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[PMID]:29458544
[Au] Autor:Aguilar-Ayala DA; Cnockaert M; Vandamme P; Palomino JC; Martin A; Gonzalez-Y-Merchand J
[Ad] Endereço:2​Laboratory of Microbiology, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
[Ti] Título:Antimicrobial activity against Mycobacterium tuberculosis under in vitro lipid-rich dormancy conditions.
[So] Source:J Med Microbiol;67(3):282-285, 2018 Mar.
[Is] ISSN:1473-5644
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although tuberculosis treatment is dependent on drug-susceptibility testing (DST) and molecular drug-resistance detection, treatment failure and relapse remain a challenge. This could be partially due to the emergence of antibiotic-tolerant dormant mycobacteria, where host lipids have been shown to play an important role. This study evaluated the susceptibility of Mycobacterium tuberculosis to two antibiotic combinations - rifampicin, moxifloxacin, amikacin and metronidazole (RIF-MXF-AMK-MTZ), and rifampicin, moxifloxacin, amikacin and pretomanid (RIF-MXF-AMK-PA) - in a lipid-rich dormancy model. Although their effectiveness in in vitro cultures with dextrose as a carbon source has been proved, we observed that none of the antibiotic mixtures were bactericidal in the presence of lipids. The presence of lipids may confer tolerance to M. tuberculosis against the mixture of antibiotics tested and such tolerance could be even higher during the dormant stages. The implementation of lipids in DST on clinical isolates could potentially lead to a better treatment strategy.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Lipídeos/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/fisiologia
[Mh] Termos MeSH secundário: Amicacina/farmacologia
Antituberculosos/farmacologia
Tolerância a Medicamentos
Fluoroquinolonas/farmacologia
Aptidão Genética
Genótipo
Seres Humanos
Metabolismo dos Lipídeos
Testes de Sensibilidade Microbiana
Modelos Biológicos
Infecções por Micobactéria não Tuberculosa/microbiologia
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/crescimento & desenvolvimento
Nitroimidazóis/farmacologia
Rifampina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine); 0 (Anti-Bacterial Agents); 0 (Antitubercular Agents); 0 (Fluoroquinolones); 0 (Lipids); 0 (Nitroimidazoles); 84319SGC3C (Amikacin); U188XYD42P (moxifloxacin); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180221
[St] Status:MEDLINE
[do] DOI:10.1099/jmm.0.000681


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[PMID]:29191556
[Au] Autor:Thompson AM; Marshall AJ; Maes L; Yarlett N; Bacchi CJ; Gaukel E; Wring SA; Launay D; Braillard S; Chatelain E; Mowbray CE; Denny WA
[Ad] Endereço:Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: am.thompson@auckland.ac.nz.
[Ti] Título:Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.
[So] Source:Bioorg Med Chem Lett;28(2):207-213, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
[Mh] Termos MeSH primário: Nitroimidazóis/farmacologia
Bibliotecas de Moléculas Pequenas/farmacologia
Tripanossomíase Africana/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Oral
Animais
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Seres Humanos
Camundongos
Estrutura Molecular
Nitroimidazóis/administração & dosagem
Nitroimidazóis/química
Bibliotecas de Moléculas Pequenas/administração & dosagem
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine); 0 (Nitroimidazoles); 0 (Small Molecule Libraries)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:28453841
[Au] Autor:Requena-Méndez A; Goñi P; Rubio E; Pou D; Fumadó V; Lóbez S; Aldasoro E; Cabezos J; Valls ME; Treviño B; Martínez Montseny AF; Clavel A; Gascon J; Muñoz J
[Ad] Endereço:Barcelona Institute for Global Health, ISGlobal-CRESIB, Universitat de Barcelona, Barcelona , Spain.
[Ti] Título:The Use of Quinacrine in Nitroimidazole-resistant Giardia Duodenalis: An Old Drug for an Emerging Problem.
[So] Source:J Infect Dis;215(6):946-953, 2017 03 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: There is little evidence regarding the management of refractory giardiasis after treatment with nitroimidazoles. This study estimates the proportion of persistent giardiasis in 3 hospitals in Barcelona, describes associated risk factors and genotype, and evaluates the efficacy rate of quinacrine in those with persistent giardiasis. Methods: A clinical, prospective, observational study was conducted in patients with giardiasis treated with nitroimidazoles. Those with persistent giardiasis were provided quinacrine. Molecular characterization of Giardia isolates was performed by polymerase chain reaction amplification of a fragment of tpi and bg genes. Results: Seventy-seven patients were recruited and treated with nitroimidazoles, and in 14 of 71 (20%) of patients followed up, Giardia persisted. Refractory giardiasis was associated with malaise (P = .007) and anorexia (P = .02), with previous giardiasis (P = .03), and with previous antibiotic (P = .02) or antiparasitic(P = .04) use. Quinacrine had an effectiveness rate of 100% in refractory giardiasis (n = 13; 95% confidence interval = 75-100). Molecular characterization showed that 17 (25%) Giardia isolates belonged to assemblage A, and 31 (43%) belonged to assemblage B. In refractory giardiasis, assemblage A and B were found responsible in 4 and 6 cases, respectively. Conclusions: Almost 20% of patients presented persistent giardiasis, belonging to both assemblages A and B, after nitroimidazole. Short course of quinacrine was effective in treating refractory cases. Further controlled studies should evaluate its efficacy and safety.
[Mh] Termos MeSH primário: Giardia lamblia/genética
Giardíase/tratamento farmacológico
Nitroimidazóis/uso terapêutico
Quinacrina/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
DNA de Protozoário/genética
Resistência a Medicamentos
Fezes/parasitologia
Feminino
Genótipo
Giardia lamblia/efeitos dos fármacos
Giardia lamblia/isolamento & purificação
Seres Humanos
Lactente
Recém-Nascido
Modelos Logísticos
Masculino
Análise Multivariada
Nitroimidazóis/efeitos adversos
Filogenia
Estudos Prospectivos
Quinacrina/efeitos adversos
Espanha
Viagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (DNA, Protozoan); 0 (Nitroimidazoles); H0C805XYDE (Quinacrine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix066


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[PMID]:29176887
[Au] Autor:Ramírez JC; Parrado R; Sulleiro E; de la Barra A; Rodríguez M; Villarroel S; Irazu L; Alonso-Vega C; Alves F; Curto MA; García L; Ortiz L; Torrico F; Gascón J; Flevaud L; Molina I; Ribeiro I; Schijman AG
[Ad] Endereço:Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres" (INGEBI-CONICET), Buenos Aires, Argentina.
[Ti] Título:First external quality assurance program for bloodstream Real-Time PCR monitoring of treatment response in clinical trials of Chagas disease.
[So] Source:PLoS One;12(11):e0188550, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Real-Time PCR (qPCR) testing is recommended as both a diagnostic and outcome measurement of etiological treatment in clinical practice and clinical trials of Chagas disease (CD), but no external quality assurance (EQA) program provides performance assessment of the assays in use. We implemented an EQA system to evaluate the performance of molecular biology laboratories involved in qPCR based follow-up in clinical trials of CD. An EQA program was devised for three clinical trials of CD: the E1224 (NCT01489228), a pro-drug of ravuconazole; the Sampling Study (NCT01678599), that used benznidazole, both conducted in Bolivia; and the CHAGASAZOL (NCT01162967), that tested posaconazole, conducted in Spain. Four proficiency testing panels containing negative controls and seronegative blood samples spiked with 1, 10 and 100 parasite equivalents (par. eq.)/mL of four Trypanosoma cruzi stocks, were sent from the Core Lab in Argentina to the participating laboratories located in Bolivia and Spain. Panels were analyzed simultaneously, blinded to sample allocation, at 4-month intervals. In addition, 302 random blood samples from both trials carried out in Bolivia were sent to Core Lab for retesting analysis. The analysis of proficiency testing panels gave 100% of accordance (within laboratory agreement) and concordance (between laboratory agreement) for all T. cruzi stocks at 100 par. eq./mL; whereas their values ranged from 71 to 100% and from 62 to 100% at 1 and 10 par. eq./mL, respectively, depending on the T. cruzi stock. The results obtained after twelve months of preparation confirmed the stability of blood samples in guanidine-EDTA buffer. No significant differences were found between qPCR results from Bolivian laboratory and Core Lab for retested clinical samples. This EQA program for qPCR analysis of CD patient samples may significantly contribute to ensuring the quality of laboratory data generated in clinical trials and molecular diagnostics laboratories of CD.
[Mh] Termos MeSH primário: Doença de Chagas/tratamento farmacológico
Nitroimidazóis/uso terapêutico
Reação em Cadeia da Polimerase em Tempo Real/métodos
Triazóis/uso terapêutico
Tripanossomicidas/uso terapêutico
[Mh] Termos MeSH secundário: Doença de Chagas/sangue
Seres Humanos
Monitorização Fisiológica/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitroimidazoles); 0 (Triazoles); 0 (Trypanocidal Agents); 6TK1G07BHZ (posaconazole); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188550


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[PMID]:29305891
[Au] Autor:Zanusso Junior G; Massago M; Kian D; Toledo MJO
[Ad] Endereço:Department of Basic Health Sciences at State University of Maringa, Maringa, Paraná, Brazil.
[Ti] Título:Efficacy of essential oil of Syzygium aromaticum alone and in combination with benznidazole on murine oral infection with Trypanosoma cruzi IV.
[So] Source:Exp Parasitol;185:92-97, 2018 Feb.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chagas disease (CD), caused by Trypanosoma cruzi, remains a serious public health problem. One of the causes of the high morbidity and mortality in patients is the lack of an effective drug therapy. Thus, the aim of this study was to evaluate the efficacy of the essential oil of Syzygium aromaticum alone and in combination with benznidazole (BZ) in mice orally inoculated with strain of T. cruzi IV obtained from oral CD outbreak occurred in Western Brazilian Amazonia. All the animals inoculated with metacyclic trypomastigote forms (AM14 strain, BZ resistant), derived from the insect Rhodnius robustus, became infected and there was no difference in the mortality rate between the experimental groups. When compared with untreated control animals (UTC), the treatment with essential oil of S. aromaticum (EOSA) alone promoted reduction in 1/5 parameters derived from the parasitemia curve, whereas the treatments with BZ alone or in combination (BZ + EOSA) promoted reduction in 4/5 of those parameters, presenting similar profiles of parasitemia curve. The animals treated with BZ and with the combination BZ + EOSA presented lower patency periods in comparison with the animals in EOSA group, and lower positivity of blood cultures when compared with the UTC group. The results of molecular analysis by qPCR in both blood and cardiac tissue did not show differences between the groups. The cure rates obtained with the different treatments presented the following ascending order: EOSA = 12.5% (1/8), BZ = 25.0% (2/8) and BZ + EOSA = 37.5% (3/8). Although there are no significant differences between them, these results claims that the use of this essential oil could be of interest for treatment of Chagas disease.
[Mh] Termos MeSH primário: Doença de Chagas/tratamento farmacológico
Nitroimidazóis/uso terapêutico
Óleos Voláteis/uso terapêutico
Syzygium/química
Tripanossomicidas/uso terapêutico
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Doença de Chagas/parasitologia
Ciclofosfamida
Quimioterapia Combinada
Seres Humanos
Imunossupressão
Imunossupressores
Insetos Vetores/parasitologia
Masculino
Camundongos
Nitroimidazóis/farmacologia
Óleos Voláteis/farmacologia
Parasitemia/tratamento farmacológico
Parasitemia/parasitologia
Óleos Vegetais/farmacologia
Óleos Vegetais/uso terapêutico
Rhodnius/parasitologia
Tripanossomicidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); 0 (Nitroimidazoles); 0 (Oils, Volatile); 0 (Plant Oils); 0 (Trypanocidal Agents); 8N3DW7272P (Cyclophosphamide); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180107
[St] Status:MEDLINE


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[PMID]:29267280
[Au] Autor:Rial MS; Scalise ML; Arrúa EC; Esteva MI; Salomon CJ; Fichera LE
[Ad] Endereço:Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben", ANLIS "Dr. Carlos G. Malbrán", Ministerio de Salud, Buenos Aires, Argentina.
[Ti] Título:Elucidating the impact of low doses of nano-formulated benznidazole in acute experimental Chagas disease.
[So] Source:PLoS Negl Trop Dis;11(12):e0006119, 2017 12.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chagas disease is a neglected parasitic infection caused by the protozoan Trypanosoma cruzi (T. cruzi) that affects more than 6 million people, mainly in Latin America. Benznidazole is still the drug of choice in many countries to treat it in spite of its dosage regimen and adverse side effects such as such as allergic dermatitis, peripheral neuropathy and anorexia. Thus, novel, safer, and more efficacious treatments for such neglected infection are urgently required. METHODOLOGY: In this study, the efficacy of orally administered low doses of benznidazole (BNZ) nanoparticles was evaluated during the acute phase in mice infected with T. cruzi Nicaragua (TcN) that were immunosuppressed during the chronic stage of the disease. Moreover, the production of T. cruzi-specific antibodies, cardiac tissue inflammation and reactive oxygen species generation by Vero cells treated with both BNZ nanoparticles (BNZ-nps) and raw BNZ (R-BNZ) were also evaluated. PRINCIPAL FINDINGS: T. cruzi infected mice treated with 10, 25 or 50 mg/kg/day of BNZ-nps survived until euthanasia (92 days post infection (dpi)), while only 15% of infected untreated mice survived until the end of the experiment. PCR analysis of blood samples taken after induction of immunosuppression showed that a dosage of 25 mg/kg/day rendered 40% of the mice PCR-negative. The histological analysis of heart tissue showed a significant decrease in inflammation after treatments with 25 and 50 mg/kg/day, while a similar inflammatory damage was observed in both infected mice treated with R-BNZ (50 mg/kg/day) and untreated mice. In addition, only BNZ-nps treated mice led to lower levels of T. cruzi-specific antibodies to 50-100%. Finally, mammalian Vero cells treated with BNZ-nps or R-BNZ lead to a significant increase in ROS production. CONCLUSIONS: Based on these findings, this research highlights the in-vitro/in-vivo efficacy of nanoformulated BNZ against T. cruzi acute infections in immunosuppressed and non-immunosuppressed mice and provides further evidence for the optimization of dosage regimens to treat Chagas disease.
[Mh] Termos MeSH primário: Doença de Chagas/tratamento farmacológico
Nanopartículas/uso terapêutico
Nitroimidazóis/uso terapêutico
Tripanossomicidas/uso terapêutico
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Anticorpos Antiprotozoários/sangue
Anticorpos Antiprotozoários/imunologia
Linhagem Celular
Cercopithecus aethiops
Doença de Chagas/parasitologia
DNA de Protozoário/sangue
DNA de Protozoário/genética
Modelos Animais de Doenças
Portadores de Fármacos/uso terapêutico
Feminino
Coração/parasitologia
Inflamação/parasitologia
Camundongos
Camundongos Endogâmicos C3H
Espécies Reativas de Oxigênio/metabolismo
Trypanosoma cruzi/imunologia
Células Vero
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Protozoan); 0 (DNA, Protozoan); 0 (Drug Carriers); 0 (Nitroimidazoles); 0 (Reactive Oxygen Species); 0 (Trypanocidal Agents); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0006119


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[PMID]:28456516
[Au] Autor:Yao YF; Wang ZC; Wu SY; Li QF; Yu C; Liang XY; Lv PC; Duan YT; Zhu HL
[Ad] Endereço:State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
[Ti] Título:Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of combretastatin A-4 as potential tubulin polymerization inhibitors.
[So] Source:Biochem Pharmacol;137:10-28, 2017 08 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC values ranging from 15 to 40nM), especially HeLa cells (with IC values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/farmacologia
Nitroimidazóis/farmacologia
Estilbenos/farmacologia
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Células A549
Animais
Antineoplásicos Fitogênicos/química
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/fisiologia
Relação Dose-Resposta a Droga
Feminino
Células HEK293
Células HT29
Células HeLa
Células Hep G2
Seres Humanos
Células MCF-7
Camundongos
Camundongos Nus
Nitroimidazóis/química
Estrutura Secundária de Proteína
Distribuição Aleatória
Estilbenos/química
Moduladores de Tubulina/química
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Nitroimidazoles); 0 (Stilbenes); 0 (Tubulin Modulators); I5590ES2QZ (fosbretabulin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:28462832
[Au] Autor:Thompson AM; Blaser A; Palmer BD; Anderson RF; Shinde SS; Launay D; Chatelain E; Maes L; Franzblau SG; Wan B; Wang Y; Ma Z; Denny WA
[Ad] Endereço:Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: am.thompson@auckland.ac.nz.
[Ti] Título:6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases.
[So] Source:Bioorg Med Chem Lett;27(11):2583-2589, 2017 06 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid" (49) is regarded as the best lead.
[Mh] Termos MeSH primário: Antituberculosos/síntese química
Nitroimidazóis/química
Tiazóis/química
[Mh] Termos MeSH secundário: Animais
Antituberculosos/farmacologia
Antituberculosos/uso terapêutico
Doença de Chagas/tratamento farmacológico
Modelos Animais de Doenças
Camundongos
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/efeitos dos fármacos
Nitroimidazóis/farmacologia
Nitroimidazóis/uso terapêutico
Oxazóis/química
Oxazóis/farmacologia
Oxazóis/uso terapêutico
Relação Estrutura-Atividade
Tiazóis/farmacologia
Tiazóis/uso terapêutico
Tuberculose/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine); 0 (Antitubercular Agents); 0 (Nitroimidazoles); 0 (OPC-67683); 0 (Oxazoles); 0 (Thiazoles)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28949997
[Au] Autor:Olivera MJ; Cucunubá ZM; Valencia-Hernández CA; Herazo R; Agreda-Rudenko D; Flórez C; Duque S; Nicholls RS
[Ad] Endereço:Red Chagas Colombia, Bogotá DC, Colombia.
[Ti] Título:Risk factors for treatment interruption and severe adverse effects to benznidazole in adult patients with Chagas disease.
[So] Source:PLoS One;12(9):e0185033, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Etiological treatment of Chagas disease in chronic asymptomatic patients is still in debate and the adverse effects of traditional drugs are one of the main concerns in clinical practice. This study evaluated retrospectively the safety profile of benznidazole (BZN) and identified predictive factors for definite treatment interruption and development of severe reactions in adult patients treated with BZN in Colombia. METHODS: Retrospective follow-up study conducted by review of medical records of adults with chronic Chagas disease treated with BZN in Colombia. A parametric survival analysis based on a generalized gamma distribution was used for assessing risk factors for treatment interruption. A multinomial logistic regression model was used to estimate the probability of severe adverse drug reactions (ADRs). Statistical associations were expressed as time ratios (TR) and adjusted odds ratios (aOR) respectively. RESULTS: In total 224 adults patients treated with BZN were included; 172 (76.8%) completed the standard therapy (60 days of treatment), 205 (91.5%) presented ADRs and 52 cases (23.2%) required treatment interruption. The predominant symptoms were: rash (37.9%), itching (33.7%), epigastric pain (26.4%), abdominal bloating (24.2%) and nausea (22.1%). ADRs were mild (57.4%), moderate (35.5%) and severe (7.3%). Time to treatment interruption was significantly shorter when using doses of BZN ≥ 6 mg/kg/day (TR 0.55; 95% CI 0.39-0.76), presenting severe ADRs (TR 0.12; 95% CI: 0.07-0.19) and eosinophilia (TR 0.68; 95% CI: 0.49-0.94). Female sex (aOR 3.98; 95% CI 1.56-10.16), dose of BZN ≥ 6 mg/kg/day (aOR 1.41; 95% CI 1.17-1.70) and presence of > 3 ADRs (aOR 6.47; 95% CI 1.24-34.34) were considered as risk factors for developing severe ADRs. CONCLUSIONS: Dose, severity of ADRs, eosinophilia and female sex were the main predictors for treatment interruption or severe ADRs. The potential implications of these findings are discussed.
[Mh] Termos MeSH primário: Doença de Chagas/tratamento farmacológico
Nitroimidazóis/uso terapêutico
Tripanossomicidas/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Feminino
Seres Humanos
Masculino
Meia-Idade
Fatores de Risco
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitroimidazoles); 0 (Trypanocidal Agents); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185033


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[PMID]:28910299
[Au] Autor:Alpern JD; Lopez-Velez R; Stauffer WM
[Ad] Endereço:Division of Infectious Disease & International Medicine, Department of Internal Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
[Ti] Título:Access to benznidazole for Chagas disease in the United States-Cautious optimism?
[So] Source:PLoS Negl Trop Dis;11(9):e0005794, 2017 Sep.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Doença de Chagas/tratamento farmacológico
Nitroimidazóis/economia
Nitroimidazóis/provisão & distribuição
Tripanossomicidas/economia
Tripanossomicidas/provisão & distribuição
[Mh] Termos MeSH secundário: Centers for Disease Control and Prevention (U.S.)
Doença de Chagas/epidemiologia
Custos de Medicamentos
Drogas em Investigação/economia
Seres Humanos
Nifurtimox/uso terapêutico
Nitroimidazóis/uso terapêutico
Tripanossomicidas/uso terapêutico
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drugs, Investigational); 0 (Nitroimidazoles); 0 (Trypanocidal Agents); M84I3K7C2O (Nifurtimox); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170924
[Lr] Data última revisão:
170924
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005794



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