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Annals of Internal Medicine Feb 2023Chagas disease, which is caused by infection with the parasite , is a leading neglected tropical disease in the United States. An estimated 240 000 to 350 000 persons... (Review)
Review
Chagas disease, which is caused by infection with the parasite , is a leading neglected tropical disease in the United States. An estimated 240 000 to 350 000 persons in the United States are infected, primarily immigrants from Mexico, Central America, and South America, where the disease is endemic. The parasite is transmitted by the triatomine bug but can also be passed through blood transfusion, via organ transplant, or congenitally. Approximately 30% of infected persons later develop cardiac and/or gastrointestinal complications. Health care providers should consider screening at-risk patients with serologic testing. Early diagnosis and treatment with benznidazole or nifurtimox can help prevent complications.
Topics: Humans; United States; Chagas Disease; Trypanosoma cruzi; Nifurtimox; Emigrants and Immigrants; Organ Transplantation
PubMed: 36780647
DOI: 10.7326/AITC202302210 -
Chemical Research in Toxicology Nov 2022The oral antiparasitic drug nifurtimox has been used to treat Chagas disease for more than 50 years. Historical studies determined that very little nifurtimox is...
The oral antiparasitic drug nifurtimox has been used to treat Chagas disease for more than 50 years. Historical studies determined that very little nifurtimox is excreted unchanged, but contemporaneous preclinical studies of radiolabeled nifurtimox found almost all of the radiolabel was rapidly excreted, suggesting that metabolism is extensive. Attempts to study nifurtimox metabolism have had limited success, yet this knowledge is fundamental to characterizing the pharmacokinetics and pharmacodynamics of the drug. We conducted studies using hepatic and renal sources with C-labeled nifurtimox as substrate and obtained samples of urine, plasma, and feces from rats administered 2.5 mg/kg [C]-nifurtimox, and samples of human urine and plasma from phase 1 clinical studies in which participants received a single dose of 120 mg nifurtimox. Analysis of metabolites was done by high-performance liquid chromatography (HPLC)-high-resolution mass spectrometry (HRMS) and HRMS/MS with offline liquid scintillation counting of radiolabeled samples. Surprisingly, only traces of a few metabolites were identified from incubations with hepatocytes and subcellular fractions, but more than 30 metabolites were identified in rat urine, mostly with atypical mass changes. We developed an HRMS scouting method for the analysis of human samples based on the sulfur atom in nifurtimox and the natural abundance of S, as well as a characteristic tandem mass spectrometry (MS/MS) fragmentation of nifurtimox and metabolites. Fragmentation patterns on HRMS/MS were used to propose structures for 18 metabolites (22 including stereoisomers), and based on these structures, the six most abundant products were synthesized and the structures of the synthetic forms were confirmed by HRMS and two-dimensional nuclear magnetic resonance (2D NMR). Overall, we determined that the metabolism of nifurtimox is almost certainly not mediated by typical hepatic and renal drug-metabolizing enzymes, and instead is rapidly metabolized mainly by reduction or nucleophilic attack, with some evidence of oxidation. Knowledge of the most abundant metabolites of nifurtimox affords the possibility of future studies to investigate levels of exposure and possible drug-drug interactions.
Topics: Humans; Rats; Animals; Tandem Mass Spectrometry; Nifurtimox; Chromatography, High Pressure Liquid; Feces; Body Fluids
PubMed: 36209416
DOI: 10.1021/acs.chemrestox.2c00210 -
The American Journal of Tropical... Nov 2017Chagas disease (CD) is caused by the protozoan parasite that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in... (Review)
Review
Chagas disease (CD) is caused by the protozoan parasite that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.
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
PubMed: 29016289
DOI: 10.4269/ajtmh.16-0761 -
Expert Review of Cardiovascular Therapy Dec 2015Over 100 years have elapsed since the discovery of Chagas disease and there is still much to learn regarding pathogenesis and treatment. Although there are antiparasitic... (Review)
Review
Over 100 years have elapsed since the discovery of Chagas disease and there is still much to learn regarding pathogenesis and treatment. Although there are antiparasitic drugs available, such as benznidazole and nifurtimox, they are not totally reliable and often toxic. A recently released negative clinical trial with benznidazole in patients with chronic Chagas cardiomyopathy further reinforces the concerns regarding its effectiveness. New drugs and new delivery systems, including those based on nanotechnology, are being sought. Although vaccine development is still in its infancy, the reality of a therapeutic vaccine remains a challenge. New ECG methods may help to recognize patients prone to developing malignant ventricular arrhythmias. The management of heart failure, stroke and arrhythmias also remains a challenge. Although animal experiments have suggested that stem cell based therapy may be therapeutic in the management of heart failure in Chagas cardiomyopathy, clinical trials have not been promising.
Topics: Animals; Arrhythmias, Cardiac; Chagas Cardiomyopathy; Chagas Disease; Disease Management; Electrocardiography; Heart Failure; Humans; Nanotechnology; Nitroimidazoles; Stem Cell Transplantation; Trypanocidal Agents; Vaccines
PubMed: 26496376
DOI: 10.1586/14779072.2015.1103648 -
British Journal of Clinical Pharmacology Feb 2022Chagas 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... (Review)
Review
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
PubMed: 33314266
DOI: 10.1111/bcp.14700 -
Acta Tropica Oct 2019Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It is a significant public health problem, affecting millions of... (Review)
Review
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
PubMed: 31351074
DOI: 10.1016/j.actatropica.2019.105107 -
The American Journal of the Medical... Nov 2022Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, is one of the leading public health problems in the Western Hemisphere. The parasite is mainly... (Review)
Review
Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, is one of the leading public health problems in the Western Hemisphere. The parasite is mainly transmitted by contact with infected insect vectors but other forms of transmission are important in endemic areas. In the United States, while the disease is largely restricted to immigrants from endemic countries in Latin America, there is some risk of local acquisition. T. cruzi circulates in a sylvatic cycle between mammals and local triatomine insects in the southern half of the country, where human residents may be at risk for incidental infection. There are several reported cases of locally-acquired Chagas disease in the United States, but there is a paucity of information in Oklahoma. We present a brief summary of the available data of Chagas disease in Oklahoma to raise awareness and serve as a foundation for future research.
Topics: Humans; Animals; United States; Oklahoma; Chagas Disease; Trypanosoma cruzi; Insect Vectors; Mammals
PubMed: 35623395
DOI: 10.1016/j.amjms.2022.03.018 -
Research and Reports in Tropical... 2022Chagas disease (CD) is caused by the parasite , and it is endemic in Central, South America, Mexico and the South of the United States. It is an important cause of early... (Review)
Review
Chagas disease (CD) is caused by the parasite , and it is endemic in Central, South America, Mexico and the South of the United States. It is an important cause of early mortality and morbidity, and it is associated with poverty and stigma. A third of the cases evolve into chronic cardiomyopathy and gastrointestinal disease. The infection is transmitted vertically and by blood/organ donation and can reactivate with immunosuppression. Case identification requires awareness and screening programmes targeting the population at risk (women in reproductive age, donors, immunocompromised patients). Treatment with benznidazole or nifurtimox is most effective in the acute phase and prevents progression to chronic phase when given to children. Treating women antenatally reduces but does not eliminate vertical transmission. Treatment is poorly tolerated, contraindicated during pregnancy, and has little effect modifying the disease in the chronic phase. Screening is easily performed with serology. Migration has brought the disease outside of the endemic countries, where the transmission continues vertically and via blood and tissue/organ donations. There are more than 32 million migrants from Latin America living in non-endemic countries. However, the infection is massively underdiagnosed in this setting due to the lack of awareness by patients, health authorities and professionals. Blood and tissue donation screening policies have significantly reduced transmission in endemic countries but are not universally established in the non-endemic setting. Antenatal screening is not commonly done. Other challenges include difficulties accessing and retaining patients in the healthcare system and lack of specific funding for the interventions. Any strategy must be accompanied by education and awareness campaigns directed to patients, professionals and policy makers. The involvement of patients and their communities is central and key for success and must be sought early and actively. This review proposes strategies to address challenges faced by non-endemic countries.
PubMed: 35912165
DOI: 10.2147/RRTM.S278135