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Amanda Fortes Francisco, Shiromani Jayawardhana, Michael D Lewis, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Maria Osuna-Cabello, Kevin D Read, Susan A Charman, Eric Chatelain, John M Kelly
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...
October 17, 2016: Scientific Reports
L N Nsiangani, D Kaimbo Wa Kaimbo, M L Kazumba
We report the case of a 13-year-old girl who consulted for blurred vision, pain, and redness in her left eye. Ophthalmologic examination revealed chronic, hypertensive, and non-granulomatous anterior uveitis. The disease course was marked by a reversal of diurnal rhythm, with daytime sleepiness and behavioral disorders. A neuropsychiatric examination suggested human African trypanosomiasis (HAT), or sleeping sickness. The diagnosis was confirmed by the detection of Trypanosoma in the cerebrospinal fluid. The NECT regimen (nifurtimox-eflornithine combination therapy) was administered as medical treatment and resulted in the disappearance of all clinical signs...
August 1, 2016: Médecine et Santé Tropicales
Monica Cal, Jean-Robert Ioset, Matthia A Fügi, Pascal Mäser, Marcel Kaiser
Total clearance of the T. cruzi infection - referred to herein as "sterile cure" - seems to be a critical prerequisite for new drug candidates for Chagas disease, ensuring long-term beneficial effects for patients in the chronic indeterminate stage. This requirement is notably supported by the recent findings of clinical studies involving posaconazole and fosravuconazole, where the majority of patients treated eventually relapsed after an apparent clearance of parasitaemia at the end of treatment. We have adapted an in vitro system to predict the ability of a compound to deliver sterile cure...
August 26, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Sergio Alegre-Gómez, Paula Sainz, M Fátima Simões, Patrícia Rijo, Cristina Moiteiro, Azucena González-Coloma, Rafael A Martínez-Díaz
Twenty-seven diterpenes, including abietanes, labdanes, abeoabietanes, halimanes, and pimaranes, have been evaluated against epimastigote and intracellular amastigote forms of Trypanosoma cruzi and also against LC5 and NCTC cell lines. Royleanones (3, 4, and 5) and a further abietane (12), obtained by purification of Plectranthus spp. extracts, were the most active compounds on epimastigotes, showing IC50 values similar (1.73 µg/mL, 12) or even lower (0.39, 0.99, and 1.20 µg/mL, 3, 4, and 5 respectively) than the positive control nifurtimox (2...
September 6, 2016: Planta Medica
Seyed Fazel Nabavi, Antoni Sureda, Maria Daglia, Morteza Izadi, Eduardo Sobarzo-Sánchez, Luca Rastrelli, Seyed Mohammad Nabavi
Chagas disease is one of the major health problems in Central and South America, which is caused by the parasitic protozoa, Trypanosoma cruzi. It is commonly transmitted by members of blood-sucking subfamily Triatominae. Chagas disease is associated with cardiac and gastrointestinal manifestations. Up to now, there are no effective vaccines for the treatment of Chagas disease and benznidazole and nifurtimox are as the only effective anti-Chagas drugs that cause different adverse and side effects. Therefore, much attention has been paid to natural products as novel therapeutic strategies for Chagas disease and its manifestations...
August 24, 2016: Current Topics in Medicinal Chemistry
Giselle Villa Flor Brunoro, Vitor Marcel Faça, Marcelle Almeida Caminha, André Teixeira da Silva Ferreira, Monique Trugilho, Kelly Cristina Gallan de Moura, Jonas Perales, Richard Hemmi Valente, Rubem Figueiredo Sadok Menna-Barreto
BACKGROUND: 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...
August 2016: PLoS Neglected Tropical Diseases
Marc Desquesnes, Sarawut Yangtara, Pawinee Kunphukhieo, Sathaporn Jittapalapong, Stéphane Herder
Beside typical human trypanosomes responsible of sleeping sickness in Africa and Chagas disease in Latin America, there is a growing number of reported atypical human infections due to Trypanosoma evansi, a livestock parasite, or Trypanosoma lewisi, a rat parasite, especially in Asia. Drugs available for the treatment of T. brucei ssp. in humans are obviously of choice for the control of T. evansi because it is derived from T. brucei. However, concerning T. lewisi, there is an urgent need to determine the efficacy of trypanocidal drugs for the treatment in humans...
October 2016: Infection, Genetics and Evolution
César Echeverría, Valentina Romero, Rodrigo Arancibia, Hugo Klahn, Ignacio Montorfano, Ricardo Armisen, Vincenzo Borgna, Felipe Simon, Rodrigo Ramirez-Tagle
Trypanosoma cruzi (T. cruzi) is the parasite that causes Chagas disease. Nifurtimox is the most used drug against the T. cruzi, this drug increases intermediaries nitro group, being mainly responsible for the high toxicity component, for this reason it is important to study new organic compounds and thus improve therapeutic strategies against Chagas disease. The electronic effects of ferrocenyl and cyrhetrenyl fragments were investigated by DFT calculation. A close correlation was found between HOMO-LUMO gap of nitro radical NO 2 (-) with the experimental reduction potential found for nitro group and IC50 of two forms the T...
August 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Colin J Forsyth, Salvador Hernandez, Wilman Olmedo, Adieb Abuhamidah, Mahmoud I Traina, Daniel R Sanchez, Jonathan Soverow, Sheba K Meymandi
BACKGROUND: 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. METHODS: 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...
October 15, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Silvia Elizondo-Jimenez, Antonio Moreno-Herrera, Rogelio Reyes-Olivares, Edith Dorantes-Gonzalez, Benjamín Nogueda-Torres, Eduardo Alves Gamosa de Oliveira, Nelilma C Romeiro, Lidia Moreira Lima, Isidro Palos, Gildardo Rivera
BACKGROUND: Chagas disease is a public health problem caused by Trypanosoma cruzi. Cruzain is a pharmacological target for designing a new drug against this parasite. Hydrazone and N-acylhydrazone derivatives have been traditionally associated as potential Cruzain inhibitors. Additionally, benzenesulfonyl derivatives show trypanocidal activity. Therefore, in this study, the combination of both structures has been taken into account for drug design. METHODS: Seven benzenesulfonylhydrazone (BS-H) and seven N-propionyl benzenesulfonylhydrazone (BS-NAH) derivatives were synthetized and elucidated by infrared spectroscopy, nuclear magnetic resonance, and elemental analysis...
June 30, 2016: Medicinal Chemistry
Juan B Rodriguez, Bruno N Falcone, Sergio H Szajnman
INTRODUCTION: Trypanosoma cruzi is the etiologic agent of American trypanosomiasis (Chagas disease), which is one of the important parasitic diseases worldwide. The number of infected people with T. cruzi diminished from 18 million in 1991 to 6 million in 2010, but it is still the most prevalent parasitic disease in the Americas. The existing chemotherapy is still deficient and based on two drugs: nifurtimox and benznidazole, which are not FDA-approved in the United States. AREAS COVERED: This review covers the current and future directions of Chagas disease chemotherapy based on drugs that interfere with relevant metabolic pathways...
September 2016: Expert Opinion on Therapeutic Patents
Rocio Paucar, Elsa Moreno-Viguri, Silvia Pérez-Silanes
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...
June 26, 2016: Current Medicinal Chemistry
Fredson T Silva, Caio H Franco, Denize C Favaro, Lucio H Freitas-Junior, Carolina B Moraes, Elizabeth I Ferreira
Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T...
October 4, 2016: European Journal of Medicinal Chemistry
Michael Du, Linna Zhang, Kathleen A Scorsone, Sarah E Woodfield, Peter E Zage
Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment...
2016: Scientific Reports
Brenda Vera, Karina Vázquez, Carolina Mascayano, Ricardo A Tapia, Victoria Espinosa, Jorge Soto-Delgado, Cristian O Salas, Margot Paulino
A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones...
May 27, 2016: Journal of Biomolecular Structure & Dynamics
María L Sbaraglini, Carolina L Bellera, Laura Fraccaroli, Luciana Larocca, Carolina Carrillo, Alan Talevi, Catalina D Alba Soto
Despite current efforts worldwide to develop new medications against Chagas disease, only two drugs are available, nifurtimox and benznidazole. Both drugs require prolonged treatment and have multiple side effects and limited efficacy on adult patients chronically infected with Trypanosoma cruzi. Recently, computer-guided drug repositioning led to the discovery of the trypanocidal effects of clofazimine and benidipine. These compounds showed inhibitory effects on cruzipain, the major cysteine protease of T...
July 2016: International Journal of Antimicrobial Agents
M R Simões-Silva, A S G Nefertiti, J S De Araújo, M M Batista, P B Da Silva, M T Bahia, R S Menna-Barreto, B P Pavão, J Green, A A Farahat, A Kumar, D W Boykin, M N C Soeiro
The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0...
August 2016: Antimicrobial Agents and Chemotherapy
Kelly Salomao, Rubem Figueiredo Sadok Menna-Barreto, Solange Lisboa de Castro
In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs...
2016: Current Topics in Medicinal Chemistry
Ajmer Singh Grewal, Deepti Pandita, Shashikant Bhardwaj, Viney Lather
Human African trypanosomiasis (HAT, better called as sleeping sickness), caused by two morphologically identicalprotozoan parasite Trypanosoma bruceiis transmitted by the bite of tsetse flies of Glossinagenus, mainly in the rural areas of the sub-Saharan Africa. HAT is one of the neglected tropical diseases and is characterized by sleep disturbance as the main symptom, hence is called as sleeping sickness. As it is epidemic in the poorest population of Africa, there is limited availability of safe and cost-effective tools for controlling the disease...
2016: Current Topics in Medicinal Chemistry
Mónica Cristina García, Nicolás Eric Ponce, Liliana Maria Sanmarco, Rubén Hilario Manzo, Alvaro Federico Jimenez-Kairuz, Maria Pilar Aoki
Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T...
June 2016: Antimicrobial Agents and Chemotherapy
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