Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.392
Filtrar
1.
Am J Trop Med Hyg ; 102(5): 1075-1077, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32207404

RESUMO

In recent decades and because of migration, Chagas disease has become a global public health problem. A significant focus has been placed on pregnant women who can transmit the disease to their offspring. Here, we report four cases of women who did not know that they were pregnant while they were being treated with benznidazole. A diagnosis was established according to serology and Trypanosoma cruzi polymerase chain reaction (PCR)-standardized tests. Treatment was discontinued when pregnancy was confirmed, and a thorough follow-up was carried out. Although each case was different, none of the mothers developed health problems during pregnancy, and their newborns were delivered without any teratogenic effects.


Assuntos
Doença de Chagas/complicações , Nitroimidazóis/uso terapêutico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Adolescente , Adulto , Bolívia , Doença de Chagas/congênito , Doença de Chagas/tratamento farmacológico , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/parasitologia , Nitroimidazóis/efeitos adversos , Gravidez , Tripanossomicidas/efeitos adversos , Trypanosoma cruzi
2.
N Engl J Med ; 382(10): 893-902, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32130813

RESUMO

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).


Assuntos
Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Linezolida/administração & dosagem , Nitroimidazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Antituberculosos/efeitos adversos , Carga Bacteriana , Diarilquinolinas/efeitos adversos , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/mortalidade , Feminino , Humanos , Análise de Intenção de Tratamento , Linezolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Nitroimidazóis/efeitos adversos , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto Jovem
3.
Am J Trop Med Hyg ; 102(5): 1086-1089, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32100696

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is transmitted by insect vectors, and through transfusions, transplants, insect feces in food, and mother to child during gestation. An estimated 30% of infected persons will develop lifelong, potentially fatal cardiac or digestive complications. Treatment of infants with benznidazole is highly efficacious in eliminating infection. This work evaluates the costs of maternal screening and infant testing and treatment for Chagas disease in the United States, including the cost of commercially available benznidazole. We compare costs of testing and treatment for mothers and infants with the lifetime societal costs without testing and consequent morbidity and mortality due to lack of treatment or late treatment. We constructed a decision-analytic model, using one tree that shows the combined costs for every possible mother-child pairing. Savings per birth in a targeted screening program are $1,314, and with universal screening, $105 per birth. At current screening costs, universal screening results in $420 million in lifetime savings per birth-year cohort. We found that a congenital Chagas screening program in the United States is cost saving for all rates of congenital transmission greater than 0.001% and all levels of maternal prevalence greater than 0.06% compared with no screening program.


Assuntos
Doença de Chagas/congênito , Programas de Rastreamento/economia , Nitroimidazóis/uso terapêutico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Doença de Chagas/complicações , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Redução de Custos/economia , Redução de Custos/métodos , Redução de Custos/estatística & dados numéricos , Análise Custo-Benefício , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa/economia , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Programas de Rastreamento/métodos , Nitroimidazóis/economia , Gravidez , Complicações Parasitárias na Gravidez/diagnóstico , Complicações Parasitárias na Gravidez/economia , Tripanossomicidas/economia , Estados Unidos/epidemiologia
4.
Mem Inst Oswaldo Cruz ; 115: e190389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074167

RESUMO

BACKGROUND: Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from ß-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES: In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS: in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS: Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION: N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.


Assuntos
Doença de Chagas/tratamento farmacológico , Naftoquinonas/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Doença Aguda , Animais , Anti-Inflamatórios , Modelos Animais de Doenças , Eletrocardiografia , Masculino , Camundongos , Naftoquinonas/química , Nitroimidazóis/química , Parasitemia/tratamento farmacológico , Fatores de Tempo , Tripanossomicidas/química
5.
Rev Soc Bras Med Trop ; 53: e20190477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049205

RESUMO

INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. METHODS: Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. RESULTS: All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Parasitemia/tratamento farmacológico , Triazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Animais , DNA de Protozoário , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Carga Parasitária , Ratos , Ratos Wistar
6.
PLoS Negl Trop Dis ; 14(2): e0008067, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32069287

RESUMO

BACKGROUND: Antitrypanosomal treatment with Benznidazole (BZ) or Nifurtimox may be recommended for patients with chronic Chagas disease (CD) to reduce the onset or progression of symptoms. However, such treatment has limited efficacy and high level of toxic effects. In addition, the current cure biomarker (serology conversion) precludes any treatment assessment unless a prolonged follow-up is arranged. PCR is thus the most useful, alternative surrogate marker for evaluating responses to treatment. The aim of this study is to describe the usefulness of real-time PCR in monitoring BZ treatment within a large cohort of chronic CD cases in Barcelona. METHODOLOGY/PRINCIPAL FINDINGS: A total of 370 chronic CD patients were monitored with real-time PCR post-BZ treatment. The median follow-up was 4 years (IQR 2.2-5.3y), with a median of 3 clinical visits (IQR 2-4). Only 8 patients (2.2%) presented with at least one incident of positive real-time PCR after treatment and were therefore considered as treatment failure. Four of those failure patients had completed full course treatment, whereas the remaining cases had defaulted with a statistical difference between both groups (p = 0.02). Half of the failure patients had undergone less than 4 years of follow-up monitoring all presented with parasitemia before treatment. CONCLUSIONS/SIGNIFICANCE: BZ treatment failure was highly infrequent in our cohort. BZ discontinuation was a risk factor for positive real-time PCR results during clinical follow-up. Regular testing with real-time PCR during follow-up allows for early detection of treatment failure in patients with chronic CD.


Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Nitroimidazóis/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico , Doença Crônica , Humanos , Estudos Retrospectivos , Espanha/epidemiologia
7.
PLoS Pathog ; 16(2): e1008287, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032366

RESUMO

Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is essential for emergence from hypoxia, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid and delamanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, before being exposed to the drug. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias , Farmacorresistência Bacteriana , Mutação , Mycobacterium tuberculosis , Nitroimidazóis/farmacologia , Nitrorredutases , Oxazóis/farmacologia , Engenharia de Proteínas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Nitrorredutases/genética , Nitrorredutases/metabolismo , Polimorfismo Genético
8.
Exp Parasitol ; 210: 107834, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978394

RESUMO

Studies suggest that the dose of the standard benznidazole (BNZ) treatment regimen might be too high. We investigated the efficacy of BNZ 20 and 40 mg/kg/day compared with standard dose (100 mg/kg/day) to induce cure in mice infected with Trypanosoma cruzi Y strain in the acute and chronic phases of Chagas' disease. Our findings indicate that an experimental treatment with a BNZ low-dose (40 mg/kg/day) is similarly effective as the usual dose in the chronic mice model (100% of cure). In addition, the treatment in the chronic model of Chagas' disease presented better results than the acute model and colon appears to be a key tissue when it comes to evaluating treatment efficacy compared to blood and heart. Therefore, our data suggest the reconsideration of the current therapy, mainly in the chronic phase of the disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Animais , Sangue/parasitologia , Doença de Chagas/parasitologia , Doença Crônica , Colo/parasitologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Feminino , Coração/parasitologia , Imunossupressão , Camundongos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Nitroimidazóis/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologia
9.
Rev Soc Bras Med Trop ; 53: e20190150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994658

RESUMO

INTRODUCTION: Benznidazole is used for treating Chagas disease (CD). This cross-sectional study aimed to characterize the adverse drug reactions (ADRs) of benznidazole at a public hospital in Brazil's Federal District. METHODS: Medical records were analyzed and ADRs were categorized by type, intensity, seriousness, and causality. RESULTS: Of the 62 patients who started benznidazole treatment for CD, 41 (66%) presented with 105 ADRs; 23 (37%) discontinued the treatment. Most reactions were classified as probable (81%), severe (63%), serious (67%), and dose-dependent (56%). CONCLUSIONS: The high incidence of ADRs because of treatment withdrawal revealed the need for safer alternatives for CD treatment.


Assuntos
Doença de Chagas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Nitroimidazóis/efeitos adversos , Tripanossomicidas/efeitos adversos , Adulto , Brasil/epidemiologia , Estudos Transversais , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Testes de Hemaglutinação , Hospitais Públicos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/uso terapêutico , Índice de Gravidade de Doença , Fatores Socioeconômicos , Tripanossomicidas/uso terapêutico
10.
Acta Trop ; 202: 105242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669531

RESUMO

The lack of useful tools for detection the impact of treatment during the follow-up of chronic Chagas disease treated patients difficult the adequate care to the affected population. The objective of this study was to evaluate the functional response of CD8+ T lymphocyte population, critical for the control of Trypanosoma cruzi infection, as a possible cellular biomarker of treated Chagas disease patients. Thus, we analyzed the antigen-specific CD8+ T-cell response before and after benznidazole treatment in asymptomatic (indeterminate) and cardiac chronic Chagas disease patients. A marked dysfunctional process of the CD8+ T cell population was found in patients with an advanced pathology. Thus, the cardiac patients have a higher co-expression of inhibitory receptors and a lower antigen-specific multifunctional capacity compared with that of asymptomatic patients. Remarkably, benznidazole treatment partially reverses this functional exhaustion process of CD8+ T cells in both asymptomatic and cardiac Chagas disease patients. Thus, the co-expression of inhibitory molecules tends to be reduced after benznidazole treatment, mainly in asymptomatic patients, finding a significant drop in the expression of inhibitory receptors such as PD-1 and 2B4. In addition, the multifunctional antigen-specific response of CD8+ T cells is enhanced after treatment in chronic patients. An increase in the subset of cells with cytotoxic capacity and production of the IFN-γ cytokine was also observed in both treated asymptomatic and cardiac chronic Chagas disease patients. The results derived from this study show the improvement of the functional capacity of CD8+ T cells after treatment which could be have a positive effect on parasitic control. In addition, the phenotypic and functional profile of the CD8+ T cells described could serve as a tool for monitoring the impact of benznidazole treatment.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Doença de Chagas , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi , Biomarcadores/sangue , Linfócitos T CD8-Positivos/imunologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/imunologia , Doença Crônica , Citocinas/sangue , Humanos , Nitroimidazóis/uso terapêutico , Receptor de Morte Celular Programada 1/sangue , Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , Tripanossomicidas/uso terapêutico
11.
Eur J Med Chem ; 186: 111887, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787363

RESUMO

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 µM) and amastigote (IC50 = 12.0 µM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 µM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.


Assuntos
Antiprotozoários/farmacologia , Nitroimidazóis/farmacologia , Salmonella enterica/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Nitrorredutases/antagonistas & inibidores , Nitrorredutases/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
12.
J Photochem Photobiol B ; 202: 111703, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810036

RESUMO

Despite the continuous development of medicine, there is still a lack of effective and fully safe protocols for the treatment of neoplastic diseases. The drug-drug conjugates approach seems to give a chance to obtain more efficient molecules. New alkoxy and metronidazole substituted porphyrins were synthesized. Novel porphyrins were purified by flash column chromatography and characterized using NMR, MS, UV-Vis and HPLC. The Nuclear Magnetic Resonance study was performed to annotate experimentally observed 1H NMR and 13C NMR signals of new compounds. The 2D NMR techniques such as 1H-1H COSY (Correlation Spectroscopy), 1H-13C HSQC (Heteronuclear Single Quantum Correlation) and 1H-13C HMBC (Heteronuclear Multiple Bond Correlation) were used for the structure elucidation of the new compounds. In the range of 250-450 nm of the absorption spectra, the Soret band was observed, whereas the Q band was noted in the range of 500-650 nm. Compounds revealed a fluorescence quantum yield in the range 0.03-0.12. Singlet oxygen generation quantum yields up to 0.54 were determined. Electrochemical properties has also been studied. It has been noticed electropolymerization of compound bearing 5-nitroimidazole substituents. The photodynamic activity of the studied porphyrins against A549 and HEK001/HPV16 cancer cells were examined. The most active against A549 and HEK 001/HPV16 was light-excited trioxanonylporphyrin with the values of IC50 equal to 0.49 µM and 50 nM respectively.


Assuntos
Nitroimidazóis/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas Eletroquímicas , Humanos , Luz , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/síntese química , Porfirinas/farmacologia , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo
13.
Lancet Infect Dis ; 20(2): e38-e46, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31879061

RESUMO

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox-eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox-eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.


Assuntos
Antiprotozoários/uso terapêutico , Nitroimidazóis/uso terapêutico , Guias de Prática Clínica como Assunto , Trypanosoma brucei gambiense/isolamento & purificação , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Eflornitina/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nifurtimox/uso terapêutico , Organização Mundial da Saúde , Adulto Jovem
14.
Mater Sci Eng C Mater Biol Appl ; 106: 110244, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753348

RESUMO

Microspheres with high specific activities of radionuclides are very interesting for internal radiotherapy treatments. This work focuses on the formulation and characterization of inorganic microspheres with a high content of holmium and therefore a high specific radioactivity of holmium-166. Two novel formulations of inorganic microspheres were obtained by dispersing solid holmium acetylacetonate microspheres (Ho2(AcAc)3-ms) in NaH2PO4 or NaOH solutions followed by 2 h incubation at room temperature. By exchange of acetylacetonate with phosphate or hydroxyl ions, holmium phosphate microspheres (HoPO4-ms) and holmium hydroxide microspheres (Ho(OH)3-ms) were formed respectively. The inorganic microspheres had a significantly smaller diameter (28.5 ±â€¯4.4 µm (HoPO4-ms) and 25.1 ±â€¯3.5 µm (Ho(OH)3-ms)) than those of Ho2(AcAc)3-ms (32.6 ±â€¯5.2 µm). The weight percentage of holmium-165 in the microspheres increased significantly from 47% (Ho2(AcAc)3-ms) to 55% (HoPO4-ms) and 73% (Ho(OH)3-ms). After preparation of both HoPO4-ms and Ho(OH)3-ms, the stable holmium-165 isotope was partly converted by neutron activation into radioactive holmium-166 to yield radioactive microspheres. High specific activities were achieved ranging from 21.7 to 59.9 MBq/mg (166HoPO4-ms) and from 28.8 to 79.9 MBq/mg (166Ho(OH)3-ms) depending on the neutron activation time. The structure of both microspheres was preserved up to neutron activations of 6 h in a thermal neutron flux of 4.72 × 1016 n m-2 s-1. After activation, both microspheres revealed excellent stability in administration fluids (saline and phosphate buffer) having less than 0.05% of holmium released after 72 h incubation. Finally, the hemocompatibility of these inorganic microspheres was evaluated and it was shown that the microspheres did cause neither hemolysis nor depletion or inhibition of the coagulation factors of the intrinsic blood coagulation pathway meaning that the microspheres have a good hemocompatibility. Overall, this work shows that radioactive inorganic microspheres with high specific activities of holmium-166 can be prepared which potentially can be used for internal radionuclide therapy.


Assuntos
Antibacterianos/química , Durapatita/química , Hólmio/química , Microesferas , Nitroimidazóis/química , Radioisótopos/química , Linhagem Celular Tumoral , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Humanos , Análise Espectral Raman
15.
J Enzyme Inhib Med Chem ; 35(1): 109-117, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31687859

RESUMO

With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IV/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Nitroimidazóis/farmacologia , Animais , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Larva/efeitos dos fármacos , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Relação Estrutura-Atividade , Peixe-Zebra
16.
Acta Trop ; 201: 105218, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610148

RESUMO

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.


Assuntos
Doença de Chagas/tratamento farmacológico , Nifurtimox/farmacologia , Nifurtimox/uso terapêutico , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos
17.
Clin Nucl Med ; 45(1): e36-e38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31693621

RESUMO

A patient enrolled in a clinical trial (NCT02802969) with suspicion of chordoma underwent an [F]FAZA PET/CT, a radiolabeled nitroimidazole analog of hypoxia PET imaging. The patient's images showed a different tumor profile compared to those observed in other hypoxic or nonhypoxic chordoma patients. The motivation for using [F]FAZA pharmacokinetic imaging was to compare this profile with histologically confirmed cases of chordoma. Through visual imaging and quantification of blood and tumor time-activity curves, we excluded the hypothesis that it was a chordoma, diagnosing a paraganglioma.


Assuntos
Processamento de Imagem Assistida por Computador , Nitroimidazóis/farmacocinética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Sacro/diagnóstico por imagem , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/metabolismo , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino
18.
Food Chem ; 311: 125924, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865112

RESUMO

LC-MS/MS method was developed for the efficient identification and quantification of 21 banned substances including various nitroimidazoles, nitrofurans, pharmacologically-active dyes and chloramphenicol, respectively in aquaculture products. The sample preparation was started by acid-treatment with 2-nitrobenzaldehyde (NBA) to liberate matrix-bound residues of nitrofurans. A modified QuEChERS method was optimized for the extraction and clean-up of the target analytes. The metabolites of the four conventional nitrofurans (nitrofurantoin, furazolidone, nitrofurazone and furaltadone) and of three other nitrofurans (nifursol, nifuroxazide, and nitrovin), and an underivatizable nitrofuran (nifurpirinol) were simultaneously detected. Furthermore, 21 banned substances were quantified by LC-MS/MS with ESI using one single injection. To evaluate and validate the performance of the method, the criteria of the Decision (EC) no 2002/657 were applied. Decision limit (CCα) of target analytes ranged 0.067-1.655 µg/kg in aquaculture products. The recovery ranged 77.2%-125.6%, and the relative standard deviations of inter-day analyses (RSD) were less than 25%.


Assuntos
Antibacterianos/análise , Cloranfenicol/análise , Cromatografia Líquida/métodos , Corantes/análise , Nitroimidazóis/análise , Espectrometria de Massas em Tandem/métodos , Animais , Aquicultura , Resíduos de Drogas/análise , Peixes/crescimento & desenvolvimento , Contaminação de Alimentos/análise , Furazolidona/análise
19.
Int J Mol Sci ; 20(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817793

RESUMO

Electron transfer induced decomposition mechanism of nitroimidazole and a selection of analogue molecules in collisions with neutral potassium (K) atoms from 10 to 1000 eV have been thoroughly investigated. In this laboratory collision regime, the formation of negative ions was time-of-flight mass analyzed and the fragmentation patterns and branching ratios have been obtained. The most abundant anions have been assigned to the parent molecule and the nitrogen oxide anion (NO2-) and the electron transfer mechanisms are comprehensively discussed. This work focuses on the analysis of all fragment anions produced and it is complementary of our recent work on selective hydrogen loss from the transient negative ions produced in these collisions. Ab initio theoretical calculations were performed for 4-nitroimidazole (4NI), 2-nitroimidazole (2NI), 1-methyl-4- (Me4NI) and 1-methyl-5-nitroimidazole (Me5NI), and imidazole (IMI) in the presence of a potassium atom and provided a strong basis for the assignment of the lowest unoccupied molecular orbitals accessed in the collision process.


Assuntos
Nitroimidazóis/química , Potássio/química , Espectrometria de Massas
20.
Drugs Today (Barc) ; 55(11): 705-712, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31840685

RESUMO

On November 15, 2018, Fexinidazole Winthrop received a positive opinion from the European Medicines Agency (EMA) (under Article 58) for treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis caused by Trypanosoma gambiense (gHAT) in adults and children 6 years and older and weighing 20 or more kg. This is the first oral regimen for gHAT that is effective in treating both disease stages. Although fexinidazole has potential to simplify current therapies, it does not entirely eliminate the need for disease staging by lumbar puncture because patients with severe stage 2 disease (CSF WBC [cerebrospinal fluid white blood cells] greater than 100 cells/µL) should only be treated with fexinidazole if no other suitable treatment is available. Nausea and vomiting are a common side effect and the drug must be administered during or after the patient's main meal under direct observation by trained health personnel. Due to late relapses, the EMA recommends follow-up to 24 months after treatment.


Assuntos
Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA