trypanocidal Agents; Trypanosoma cruzi

The immunodominant B13 protein of Trypanosoma cruzi is found on the surface of trypomastigotes and exhibits cross-reactivity with the human cardiac myosin heavy chain; for which antibodies against this parasitic antigen may be involved in the development of disease pathology. In a cohort of chronically T. cruzi-infected adults, undergoing trypanocidal treatment, or not, we, therefore, decided to evaluate the levels of anti-B13 antibodies (ELISA-B13) and its eventual relationship with heart complaints. Two hundred twenty-eight serum samples from 76 chronically infected adults with an average follow-up of 24 years were analyzed. Thirty of them had received trypanocidal treatment. Among treated patients, anti-B13 Ab levels in successive samples showed a significant decrease in reactivity as the years after treatment increased (ANOVA test, p = 0.0049). At the end of the follow-up, 36.7% became non-reactive for ELISA B13. Untreated patients did not have significant variations in the level of anti-B13 antibodies during follow-up. None of the treated patients had electrocardiographic changes compatible with chronic chagasic cardiomyopathy, whereas 21.7% of those undergoing no treatment did show such kind of pathological electrocardiogram tracings. ELISA-B13 was reactive in all cases with heart involvement. Among untreated patients, there were no significant differences in anti-B13 antibodies when comparing individuals without proven pathology with those with chronic chagasic cardiomyopathy. Although treatment with trypanocidal drugs was followed by decreased anti-B13 antibody levels, such assessment was unhelpful in differentiating the evolution of chronic chagasic heart disease.

Topics: Adult; Animals; Antibodies, Protozoan; Antigens, Protozoan; Argentina; Chagas Disease; Chronic Disease; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Nifurtimox; Nitroimidazoles; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.

Topics: Animals; Chagas Disease; Drug Therapy, Combination; Female; Humans; Inhibitory Concentration 50; Mice; Neglected Diseases; Nifurtimox; Nitro Compounds; Nitroimidazoles; Real-Time Polymerase Chain Reaction; Sulfones

This study compared the serological and electrocardiographic evolution among patients with chronic T. cruzi infection treated during childhood or left untreated. A retrospective cohort study was conducted during a mean follow-up period of 25 years in 82 patients: half of them underwent treatment (nifurtimox 8, benznidazole 33) before being 15 years old, whereas the other half remained untreated. During the follow-up, negative seroconversion occurred in 92.7% of the treated children, while all the untreated ones remained positive for conventional serology. At baseline, 2 patients from each group had electrocardiographic abnormalities. During the study period, 4/41 (9.75%) and 9/41 (21.95%) of treated and untreated patients displayed an altered electrocardiogram, respectively. In multivariate analyses, the probability of developing electrocardiographic abnormalities was significantly reduced among treated patients (OR = 0.18, 95% CI = 0.04-0.79; p = 0.023). Electrocardiographic abnormalities attributable to Chagas cardiomyopathy were seen in 3 patients from the untreated group (complete right bundle branch block + left anterior fascicular block, frequent ventricular extrasystole, and left anterior fascicular block). The remarkable seronegativization seen in Benznidazole and Nifurtimox recipients underlines the parasiticidal effect of both compounds. Such demonstration along with the fact that CCC-related alterations were only present in the untreated group, reinforces the view of trypanocidal treatment in chronically T. cruzi-infected children as decreasing the risk for cardiomyopathy development.

Topics: Adolescent; Chagas Cardiomyopathy; Chagas Disease; Child; Follow-Up Studies; Humans; Nifurtimox; Nitroimidazoles; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi

Chagas Disease, also known as American trypanosomiasis, is a Neglected Tropical Disease that affects around seven million people, especially in Latin America. Noteworthy, there has been an increase in the numbers of case reports in non-endemic areas, such as North America, Europe, Japan, and Australia. The disease is a vector-borne disease caused by the pathogen Trypanosoma cruzi being transmitted by infected bugs. It is known that about forty percent of infected patients develop cardiac, digestive, or neurological alterations. There are only two drugs currently used for treatment, benznidazole and nifurtimox. However, both therapeutic regimens present several limitations, such as toxicity, mutagenicity and low efficiency during the chronic phase. Some reports in the literature point to the occurrence of parasite resistance. To overcome these limitations, the bioprospection of novel molecules as alternatives is one of the major goals to improve therapeutic success in this chronic disease. Bioprospecting active metabolites from natural resources might bring new hopes for disease control and parasite elimination. Here we summarize the most recent advances to identify and test Algae, Bacteria and Fungi-derived bioactive compounds with trypanocidal activity using experimental models, in vitro testing and in silico approaches.

Topics: Bacteria; Chagas Disease; Fungi; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

Topics: Animals; Chagas Disease; Drug Evaluation, Preclinical; Mice; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Current options for Chagas' disease treatment are restricted to benznidazole and nifurtimox. To the best of our knowledge, no study has ever compared their tolerance in adults in a non-endemic country.. To compare the completion rates and drug tolerance in a cohort of patients treated according to current guidelines.. We analysed the medical records of all Chagas' disease patients aged 18 years or over who started antiparasitic treatment at the Geneva University Hospitals, Switzerland, from 2008 to 2016. We recorded treatment duration and all adverse events.. We included 176 patients, 92 and 84 of whom received benznidazole or nifurtimox, respectively. The overall treatment completion rate was 62.5%, without a significant difference between the groups (P=0.436). Most patients (89.8%) suffered at least one adverse event. Those receiving nifurtimox had more events (6.2 versus 3.5, P<0.001). Mucocutaneous symptoms predominated in the benznidazole group, whereas digestive symptoms were most frequent with nifurtimox. Neuropsychiatric events frequently occurred in both groups, most notably in patients receiving nifurtimox. Arthralgia, dyspnoea, sensitive neuropathy and pruritus were independent predictors of treatment interruption.. Currently recommended drug regimens for Chagas' disease are not well tolerated and entail frequent treatment discontinuation irrespective of the drug used. This highlights the need to improve treatment tolerance in adults with Chagas' disease with new therapeutic options.

Topics: Adult; Chagas Disease; Chronic Disease; Drug Tolerance; Humans; Nifurtimox; Nitroimidazoles; Switzerland; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects. Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no tests-of-cure either, which greatly undermines patients follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite- and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

Topics: Biomarkers; Chagas Disease; Chronic Disease; Gastrointestinal Tract; Heart; Host-Parasite Interactions; Humans; Nifurtimox; Nitroimidazoles; Prognosis; Treatment Outcome; Trypanosoma cruzi

In the indeterminate chronic period of Chagas disease (ChD) the treatment has not been conclusive, because the serological negativization requires many years. This study aims to evaluate the efficacy of nifurtimox (NF) in the treatment of chronic ChD in prolonged follow-up by serological techniques of indirect immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA) IgG comparing 2 groups of patients, treated and non treated. Mann-Whitney test was performed for ELISA and IFA, with significant difference between the groups (P < 0.05). IgG levels were lower in individuals treated compared with untreated patients, indicating chemotherapeutic efficacy in prolonged follow-up.

Topics: Antibodies, Protozoan; Chagas Disease; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Humans; Immunoglobulin G; Male; Middle Aged; Nifurtimox; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

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

This work aims to collect publications of available drugs for reposition and new substance development against the Chagas disease, since they represent the beginning of a path for new discoveries of viable alternatives to improve the prognosis of millions of patients around the world.. An extended research on English and Portuguese-language literature in the Scientific Electronic Library Online - Scielo, SciFinder and PubMed - database was made. The bibliography was screened using the keywords "Chagas Disease" and "Treatment".. Despite the low resources available for research and development of drugs against Chagas disease, the knowledge produced in this area is large but not directly proportional to the therapeutic advances. Two categories were analyzed, such as drug repositioning, and new substances were researched.. Even if great findings were reported, more efforts are necessary to find new therapies against Trypanosoma cruzi (T. cruzi).

Topics: Chagas Disease; Drug Repositioning; Humans; Molecular Structure; Nifurtimox; Nitroimidazoles; Prognosis; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is a tropical illness caused by the protozoan

Topics: Animals; Cell Line; Cell Proliferation; Chagas Disease; Coloring Agents; Humans; Methylene Blue; Nifurtimox; Nitroimidazoles; Phenothiazines; Tolonium Chloride; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.

Topics: Cell Line; Chagas Disease; Drug Design; Humans; Models, Molecular; Nitrofurans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC

Topics: 14-alpha Demethylase Inhibitors; Animals; Chagas Disease; Mice; Molecular Docking Simulation; Parasitemia; Pyrazolones; Structure-Activity Relationship; Survival Rate; Thiazepines; Trypanosoma cruzi

Chagas disease is a neglected pathology responsible for about 12,000 deaths every year across Latin America. Although six million people are infected by the Trypanosoma cruzi, current therapeutic options are limited, highlighting the need for new drugs. Here we report the preliminary structure activity relationships of a small library of 17 novel pyridyl sulfonamide derivatives. Analogues 4 and 15 displayed significant potency against intracellular amastigotes with EC

Topics: Animals; Cell Survival; Cells, Cultured; Chagas Disease; Dose-Response Relationship, Drug; Mice; Molecular Structure; Pyridines; Structure-Activity Relationship; Sulfonamides

In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3-arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and D) were synthesized and molecular docking, TcTS enzyme inhibition and determination of trypanocidal activity were carried out. From four series obtained, compound D-11 had the highest binding affinity value (-11.1 kcal/mol) compared to reference DANA (-7.8 kcal/mol), a natural ligand for TS enzyme. Furthermore, the 3D and 2D interactions analysis of compound D-11 showed a hydrogen bond, π-π stacking, π-anion, hydrophobic and Van der Waals forces with all important amino acid residues (Arg35, Arg245, Arg314, Tyr119, Trp312, Tyr342, Glu230 and Asp59) on the active site of TcTS. Additionally, D-11 showed the highest TcTS enzyme inhibition (86.9% ± 5) by high-performance ion exchange chromatography (HPAEC). Finally, D-11 showed better trypanocidal activity than the reference drugs nifurtimox and benznidazole with an equal % lysis (63 ± 4 and 65 ± 2 at 10 μg/mL) and LC

Topics: Amination; Chagas Disease; Drug Design; Glycoproteins; Humans; Molecular Docking Simulation; Neuraminidase; Propionates; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3-10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease.

Topics: Animals; Chagas Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Mice; Nifurtimox; Parasitemia; Trypanocidal Agents; Trypanosoma cruzi

Although many Trypanosoma cruzi (T. cruzi) strains isolated from a wide range of hosts have been characterized, there is a lack of information about biological features from vertically transmitted strains. We describe the molecular and biological characteristics of the T. cruzi VD strain isolated from a congenital Chagas disease patient. The VD strain was typified as DTU TcVI; in vitro sensitivity to nifurtimox (NFX) and beznidazole (BZ) were 2.88 μM and 6.19 μM respectively, while inhibitory concentrations for intracellular amastigotes were 0.24 μM for BZ, and 0.66 μM for NFX. Biological behavior of VD strain was studied in a mouse model of acute infection, resulting in high levels of parasitemia and mortality with a rapid clearence of bloodstream trypomastigotes when treated with BZ or NFX, preventing mortality and reducing parasitic load and intensity of inflammatory infiltrate in skeletal and cardiac muscle. Treatment-induced parasitological cure, evaluated after immunossupression were 41% and 35% for BZ and NFX treatment respectively, suggesting a partial response to these drugs in elimination of parasite burden. This exhaustive characterization of this T. cruzi strain provides the basis for inclusion of this strain in a panel of reference strains for drug screening and adds a new valuable tool for the study of experimental T. cruzi infection.

Topics: Animals; Brain; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; DNA, Protozoan; Female; Heart; Humans; Infant; Infectious Disease Transmission, Vertical; Inhibitory Concentration 50; Male; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Myocardium; Nifurtimox; Nitroimidazoles; Parasitemia; Random Allocation; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Chagas disease has spread throughout the world mainly because of the migration of infected individuals. In Brazil, only benznidazole (Bnz) is used; however, it is toxic and not active in the chronic phase, and cases of resistance are described. This work aimed at the synthesis and the trypanocidal evaluation in vitro and in vivo of six new Bnz analogues (3-8). They were designed by exploring the bioisosteric substitution between the amide group contained in Bnz and the 1,2,3-triazole ring. All the compounds were synthesized in good yields. With the exception of compound 7, the in vitro biological evaluation shows that all Bnz analogues were active against the amastigote form, whereas only compounds 3, 4, 5, and 8 were active against trypomastigote. Compounds 4 and 5 showed the most promising activities in vitro against the form of trypomastigote, being more active than Bnz. In vivo evaluation of compounds, 3-8 showed lower potency and higher toxicity than Bnz. Although the 1,2,3-triazole ring has been described in the literature as an amide bioisostere, its substitution here has reduced the activity of the compounds and made them more toxic. Thus, further molecular optimization could provide novel therapeutic agents for Chagas' disease.

Topics: Animals; Cell Line; Cell Survival; Chagas Disease; Male; Mice; Nifurtimox; Nitroimidazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole.. We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs.. A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths.. Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.

Topics: Adult; Chagas Disease; Chronic Disease; Cohort Studies; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Prospective Studies; Retreatment; Trypanosoma cruzi

Chagas disease is a parasite infection primarily transmitted to humans via the bite of triatomine insect vectors. Up to 8 million people are estimated to be infected with Chagas disease in the Americas. Patients who do not receive treatment can develop severe cardiac debility, gastrointestinal organ dysfunction, and may die. The changing demographics of the United States, a consequence of changing immigration patterns, means that healthcare providers are more likely to encounter patients with Chagas disease, and must understand its cause, pathogenesis, diagnosis, and treatment.

Topics: Acute-Phase Reaction; Cardiomyopathies; Chagas Disease; Chronic Disease; Diagnosis, Differential; Female; Humans; Male; Megacolon; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi; United States

The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC

Topics: Chagas Disease; Drug Design; Enzyme Inhibitors; HeLa Cells; Humans; Molecular Docking Simulation; NADH, NADPH Oxidoreductases; Nitrofurans; Trypanocidal Agents; Trypanosoma cruzi

Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity towards epimastigotes stage of the parasite T. cruzi (IC

Topics: Animals; Antioxidants; Cell Survival; Chagas Disease; Chlorocebus aethiops; Coumarins; Dose-Response Relationship, Drug; Mice; Molecular Structure; Parasitic Sensitivity Tests; RAW 264.7 Cells; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Topics: Chagas Disease; Follow-Up Studies; HIV Infections; Humans; Immunocompetence; Immunocompromised Host; Nifurtimox; Nitroimidazoles; Treatment Outcome; Trypanocidal Agents

During Trypanosoma cruzi infection, oxidative stress is considered a contributing factor for dilated cardiomyopathy development. In this study, the effects of astaxanthin (ASTX) were evaluated as an alternative drug treatment for Chagas disease in a mouse model during the acute infection phase, given its anti-inflammatory, immunomodulating, and anti-oxidative properties. ASTX was tested in vitro in parasites grown axenically and in co-culture with Vero cells. In vivo tests were performed in BALB/c mice (4-6 weeks old) infected with Trypanosoma cruzi and supplemented with ASTX (10 mg/kg/day) and/or nifurtimox (NFMX; 100 mg/kg/day). Results show that ASTX has some detrimental effects on axenically cultured parasites, but not when cultured with mammalian cell monolayers. In vivo, ASTX did not have any therapeutic value against acute Trypanosoma cruzi infection, used either alone or in combination with NFMX. Infected animals treated with NFMX or ASTX/NFMX survived the experimental period (60 days), while infected animals treated only with ASTX died before day 30 post-infection. ASTX did not show any effect on the control of parasitemia; however, it was associated with an increment in focal heart lymphoplasmacytic infiltration, a reduced number of amastigote nests in cardiac tissue, and less hyperplasic spleen follicles when compared to control groups. Unexpectedly, ASTX showed a negative effect in infected animals co-treated with NFMX. An increment in parasitemia duration was observed, possibly due to ASTX blocking of free radicals, an anti-parasitic mechanism of NFMX. In conclusion, astaxanthin is not recommended during the acute phase of Chagas disease, either alone or in combination with nifurtimox.

Topics: Animals; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; Drug Therapy, Combination; Female; Heart; Malondialdehyde; Mice; Mice, Inbred BALB C; Myocardium; Nifurtimox; Organ Size; Parasitemia; Spleen; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells; Xanthophylls

Describe a tool to estimate demand for benznidazole and nifurtimox to treat Chagas disease, and report on its implementation in a group of Latin American countries.. The project was carried out in the following stages: 1) development of a tool to estimate demand, and definition of the evaluation and decision variables to estimate demand 2) data collection via a questionnaire completed by representatives of control programs, complemented with data from the literature; 3) presentation of the tool, followed by validation, and adaptation by representatives of the control programs in order to plan drug procurement for 2012 and 2013; and 4) further analysis of the obtained data, especially regarding benznidazole, and comparison of country estimates.. Fourteen endemic countries of Latin America took part in the third stage, and a consolidated estimate was made. The number of estimated treatments, based on the number of tablets per treatment established in the regimen of reference was: 867 in the group under 1 year of age; 2 042 835 in the group from 1 to 15 years old; 2 028 in the group from 15 to 20 years old; and 10 248 in adults over 20. This means that it is possible to provide benznidazole to less than 1% of people for whom treatment is indicated.. The development and systematic use of demand management tools can play a key role in helping to provide access to the anti-Chagas drugs. There is a significant gap between the projected demand for drugs and current estimates of prevalence rates.

Topics: Adolescent; Adult; Chagas Disease; Child; Child, Preschool; Humans; Infant; Latin America; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Young Adult

Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Topics: Centers for Disease Control and Prevention, U.S.; Chagas Disease; Drug Costs; Drugs, Investigational; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; United States; United States Food and Drug Administration

American Trypanosomiasis or Chagas disease is a prevalent, neglected and serious debilitating illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. The current chemotherapy is limited only to nifurtimox and benznidazole, two drugs that have poor efficacy in the chronic phase and are rather toxic. In this scenario, more efficacious and safer drugs, preferentially acting through a different mechanism of action and directed against novel targets, are particularly welcome. Cruzipain, the main papain-like cysteine peptidase of T. cruzi, is an important virulence factor and a chemotherapeutic target with excellent pre-clinical validation evidence. Here, we present the identification of new Cruzipain inhibitory scaffolds within the GlaxoSmithKline HAT (Human African Trypanosomiasis) and Chagas chemical boxes, two collections grouping 404 non-cytotoxic compounds with high antiparasitic potency, drug-likeness, structural diversity and scientific novelty. We have adapted a continuous enzymatic assay to a medium-throughput format and carried out a primary screening of both collections, followed by construction and analysis of dose-response curves of the most promising hits. Using the identified compounds as a starting point a substructure directed search against CHEMBL Database revealed plausible common scaffolds while docking experiments predicted binding poses and specific interactions between Cruzipain and the novel inhibitors.

Topics: Antiprotozoal Agents; Chagas Disease; Cysteine Endopeptidases; High-Throughput Screening Assays; Host-Parasite Interactions; Humans; Kinetoplastida; Molecular Docking Simulation; Molecular Structure; Nifurtimox; Nitroimidazoles; Protein Domains; Protozoan Proteins; Trypanosoma cruzi

The clonal evolution of Trypanosoma cruzi sustains scientifically the hypothesis of association between parasite's genetic, biological behavior and possibly the clinical aspects of Chagas disease in patients from whom they were isolated. This study intended to characterize a range of biological properties of TcI, TcII and TcVI T. cruzi samples in order to verify the existence of these associations. Several biological features were evaluated, including in vitro epimastigote-growth, "Vero"cells infectivity and growth, along with in vivo studies of parasitemia, polymorphism of trypomastigotes, cardiac inflammation, fibrosis and response to treatment by nifurtimox during the acute and chronic murine infection. The global results showed that the in vitro essays (acellular and cellular cultures) TcII parasites showed higher values for all parameters (growth and infectivity) than TcVI, followed by TcI. In vivo TcII parasites were more virulent and originated from patients with severe disease. Two TcII isolates from patients with severe pathology were virulent in mice, while the isolate from a patient with the indeterminate form of the disease caused mild infection. The only TcVI sample, which displayed low values in all parameters evaluated, was also originated of an indeterminate case of Chagas disease. Response to nifurtimox was not associated to parasite genetic and biology, as well as to clinical aspects of human disease. Although few number of T. cruzi samples have been analyzed, a discreet correlation between parasite genetics, biological behavior in vitro and in vivo (murine model) and the clinical form of human disease from whom the samples were isolated was verified.

Topics: Animals; Cells, Cultured; Chagas Disease; Disease Models, Animal; Humans; Mice; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi; Virulence

Two old drugs are the only choice against Trypanosoma cruzi and little is known about their secondary effects in the acute stage of oral-transmitted Chagas disease (ChD).. A cross-sectional analytical surveillance study was conducted in a sizable cohort of patients seen during the largest acute foodborne ChD microepidemic registered so far. Individuals were treated with benznidazole (BNZ) or nifurtimox (NFX). 'Common Terminology Criteria for Adverse Events' was assessed to categorize side effects according to severity.. Out of 176 treatments applied, 79% had one or more adverse effects, which predominated in adults (97.8%) as compared to children (75.5%). Risk of side effects with NFX was significantly higher than BNZ. Four adults and a child treated with NFX had severe side effects (pulmonary infarction, facial paralysis, neutropenia, blurred vision, bone marrow hypoplasia) warranting hospitalization, and drug suspension. Adverse effects frequently reported with NFX were abdominal pain, hyporexia, weight loss, headache, nausea and lymphocytosis, whereas skin rash, neurosensory effects, hyporexia, fatigue, pyrosis, abdominal pain and eosinophilia were observed with BNZ.. Frequency and severity of side effects during treatment of acute oral infection by T. cruzi demand direct supervision and close follow-up, even in those asymptomatic, to prevent life-threatening situations.

Topics: Chagas Disease; Cross-Sectional Studies; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Pharmacovigilance; Trypanocidal Agents; Trypanosoma cruzi

Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Two very common neglected tropical diseases are Chagas' disease and leishmaniasis. Chagas' disease is a severe health problem, mainly in Latin America, causing approximately 50000 deaths a year and millions of people are infected. About 25-30% of the patients infected with Trypanosoma cruzi develop the chronic form of the disease. On the other hand, Leishmaniasis represents complex diseases with an important clinical and epidemiological diversity. It is endemic in 88 countries 72 of which are developing countries and it has been estimated that are 12 million people infected and 350 million are in areas with infection risk. On this basis, research on organic compounds that can be used against these two diseases is an important target. A very simple, green, and efficient protocol is developed in which bismuth nitrate pentahydrate is employed as a Lewis acid catalyst in aqueous media under microwave irradiation for the synthesis of various 2-aryl substituted benzimidazoles from aldehydes and o-phenylenediamine. Other salient features of this protocol include milder conditions, atom-economy, easy extraction, and no wastes. Nine 1H-benzimidazole derivatives (1-9) with substituents at positions 2 and 5 were synthesized and the structure of the compounds was elucidated by spectroscopic methods. The compounds were screened to identify whether they posses pharmacological activity against Chagas' disease and leishmaniasis. Compound 8 showed better activity than the control Nifurtimox against INC-5 Trypanosoma cruzi strain whereas compounds 3 and 9 have demonstrated potent leshmanicidal activity. A systematic green synthetic procedure and in vitro biological evaluation of nine 1H-benzimidazoles are described.

Topics: Amphotericin B; Antiprotozoal Agents; Benzimidazoles; Chagas Disease; Green Chemistry Technology; Heating; Leishmania mexicana; Leishmaniasis; Microwaves; Nifurtimox; Nitroimidazoles; Trypanosoma cruzi

A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR).

Topics: Amides; Antiprotozoal Agents; Cell Line; Chagas Disease; Humans; Leishmania; Parasitic Sensitivity Tests; Structure-Activity Relationship; Thiazoles; Trypanocidal Agents; Trypanosoma

Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.

Topics: Amino Acid Sequence; Chagas Disease; Drug Design; Humans; Polymerization; Sequence Homology, Amino Acid; Trypanocidal Agents; Trypanosoma cruzi; Tubulin

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.

Topics: Animals; Cells, Cultured; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Mannich Bases; Mice; Mice, Inbred BALB C; Molecular Structure; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Nifurtimox is 1 of only 2 medications available for treating Chagas disease (CD) and currently the only drug available in the United States, but its safety and tolerance have not been extensively studied. This is the first study to evaluate tolerance of nifurtimox in US patients with CD.. This investigation assessed side effects in a sample of 53 patients with CD, all Latin American immigrants, who underwent treatment with nifurtimox (8-10 mg/kg in 3 daily doses for 12 weeks) from March 2008 to July 2012. The frequency and severity of adverse events (AEs) was recorded.. A total of 435 AEs were recorded; 93.8% were mild, 3.0% moderate, and 3.2% severe. Patients experienced a mean of 8.2 AEs; the most frequent were anorexia (79.2%), nausea (75.5%), headache (60.4%), amnesia (58.5%), and >5% weight loss (52.8%). Eleven patients (20.8%) were unable to complete treatment. Experiencing a moderate or severe AE (odds ratio [OR], 3.82; P < .05) and Mexican nationality (OR, 2.29; P < .05) were significant predictors of treatment discontinuation, but sex and cardiac progression at baseline were not. Patients who did not complete treatment experienced nearly 3 times more AEs per 30-day period (P = .05).. Nifurtimox produces frequent side effects, but the majority are mild and can be managed with dose reduction and/or temporary suspension of medication. The high frequency of gastrointestinal symptoms and weight loss mirrors results from prior investigations. Special attention should be paid during the early stages of treatment to potentially severe symptoms including depression, rash, and anxiety.

Topics: Adult; Aged; Chagas Disease; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nifurtimox; Phenotype; Risk Factors; Severity of Illness Index; Symptom Assessment; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; United States

The obligate intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness affecting millions of people in Latin America that recently entered non-endemic countries through immigration, as a consequence of globalization. The chemotherapy for this disease is based mainly on benznidazole and nifurtimox, which are very efficient nitroderivatives against the acute stage but present limited efficacy during the chronic phase. Our group has been studying the trypanocidal effects of naturally occurring quinones and their derivatives, and naphthoimidazoles derived from β-lapachone N1, N2 and N3 were the most active. To assess the molecular mechanisms of action of these compounds, we applied proteomic techniques to analyze treated bloodstream trypomastigotes, which are the clinically relevant stage of the parasite.. The approach consisted of quantification by 2D-DIGE followed by MALDI-TOF/TOF protein identification. A total of 61 differentially abundant protein spots were detected when comparing the control with each N1, N2 or N3 treatment, for 34 identified spots. Among the differentially abundant proteins were activated protein kinase C receptor, tubulin isoforms, asparagine synthetase, arginine kinase, elongation factor 2, enolase, guanine deaminase, heat shock proteins, hypothetical proteins, paraflagellar rod components, RAB GDP dissociation inhibitor, succinyl-CoA ligase, ATP synthase subunit B and methionine sulfoxide reductase.. Our results point to different modes of action for N1, N2 and N3, which indicate a great variety of metabolic pathways involved and allow for novel perspectives on the development of trypanocidal agents.

Topics: Animals; Chagas Disease; Electrophoresis, Gel, Two-Dimensional; Mice; Naphthoquinones; Nifurtimox; Nitroimidazoles; Proteomics; Protozoan Proteins; Trypanocidal Agents; Trypanosoma cruzi

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.

Topics: Animals; Area Under Curve; Chagas Disease; Disease Models, Animal; Female; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Nifurtimox; Nitroimidazoles; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity. Lipinski's rules were considered in order to support drug-likeness designing. The set of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides was assayed against three T. cruzi strains, which represent the discrete typing units more prevalent in human patients: Y (TcII), Silvio X10 cl1 (TcI), and Bug 2149 cl10 (TcV). All the derivatives, except one, showed enhanced trypanocidal activity against the three strains as compared to BZD. In the Y strain 62% of the compounds were more active than NFX. The most active compound was N'-((5-nitrofuran-2-yl) methylene)biphenyl-4-carbohydrazide (C20), which showed IC50 values of 1.17 ± 0.12 μM; 3.17 ± 0.32 μM; and 1.81 ± 0.18 μM for Y, Silvio X10 cl1, and Bug 2149 cl10 strains, respectively. Cytotoxicity assays with human fibroblast cells have demonstrated high selectivity indices for several compounds. Exploratory data analysis indicated that primarily topological, steric/geometric, and electronic properties have contributed to the discrimination of the set of investigated compounds. The findings can be helpful to drive the designing, and subsequently, the synthesis of additional promising drugs against Chagas disease.

Topics: Antiprotozoal Agents; Cells, Cultured; Chagas Disease; Dose-Response Relationship, Drug; Drug Design; Fibroblasts; Humans; Hydrazines; Hydrazones; Models, Molecular; Molecular Structure; Nitrofurans; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanosoma cruzi

3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.

Topics: Animals; Binding Sites; Cell Line; Chagas Disease; Disease Models, Animal; Leishmania donovani; Mice; Mice, Inbred BALB C; Nitroreductases; Parasitic Sensitivity Tests; Prodrugs; Protein Structure, Tertiary; Protozoan Proteins; Rats; Sterol 14-Demethylase; Structure-Activity Relationship; Triazoles; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

Novel linear 3-nitro-1H-1,2,4-triazole-based piperazides were synthesized and evaluated as antitrypanosomal agents. In addition, some bisarylpiperazine-ethanones which were formed as by-products were also screened for antiparasitic activity. Most 3-nitrotriazole-based derivatives were potent and selective against Trypanosoma cruzi parasites, but only one displayed these desired properties against Trypanosoma brucei rhodesiense. Moreover, two 3-nitrotriazole-based chlorophenylpiperazides were moderately and selectively active against Leishmania donovani. Although the bisarylpiperazine-ethanones were active or moderately active against T. cruzi, none of them demonstrated an acceptable selectivity. In general, 3-nitrotriazole-based piperazides were less toxic to host L6 cells than the previously evaluated 3-nitrotriazole-based piperazines and seven of 13 were 1.54- to 31.2-fold more potent antichagasic agents than the reference drug benznidazole. Selected compounds showed good ADMET characteristics. One potent in vitro antichagasic compound (3) was tested in an acute murine model and demonstrated antichagasic activity after a 10-day treatment of 15 mg/kg/day. However, neither compound 3 nor benznidazole showed a statistically significant P value compared to control due to high variability in parasite burden among the untreated animals. Working as prodrugs, 3-nitrotriazole-based piperazides were excellent substrates of trypanosomal type I nitroreductases and constitute a novel class of potentially effective and more affordable antitrypanosomal agents.

Topics: Animals; Cell Line; Chagas Disease; Dose-Response Relationship, Drug; Humans; Leishmania donovani; Mice; Mice, Inbred BALB C; Molecular Structure; Parasitic Sensitivity Tests; Piperazines; Rats; Structure-Activity Relationship; Triazoles; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

Chagas disease constitutes a major public health problem in Latin America. Human breast milk is a biological sample of great importance for the analysis of therapeutic drugs, as unwanted exposure through breast milk could result in pharmacological effects in the nursing infant. Thus, the goal of breast milk drug analysis is to inquire to which extent a neonate may be exposed to a drug during lactation. In this work, we developed an analytical technique to quantify benznidazole and nifurtimox (the two antichagasic drugs currently available for medical treatment) in human breast milk, with a simple sample pretreatment followed by an ionic-liquid-based dispersive liquid-liquid microextraction combined with high-performance liquid chromatography and UV detection. For this technique, the ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate has been used as the "extraction solvent." A central composite design was used to find the optimum values for the significant variables affecting the extraction process: volume of ionic liquid, volume of dispersant solvent, ionic strength, and pH. At the optimum working conditions, the average recoveries were 77.5 and 89.7%, the limits of detection were 0.06 and 0.09 μg/mL and the interday reproducibilities were 6.25 and 5.77% for benznidazole and nifurtimox, respectively. The proposed methodology can be considered sensitive, simple, robust, accurate, and green.

Topics: Chagas Disease; Chromatography, High Pressure Liquid; Humans; Imidazoles; Ionic Liquids; Liquid Phase Microextraction; Milk, Human; Molecular Structure; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Ultraviolet Rays

Chagas disease is an anthropozoonosis caused by Trypanosoma cruzi. Two drugs are currently used for the etiological treatment of the disease: Nifurtimox (Lampit) and Benznidazole. This study presents a quasi-experimental trial (non-control group) of sixty-two patients who were treated for Chagas disease with Nifurtimox (Lampit), and were then followed for 30 months post-treatment. The safety of Nifurtimox (Lampit) for Chagas disease in this group of children primarily between 4 and 19 years old was also evaluated.. The 62 patients included in the study were selected when resulted seropositive for two out of three fundamentally different serological tests. All children were treated during two months according to protocols established by WHO. Monitoring was performed every twenty days to evaluate treatment safety. In 43 patients, two different serological tests: ELISA and IFAT; and two parasitological tests: blood culture, and real time PCR, (qPCR) were performed to assess therapeutic response, defined as post-treatment serological negativization.. All patients completed the treatment successfully, and six patients abandoned the post-treatment follow-up. Adverse effects occurred in 74% of patients, but only 4.8% of cases required temporary suspension to achieve 100% adherence to the 60-day treatment, and all symptoms reverted after treatment completion. Both parasite load (measured through qPCR) and antibodies (ELISA absorbance) evidenced a significant median reduction 6 months after treatment from 6.2 to 0.2 parasite equivalents/mL, and from 0.6 to 0.2 absorbance units respectively (p<0.001). Serological negativization by ELISA was evident since 6 months post-treatment, whereas by IFAT only after 18 months. Serological negativization by the two tests (ELISA and IFAT) was 41.9% (95%CI: 26.5-57.3) after 30 months post-treatment. qPCR was positive in 88.3% of patients pre-treatment and only in 12.1% of patients after 30 months. Survival analysis indicated that only 26.3% (95%CI: 15.5-44.8) persisted with negative qPCR during the whole follow-up period.. Nifurtimox was very well tolerated and successfully reduced parasite load and antibody titers. Re-infection, lysed parasites or a lack of anti-parasitic activity could explain these persistently positive qPCR cases.

Topics: Adolescent; Adult; Asymptomatic Diseases; Chagas Disease; Child; Child, Preschool; Colombia; DNA, Protozoan; Female; Follow-Up Studies; Humans; Male; Nifurtimox; Real-Time Polymerase Chain Reaction; Trypanocidal Agents; Trypanosoma cruzi

With the aim of improving the available drugs for the treatment of Chagas disease, individual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in their in vitro activity against a panel of Trypanosoma cruzi strains; in vivo efficacy in a murine model of Chagas disease; in vitro toxicity and absorption, distribution, metabolism, and excretion characteristics; and in vivo pharmacokinetic properties. There is unlikely to be any therapeutic benefit of an individual nifurtimox enantiomer over the racemic mixture.

Topics: Animals; Chagas Disease; Female; Humans; Male; Mice; Nifurtimox; Rats; Rats, Sprague-Dawley; Stereoisomerism; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.. The benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.. Polar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.. B-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.

Topics: Alcohol Oxidoreductases; Animals; Cell Line; Cell Survival; Chagas Disease; Disease Models, Animal; Esters; Isoenzymes; Male; Mice; Nifurtimox; Nitroimidazoles; Oxamic Acid; Prodrugs; Trypanocidal Agents; Trypanosoma cruzi

There are 300,000 estimated cases of Chagas disease in the United States but limited data on access to care. This study analyzed trends in access to care for Chagas disease in the United States and assessed the national and state barriers to access. Data on cases in blood donors and drug releases were obtained from the AABB (formerly American Association of Blood Banks) and U.S. Centers for Disease Control and Prevention (CDC), respectively. Semi-structured in-depth interviews were conducted with 30 key informants at the national level and in five states where treatment had been released. Interview responses were analyzed according to the health systems dimensions of regulation, financing, payment, organization, and persuasion. Data indicate that 1,908 cases were identified in the blood donation system from 2007 to 2013 and that CDC released 422 courses of benznidazole or nifurtimox during this period. The barriers to access at the national level include limited diagnostic and institutionalized referral and care processes, lack of financing for patient-care activities, and limited awareness and training among providers. This study demonstrates that access to treatment of Chagas disease in the United States is limited. The lack of licensing is only one of several barriers to access, highlighting the need for a health systems perspective when scaling up access to these essential medicines.

Topics: Blood Donors; Centers for Disease Control and Prevention, U.S.; Chagas Disease; Clinical Competence; Delivery of Health Care; Drugs, Investigational; Health Services Accessibility; Humans; Nifurtimox; Nitroimidazoles; Referral and Consultation; Systems Analysis; Trypanocidal Agents; United States

Chagas disease is a major unsolved health issue in Latin America and an emerging threat worldwide. New drugs are urgently needed for chemotherapy as those available (benznidazole and nifurtimox) have variable efficacy and elevated toxicity. Efforts are actually oriented to improve tools and technologies (e.g. transgenic parasites, flow cytometry or image-based systems) for the screening of large numbers of candidate compounds for their activity against Trypanosoma cruzi (T. cruzi). Methods that test drug efficacy and selectivity in the same assay are suitable to accelerate the process of drug discovery. Here, we developed a GFP expressing T. cruzi from a moderate virulence stock and confirmed that the transgenic parasite retained the biological characteristics of the parental strain. With this tool, we established a flow cytometer-based method to simultaneously test drug activity against intracellular amastigotes and toxicity to the host cell. This one-step procedure allows determining the selectivity index of the tested compound in a sensitive and accurate manner even with low infection rates. This method can provide additional information on the interactions between drug, parasites and host cell and could be adapted to other trypanosomatids and protozoa with intracellular multiplication.

Topics: Chagas Disease; Drug Discovery; Flow Cytometry; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox (NFX) is one of the approved drugs used to treat Chagas disease. Safety profile studies and models on risk factors for treatment interruption in adults are scarce in Latin America. This study evaluated retrospectively the medical records of adult Chagas disease patients treated with NFX between 2007 and 2012 in Bogotá, Colombia. An accelerated failure time model was used, and associations were expressed as time ratio (TR). In total, 76 adult patients with NFX were included: 60 (79.0%) completed 60 days of treatment, 61 (80.3%) presented adverse drug reactions (ADRs), and 16 (21.0%) required treatment interruption. The predominant symptoms were epigastric pain (23.7%), nauseas (18.4%), sleep disturbances (18.4%), loss of appetite (17.1%), and temporary loss of memory (15.2%). ADRs were classified as mild (64.5%), moderate (30.4%), and severe (5.1%). Time of treatment was significantly longer when presenting ≤ 3 ADRs (TR: 1.78; 95% CI: 1.04-3.03), presence of non-severe ADRs (TR: 6.52; 95% CI: 3.24-13.1), doses of NFX ≤ 8 mg/kg/day (TR: 1.78; 95% CI: 0.90-3.49), and age < 48 years (TR: 1.57; 95% CI: 0.90-2.74). Treatment with NFX in adults caused a high frequency of ADRs, but most of the cases were mild and did not require treatment interruption. Severity and number of ADRs were the main predictors for treatment interruption.

Topics: Adolescent; Adult; Aged; Antiprotozoal Agents; Chagas Disease; Chronic Disease; Colombia; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Nifurtimox; Retrospective Studies; Time Factors; Young Adult

Topics: Animals; Arrhythmias, Cardiac; Chagas Cardiomyopathy; Chagas Disease; Death, Sudden, Cardiac; Defibrillators, Implantable; Disease Management; Heart Failure; Humans; Insect Control; Insect Vectors; Nifurtimox; Nitroimidazoles; Thromboembolism; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

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

Chagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year. T. cruzi is susceptible to thiosemicarbazones, making this class of compounds appealing for drug development. Previously, the homologation of aryl thiosemicarbazones resulted in an increase in anti-T. cruzi activity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new aryl thiosemicarbazones (9a-x), designed as more conformationally restricted compounds. By varying substituents attached to the phenyl ring, substituents were observed to retain, enhance or greatly increase the anti-T. cruzi activity, in comparison to the nonsubstituted derivative. In most cases, hydrophobic and bulky substituents, such as bromo, biphenyl and phenoxyl groups, greatly increased antiparasitic activity. Specifically, thiosemicarbazones were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting mouse splenocytes viability. The most potent anti-T. cruzi thiosemicarbazones were evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these thiosemicarbazones induce apoptosis. In conclusion, the structural design executed within the series of aryl thiosemicarbazones (9a-x) led to the identification of new potent anti-T. cruzi agents, such as compounds (9h) and (9r), which greatly inhibited epimastigote proliferation, and demonstrated a toxicity for trypomastigotes, but not for splenocytes. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process.

Topics: Animals; Cell Line; Cells, Cultured; Chagas Disease; Cysteine Proteases; Cysteine Proteinase Inhibitors; Drug Design; Humans; Mice; Mice, Inbred BALB C; Molecular Conformation; Spleen; Structure-Activity Relationship; Thiosemicarbazones; Trypanocidal Agents; Trypanosoma cruzi

In this study thiosemicarbazones derivatives of 5-[(trifluoromethyl)phenylthio]-2-furaldehyde were synthesized and evaluated in terms of their efficiency in challenging the growth of epimastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. A number of compounds were synthesized from 5-bromo-2-furfuraldehyde using nucleophilic aromatic substitution, with a series of trifluoromethyl thiolates, followed by condensation reactions with thiosemicarbazide. Their molecular structures were determined by (1)H, (13)C and (19)F NMR, MS and IR spectroscopy. When tested with T. cruzi, they showed a stronger reaction, similar to nifurtimox and benznidazole, with the 5-[nitro-4-(trifluoromethyl)phenyltio]-2-furaldehyde thiosemicarbazone (compound 4) showing the highest antiparasitic activity. This improved activity may be explained due to the nitro group present in the molecule, which potentiates its activity. The thiosemicarbazone derivatives in this study showed no apoptosis in platelets or monocytes, nor did they induce platelet activation. The trypanocidal activity of these substances represents a good starting point for a medicinal chemistry program aimed at therapy for Chagas' disease.

Topics: Apoptosis; Blood Platelets; Cells, Cultured; Chagas Disease; Flow Cytometry; Humans; In Vitro Techniques; Molecular Structure; Monocytes; Platelet Activation; Thiosemicarbazones; Trypanocidal Agents; Trypanosoma cruzi

We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.

Topics: Amides; Apoptosis; Blood Platelets; Cells, Cultured; Chagas Disease; Flow Cytometry; Heterocyclic Compounds; Humans; Imidazoles; In Vitro Techniques; Leishmania donovani; Leishmaniasis, Visceral; Molecular Structure; Monocytes; Platelet Activation; Sulfonamides; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, remains an important public health issue in many Central and South American countries, as well as non-endemic areas with high rates of immigration from these countries. Existing treatment options for CD are limited and often unsatisfactory. Moreover the lack of post-treatment tests of cure limits the development of new drugs. To address this issue, we sought to identify serum biomarkers following nifurtimox (Nfx) treatment that could be used as an early test of cure and/or markers of a therapeutic response.. Human sera from Chagas patients pre- and post-treatment with Nfx (n = 37) were compared to samples from healthy subjects (n = 37) using a range of proteomic and immunologic techniques. Biomarker peaks with the best discriminatory power were further characterized.. Using serum samples (n = 111), we validated the presence of five key biomarkers identified in our previous study, namely human apolipoprotein A-I (APOA1) and specific fragments thereof and one fragment of human fibronectin (FN1). In chagasic serum samples all biomarkers except full-length APOA1 were upregulated. These five biomarkers returned to normal in 43% (16/37) of the patients treated with Nfx at three years after treatment.. The normalization of biomarker patterns strongly associated with CD suggests that these markers can be used to identify patients in whom Nfx treatment is successful. We believe that these are the first biomarkers predictive of cure in CD patients.

Topics: Adult; Apolipoprotein A-I; Biomarkers; Chagas Disease; Female; Fibronectins; Humans; Male; Nifurtimox; Predictive Value of Tests; Prognosis; South America; Trypanocidal Agents; Trypanosoma cruzi

Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known.. HepG2 cells dose response to NFOH and BZL (5-100 µM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored.. HepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-α), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT) and a 20-40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment.. NFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted.

Topics: Animals; Cell Death; Cell Line, Tumor; Chagas Disease; Chemical and Drug Induced Liver Injury; DNA Damage; Female; Hep G2 Cells; Humans; Liver; Male; Mice; Mitochondria; Nifurtimox; Nitrofurazone; Nitroimidazoles; Parasites; Reactive Oxygen Species; Trypanocidal Agents; Trypanosoma cruzi; Tumor Necrosis Factor-alpha; Tyrosine

The outbreak of acute Chagas disease due to oral transmission of the parasite is a well-known phenomenon mainly occurring in the Amazon. Such an event is described here for the first time in French Guiana. Eight patients of the same family, presenting epidemiological and clinical histories compatible with recent Trypanosoma cruzi infection of Chagas disease due to the ingestion of palm Oenocarpus bacaba juice were, rather late after the putative date of infection, underwent four parasitological and two serological specific tests for confirmation of the diagnosis. Real-time PCR results were positive for all the patients; strains were isolated by hemoculture from four patients, PCR identification of TcI DTU was made for six patients, while parasites were not detected in any of the patients by direct microscopic examination. The results of two serologic tests were positive. All patients were treated with benznidazole, and two patients were additionally given nifurtimox. A 6-year follow-up was possible for six patients. Real-time PCR was negative for these patients after 1 year, while the antibody rates decreased slowly and serology results were negative only after several years (1-5 years). Our findings confirm the occurrence of an outbreak of Chagas infection in members of the same family, with the oral mode of infection being the most likely hypothesis to explain this group of cases. Our results show the successful treatment of patients infected by TcI and the usefulness of real-time PCR for the emergency diagnosis of recent Chagas disease cases and in posttreatment follow-up.

Topics: Adolescent; Adult; Aged; Arecaceae; Chagas Disease; Child; Family; Female; French Guiana; Humans; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Plant Extracts; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease (CD) is endemic in Central and South America, Mexico and even in some areas of the United States. However, cases have been increasingly recorded also in non-endemic countries. The estimated number of infected people in Europe is in a wide range of 14000 to 181000 subjects, mostly resident in Spain, Italy and the United Kingdom.. Retrospective, observational study describing the characteristics of patients with CD who attended the Centre for Tropical Diseases (Negrar, Verona, Italy) between 2005 and 2013. All the patients affected by CD underwent chest X-ray, ECG, echocardiography, barium X-ray of the oesophagus and colonic enema. They were classified in the indeterminate, cardiac, digestive or mixed category according to the results of the screening tests. Treatment with benznidazole (or nifurtimox in case of intolerance to the first line therapy) was offered to all patients, excluding the ones with advanced cardiomiopathy, pregnant and lactating women. Patients included were 332 (73.9% women). We classified 68.1% of patients as having Indeterminate Chagas, 11.1% Cardiac Chagas, 18.7% as Digestive Chagas and 2.1% as Mixed Form. Three hundred and twenty-one patients (96.7%) were treated with benznidazole, and most of them (83.2%) completed the treatment. At least one adverse effect was reported by 27.7% of patients, but they were mostly mild. Only a couple of patients received nifurtimox as second line treatment.. Our case series represents the largest cohort of T. cruzi infected patients diagnosed and treated in Italy. An improvement of the access to diagnosis and cure is still needed, considering that about 9200 infected people are estimated to live in Italy. In general, there is an urgent need of common guidelines to better classify and manage patients with CD in non-endemic countries.

Topics: Adolescent; Adult; Aged; Chagas Disease; Child; Echocardiography; Electrocardiography; Female; Humans; Italy; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Pregnancy; Retrospective Studies; Tropical Medicine; United States

As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.

Topics: Animals; Antiprotozoal Agents; Cell Line; Chagas Disease; Electrochemistry; Mice; Mutagenesis; Oxides; Quinoxalines; Trypanosoma cruzi

With declining vectorial transmission, Chagas disease predominantly affects adults nowadays. The efficacy of nifurtimox in the chronic phase in adult patients is poorly known, particularly in regions where there is no risk of reinfection. Recommendations for treatment outcome assessment rely on serological follow-up. We evaluated the serological and parasitological response to nifurtimox in a cohort of adult patients three years post-treatment in Switzerland.. Patients treated with nifurtimox in 2008 during a cross-sectional study in Geneva, Switzerland, were contacted for follow-up in 2011. Two ELISAs and a rapid immunochromatographic test were used to test 2008 and 2011 serum samples simultaneously. In addition, conventional and real-time PCR were performed on 2011 samples.. Thirty-seven (84.1%) of 44 eligible patients, predominantly female, middle-aged, Bolivians at the indeterminate stage, were enrolled. All 2011 ELISA and immunochromatographic tests were positive. Twenty-eight (75.7%) patients presented a lower optical density (OD) in 2011 compared to 2008. This OD difference was significant in both commercial (P < 0.001) and in-house (P = 0.002) ELISAs. Agreement between the two ELISAs was low (Kappa = 0.469). All patients had negative conventional PCR results but one (2.7%) was positive with real-time PCR.. Our results highlight the inadequacy of serology for assessing response in adults, three years after treatment. In our cohort, 97.3% had results that could either indicate treatment failure or persistant humoral response despite treatment. The lack of accurate early post-treatment tests of cure prevents appropriate patients information and councelling. New follow-up tests are needed to assess treatments efficacy given the large adult population in need of antiparasitic therapy.

Topics: Adult; Chagas Disease; Chronic Disease; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nifurtimox; Real-Time Polymerase Chain Reaction; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and it affects as many as 10 million people in North and South America, where it represents a major public health problem. T. cruzi is a parasite with high genetic diversity, and it has been grouped into 6 discrete typing units (DTUs), designated as T. cruzi I (TcI) to T. cruzi VI (TcVI). Mexican isolates from humans and from vector insects have been primarily found to be TcI, and these isolates are likely to be the strains that cause the clinical manifestations observed in Mexico. However, genetic characterization and drug susceptibility assays are limited in Mexican TcI strains. In this work, 24 Mexican T. cruzi strains, obtained primarily from humans, were studied with 7 locus microsatellites and mini-exon gene by PCR. Also, drug susceptibility was evaluated by growth and mobility assays. All of the human strains belonged to TcI, and they could be further grouped through microsatellite analysis into 2 subgroups (microsatellite genotypes 1 and 2), which were not related to the host clinical status or biological origin of the strain. Two strains, both from wild mammals, belonged to the TcII-TcVI groups; these strains and the CL Brener strain constituted microsatellite genotype 3. The number of alleles in each locus was lower than reported for South American strains, and a departure from the Hardy-Weinberg equilibrium was observed. The susceptibility of these strains to nifurtimox and benznidazole was heterogeneous. T. cruzi strains characterized as microsatellite genotypes 2 and 3 were significantly more susceptible to benznidazole than strains of microsatellite genotype 1. Only 1 Mexican strain resistant to both drugs was found in this study.

Topics: Animals; Chagas Disease; DNA, Protozoan; Drug Resistance; Exons; Genetic Variation; Genotype; Humans; Insect Vectors; Mexico; Microsatellite Repeats; Nifurtimox; Nitroimidazoles; Opossums; Phylogeny; Polymerase Chain Reaction; Triatoma; Trypanocidal Agents; Trypanosoma cruzi

Currently, only two drugs are approved for treating Trypanosoma cruzi infection: benznidazole and nifurtimox. Adverse reactions are frequent with both drugs: they have chemical similarities and common metabolic pathways making cross reactions a possibility. Our objective was to describe the safety/tolerability profile of nifurtimox in patients who had previously discontinued benznidazole due to hypersensitivity reactions. We performed a prospective observational study from September 2009 to December 2011. Patients who discontinued benznidazole therapy due to hypersensitivity reactions (HR) and were later treated with nifurtimox were included. HR to benznidazole were defined as presence of a rash with or without mucosal involvement, fever or laboratory abnormalities (such as eosinophilia, leucopaenia or impaired liver function tests). The drugs were prescribed for 60 days (benznidazole) or 60-90 days (nifurtimox). The National Cancer Institute criteria (CTCAE, 2006, Version 3.0) were used for grading and reporting of adverse reactions (AR). Eighteen patients (16 females, two males, median age 35.5 years, range 15-50 years) with asymptomatic late chronic infection, were included. Median time between benznidazole interruption and start of therapy with nifurtimox was 121.5 days (IQR 72-223 days). Fifteen patients (83.3%) developed an AR to nifurtimox, gastrointestinal complaints and anorexia being the most common, and 13 patients (72%) completed the treatment schedule. Five patients interrupted therapy (27.8%) mainly because of gastrointestinal intolerance and/or nervous system toxicity. Only one patient developed skin lesions, a mild maculopapular rash not requiring specific therapy or treatment withdrawal. There was no severe AR. Nifurtimox as second line therapy in patients who discontinued benznidazole specifically due to HR appears to be safe and does not seem to be associated with a higher incidence of AR.

Topics: Adolescent; Adult; Chagas Disease; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Young Adult

This work compared the time at which negative seroconversion was detected by conventional serology (CS) and by the ELISA-F29 test on a cohort of chronic chagasic patients treated with nifurtimox or benznidazole. A retrospective study was performed using preserved serum from 66 asymptomatic chagasic adults under clinical supervision, and bi-annual serological examinations over a mean follow-up of 23 years. Twenty nine patients received trypanocide treatment and 37 remained untreated. The ELISA-F29 test used a recombinant antigen which was obtained by expressing the Trypanosoma cruzi flagellar calcium-binding protein gene in Escherichia coli. Among the untreated patients, 36 maintained CS titers. One patient showed a doubtful serology in some check-ups. ELISA-F29 showed constant reactivity in 35 out of 37 patients and was negative for the patient with fluctuating CS. The treated patients were divided into three groups according to the CS titers: in 13 they became negative; in 12 they decreased and in four they remained unchanged. ELISA-F29 was negative for the first two groups. The time at which negativization was detected was significantly lower for the ELISA-F29 test than for CS, 14.5 ± 5.7 and 22 ± 4.9 years respectively. Negative seroconversion was observed in treated patients only. The results obtained confirm that the ELISA-F29 test is useful as an early indicator of negative seroconversion in treated chronic patients.

Topics: Adolescent; Adult; Antibodies, Protozoan; Antigens, Protozoan; Case-Control Studies; Chagas Disease; Chronic Disease; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Retrospective Studies; Time Factors; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Currently, evaluation of drug efficacy for Chagas disease remains a controversial issue with no consensus. In this work, we evaluated the parasitological efficacy of Nifurtimox treatment in 21 women with chronic Chagas disease from an area of endemicity in Chile who were treated according to current protocols. Under pre- and posttherapy conditions, blood (B) samples and xenodiagnosis (XD) samples from these patients were subjected to analysis by real-time PCR targeting the nuclear satellite DNA of Trypanosoma cruzi (Sat DNA PCR-B, Sat DNA PCR-XD) and by PCR targeting the minicircle of kinetoplast DNA of T. cruzi (kDNA PCR-B, kDNA PCR-XD) and by T. cruzi genotyping using hybridization minicircle tests in blood and fecal samples of Triatoma infestans feed by XD. In pretherapy, kDNA PCR-B and kDNA PCR-XD detected T. cruzi in 12 (57%) and 18 (86%) cases, respectively, whereas Sat DNA quantitative PCR-B (qPCR-B) and Sat DNA qPCR-XD were positive in 18 cases (86%) each. Regarding T. cruzi genotype analysis, it was possible to observe in pretherapy the combination of TcI, TcII, and TcV lineages, including mixtures of T. cruzi strains in most of the cases. At 13 months posttherapy, T. cruzi DNA was detectable in 6 cases (29.6%) and 4 cases (19.1%) by means of Sat DNA PCR-XD and kDNA PCR-XD, respectively, indicating treatment failure with recovery of live parasites refractory to chemotherapy. In 3 cases, it was possible to identify persistence of the baseline genotypes. The remaining 15 baseline PCR-positive cases gave negative results by all molecular and parasitological methods at 13 months posttreatment, suggesting parasite response. Within this follow-up period, kDNA PCR-XD and Sat DNA qPCR-XD proved to be more sensitive tools for the parasitological evaluation of the efficacy of Nifurtimox treatment than the corresponding PCR methods performed directly from blood samples.

Topics: Adult; Animals; Chagas Disease; Chronic Disease; DNA, Protozoan; Female; Genotyping Techniques; Humans; Middle Aged; Nifurtimox; Polymerase Chain Reaction; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

In this article, we present a sensitivity analysis for drawing inferences about parameters that are not estimable from observed data without additional assumptions. We present the methodology using two different examples: a causal parameter that is not identifiable due to violations of the randomization assumption, and a parameter that is not estimable in the nonparametric model due to measurement error. Existing methods for tackling these problems assume a parametric model for the type of violation to the identifiability assumption and require the development of new estimators and inference for every new model. The method we present can be used in conjunction with any existing asymptotically linear estimator of an observed data parameter that approximates the unidentifiable full data parameter and does not require the study of additional models.

Topics: Biometry; Chagas Disease; Data Interpretation, Statistical; Humans; Lost to Follow-Up; Middle Aged; Models, Statistical; Motor Activity; Nifurtimox; Patient Dropouts

American Trypanosomiasis or Chagas Disease is a major public health problem, endemic in the American continent since prehistoric times. Its natural course is towards chronicity in the immunocompetent host, often leading to severe cardiopathy or bowel involvement. Pharmacologic therapy is restricted to two drugs and only one of them is currently available in Chile. Both have poor effectiveness in the chronic stages of the disease and cause frequent adverse reactions. Many physicians avoid their use, despite published evidences about the usefulness. We herein report the experience of our Center in the treatment of Chronic Chagas Disease in adults using the drug nifurtimox, emphasizing its degree of acceptability and its secondary effects.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chagas Disease; Chile; Chronic Disease; Female; Humans; Male; Medication Adherence; Middle Aged; Nifurtimox; Trypanocidal Agents; Young Adult

A series of 25 N,N'-substituted diamines were prepared by controlled reductive amination of free aliphatic diamines with different substituted benzaldehydes. The library was screened in vitro for antiparasitic activity on the causative agents of human African trypanosomiasis, Chagas' disease and visceral leishmaniasis. The most potent compounds were derived from a subset of diamines that contained a 4-OBn substitution, having a 50% parasite growth inhibition in the submicromolar (against Trypanosoma cruzi) or nanomolar (against Trypanosoma brucei and Leishmania donovani) range. We conclude that members of this series of N,N'-substituted diamines provide new lead structures that have potential to treat trypanosomal and leishmanial infections.

Topics: Animals; Antiprotozoal Agents; Chagas Disease; Diamines; Humans; Inhibitory Concentration 50; Kinetoplastida; Leishmaniasis, Visceral; Molecular Structure; Small Molecule Libraries; Trypanosomiasis, African

In the present communication we prepared a series of six 4-hydroxycoumarin derivatives, isosters of quercetin, recognized as an antioxidant natural compound, with the aim of evaluating the antitrypanosomal activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, and the antioxidant properties. We have used the 4-hydroxycoumarin moiety (compound 1) as the molecular template for the synthesis of compounds 2-7. These derivates have shown moderate trypanocidal activity. However they have been proved to be good antioxidants. In particular compound 7 is the most active antioxidant and it is, therefore, a potential candidate for a successful employment in conditions characterized by free radicals overproduction.

Topics: 4-Hydroxycoumarins; Antioxidants; Chagas Disease; Humans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

Topics: Animals; Cell Proliferation; Chagas Disease; Computer Simulation; Cysteine Endopeptidases; Female; Imines; Mice; Mice, Inbred BALB C; Models, Molecular; Protein Binding; Protozoan Proteins; Spleen; Stereoisomerism; Structure-Activity Relationship; Thiazolidines; Trypanocidal Agents; Trypanosoma cruzi

Topics: Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Chagas Disease; Humans; Nifurtimox; Trypanocidal Agents; Trypanosoma cruzi

Topics: Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas' disease is a zoonosis caused by a protozoan agent, Trypanosoma cruzi. Patients undergoing immunosuppressive treatment due to organ transplant, malignancies, infections, or chemotherapy may reactivate a preexisting chronic or indeterminate Trypanosoma cruzi infection.. We present two transplant patients who underwent reactivation of Chagas' disease with cutaneous manifestations after an augmentation in their immunosuppressive therapy. A 38-year-old man was hospitalized on day 69 after receiving an allogeneic bone marrow transplant; he developed multiple painful erythematous plaques with diffuse borders, confined to the right cheek, trunk, thigh, elbows, and feet. A 59-year-old woman with a 14-year history of Chagasic cardiomyopathy presented one month after heart transplantation with a painful infiltrated purpuric plaque on the back of her right leg.. In both cases, histologic examination of skin biopsies showed dermal infiltration with intrahistiocytic amastigotes. In one of the reported cases, the Strout method detected parasitemia. Treatments with nifurtimox (600 mg/d) in case 1 and benznidazole (400 mg/d) in case 2 were started. Fever and cutaneous lesions resolved immediately after seven days of treatment.. Reactivation of Chagas' disease is a serious complication that usually occurs in immunocompromised patients. Clinical manifestations include febrile illness occasionally associated with painful skin lesions. Early diagnosis and proper treatment can significantly improve these patients' outcome.

Topics: Adult; Bone Marrow Transplantation; Chagas Disease; Female; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Recurrence; Trypanocidal Agents

The present work aimed to investigate the curative effect of benznidazole (BZL) in combination with other patented drugs [nifurtimox (NFX), posaconazole (POS) or AmBisome(®) (AMB)] in mice acutely or chronically infected with either a BZL-susceptible (Tulahuen) or a BZL-partially-resistant (Y) strain of Trypanosoma cruzi. To appreciate the eventual advantage of such combinations, infected mice were treated for short durations (non-curative) of each individual treatment. Cure rates were determined by investigating blood parasites (microscopic examination) and parasite DNA (quantitative PCR) after submitting treated mice to immune suppression with cyclophosphamide. The results mainly suggest that shorter durations of treatment combining BZL and POS or NFX might cure mice acutely or chronically infected with the Tulahuen strain, whereas the combination of BZL with AMB does not have such an effect. Moreover, the association BZL+POS does not improve the curative effect of POS (all used for shorter durations) in infection with the Y strain. Shortening the duration of treatment whilst keeping a complete curative effect deserves interest in limiting adverse reactions due to dose-cumulative toxic effects of long treatment. Genotyping of the T. cruzi strain(s) infecting patients might also allow a better adaptation of individual therapeutic schedules, improving both the efficiency and safety of trypanocidal treatment. This preliminary experimental study should encourage further investigations to find the best combination of adequate drug concentrations and timing of treatment.

Topics: Amphotericin B; Animals; Chagas Disease; Disease Models, Animal; DNA, Protozoan; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Nifurtimox; Nitroimidazoles; Parasite Load; Parasitemia; Real-Time Polymerase Chain Reaction; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Acute Chagas disease is rarely recognized, and the risk for acquiring the disease is undefined in travelers to Central America. We describe a case of acute Chagas disease in a traveler to Costa Rica and highlight the need for increased awareness of this infection in travelers to Chagas-endemic areas.

Topics: Chagas Disease; Costa Rica; Female; Humans; Middle Aged; Nifurtimox; Travel; Trypanocidal Agents

Chagas disease is a zoonosis caused by T. cruzi. The estimated prevalence in endemic areas is 0.6-0.9 / 100,000. In immunocompromised behaves as an opportunistic pathogen highly aggressive and can evolve with meningoencephalitis, myocarditis or systemic disease. We recommend obtaining serology for all donor and recipient of SOT and HSCT. An infected donor should be discarded as such. In the case of D (-) R (+) exists controversy between prophylaxis and pre emptive therapy. The chosen drug for prophylaxis is nifurtimox for 3 months, effective but with relevant adverse effects. Monitoring should be done with RPC and MicroStrout weekly until six months post-transplant, then on a monthly basis for the duration of immunosuppression and continued for life clinical monitoring (C3).

Topics: Adult; Chagas Disease; Child; Drug Administration Schedule; Follow-Up Studies; Humans; Nifurtimox; Organ Transplantation; Postoperative Complications; Practice Guidelines as Topic; Stem Cell Transplantation; Trypanocidal Agents

Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A database with 143 anti-trypanosomal and 297 compounds having other clinical uses, are utilized to develop the theoretical models. The best discriminant models computed using bond-based linear indices provides accuracies greater than 90 for both training and test sets. Our models identify as anti-trypanosomals five out of nine compounds of a set of already-synthesized substances. The in vitro anti-trypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a perfect agreement between theoretical predictions and experimental results. The compounds identified as active ones show more than 98% of anti-epimastigote elimination (AE) at a concentration of 100 μg/mL. Besides, three compounds show more than 70% of AE at a concentration of 10 μg/mL. Finally, compounds with the best "activity against epimastigote forms/unspecific cytotoxicity" ratio are evaluated using an amastigote susceptibility assay. It should be noticed that, compound Va7-71 exhibit a 100% of intracellular amastigote elimination and shows similar activity when compared to a standard trypanosomicidal as nifurtimox. Finally, we can emphasize that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new anti-trypanosomal compounds.

Topics: Algorithms; Animals; Cell Survival; Chagas Disease; Databases, Factual; Discriminant Analysis; Drug Discovery; Fibroblasts; High-Throughput Screening Assays; Humans; Life Cycle Stages; Ligands; Models, Theoretical; Quantitative Structure-Activity Relationship; Software; Trypanocidal Agents; Trypanosoma cruzi

A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.

Topics: Amines; Animals; Cells, Cultured; Chagas Disease; Leishmania donovani; Mice; Nitro Compounds; Parasitic Sensitivity Tests; Rats; Structure-Activity Relationship; Triazoles; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

We investigated the relationship between potentially pathogenic antibodies against a Trypanosoma cruzi ribosomal protein (P2β) and the evolution of Chagas disease and the effect of trypanocidal treatment on these variables. Seventy-eight patients with chronic Chagas disease who were followed-up for more than 20 years were divided into three groups: 30 asymptomatic persons undergoing specific treatment (group A), 37 asymptomatic persons not undergoing specific treatment (group B), and 11 patients with chronic chagasic cardiomyopathy (CCC) who were not treated. Five patients in group B showed evolution to myocardial abnormalities. Among persons with CCC, six showed no changes; the remaining persons showed progression of cardiac involvement. Levels of antibodies to P2β in persons in group A decreased from their initial values. This finding was not observed in persons in groups B and C. Comparisons at the end of the follow-up showed lower amounts of antibodies to P2β in groups A and C. These findings support the benefits of specific treatment during chronic infection.

Topics: Animals; Antibodies, Protozoan; Cardiomyopathies; Chagas Disease; Chronic Disease; Female; Humans; Immunity, Humoral; Male; Nifurtimox; Nitroimidazoles; Protozoan Proteins; Ribosomal Proteins; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox is one of the two molecules used for treatment of Chagas disease. Although posology has not yet been clearly defined, nifurtimox is increasingly used, especially in combination with eflonithin. Nifurtimox is perfectly suited to the WHO's Chagas disease eradication program.

Topics: Chagas Cardiomyopathy; Chagas Disease; Drug Therapy, Combination; Eflornithine; Humans; Nifurtimox; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas' disease, caused by infection with the parasite Trypanosoma cruzi, is the major cause of heart failure in Latin America. Classic clinical manifestations result from the infection of heart muscle cells leading to progressive cardiomyopathy. To ameliorate disease, chemotherapy must eradicate the parasite. Current drugs are ineffective and toxic, and new therapy is a critical need. To expedite drug screening for this neglected disease, we have developed and validated a cell-based, high-throughput assay that can be used with a variety of untransfected T. cruzi isolates and host cells and that simultaneously measures efficacy against the intracellular amastigote stage and toxicity to host cells. T. cruzi-infected muscle cells were incubated in 96-well plates with test compounds. Assay plates were automatically imaged and analyzed based on size differences between the DAPI (4',6-diamidino-2-phenylindole)-stained host cell nuclei and parasite kinetoplasts. A reduction in the ratio of T. cruzi per host cell provided a quantitative measure of parasite growth inhibition, while a decrease in count of the host nuclei indicated compound toxicity. The assay was used to screen a library of clinically approved drugs and identified 55 compounds with activity against T. cruzi. The flexible assay design allows the use of various parasite strains, including clinical isolates with different biological characteristics (e.g., tissue tropism and drug sensitivity), and a broad range of host cells and may even be adapted to screen for inhibitors against other intracellular pathogens. This high-throughput assay will have an important impact in antiparasitic drug discovery.

Topics: Animals; Cattle; Cell Line; Cell Line, Tumor; Chagas Disease; Drug Evaluation, Preclinical; Hepatocytes; High-Throughput Screening Assays; Humans; Image Processing, Computer-Assisted; Muscle, Skeletal; Parasitic Sensitivity Tests; Trypanocidal Agents; Trypanosoma cruzi

Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.

Topics: Animals; Chagas Disease; Enzyme Inhibitors; Molecular Structure; Phosphoric Diester Hydrolases; Protozoan Proteins; Trypanosoma cruzi

Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepine derivatives were synthesized and fully characterized. All compounds were tested in vitro against both Trypanosoma cruzi and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines. Many of the evaluated compounds showed remarkable activity against the epimastigote and intracellular amastigote forms of T. cruzi, with IC₅₀ values comparable with that of control drug nifurtimox, a nitrofuran derivative currently used in the treatment of Chagas' disease. Other derivatives were found to have good activity against L. chagasi promastigotes, with low toxicity against the mammalian cells, but neither of them was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages.

Topics: Animals; Antiprotozoal Agents; Benzazepines; Cell Line; Chagas Disease; Humans; Leishmania donovani; Magnetic Resonance Spectroscopy; Molecular Conformation; Trypanosoma cruzi

Women with Chagas disease receiving treatment with nifurtimox are discouraged from breast feeding. Many patients who would receive treatment with nifurtimox live in extreme poverty, have limited access to resources such as clean water and baby formula and may not have safe alternatives to breast milk.. We aimed to estimate, using limited available pharmacokinetics data, potential infant exposure to nifurtimox through breast milk.. Original nifurtimox plasma concentrations were obtained from published studies. Pharmacokinetic parameters were estimated using non-linear mixed-effect modelling with NONMEM V.VI. A total of 1000 nifurtimox plasma-concentration profiles were simulated and used to calculate the amount of drug that an infant would be exposed to, if breast fed 150 ml/kg/day.. Breast milk concentrations on the basis of peak plasma levels (1361 ng/ml) and milk-plasma ratio were estimated. We calculated infant nifurtimox exposure of a breastfed infant of a mother treated with this drug to be below 10% of the maternal weight-adjusted dose, even if milk-plasma ratio were overestimated. Simulation led to similar estimates.. Risk for significant infant exposure to nifurtimox through breast milk seems small and below the level of exposure of infants with Chagas disease receiving nifurtimox treatment. This potential degree of exposure may not justify discontinuation of breast feeding.

Topics: Breast Feeding; Chagas Disease; Female; Humans; Infant; Infant, Newborn; Milk, Human; Nifurtimox; Risk Assessment; Trypanocidal Agents

Topics: Abdominal Pain; Chagas Cardiomyopathy; Chagas Disease; Diagnosis, Differential; Flank Pain; Heart Aneurysm; Humans; Infarction; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Nifurtimox; Radiography, Abdominal; Tomography, X-Ray Computed; Trypanocidal Agents; Ultrasonography

Chagas' disease (CD) is caused by the protozoan Trypanosoma cruzi (Tc) and remains an important cause of morbidity and mortality. Most researchers in the field now agree that chronic low grade parasite persistence in tissue drives tissue damage and the autoimmune component of CD. Current therapy relies on two compounds: benznidazole and nifurtimox. Despite their long history in the treatment of CD, both compounds induce significant side-effects. In the current issue of the BJP, two contributions demonstrate that NO-donors are active, especially in combination with benznidazole, against Tc in vitro and in experimental models in vivo. The basic concept used by the authors to develop novel anti-Tc compounds relied on the demonstrated ability of nitric oxide to kill the parasite. There are several issues still to be resolved but the reported studies are a clear advance to the field and should be considered for further pre-clinical development.

Topics: Animals; Chagas Disease; Humans; Nifurtimox; Nitric Oxide Donors; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Immunocompromised patients as those with renal transplant, hematological neoplasia or cancer and HIV/AIDS infection can suffer acute reactivation of Chagas disease. Central nervous system (CNS) evolvement (cerebral tumor or chagoma and diffuse meningoencephalitis) is similar to other opportunistic infections that present with cerebral expansive processes like toxoplasmosis or CNS primary lymphoma. Survival is infrequent, depending on antiparasitic therapy and early starting antiretroviral therapy. The case of an HIV/AIDS positive patient that evolved with a chagasic meningoencephalitis and improved after beginning early antiparasitic therapy and antiretroviral therapy antiretroviral is described.

Topics: Adult; Antiretroviral Therapy, Highly Active; Chagas Disease; Disease-Free Survival; HIV Infections; Humans; Male; Meningoencephalitis; Nifurtimox; Treatment Outcome; Trypanocidal Agents

Topics: Chagas Cardiomyopathy; Chagas Disease; Clinical Trials as Topic; Drug Administration Schedule; Drug Eruptions; Humans; Meta-Analysis as Topic; Nifurtimox; Nitroimidazoles; Polyneuropathies; Trypanocidal Agents; Trypanosoma cruzi; United States

Little is known about the immune responses of newborns with congenital Chagas disease (CCD) or congenital toxoplasmosis (CT) but they probably differ to those seen in adults with Chagas disease or toxoplasmosis, leading to differences in pathology. The concentrations of interleukin-18 (IL-18), interferon-γ (IFN-γ) and interleukin 10 (IL-10) in the sera of infants with CCD or CT were determined and compared with those in the sera of uninfected controls (born to mothers who were seropositive or seronegative for Trypanosoma cruzi). The infants with CCD or CT were found to have lower IL-18 and IFN-γ concentrations but higher IL-10 concentrations than the uninfected controls. The IL-18 and IFN-γ concentrations were also significantly lower in the infants with CCD than in those with CT. Although the infants with symptomatic CT had significantly higher serum concentrations of IL-18 than those with asymptomatic infection with Toxoplasma, the infants with symptomatic CCD had similar serum concentrations of IL-18 to the infants with asymptomatic Tr. cruzi infection. Taken together, these results indicate that IL-10 contributes to the suppression of pro-inflammatory immune responses and therefore, perhaps, to clinically overt CCD and CT.

Topics: Chagas Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Interferon-gamma; Interleukin-10; Interleukin-18; Male; Nifurtimox; Nitroimidazoles; Toxoplasmosis, Congenital; Trypanocidal Agents

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.. 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.. 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).. 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.

Topics: Adolescent; Adult; Aged; Chagas Disease; Chronic Disease; Female; Humans; Kaplan-Meier Estimate; Latin America; Longitudinal Studies; Male; Medication Adherence; Middle Aged; Nifurtimox; Switzerland; Trypanocidal Agents

A series of novel benzoimidazo and N-aryl-5-oxo-imidazo[1,2-b]isoquinoline-10-carbothioamides was developed. All the compounds were evaluated for their in vitro action against the epimastigote form of Trypanosoma cruzi. Four of them showed higher activity than Nifurtimox. Their unspecific cytotoxicity was evaluated using HeLa and L6 cells, being non-toxic at concentrations at least 15 and 200 times higher than that of T. cruzi IC(50.) To gain insight into the mechanism of action, their DNA binding properties and reactivity with glutathione were studied, and QSAR study was performed.

Topics: Animals; Chagas Disease; DNA, Protozoan; Dose-Response Relationship, Drug; Glutathione; HeLa Cells; Humans; Imidazoles; Isoquinolines; Models, Molecular; Oxidation-Reduction; Quantitative Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Ten 5-nitro-2-furyl derivatives, with good to excellent in vitro anti-Trypanosoma cruzi activity, and nifurtimox were tested oral and intraperitoneally on healthy animals for its acute toxicity on murine models. According to animals' survival percentage, organ histological results, biochemical and haematological findings, three new derivatives, with toxicity like nifurtimox, were selected to test in vivo as antichagasic agents. Clearly, dependences between chemical structure and both acute toxicity and in vivo anti-T. cruzi activity were observed. 4-Hexyl-1-[3-(5-nitro-2-furyl)-2-propenylidene]semicarbazide displayed good profile as anti-T. cruzi agent and better acute toxicity profile than nifurtimox.

Topics: Animals; Chagas Disease; Female; Mice; Nifurtimox; Nitrofurans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Exploring the influence of different substitution patterns of 2H-benzimidazole 1,3-dioxide derivatives (BzNO) we prepared fifteen new derivatives. Initially the BzNO were tested against Trypanosoma cruzi Tulahuen 2 strain epimastigote form rendering very potent anti-T. cruzi agents. Moreover, the BzNO were able to inhibit the growth of virulent and resistant to Benznidazole strains (CL Brener clone, Colombiana, and Y strains) and to Leishmania braziliensis. Interestingly, BzNO exhibited very high selectivity index and particularly the spiro-BzNO 13 provokes an important diminution of amastigotes in Vero cells. Besides, it was found a diminution of acetate and glycine as excreted metabolites but without increase of parasite glucose uptake indicating that the glycosome is probably not involucrate in the 2H-benzimidazole 1,3-dioxides mechanism of action.

Topics: Animals; Benzimidazoles; Cell Line; Cell Survival; Chagas Disease; Glucose; Leishmania braziliensis; Leishmaniasis; Macrophages; Mice; Mitochondria; Oxidoreductases; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.

Topics: Animals; Chagas Disease; Drug Design; Humans; Mice; Nitrofurans; Quantitative Structure-Activity Relationship; Squalene; Squalene Monooxygenase; Thiophenes; Trypanocidal Agents; Trypanosoma cruzi

New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.

Topics: Chagas Disease; Crystallography, X-Ray; DNA, Protozoan; HeLa Cells; Humans; Indazoles; Nitroimidazoles; Oxidation-Reduction; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease (human American trypanosomiasis) is a zoonose caused by the protozoan Trypanosoma cruzi. Vectors are Triatoma spp. insects. T. cruzi can also be transmitted by blood transfusion, organ transplantation, and transplacentally. Infection is generally acquired during infancy. The acute infection is rarely symptomatic and is followed by a chronic phase. Chronic infected people are asymptomatic (indeterminate stage) and may remain at this stage for the rest of their lives. About a third of infected people will develop a chronic Chagas disease which affects the heart and the digestive tract. Morbidity and mortality of chronic Chagas cardiomyopathy (CCC) are high. Specific treatment of asymptomatic infected individual could reduce the risk of progression to CCC. With control initiatives case incidence declined in most endemic countries. American trypanosomiasis has become an emerging imported disease in North America and Europe because of the migration of population originating from endemic zones. They are only two available drugs for specific treatment of Chagas disease: benznidazole and nifurtimox. Both have frequent side effects and variable efficacy according the phase of the disease. There is an urgent need for new treatments and better serological tests. Policies must be developed to avoid the risk of transmission trough blood transfusion and transplantation in developed countries.

Topics: Animals; Chagas Disease; Emigration and Immigration; Humans; Insect Vectors; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Americas; Central Nervous System Diseases; Chagas Disease; History, 20th Century; History, 21st Century; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

In the immunocompromised patients, the main features of Chagas disease are severe clinical manifestations during the acute phase and reactivations occurring during the chronic phase. Reactivation is defined by a demonstration of trypomastigots on microscopic examination of blood or the identification of amastigots on biopsy samples and/or acute clinical manifestations during the chronic phase. In HIV patients, meningo-encephalitis and myocarditis are the major clinical syndromes of reactivation. In transplanted patients, cutaneous lesions often reveal the reactivation. A parasiticidal treatment (nifurtimox or benznidazole) should be initiated immediately. A secondary prophylaxis is indicated for HIV patients with CD4 cells count < 200/mm3. In the near future, quantitative PCR could allow to diagnose early reactivation, to initiate preemptive therapy and to closely monitor the therapeutic response. Due to the severe manifestations and prognosis of Chagas disease in the immunocompromised host, two serologic tests must be performed in the patient with an history of residency in endemic countries.

Topics: Anti-HIV Agents; Chagas Disease; France; HIV Infections; Humans; Meningoencephalitis; Nifurtimox; Nitroimidazoles; Transplantation; Trypanocidal Agents

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

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

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

New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.

Topics: Animals; Antibodies, Protozoan; Benzoxazoles; Cell Line; Chagas Disease; Cysteine Endopeptidases; Female; Glutathione; Humans; Macrophages; Mice; Models, Molecular; NADH, NADPH Oxidoreductases; Oxidation-Reduction; Oxygen Consumption; Protozoan Proteins; Stereoisomerism; Structure-Activity Relationship; Sulfones; Trypanocidal Agents; Trypanosoma cruzi; Vinyl Compounds

The trypanocidal activity of N-allyl (NAOx) and N-propyl (NPOx) oxamates and that of the ethyl esters ofN-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested on cultured epimastigotes (in vitro) and murine trypanosomiasis (in vivo) using five different T. cruzi strains. NAOx and NPOx did not penetrate intact epimastigotes and therefore we were not able to detect any trypanocidal effect with these oxamates. Whereas the ethyl esters (Et-NAOx and Et-NPOx), acting as prodrugs, exhibited in vitro and in vivo trypanocidal activity on the five tested T. cruzi strains. On the contrary, when Nifurtimox and Benznidazole used as reference drugs were tested, we found that only three of the five tested T cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and in vivo trypanocidal activity of these compounds.

Topics: Animals; Chagas Disease; Mice; Nifurtimox; Nitroimidazoles; Oxamic Acid; Trypanocidal Agents; Trypanosoma cruzi

Chagas' disease, caused by the parasite Trypanosoma cruzi, remains the leading cause of cardiopathy in Latin America with about 12 million people infected. Classic clinical manifestations derive from infection of muscle cells leading to progressive cardiomyopathy, while some patients develop megacolon or megaesophagus. A very aggressive clinical course including fulminant meningoencephalitis has been reported in patients who contract Chagas' disease in the background of immunodeficiency. This includes patients with human immunodeficiency virus infection as well as patients receiving immunosuppressive therapy for organ transplant. Currently, only two drugs are approved for the treatment of Chagas' disease, nifurtimox and benznidazole. Both have significant limitations due to common and serious side effects as well as limited availability. A promising group of new drug leads for Chagas' disease is cysteine protease inhibitors targeting cruzain, the major protease of T. cruzi. The inhibitor N-methyl-Pip-F-homoF-vinyl sulfonyl phenyl (N-methyl-Pip-F-hF-VS phi) is in late-stage preclinical development. Therefore, the question arose as to whether protease inhibitors targeting cruzain would have efficacy in Chagas' disease occurring in the background of immunodeficiency. To address this question, we studied the course of infection in recombinase-deficient (Rag1(-/-)) and normal mice infected with T. cruzi. Infections localized to heart and skeletal muscle in untreated normal animals, while untreated Rag1(-/-) mice showed severe infection in all organs and predominantly in liver and spleen. Treatment with the dipeptide N-methyl-Pip-F-hF-VS phi rescued immunodeficient animals from lethal Chagas' infection. The majority (60 to 100%) of inhibitor-treated Rag1(-/-) mice had increased survival, negative PCR, and normal tissues by histopathological examination.

Topics: Animals; Cattle; Cells, Cultured; Chagas Disease; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Disease Models, Animal; Female; Homeodomain Proteins; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Nifurtimox; Nitroimidazoles; Protozoan Proteins; Survival Analysis; 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

Topics: Animals; Chagas Disease; Child; Diagnosis, Differential; Humans; Nifurtimox; Nitroimidazoles; Poverty; Risk Factors; Trypanocidal Agents; Trypanosoma cruzi

Chemotherapy-resistant neuroblastoma is a difficult disease to treat with poor survival.. We treated a patient with neuroblastoma who had progressed on conventional chemotherapy. This 5-year-old girl with chemotherapy-resistant neuroblastoma developed Chagas disease at the start of salvage chemotherapy for which she was also started on nifurtimox. The neuroblastoma response to these treatments resulted in clinical remission. In vitro, treatment of a neuroblastoma cell line with nifurtimox resulted in decreased cell viability whereas no effect was seen on an endothelial cell line.. Nifurtimox shows promise as a potential new treatment for neuroblastoma and warrants further testing.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chagas Disease; Child, Preschool; Cyclophosphamide; Disease Progression; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Neuroblastoma; Nifurtimox; Recurrence; Remission Induction; Tomography, X-Ray Computed; Topotecan; Treatment Outcome

Topics: Chagas Disease; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infectious Disease Transmission, Vertical; Nifurtimox; Nitroimidazoles; Patient Compliance; Trypanocidal Agents

Epidemiological, clinical, diagnostic, and therapeutic data from children who were born to mothers infected with T. cruzi who came to our hospital are presented. In addition, we exhibit the preliminary results of a technique that detects the anti F2/3 antibodies: these would be able to confirm the cure earlier than conventional serology. We also show the results of PCR diagnosis. Most of the mothers (76,1%) resided in Argentina, the rest were from Bolivia and Paraguay The median average age at diagnosis of the patients was 8,5 months (range 15 days-10 years). Out of 168 children, 64,98% were asymptomatic at diagnosis. The diagnosis criteria were: T. cruzi observation by microhematocrit technique in patients less than 7 month old. Two reactive serological tests in patients older than 8 months. A nifurtimox dose used in these patients was 10-13 mg/kg/d during 60 days. Although 31% presented side effects, none of them had to be dropped from the treatment. Cure criteria was conventional serology negativization. Of the patient population, we cured 87,2% of them, 98% of those under 3 years, and 100% of those who received treatment before age 8 months. We compared the time of negativization between conventional serology and anti F2/3 in 21 children. The latter were very useful to demonstrate (p>0,001) the success of the treatment, in those that started treatment after 8 months of age. PCR testing of a group of all patients, showed a diagnostic sensibility of 80,3% and a specificity of 97,8%.

Topics: Animals; Antibodies, Protozoan; Argentina; Chagas Disease; Child; Child, Preschool; Female; Follow-Up Studies; Hematocrit; Humans; Infant; Infant, Newborn; Male; Nifurtimox; Polymerase Chain Reaction; Pregnancy; Sensitivity and Specificity; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Four new diterpenes (1-4) were isolated from the leaves of Myrospermum frutescens as minor constituents. Chagresnol (1), 6beta,18-diacetoxycassan-13,15-diene (2), and chagreslactone (3) possess cassane skeletons, while chagresnone (4) exhibits a cleistanthane skeleton. Molecular structures and their relative stereochemistries were elucidated using NMR spectroscopy in combination with UV, IR, and MS spectral data. Although compound 2 was previously reported as a synthetic product, we report its first isolation as a natural product. Derivative products (10-13) were obtained to test their activities against Chagas's disease. In addition, the absolute stereochemistry of the previously isolated cassane diterpene 5 from M. frutescens is presented.

Topics: Animals; Chagas Disease; Diterpenes; Fabaceae; Mass Spectrometry; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Leaves; Plants, Medicinal; Structure-Activity Relationship; Trypanocidal Agents

Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas' disease.

Topics: Animals; Chagas Disease; Dogs; Enzyme-Linked Immunosorbent Assay; Immunoglobulin G; Monocytes; Nifurtimox; Nitroimidazoles; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Topics: Antiparasitic Agents; Chagas Disease; Child; Chronic Disease; Humans; Nifurtimox

Biological parameters of five Trypanosoma cruzi strains from different sources were determined in order to know the laboratory behaviour of natural populations. The parameters evaluated were growth kinetics of epimastigotes, differentiation into metacyclic forms, infectivity in mammalian cells grown in vitro and parasite susceptibility to nifurtimox, benznidazole and gentian violet. Differences in transformation to metacyclic, in the percentage of infected cells as well as in the number of amastigotes per cell were observed among the strains. Regarding to pharmacological assays, Y strain was the most sensitive to the three assayed compounds. These data demonstrate the heterogeneity of natural populations of T. cruzi, the only responsible of infection in humans.

Topics: Animals; Chagas Disease; Chlorocebus aethiops; Genetic Variation; Genetics, Population; Gentian Violet; Life Cycle Stages; Macrophages; Mice; Nifurtimox; Nitroimidazoles; Parasitic Sensitivity Tests; Trypanosoma cruzi; Vero Cells

The effect of nifurtimox and 5-nitro-2-thienylmalononitrile (5NO2TM), a novel compound with anti-Trypanosoma cruzi activity, upon vitality and HSP60 immunoreactivity of epimastigotes, has been determined. Both products showed no activity against epimastigotes at 0.1 microg/ml, while at 0.5 and 1 microg/ml, after 24 h of incubation, densities of these groups were significantly reduced, when compared to controls. An enhancement of HSP60 immunoreactivity was observed after 24 h in groups treated with 0.5 and 1 microg/ml nifurtimox. On the other hand, 5NO2TM had no effect.

Topics: Animals; Chagas Disease; Chaperonin 60; Nifurtimox; Nitro Compounds; Parasitic Sensitivity Tests; Trypanocidal Agents; Trypanosoma cruzi

Patients suffering from Chagas' disease, as determined by positive serological results, were tested for further evidence of Trypanosoma cruzi infection by xenodiagnosis and PCR. The patients included 67 children aged from 0 to 10 years and 75 adults. All children were positive by PCR on their pre-therapy sample, while only 69% of the seropositive adults and none of the 78 seronegative control adults were PCR positive. Xenodiagnosis was positive in 79% of the children, but only in 21% of the adults. A group of 66 children was treated with nifurtimox, and followed up every 3 months during the first year and every 6 months during the second and third year post-therapy, by PCR, xenodiagnosis and serology. We concluded that PCR was the most effective test to monitor children for 3 years post-chemotherapy, when all the cases converted from positive to negative. Conventional serology, however, remained positive after that period in most cases. In contrast, conversion to negative xenodiagnosis occurred very early after treatment.

Topics: Adult; Animals; Antibodies, Protozoan; Chagas Disease; Child; Child, Preschool; DNA, Protozoan; Female; Humans; Infant; Infant, Newborn; Male; Nifurtimox; Polymerase Chain Reaction; Treatment Outcome; Triatoma; Trypanocidal Agents; Trypanosoma cruzi; Xenodiagnosis

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Chagas Disease; Drug Resistance; Gene Amplification; Glycoproteins; Humans; Karyotyping; Mice; Nifurtimox; Nitroimidazoles; Parasitic Sensitivity Tests; Polymorphism, Restriction Fragment Length; Protozoan Proteins; Trypanocidal Agents; 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

We designed a set of procedures for first-line local health services to detect and treat the congenital transmission of Trypanosoma cruzi at a province-wide scale, and field-tested the programme in the province of Tucumán, northwestern Argentina, from 1992 to 1994. The programme consists of routine screening of pregnant women for seroreactivity to T. cruzi, serological and parasitological follow-up of the newborn at least twice during the first year of age, treatment of the infected infants, and evaluation of the outcome. 927 (5.5%) of 16 842 pregnant women were seroreactive to T. cruzi by indirect haemagglutination assay and ELISA. Twenty-one (6.7%) of 315 newborns to seroreactive mothers were diagnosed as infected with T. cruzi parasites microhaematocrit concentration before 30 days of age. Five newborns who initially tested negative had a T. cruzi infection detected by microhaematocrit and/or serological techniques at 3 or 6 months of age. Thus, congenital infection was diagnosed in 26 (7.1%) infants born to seroreactive women and residing in houses free of triatomine bugs. Four of 6 infants born to seroreactive mothers died during the first year of age and had some evidence of T. cruzi infection; one of the deaths was attributed to T. cruzi based on clinical evidence. After specific treatment with nifurtimox or benznidazole, 30 of 32 infants remained parasitologically and serologically negative. This study shows the feasibility of controlling the incidence of congenitally acquired T. cruzi infections at a province-wide scale by means of a specific screening programme at first-line health services level.

Topics: Adult; Animals; Argentina; Chagas Disease; Enzyme-Linked Immunosorbent Assay; Female; Hemagglutination Tests; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Middle Aged; Nifurtimox; Nitroimidazoles; Pregnancy; Pregnancy Complications, Parasitic; Trypanocidal Agents

In the present work we show that acute infection of C3H mice with the CL strain of Trypanosoma cruzi is characterized by an exponential growth of parasites and high mortality accompanied by anemia, thrombocytopenia, leukopenia, and bone marrow hypoplasia. Administration of nifurtimox, a trypanocydal drug currently in clinical use at different days postinfection, modulates parasitemia and prevents mortality. More importantly, none of blood and bone marrow alterations were observed in nifurtimox-treated animals when treatment was initiated early in infection, one or seven days postinoculation. The bone marrow alterations were characterized by a decrease in the total number cells as well in the number of megakaryoblasts and erythroblasts. Transfer experiments of bone marrow cells from infected mice to noninfected lethally irradiated recipients revealed a poor marrow-repopulating activity. The colony forming units-spleen assay confirmed the depression of committed clonal progenitors cells and revealed a decreased number of granulocyte/macrophage, megacariocyte and erythrocyte colonies. In summary, this is the first report showing that acute T. cruzi infection results in profound alterations of the hematopoietic system and that these alterations can be prevented by nifurtimox treatment.

Topics: Anemia; Animals; Blood Cell Count; Bone Marrow; Chagas Disease; Female; Hematopoietic Stem Cells; Leukopenia; Mice; Mice, Inbred C3H; Nifurtimox; Parasitemia; Thrombocytopenia; Trypanocidal Agents; Trypanosoma cruzi

The nitroimidazole derivative Megazol is a highly active compound used against several strains of Trypanosoma cruzi, the causative agent of Chagas' disease (American trypanomiasis). With the aim of gaining an insight into the probable mode of action, the interaction of Megazol with different redox enzymes was studied in comparison to that of Nifurtimox and Metronidazole. The three nitroaromatic compounds are reduced by L-lactate cytochrome c-reductase, adrenodoxin reductase, and NADPH:cytochrome P-450 reductase (EC 1.6.2.4), the efficiencies of the enzymatic reductions being roughly related to the reduction potentials of these pseudo-substrates. As the enzyme responsible for the reduction of Megazol within the parasite has not yet been identified, the nitroimidazole was assayed with T. cruzi lipoamide dehydrogenase and trypanothione reductase. Megazol did not inhibit the physiological reactions but proved to be a weak substrate of both flavoenzymes. The single electron reduction of the compound by NADPH:cytochrome P-450 reductase, by rat liver as well as by trypanosome microsomes was confirmed by ESR experiments. As shown here, Megazol interferes with the oxygen metabolism of the parasite, but its extra activity when compared to Nifurtimox may be related to other features not yet identified.

Topics: Animals; Biotransformation; Chagas Disease; Electron Spin Resonance Spectroscopy; Ferredoxin-NADP Reductase; L-Lactate Dehydrogenase; L-Lactate Dehydrogenase (Cytochrome); Metronidazole; Molecular Structure; NADH Dehydrogenase; NADPH-Ferrihemoprotein Reductase; Nifurtimox; Nitroimidazoles; Oxidation-Reduction; Rats; Thiadiazoles; Trypanosoma cruzi

Topics: AIDS-Related Opportunistic Infections; Chagas Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Trypanosoma cruzi populations are subdivided into natural clones that can exhibit considerable genetic differences. It has been proposed that T. cruzi clonal structure has a major impact on this parasite's biological properties. The present work aims at testing this hypothesis. Twenty-one stocks isolated from various ecological cycles, places, and hosts were characterized by multilocus enzyme electrophoresis (MLEE) with 22 genetic loci and random amplification of polymorphic DNA (RAPD) with 10 primers on the one hand and by 14 different biological parameters on the other hand. These parameters were related to: (i) growth kinetics of epimastigotes and amastigotes; (ii) infection of culture cells by amastigotes; (iii) viability of extracellular trypomastigotes; or (iv) sensitivity of epimastigotes, trypomastigotes, and amastigotes to Benznidazole and Nifurtimox. MLEE and RAPD results exhibited parity to each other, as previously noted (M. Tibayrenc, K. Neubauer, C. Barnabé, F. Guerrini, D. Skarecky, and F. J. Ayala, 1993, Proceedings of the National Academy of Sciences of the USA 90, 1335-1339), and showed that the 21 stocks were distributed into three main genetic groups, 19/20, 32, and 39, corresponding to the major clones 19, 20, 32, and 39 previously described on the basis of 15 isozyme loci. Most biological parameters showed a strong correlation to the genetic distances evaluated from either MLEE or RAPD, which favors the working hypothesis. The only exception came from drug sensitivity estimated on trypomastigote forms. The overall results made it possible to firmly reject the null hypothesis that there is no relationships between evolutionary distances and biological differences in T. cruzi natural clones.

Topics: Animals; Biological Evolution; Chagas Disease; Chlorocebus aethiops; Cluster Analysis; Discriminant Analysis; DNA, Protozoan; Electrophoresis, Cellulose Acetate; Genetic Variation; Genotype; Humans; Isoenzymes; Monte Carlo Method; Nifurtimox; Nitroimidazoles; Phylogeny; Random Amplified Polymorphic DNA Technique; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Topics: Administration, Oral; Animals; Benzofurans; Chagas Disease; Female; Mice; Nifurtimox; Nitrofurans; Trypanocidal Agents

Chagas' disease, which is caused by Trypanosoma cruzi, remains essentially incurable. Due principally to a lack of profit incentive, the pharmaceutical industry has had limited interest in developing new antichagasic drugs. Thus, a search for agents that exhibit activity against T. cruzi, although medicaments have been developed for the treatment of other diseases, seems justifiable. Responding to evidence that the principal biochemical differences between mammalian cells and African trypanosomes apply equally to T. cruzi, our evaluations were conducted. Previous work showed the effectiveness of anticancer agents against T. rhodesiense. In the present studies, 76 anticancer compounds were assessed for their ability to suppress the trypomastigotes of T. cruzi- infected mice. Five compounds were found to be active. The most effective was cycloheximide, which was more than six times as effective as the standard, nifurtimox.

Topics: Animals; Antineoplastic Agents; Berberine Alkaloids; Chagas Disease; Cycloheximide; Disease Models, Animal; Female; Mice; Nifurtimox; Quinolinium Compounds; Reserpine; Streptozocin

Twenty-seven Trypanosoma cruzi strains, susceptible or naturally resistant to the nitroderivatives benznidazole and nifurtimox, were analyzed using the following molecular markers: (i) isoenzyme patterns of six enzymes; (ii) genetic variability assayed by randomly amplified polymorphic DNA (RAPD) with two different primers; and (iii) gene probes for P-glycoprotein (TcPGP), hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the ribosomal RNA gene (rDNA) and the mini-exon gene (MEX), RAPD and isoenzyme profiles divided the T. cruzi strains into three groups, whereas the gene probes divided the T. cruzi strains in two groups. Strains classified as group I or II by RAPD or zymodemes Z1 or Z2 by isoenzyme analysis were either susceptible or naturally resistant to the nitroderivatives. In contrast, strains classified as group III by RAPD and zymodeme ZB by isoenzyme analysis were only drug susceptible and showed polymorphisms for HGPRT and TcPGP. No correlation was observed between drug susceptibility and polymorphisms of rDNA and MEX. Eighteen T. cruzi strains isolated from different geographic regions were included in this study. Thus, from a total of 45 T. cruzi strains analyzed, all 19 of zymodeme B were susceptible to the experimental treatment independent of their geographic origin.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brazil; Chagas Disease; DNA, Protozoan; DNA, Ribosomal; Drug Resistance; Exons; Genes, Protozoan; Genetic Variation; Glucose-6-Phosphate Isomerase; Humans; Hypoxanthine Phosphoribosyltransferase; Isoenzymes; Nifurtimox; Nitroimidazoles; Polymorphism, Genetic; Random Amplified Polymorphic DNA Technique; Trypanocidal Agents; Trypanosoma cruzi

If military forces are required to operate in areas that are endemic for Chagas' disease, the occupation should be of critical concern. These areas, located in Central and South America, are many. The matter is of particular importance because no suitable drug exists to treat individuals who contract the disease. We examined 60 compounds of a chemical class, thiosemicarbazones, known to have some activity against the disease. The work was carried out using Trypanosoma cruzi-infected mice. Of the 60 potential drugs evaluated, 12 showed significant suppressive activity. One of these compounds was almost 50% greater than the reference drug used in the test system.

Topics: Animals; Chagas Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Mice; Mice, Inbred Strains; Military Medicine; Nifurtimox; Thiosemicarbazones; Trypanocidal Agents

Forty 8-aminoquinolines (a chemical class with members having some activity against Trypanosoma cruzi infections) were evaluated for their effectiveness in reducing the 14-day parasitaemias of 4-6 week-old, female, albino mice infected with a Brazilian strain of T. cruzi. Six of the compounds were more active or as active as the reference drug, nifurtimox, and one was > 13-fold as efficacious. Certain members of the series tested warrant further evaluation.

Topics: Aminoquinolines; Animals; Antiparasitic Agents; Chagas Disease; Drug Evaluation, Preclinical; Female; Mice; Nifurtimox; Parasitemia

Forty-nine "standard" compounds known to be useful in the treatment of other diseases were tested for their suppressive activity against the trypomastigotes of Trypanosoma cruzi-infected mice. The most active was the antidepressant protriptyline, which was almost three times as effective as the reference drug, nifurtimox. A major value of the present data is to demonstrate the refractoriness of the T. cruzi parasite against many of the drug standards that have known biological activity.

Topics: Animals; Antiprotozoal Agents; Chagas Disease; Disease Models, Animal; Female; Imipramine; Ketoconazole; Mice; Mice, Inbred Strains; Nifurtimox; Nigericin; Niridazole; Protriptyline; Trypanosoma cruzi

Chagas' disease, a protozoan infection by the kinetoplastid Trypanosoma cruzi, constitutes a major public health problem in Latin America. With the use of mouse models of both short- and long-term forms of the disease, the efficacy of D0870, a bis-triazole derivative, was tested. D0870 was able to prevent death and induced parasitological cure in 70 to 90 percent of animals, in both the short- and long-term disease. In contrast, currently used drugs such as nifurtimox or ketoconazole prolonged survival but did not induce significant curing effects. D0870 may be useful in the treatment of human long-term Chagas' disease, a condition that is currently incurable.

Topics: Animals; Base Sequence; Chagas Disease; Drug Administration Schedule; Ketoconazole; Molecular Sequence Data; Nifurtimox; Sterols; Time Factors; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

We studied 6123 pregnant women and their 341 newborn (NB), from Santa Fe city, by the following serological tests for chagasic infection: Direct Agglutination with and without 2-mercaptoethanol, Indirect Hemagglutination and Indirect Immunofluorescence test, and by identification of parasites by Fresh drops, Strout and/or by Xenodiagnosis. The prevalence of seropositivity found in pregnant women was of 14.62% with a 73% of migratory history. The parasitological studies yielded 9/341 incidence of transplacentary infection. Clinical examinations were made in the infected newborn (NB). They were treated with Benznidazol or Nifurtimox, and post-treatment evolution was evaluated. We registered connatal infection in twin-brothers. Brothers/sisters (siblings) of infected NB were also studied. Some of them were seropositive and the others seronegative. Results here obtained show that this way of transmission is important, and should be considered even in low endemicity areas. The parasitological assays proved to be decisive for the NB infection diagnosis (Table 1). The serological assays enabled us to follow the non-infected NB up to their negativization. A 6 month follow-up is recommended. It is impossible to define only one clinical outline because both symptomatic and asymptomatic infected NB may be found with gestational age at term and pre-term and when born with a weight above or below 2000 g. We obtained parasitological and serological negativization in all cases. The chagasic pregnant woman does not necessarily transmit the infection to all her descendents. Only 2.64% are infected. It is possible to systematize the diagnosis without extra resources beyond the usual ones.

Topics: Animals; Argentina; Chagas Disease; Female; Humans; Incidence; Infant, Newborn; Male; Nifurtimox; Nitroimidazoles; Pregnancy; Pregnancy Complications, Parasitic; Prevalence; Trypanosoma cruzi

The diagnostic and clinical aspects of congenital Chagas' disease were studied in 71 children in Buenos Aires. The children's ages ranged from 2 days to 10 years. In infants < 6 months old, the disease was diagnosed by detection of Trypanosoma cruzi in the blood; the microhematocrit test was positive in 38 (97.4%) of 39 cases. This test was the fastest and most reliable diagnostic method in this group, whereas two conventional serological methods were useful in children > or = 6 months of age. Forty-six (64.8%) of the 71 children had no clinical signs of infection. The clinical sign most frequently documented was hepatomegaly (18.3%). Three children were coinfected with human immunodeficiency virus; the latter infection was severe in two instances. Nifurtimox (10-15 mg/[kg.d] for 2 months) was used for parasiticidal treatment, and use of this drug resulted in mild adverse effects.

Topics: Animals; Antibodies, Protozoan; Argentina; Chagas Disease; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Nifurtimox; Parasitemia; Pregnancy; Serologic Tests; Trypanocidal Agents; Trypanosoma cruzi

Several sets of compounds, active against different trypanosomes, Trypanosoma brucei and Trypanosoma cruzi are presented, the lethal doses for some of them being less than the micro-molar concentration. These compounds are designed by taking advantage of two metabolic features of these parasites, glucose metabolism and oxidative stress.

Topics: Animals; Chagas Disease; DNA, Protozoan; Enzyme Inhibitors; Fructose-Bisphosphate Aldolase; Glucose; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Hexokinase; Humans; Nifurtimox; Oxidative Stress; Polyamines; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis, African

The carcinogenic activity of antitrypanosomal 2-nitroimidazole, 5-nitroimidazole and 5-nitrofuran derivatives was assessed in female Swiss mice of the same age group. A statistically significantly higher incidence of growths was seen in mice into which 2-nitro had been injected than in mice receiving 5-nitro derivatives intraperitoneally. A histologic type of lymphoblastic lymphoma that invades lymph nodes, spleen, liver, lungs and lymphatic tissue elsewhere was frequently found in nitroarene-treated mice. Further, it is shown that the potency of the drug, rather than the duration of its administration, was usually associated with the growth of lymphomas. The 2-nitro derivative which induced the highest incidence of lymphomas significantly decreased the survival of treated mice; this probably occurred because it undergoes enzymatic reduction of the nitro group more efficiently than the 5-nitro compounds used. The differences of incidence of lymphomas in mice receiving any of these nitroarenes and in control mice that received daily injections of 0.15 M saline were statistically significant (alpha = 0.05). The indiscriminate use of these nitroarenes to treat Trypanosoma cruzi infections in man could therefore induce a significant number of lymphomas.

Topics: Animals; Carcinogens; Cell Division; Chagas Disease; Female; Liver; Lymph Nodes; Lymphoma; Mice; Molecular Structure; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

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

1. Nifurtimox uptake and metabolism by epimastigote forms of three strains of Trypanosoma cruzi (Basileu, Y, YuYu) with different drug responsiveness in mice experimental infections were compared. 2. Statistical analysis of the results demonstrated no correlation between the ability of the strains to catalyze nifurtimox redox-cycling (Basileu = Y = YuYu) nor nifurtimox multiple electron reduction (Basileu = Y greater than Y) and drug susceptibility (Basileu greater than Y greater than YuYu). 3. A partial correlation however, was observed between drug responsiveness and nifurtimox uptake (Basileu greater than Y = YuYu). 4. The results suggest that drug uptake may be more important than drug metabolism in modulating resistance to nifurtimox in T. cruzi strains.

Topics: Animals; Chagas Disease; Drug Resistance; Mice; Nifurtimox; Trypanosoma cruzi

A series of ten 1-[(5-nitrothenylidene)amino]azoles has been synthesized by the reaction of 5-nitrothiophene-2-carbaldehyde with 1-aminopyrazole, 1-aminoimidazole, 1- and 4- amino-1,2,4-triazoles, 1-aminoindole, 1- and 2-aminoindazoles, 1-aminobenzimidazole and 1- and 2-aminobenzotriazoles. Physical data, spectroscopic characteristics and biological properties of all the derivatives have been examined. The antiprotozoal activity has been tested against Trypanosoma cruzi, comparative to Nifurtimox (Lampit).

Topics: Animals; Azoles; Benzimidazoles; Chagas Disease; Imidazoles; Indazoles; Indoles; Mice; Nifurtimox; Nitro Compounds; Thiophenes; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Mice infected with Trypanosoma cruzi, but parasitologically cured after specific chemotherapy, continued to exhibit positive indirect immunofluorescence serological tests 3-6 months after the therapy. Treatment of trypanosome antigens with monospecific antisera produced in rabbits, and examination by immunoelectron-microscopy following peroxidase labelling disclosed the presence of membrane deposits in cell processes in the spleens of the mice. Similar deposits were observed in the external membranes of T. cruzi amastigotes in the spleens of acutely infected mice, but not in normal control mice. No reaction occurred in tissues not previously treated with the monospecific anti-T. cruzi serum. Positive cells in treated and cured mice, as well as in the not cured or untreated control mice, were located in germinal centres of the splenic white pulp and presented long and branching cytoplasmic processes, which are indicative of dendritic cells of the lymphoid follicles of the spleen.

Topics: Animals; Antigens, Protozoan; Chagas Disease; Mice; Microscopy, Immunoelectron; Nifurtimox; Nitroimidazoles; Spleen; Trypanocidal Agents

Reactivation of Chagas' disease in immuno-compromised hosts may represent a recognizable clinical syndrome that can be diagnosed by examination of skin biopsy specimens of characteristic lesions resembling ordinary bacterial cellulitis. This syndrome appears to result in significant morbidity, which can be avoided with the institution of prophylactic therapy for Chagas' disease. An awareness of this complication of immunosuppression is of paramount importance for the thousands of asymptomatic persons infected with Chagas' disease currently living in the United States and abroad.

Topics: Adult; Antiparasitic Agents; Biopsy; Cellulitis; Chagas Cardiomyopathy; Chagas Disease; Diagnosis, Differential; Heart Transplantation; Humans; Leg Dermatoses; Male; Nifurtimox; Recurrence; Skin Diseases, Parasitic

Topics: Animals; Chagas Disease; Chronic Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Mice; Nifurtimox; Protozoan Infections; Toxoplasmosis; Trypanosoma cruzi

No studies exist on sister-chromatid exchange (SCE) formation in chagasic patients therapeutically exposed to nifurtimox (NFX) or benznidazol (BZ). In the present study SCE was analyzed in cultures of peripheral lymphocytes of patients aged 11 months to 11 years treated with NFX 12-15 mg/kg/d for 60 days or with BZ 5 mg/kg/d for 30 days. Chagasic patients before treatment constituted a control group. A mean of 30 metaphases were examined for each individual. All treated patients compared with untreated controls did not show a significant increase in SCE frequency. Compared with the percentage of chromosomal aberrations in these patients and others belonging to the same epidemic protocol, SCE seems to be less sensitive in the detection of lymphocyte chromosomal damage caused by NFX or BZ.

Topics: Chagas Disease; Child; Child, Preschool; Chromosomes; Dose-Response Relationship, Drug; Female; Humans; Lymphocytes; Male; Nifurtimox; Nitroimidazoles; Sister Chromatid Exchange; Trypanocidal Agents

Topics: Animals; Chagas Cardiomyopathy; Chagas Disease; Nifurtimox; Nitroimidazoles; Rabbits; Trypanocidal Agents

Chromosomal aberrations were analyzed from cultures of peripheral lymphocytes in 2 groups of chagasic children, before and after treatment with nifurtimox. The mean incidence of chromosomal aberrations increased from control values of 1.75 +/- 1.39 (8 patients) to 23.55 +/- 9.55 (6 patients) at a significance of P less than 0.0001. G-banding analysis of chromosomal aberration sites revealed that treated patients present coincidence in the chromosome regions affected: 1p11, 1q11-12, 9q11-13, 17q11-21, 2p21, 2q23, 2q31, 2q33, 6p21, 6p21, 7q32, 13q14, 13q22, 15q22. These data indicate a non-random distribution of chromosomal aberrations induced by nifurtimox therapeutic treatment.

Topics: Adolescent; Chagas Disease; Child; Child, Preschool; Chromosome Aberrations; Chromosome Banding; Female; Humans; Infant; Male; Nifurtimox; Nitrofurans

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

The bioreductive activation of megazol [2-amino-5(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole] promoted by ferredoxin: NADP+ oxidoreductase, rat liver microsomes and cellular fractions of Trypanosoma cruzi, Y strain, was investigated. Direct ESR detection and characterization by computer simulation of the megazol nitro anion radical were possible in the presence of NADPH and ferredoxin: NADP+ oxidoreductase under anaerobic conditions. By contrast, the megazol nitro anion radical was not detected in the presence of either rat liver microsomes or cellular fractions of T. cruzi under conditions where the corresponding nifurtimox anion radical was observed. The inefficiency of rat liver microsomes in catalyzing megazol reduction was also attested by visible light absorption spectroscopy. In the presence of cellular fractions of T. cruzi supplemented with NAD(P)H, megazol marginally affected oxygen consumption and decreased the yield of oxyradicals that can be spin-trapped with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Our results indicate a restricted bioreductive metabolism of megazol and suggest that its trypanocidal activity is unrelated to a redox-cycling process.

Topics: Animals; Chagas Disease; Ferredoxins; Microsomes, Liver; Mitochondria; Nifurtimox; Nitrofurans; Nitroimidazoles; Oxidation-Reduction; Oxygen Consumption; Rats; Subcellular Fractions; Thiadiazoles; Trypanosoma cruzi

After observing a fatal chagasic infection in a renal transplant recipient we investigated Chagas disease in 84 recipients of renal transplants. The indirect hemagglutination test was used for screening and xenodiagnosis followed in positive cases, along with ECG and gastrointestinal X ray series. Nine cases were detected (10%); parasites were found in the blood of 6 of them (66%). No patient had cardiac or gastrointestinal involvement. Patients with a positive serology were treated with nifurtimox (2) or benzonidazol (7); xenodiagnosis every 6 months up to 67 months remains negative in these patients. Blood transfusions are suspected as the mechanism for infection in these cases.

Topics: Adolescent; Adult; Chagas Disease; Female; Humans; Immune Tolerance; Kidney Transplantation; Male; Nifurtimox; Nitroimidazoles; Serologic Tests; Transfusion Reaction; Trypanocidal Agents

Reinfection of chronic chagasic mice after treatment with nifurtimox resulted in different outcomes according to the number of parasites used for inoculation. Nifurtimox-treated chagasic animals injected with 2,500 trypomastigotes developed higher parasitemia and increased mortality compared with nontreated chagasic mice. When reinfection was done with 25 trypomastigotes, treated and nontreated animals showed similar parasitemias and mortalities, which were significantly higher in nonchagasic controls infected for the first time. Immunological studies showed that treatment with nifurtimox led to a decrease in anti-Trypanosoma cruzi antibodies engaged in parasite destruction, inducing either complement-dependent lysis or antibody-dependent cytotoxicity, but no difference in anti-T. cruzi cell-mediated immunity was found between treated and nontreated chagasic animals. It is concluded that treatment with nifurtimox leads to a loss of resistance to reinfection with a large number of trypanosomes, which is maintained with challenge with a few parasites, and that these two thresholds of premunition are probably associated with humoral and cell-mediated anti-T. cruzi immune responses, respectively.

Topics: Animals; Antibodies, Protozoan; Antibody-Dependent Cell Cytotoxicity; Chagas Disease; Female; Immunity, Cellular; Mice; Mice, Inbred BALB C; Nifurtimox; Nitrofurans; Recurrence; Trypanosoma cruzi

Topics: Animals; Antibodies, Protozoan; Antibody-Dependent Cell Cytotoxicity; Chagas Disease; Mice; Mice, Inbred BALB C; Nifurtimox; Nitrofurans; Trypanosoma cruzi

Topics: Adolescent; Chagas Disease; Child; Child, Preschool; Chromosome Banding; Chromosome Fragility; Humans; Infant; Metaphase; Micronucleus Tests; Nifurtimox; Nitrofurans; Nitroimidazoles; Trypanocidal Agents

Topics: Animals; Antibodies, Protozoan; Antibody Formation; Chagas Disease; Male; Mice; Nifurtimox; Trypanosoma cruzi

The susceptibility and natural resistance to two nitroheterocyclic derivatives used clinically in Chagas disease (nifurtimox and benznidazole) were investigated in 47 Trypanosoma cruzi strains isolated from human patients, domestic vectors and sylvatic reservoirs or vectors. A large gradient of drug efficacy from 0% to 100% was detected. Drug susceptibility apparently related to geographical distribution of some T. cruzi strains was also observed. Drug resistance was identified among T. cruzi populations isolated from sylvatic vectors from an area where autochthonous human Chagas disease does not exist. Thus, natural drug-resistance of sylvatic strains might be a way of introducing this character into a T. cruzi domestic cycle. Most of the 47 studied strains were either sensitive or resistant to both compounds, an intriguing finding considering that nifurtimox and benznidazole apparently have different mechanisms of action against T. cruzi.

Topics: Animals; Chagas Disease; Drug Resistance; Male; Mice; Nifurtimox; Nitrofurans; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

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

A test was made of the susceptibility of 30 strains of Trypanosoma cruzi to chemotherapy with nifurtimox (Bay 2502) and benznidazole (Ro 7-1051). The strains had previously been classified as type I, II, or III according to their morphobiological and isoenzymic characteristics. Three type I strains, 14 type II strains, and 13 type III strains were studied. Mice were infected with 2 x 10(5) blood forms of these parasites and treated for 90 days with benznidazole or nifurtimox. All the surviving mice were submitted to parasitological tests (direct parasitaemia, xenodiagnosis, inoculation in new-born mice, and haemoculture) and serological tests (indirect immunofluorescence). As the latter remained positive in about 80% of the parasitologically negative animals, the cure rates were based on the more reliable parasitological tests. Type I strains displayed high susceptibility, type II strains showed medium to high susceptibility, and type III strains were highly resistant to both drugs. The fact that a particular strain type, with its own level of susceptibility, usually predominates in a given geographical area may explain the contradictory results after chemotherapy from different endemic areas.

Topics: Animals; Chagas Disease; Mice; Nifurtimox; Nitrofurans; Nitroimidazoles; Species Specificity; Trypanocidal Agents

Topics: Body Weight; Chagas Disease; Female; Humans; Infant; Infant, Newborn; Male; Nifurtimox; Nitrofurans

A newly developed enzyme-hydrolyzed toxoplasma-hyperimmune bovine serum preparation, Obioactin , was examined for its anti-microbial and related actions against heterologous protozoa, bacteria, and viruses both in-vivo and in-vitro. An appreciable efficacy of Obioactin in a combination with nifurtimox, Lampit was observed in experimental Trypanosoma cruzi infections in mice. But prophylactic applications of the agent alone or joint with Lampit were in vain in mice. In-vitro digestion of certain bacteria in mouse peritoneal macrophages was accelerated in the presence of the agent being three to ten times stronger than that in untreated macrophages. Inhibitory effect of Obioactin on in-vitro infectivity of viruses was suggested.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cell Line; Chagas Disease; Chikungunya virus; Cricetinae; Drug Therapy, Combination; Encephalitis Virus, Japanese; Female; Humans; Immunoglobulins; Listeriosis; Macrophages; Male; Mice; Mice, Inbred Strains; Nifurtimox; Phagocytosis; Rats; Rats, Inbred Strains; Simplexvirus; Virus Replication

Topics: Antigens, Protozoan; Chagas Disease; Drug Resistance, Microbial; Female; Humans; Infant, Newborn; Nifurtimox; Trypanosoma cruzi

Experimental studies were undertaken in tissue culture and mice infected with a cloned derivative of Trypanosoma cruzi, Y strain to determine the efficacy of two 2-substituted 5-nitroimidazole compounds, MK-436 and L634,549. The use of an X-irradiated myoblast culture system proved better than a conventional fibroblast culture for assaying the activity of compounds against intracellular parasite stages. MK-436 showed activity against amastigotes at a level of 25 micrograms/ml and L634,549 a dihydroxy metabolite of MK-436 showed activity 2 micrograms/ml. Neither compound caused morphological damage to the host cells at levels tested (250 micrograms/ml). By contrast, nifurtimox, which was active at 2 micrograms/ml, caused significant host cell damage at 100 micrograms/ml. In mice, studies in the chronic infection showed that MK-436 was curative at a level of 30 mg/kg if given daily for 20 days. Neither nifurtimox nor benznidazole were fully curative when given at a level of 100 mg/kg daily for 20 days. These studies showed that administration of MK-436 with a suitable solvent, PEG 400, enhanced its efficacy fourfold, and that efficacy was also enhanced by increasing the treatment interval. Since MK-436 showed better efficacy in chronic rodent infections than either nifurtimox or benznidazole, such compounds should be evaluated for efficacy in human Chagas' disease.

Topics: Animals; Antiprotozoal Agents; Benzimidazoles; Cell Line; Chagas Disease; Drug Evaluation, Preclinical; Female; Fibroblasts; Humans; Mice; Mice, Inbred BALB C; Muscles; Nifurtimox; Nitroimidazoles; Rats; Trypanosoma cruzi

Topics: Animals; Chagas Cardiomyopathy; Chagas Disease; Female; Intestinal Diseases, Parasitic; Mice; Mice, Inbred Strains; Myositis; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Anti-Infective Agents, Urinary; Chagas Disease; Glycoproteins; Histocytochemistry; Humans; Nifurtimox; Nitrofurans; Oxazolidinones; Periodic Acid-Schiff Reaction; T-Lymphocytes; Trypanocidal Agents; Trypanosoma cruzi

The biological properties of a novel compound 353C with high activity against Trypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C has a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.

Topics: Animals; Biphenyl Compounds; Chagas Disease; Drug Evaluation, Preclinical; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Mice experimentally inoculated with metacyclic forms of Trypanosoma rangeli were given orally 10, 25, 50 or 100 mg/kg of body weight/day of Lampit on 20 consecutive days. The results of combined examinations of fresh blood, Giemsa stained blood preparations, blood cultures, blood concentration, repeated xenodiagnosis with Rhodnius prolixus and blind passages via triatomine bites to other mice demonstrated that a dose of 50 to 100 mg/kg/day of the drug eliminated T. rangeli from the blood of all mice in the first seven days of treatment. In mice receiving 10 or 25 mg/kg/day of drug, 60% and 30% respectively still harboured trypanosomes 90 days after infection. The results indicate that Lampit is at least as effective against T. rangeli as it is against T. cruzi in mice.

Topics: Administration, Oral; Animals; Chagas Disease; Dose-Response Relationship, Drug; Mice; Nifurtimox; Nitrofurans; Trypanosoma

The ability of a range of trypanocidal drugs, including a number known to be active in Trypanosoma cruzi infections were tested against Trypanosoma musculi infections in the mouse. The ability of these drugs, particularly in their ability to eliminate the "cryptic phase" of T. musculi infections remaining in the kidneys, was investigated and their activity against this phase of T. musculi largely paralleled their known activity against T. cruzi infections. It is suggested that this could be used as a preliminary screening test for potential T. cruzi-active drugs.

Topics: Animals; Chagas Disease; Diminazene; Drug Evaluation, Preclinical; Ethidium; Female; Kidney; Mice; Nifurtimox; Nitroimidazoles; Phenanthridines; Trypanocidal Agents; Trypanosomiasis

Topics: Animals; Chagas Disease; Humans; Mice; Nifurtimox; Nitrofurans; Nitrofurazone; Nitroimidazoles; Trypanosoma cruzi

After the successful struggle against malaria, smallpox and tuberculosis, Chagas' disease must be considered the commonest and most serious scourge of the American continent. Experts assess the number of persons suffering from Chagas' disease at about 7 millions with about 35 millions at risk. The acute infection with Trypanosoma cruzi in the blood stream is found chiefly in children in the first few years of life but rarely in adults. Mortality in the acute phase is about 10%. The disease tends to run a chronic course. After an asymptomatic phase (usually 10--12 years), chronic Chagas' myocarditis dominates the chronic form. A great therapeutic advance has been achieved with the nitrofurfurylidene preparation Lampit. For the first time it has become possible to eliminate trypanosomes found in both blood and tissues. Success is particularly to be expected in the treatment of the acute infection.

Topics: Animals; Central America; Chagas Cardiomyopathy; Chagas Disease; Disease Vectors; Hemiptera; Humans; Infant; Nifurtimox; South America; Trypanosoma cruzi

Topics: Amphotericin B; Animals; Chagas Disease; Drug Evaluation, Preclinical; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

A novel 8-aminoquinolone compound, 8(6-4' 3-hydroxybutyl)piperazin-1'-ylhexylamino)-6-methoxyquinoline di(hydrogen maleate), moxipraquine, 349C59, was shown to be active against experimental infections with Trypanosoma cruzi. It was effective in suppressing parasitaemia but did not eradicate the infection from mice or guinea-pigs. Other clinically tested drugs, including nifurtimox, were likewise incapable of eradicating the parasite from infected mice. Moxipraquine was less potent against mouse infections with strain Peru than it was against other strains of T. cruzi. In limited tests, moxipraquine was effective on experimental infections of Leishmania major, L. mexicana mexicana and L. brasiliensis panamensis but not L.b. brasiliensis. Significant foetal toxicity, observed experimentally in rats and rabbits, resulted in the termination of clinical trials.

Topics: Aminoquinolines; Animals; Chagas Disease; Culture Techniques; Female; Fetus; Furazolidone; Guinea Pigs; Leishmaniasis; Lethal Dose 50; Maternal-Fetal Exchange; Mice; Nifurtimox; Nitrofurazone; Pregnancy; Primaquine; Rabbits; Rats; Time Factors

In order to study the effect of combined treatment of Trypanosoma cruzi infection with a nitrofuranic drug and a corticoid, 27 dogs from three different litters infected with T. cruzi (12 SF strain) were randomly litter-paired in three experimental groups: animals infected and not treated; infected and treated with Bay 2502 (2-methyl-4-[5'nitrofurfurylideneamino]-tetrahydro-4H-1,4-thiazine-1,1-dioxine) (nifurtimox); infected and treated with nifurtimox plus betamethasone. While an enhanced myocarditis appeared in the animals treated with a nitrofuranic drug alone, inflammation was almost abolished when corticoid treatment was added. Both groups showed considerable intracellular parasite destruction. These changes were monitored by serial electrocardiograms and a final histopathologic study which included an investigation of the changes in the conducting tissue by serial sectioning. The survival period was prolonged in animals treated with the combination of the nitrofuranic drug and corticoid, and only in this group did some of the animals reach the chronic phase of the infection. Thus, the association of a nitrofuranic drug with a corticoid in the treatment of acute Chagas' disease produced parasite destruction and inhibited the inflammatory responses that are enhanced by such destruction

Topics: Animals; Betamethasone; Chagas Disease; Dogs; Drug Therapy, Combination; Electrocardiography; Myocardium; Nifurtimox; Nitrofurans

Topics: Adult; Aged; Antineoplastic Agents; Chagas Disease; Chronic Disease; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Neoplasms; Nifurtimox; Prednisone

Topics: Chagas Disease; Humans; Nifurtimox; Nitrofurans; Nitroimidazoles; Trypanosoma cruzi

Mice infected with bloodstream forms of Trypanosoma cruzi were treated with an active Nitrofuran compound (Nifurtimox, Lampit). Determination of the number of intracellular forms of T. cruzi in the liver and the spleen of control and Lampit-treated mice showed that the drug induced a decrease in the number of parasites inside the cells. A decrease in the number of bloodstream forms was also observed. Ultrastructural observations showed that Lampit induces several alterations in T. cruzi, the most characteristic alteration being the appearance of dense masses localized in the mitochondrial matrix of the parasites.

Topics: Animals; Chagas Disease; Liver; Mice; Mitochondria; Nifurtimox; Nitrofurans; Ribosomes; Spleen; Trypanosoma cruzi; Vacuoles

Immunoglobulin M, G, and A concentrations were studied by radial immunodiffusion technique in 16 individuals (two were 16 and 14 yr of age, respectively, while the remaining 14 uere 15 yr of age or less) with acute Trypanosoma cruzi infection. Serum samples were obtained from these patients beginning with the onset of symptoms and continuing until several months after treatment with nifurtimox was completed. Soon after infection the concentration of IgM was higher than the average found in healthy children. Some of the samples also had higher values than those found in children with other acute infections. At this time isolated increases in IgG and/or IgA concentrations were also found in T. cruzi-infected patients. Immunoglobulin concentrations had usually returned to normal when treatment with nifurtimox was completed, both in the patients with negative serology and in those who remained positive. However, some of the sera showed isolated higher IgM, IgG, and/or IgA values than those found in healthy controls.

Topics: Adolescent; Chagas Disease; Child; Child, Preschool; Follow-Up Studies; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Nifurtimox

Topics: Chagas Disease; Humans; Nifurtimox; Nitrofurans; Nitroimidazoles; Placebos

Antibodies reacting against endothelial cells, vascular structures, and heart and skeletal muscle cells (EVI antibodies) were studied in 10 patients (one to 14 years of age) treated with Nifurtimox. The patients were observed for several months to two years after the onset of symptoms of acute infection with Trypanosoma cruzi. Although these 10 patients were selected because after treatment their sera became negative for antibodies to T. cruzi as detected by the immunofluorescence test, sera from six patients remained positive for EVI antibodies. It is suggested that EVI antibodies may be self-perpetuated in the absence of infection. Further studies are needed to determine the pathogenic significance of EVI antibodies.

Topics: Adolescent; Antibodies; Antibodies, Anti-Idiotypic; Blood Vessels; Chagas Disease; Child; Child, Preschool; Endothelium; Female; Fluorescent Antibody Technique; Humans; Immunoglobulin M; Infant; Male; Muscles; Myocardium; Nifurtimox; Nitrofurans

Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.

Topics: 5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole; Aminoquinolines; Animals; Chagas Disease; Disease Models, Animal; Male; Mice; Nifurtimox; Onium Compounds; Structure-Activity Relationship; Trityl Compounds; Trypanocidal Agents; Trypanosoma cruzi

Ten 2-substituted 4-thiazolecarboxaldehyde hydrazones bearing 5-nitro-2-furyl, 5-nitro-2-thiazolyl, and 1-methyl-5-nitro-2-imidazolyl functions have been prepared and screened for activity against Trypanosoma cruzi infections in mice. The results permitted the ranking of these substituents in decreasing order of activity: 1-methyl-5-nitro-2-imidazolyl greater than 5-nitro-2-furyl greater than 5-nitro-2-thiazolyl, the last being inactive. Some structural features of the side chain necessary for optimum activity are discussed. The most active compound, 4-[[[2-(1-methyl-5-nitro-2-imidazolyl)-4-thiazolyl]methylene]amino]thiomorpholine 1,1-dioxide, compared favorably with the standard Nifurtimox against three recent clinical isolates of T. cruzi, including one with a high myocardial tissue infiltration.

Topics: Animals; Chagas Disease; Mice; Thiazoles; Trypanocidal Agents

The effect of length of treatment of Trypanosoma cruzi with Bayer 2502 (Bay 2502, Lampit, Nifurtimox) on resistance to challenge and parasite isolation was studied in two experiments. In each, 200 mice were divided into groups of 20, infected with T. cruzi, and then treated with Bay 2502 for 1 to 8 consecutive weeks. Sixteen weeks after exposure, 10 mice from each experimental group were challenged with 150,000 trypomastigotes. The remainder were maintaned for 8 more weeks and killed for isolation of parasites. Mice treated with Bay 2502 for up to 8 consecutive weeks were uniformly resistant to challenge, and parasites could not be isolated from groups treatef for over 6 weeks. Results suggest that prolonged treatment with Bay 2502 eliminates T. cruzi from infected hosts and that resistance to challenge is not dependent on the presence of the organisms in mice.

Topics: Animals; Chagas Disease; Drug Evaluation, Preclinical; Female; Mice; Nifurtimox; Nitrofurans; Time Factors; Trypanocidal Agents; Trypanosoma cruzi

Topics: Animals; Chagas Disease; Mice; Nifurtimox; Nitrofurans; Trypanosoma cruzi

Peripheral leucocyte migration inhibition (LMI) with Trypanosoma cruzi-specific antigens, measured as a migration index (MI), was studied in chronic Chagas' disease patients. The MI of untreated patients with polymerized antigens from culture forms (epimastigotes) of T. cruzi was significantly lower than that of controls. In contrast, when chronic Chagas' patients were treated with nifurtimox, 10 mg/kg/day for 2 months, the MI was not different from control values. Treated and untreated patients had normal T- and B-lymphocyte markers, measured by the ability to form rosettes either with sheep erythrocytes (E-RFC) or with sheep erythrocytes--antibody--complement (EAC-RFC). In addition, the number of lymphocytes bearing surface membrane Ig (SMIg) was the same as that of controls. Non-specific functional assays, such as PHA-induced blastogenesis and antibody-dependent cell-mediated cytotoxicity (ADCC) to sensitized chicken erythrocytes were also normal, both in treated and untreated patients. Thus, nifurtimox produced a particularly effect on cell-mediated immunity, specially detectable using LMI.

Topics: Cell Migration Inhibition; Chagas Disease; Humans; Immunity, Cellular; Leukocytes; Nifurtimox; Nitrofurans; Receptors, Antigen, B-Cell; Rosette Formation; Trypanosoma cruzi

Positive skin reactions to PPD in guinea-pigs immunized with Freund's complete adjuvant (FCA) were reversed after treatment with 10 mg/kg/day nifurtimox for 12 days. The in vitro migration of peripheral blood leucocytes from FCA-immunized guinea-pigs was inhibited with PPD, but it returned to normal values after nifurtimox treatment. Furthermore, the cell-free supernatant from PPD-stimulated lymphocytes from FCA-immunized nifurtimox-treated guinea-pigs did not inhibit the migration of normal cells. Thus the administration of nifurtimox impaired the specific cell-mediated immune response to PPD both in vivo and in vitro.

Topics: Animals; Cell Migration Inhibition; Chagas Disease; Freund's Adjuvant; Guinea Pigs; Immunity, Cellular; Leukocytes; Nifurtimox; Nitrofurans; Skin Tests; T-Lymphocytes; Tuberculin

Two different histological types of congenital Chagas disease are defined. In one type, parasites were seen within the skeletal and cardiac fibers, and in the other, they are found mostly within the cells of the reticuloendothelial system. The latter was often associated with parasitized giant-cells with a single, lobulated, hyperchromatic nucleus. In 24 placentas, the most consistent findings were villous and intervillous inflammatory infiltrates. Amastigotes of Trypanosoma cruzi were found mostly in the chorionic villi and in the chorionic plate, and less frequently in the fetal membranes.

Topics: Brain; Chagas Disease; Chorionic Villi; Diagnosis, Differential; Esophagus; Female; Humans; Infant, Newborn; Intestines; Mononuclear Phagocyte System; Myocardium; Nifurtimox; Placenta; Pregnancy; Pregnancy Complications, Infectious; Species Specificity; Trophoblasts; Trypanosoma cruzi