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1.
Insect Sci ; 27(2): 276-291, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30136378

RESUMO

Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are widely distributed within living organisms and share roles in biotransformation of various lipophilic endo- and xenobiotics with activated UDP sugars. In this study, it was found that the activity of UGTs in abamectin-resistant (AbR) strain was significantly higher (2.35-fold) than that in susceptible strain (SS) of Tetranychus cinnabarinus. Further analysis showed that 5-nitrouracil, the inhibitor of UGTs, could enhance the lethal effect of abamectin on mites. From the previous microarray results, we found an UGT gene (UGT201D3) overexpressed in AbR strain. Quantitative PCR analysis showed that UGT201D3 was highly expressed and more inducible with abamectin exposure in the AbR strain. After silencing the transcription of UGT201D3, the activity of UGTs was decreased and the susceptibility to abamectin was increased in AbR strain whereas it was not in SS. Furthermore, UGT201D3 gene was then successfully expressed in Escherichia coli. The recombinant UGT201D3 exhibited α-naphthol activity (2.81 ± 0.43 nmol/mg protein/min), and the enzyme activity could be inhibited by abamectin (inhibitory concentration at 50%: 57.50 ± 3.54 µmol/L). High-performance liquid chromatography analysis demonstrated that the recombinant UGT201D3 could effectively deplete abamectin (15.77% ± 3.72%) incubating with 150 µg protein for 6 h. These results provided direct evidence that UGT201D3 was involved in abamectin resistance in T. cinnabarinus.


Assuntos
Glucuronosiltransferase/metabolismo , Inseticidas , Ivermectina/análogos & derivados , Tetranychidae/metabolismo , Sequência de Aminoácidos , Animais , Escherichia coli , Feminino , Glucuronosiltransferase/genética , Resistência a Inseticidas , Interferência de RNA , Tetranychidae/genética , Uracila/análogos & derivados
2.
Chemosphere ; 238: 124625, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31466008

RESUMO

The cyanotoxin cylindrospermopsin was discovered during a drinking water-related outbreak of human poisoning in 1979. Knowledge about the degradation of cylindrospermopsin in waterbodies is limited. So far, only few cylindrospermopsin-removing bacteria have been described. Manganese-oxidizing bacteria remove a variety of organic compounds. However, this has not been assessed for cyanotoxins yet. We investigated cylindrospermopsin removal by manganese-oxidizing bacteria, isolated from natural and technical systems. Cylindrospermopsin removal was evaluated under different conditions. We analysed the correlation between the amount of oxidized manganese and the cylindrospermopsin removal, as well as the removal of cylindrospermopsin by sterile biogenic oxides. Removal rates in the range of 0.4-37.0 µg L-1 day-1 were observed. When MnCO3 was in the media Pseudomonas sp. OF001 removed ∼100% of cylindrospermopsin in 3 days, Comamonadaceae bacterium A210 removed ∼100% within 14 days, and Ideonella sp. A288 and A226 removed 65% and 80% within 28 days, respectively. In the absence of Mn2+, strain A288 did not remove cylindrospermopsin, while the other strains removed 5-16%. The amount of manganese oxidized by the strains during the experiment did not correlate with the amount of cylindrospermopsin removed. However, the mere oxidation of Mn2+ was indispensable for cylindrospermopsin removal. Cylindrospermopsin removal ranging from 0 to 24% by sterile biogenic oxides was observed. Considering the efficient removal of cylindrospermopsin by the tested strains, manganese-oxidizing bacteria might play an important role in cylindrospermopsin removal in the environment. Besides, manganese-oxidizing bacteria could be promising candidates for biotechnological applications for cylindrospermopsin removal in water treatment plants.


Assuntos
Toxinas Bacterianas/análise , Burkholderiales/metabolismo , Comamonadaceae/metabolismo , Manganês/metabolismo , Pseudomonas/metabolismo , Uracila/análogos & derivados , Purificação da Água/métodos , Água Potável/metabolismo , Compostos de Manganês/metabolismo , Oxirredução , Óxidos/metabolismo , Uracila/análise
3.
Eur J Med Chem ; 185: 111787, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675511

RESUMO

New uncharged conjugates of 6-methyluracil derivatives with imidazole-2-aldoxime and 1,2,4-triazole-3-hydroxamic acid units were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. Using paraoxon (POX) as a model organophosphate, it was shown that 6-methyluracil derivatives linked with hydroxamic acid are able to reactivate POX-inhibited human acetylcholinesterase (AChE) in vitro. The reactivating efficacy of one compound (5b) is lower than that of pyridinium-2-aldoxime (2-PAM). Meanwhile, unlike 2-PAM, in vivo study showed that the lead compound 5b is able: (1) to reactivate POX-inhibited AChE in the brain; (2) to decrease death of neurons and, (3) to prevent memory impairment in rat model of POX-induced neurodegeneration.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ácidos Hidroxâmicos/farmacologia , Paraoxon/antagonistas & inibidores , Uracila/análogos & derivados , Animais , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Humanos , Ácidos Hidroxâmicos/química , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Paraoxon/farmacologia , Paraoxon/toxicidade , Teoria Quântica , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/química , Uracila/farmacologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-31704620

RESUMO

A novel, high throughput and sensitive LC-MS/MS assay method was developed and fully validated for quantitative determination of pioglitazone, its hydroxyl metabolite and alogliptin in human plasma. A simple and rapid sample preparation procedure based on protein precipitation technique with acetonitrile was utilized. Chromatographic separation was achieved on C8 (50 × 4.6 mm, 5 µm) Kinetex® analytical column using methanol and 0.1% formic acid in a gradient elution mode at a flow rate of 0.7 mL/min with injection volume of 8 µL. Detection was performed on a triple quadrupole mass spectrometer accompanied with electrospray ionization (ESI) technique in positive mode, operating in multiple reaction monitoring, with the transitions of 357.2 → 119.1, 373.1 → 150.1, 340.3 → 116.1, 361.1 → 138.1 and 343.2 → 116.1 m/z for pioglitazone, its hydroxyl metabolite, alogliptin, pioglitazone-d4 (IS-1) and alogliptin-d3 (IS-2), in order. Analysis was achieved within 4 min over a linear concentration range of 10-3000 ng/mL, 5-2000 ng/mL and 3-300 ng/mL, for pioglitazone, hydroxyl pioglitazone and alogliptin, in order. The method was fully validated according to FDA guidelines. The developed method was used for estimation of the three studied analytes in human plasma and pharmacokinetic parameters were demonstrated after oral dose administration of Oseni® tablets to Egyptian healthy volunteers.


Assuntos
Cromatografia Líquida/métodos , Pioglitazona/sangue , Piperidinas/sangue , Espectrometria de Massas em Tandem/métodos , Uracila/análogos & derivados , Humanos , Modelos Lineares , Pioglitazona/química , Pioglitazona/metabolismo , Pioglitazona/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Uracila/sangue , Uracila/química , Uracila/farmacocinética
5.
Lancet ; 394(10213): 2012-2024, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727409

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-ß agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. METHODS: MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. FINDINGS: 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. INTERPRETATION: Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. FUNDING: Madrigal Pharmaceuticals.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piridazinas/uso terapêutico , Receptores beta dos Hormônios Tireóideos/agonistas , Uracila/análogos & derivados , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Inflamação/patologia , Lipídeos/sangue , Fígado/diagnóstico por imagem , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Piridazinas/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
7.
New Microbiol ; 42(4): 189-196, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31609453

RESUMO

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.


Assuntos
Antivirais , Hepatite C , Antivirais/administração & dosagem , Antivirais/normas , Biomarcadores Farmacológicos/análise , Quimioterapia Combinada , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Compostos Macrocíclicos/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/análogos & derivados
8.
Org Biomol Chem ; 17(40): 8992-9000, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31497838

RESUMO

Mucosal-associated invariant T (MAIT) cells are a subset of recently identified innate-like T lymphocytes that appear to play an important role in many pathologies ranging from viral and bacterial infection, to autoimmune disorders and cancer. MAIT cells are activated via the presentation of ligands by MR1 on antigen presenting cells to the MAIT T cell receptor (TCR), however few studies have explored the effects of systematic changes to the ligand structure on MR1 binding and MAIT cell activation. Herein, we report on the first study into the effects of changes to the sugar motif in the known MAIT cell agonists 7-hydroxy-6-methyl-8-d-ribityllumazine (RL-6-Me-7-OH) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Tetramer staining of MAIT cells revealed that the absence of the 2'-hydroxy group on the sugar backbone of lumazines improved MR1-MAIT TCR binding, which could be rationalised using computational docking studies. Although none of the lumazines activated MAIT cells, all 5-OP-RU analogues showed significant MAIT cell activation, with several analogues exhibiting comparable activity to 5-OP-RU. Docking studies with the 5-OP-RU analogues revealed different interactions between the sugar backbone and MR1 and the MAIT TCR compared to those observed for the lumazines and confirmed the importance of the 2'-hydroxy group for ligand binding and activity. Taken together, this information will assist in the development of future potent agonists and antagonists of MAIT cells.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/efeitos dos fármacos , Pteridinas/farmacologia , Ribitol/análogos & derivados , Uracila/análogos & derivados , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Células T Invariáveis Associadas à Mucosa/metabolismo , Pteridinas/síntese química , Pteridinas/química , Receptores de Antígenos de Linfócitos T , Ribitol/síntese química , Ribitol/química , Ribitol/farmacologia , Uracila/síntese química , Uracila/química , Uracila/farmacologia
9.
Nat Commun ; 10(1): 3593, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399564

RESUMO

Filopodia, dynamic membrane protrusions driven by polymerization of an actin filament core, can adhere to the extracellular matrix and experience both external and cell-generated pulling forces. The role of such forces in filopodia adhesion is however insufficiently understood. Here, we study filopodia induced by overexpression of myosin X, typical for cancer cells. The lifetime of such filopodia positively correlates with the presence of myosin IIA filaments at the filopodia bases. Application of pulling forces to the filopodia tips through attached fibronectin-coated laser-trapped beads results in sustained growth of the filopodia. Pharmacological inhibition or knockdown of myosin IIA abolishes the filopodia adhesion to the beads. Formin inhibitor SMIFH2, which causes detachment of actin filaments from formin molecules, produces similar effect. Thus, centripetal force generated by myosin IIA filaments at the base of filopodium and transmitted to the tip through actin core in a formin-dependent fashion is required for filopodia adhesion.


Assuntos
/metabolismo , Miosinas/metabolismo , Neoplasias/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Pseudópodes/fisiologia , Citoesqueleto de Actina , Animais , Células COS , /genética , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Proteínas dos Microfilamentos , Miosina não Muscular Tipo IIA/antagonistas & inibidores , Miosina não Muscular Tipo IIA/genética , Miosina não Muscular Tipo IIA/ultraestrutura , Pseudópodes/patologia , Tionas/farmacologia , Uracila/análogos & derivados , Uracila/farmacologia
10.
Nat Immunol ; 20(9): 1244-1255, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31431722

RESUMO

Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified 5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated into CD44- naive T cells. MAIT cell positive selection required signaling through the adapter, SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes selected on either thymic epithelial cells or hematopoietic cells. The resulting model illustrates T cell lineage decisions.


Assuntos
Linhagem da Célula/imunologia , Células T Invariáveis Associadas à Mucosa/citologia , Células T Invariáveis Associadas à Mucosa/imunologia , Ribitol/análogos & derivados , Timócitos/citologia , Timócitos/imunologia , Uracila/análogos & derivados , Animais , Sequência de Bases , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores de Hialuronatos/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Ribitol/imunologia , Análise de Sequência de RNA , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Timo/citologia , Timo/imunologia , Uracila/imunologia
11.
Recenti Prog Med ; 110(7): 325-329, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379366

RESUMO

TAS-102 represents an important therapeutic resource for patients with metastatic refractory colorectal cancer. Albeit generally well tolerated, clinically relevant neutropenia may interfere with the regular delivery of full-dose cycles with a possible detrimental effect on the dose-intensity. Judicious and personalized use of colony-stimulating growth factors as well as alterative schedules of drug delivery could mitigate neutropenia, so contributing to an even better therapeutic index of the drug.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Pirrolidinas/efeitos adversos , Trifluridina/efeitos adversos , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Neutropenia/prevenção & controle , Pirrolidinas/administração & dosagem , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/efeitos adversos
12.
Anticancer Res ; 39(8): 4343-4350, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366528

RESUMO

BACKGROUND/AIM: TAS-102 is recommended as salvage-line therapy for metastatic colorectal cancer (mCRC), but practical predictors for its efficacy are lacking. PATIENTS AND METHODS: In a single-institutional retrospective study of 33 patients treated with TAS-102, we investigated the predictive value of the pretreatment neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-monocyte (LMR) ratios for progression-free (PFS) and overall (OS) survival. Predictive ability using cut-offs of the median value (3.14) and 5 for NLR were compared. RESULTS: In univariate analysis, Eastern Cooperative Oncology Group performance score, NLR, and PLR were negatively significantly associated with PFS and OS. The number of treatment lines was negatively associated with PFS. The NLR cut-off of 5 was superior to the median value. Multivariate analyses showed a significant prognostic impact for NLR at cut-off 5 (hazard ratio(HR)=6.26, p=0.02 for PFS; HR=6.97, p=0.07 for OS). CONCLUSION: The pretreatment NLR is a prognostic biomarker for patients with mCRC who receive TAS-102 treatment.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Prognóstico , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutrófilos/patologia , Contagem de Plaquetas , Intervalo Livre de Progressão , Pirrolidinas , Estudos Retrospectivos , Uracila/análogos & derivados
13.
N Engl J Med ; 381(9): 803-815, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31339677

RESUMO

BACKGROUND: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. METHODS: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTS: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONS: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.).


Assuntos
Adenina/análogos & derivados , Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Fosforosos/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adolescente , Adulto , Antirretrovirais/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Inibidores de Integrase de HIV/administração & dosagem , HIV-1/genética , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Ácidos Fosforosos/efeitos adversos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pró-Fármacos/administração & dosagem , RNA Viral/sangue , Uracila/administração & dosagem , Uracila/análogos & derivados , Carga Viral , Adulto Jovem
14.
Expert Opin Pharmacother ; 20(14): 1679-1687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335214

RESUMO

Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.


Assuntos
Benzoatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Meia-Vida , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêutico
15.
EMBO J ; 38(16): e102003, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31313851

RESUMO

Many eukaryotic proteins are regulated by modification with the ubiquitin-like protein small ubiquitin-like modifier (SUMO). This linkage is reversed by SUMO proteases, of which there are two in Saccharomyces cerevisiae, Ulp1 and Ulp2. SUMO-protein conjugation regulates transcription, but the roles of SUMO proteases in transcription remain unclear. We report that Ulp2 is recruited to transcriptionally active genes to control local polysumoylation. Mutant ulp2 cells show impaired association of RNA polymerase II (RNAPII) with, and diminished expression of, constitutively active genes and the inducible CUP1 gene. Ulp2 loss sensitizes cells to 6-azauracil, a hallmark of transcriptional elongation defects. We also describe a novel chromatin regulatory mechanism whereby histone-H2B ubiquitylation stimulates histone sumoylation, which in turn appears to inhibit nucleosome association of the Ctk1 kinase. Ctk1 phosphorylates serine-2 (S2) in the RNAPII C-terminal domain (CTD) and promotes transcript elongation. Removal of both ubiquitin and SUMO from histones is needed to overcome the impediment to S2 phosphorylation. These results suggest sequential ubiquitin-histone and SUMO-histone modifications recruit Ulp2, which removes polySUMO chains and promotes RNAPII transcription elongation.


Assuntos
Endopeptidases/metabolismo , Histonas/metabolismo , Mutação , Proteínas de Saccharomyces cerevisiae/metabolismo , Elongação da Transcrição Genética , Endopeptidases/genética , Regulação Fúngica da Expressão Gênica , Metalotioneína/genética , RNA Polimerase II/metabolismo , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética , Sumoilação , Elongação da Transcrição Genética/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Uracila/análogos & derivados , Uracila/farmacologia
16.
Water Res ; 163: 114853, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310856

RESUMO

The occurrence of harmful cyanobacterial blooms has unabated increased over the last few decades, posing a significant risk for public health. In this work, we investigate the feasibility of catalytic wet peroxide oxidation (CWPO) promoted by modified natural magnetite (Fe3O4-R400/H2O2), as an inexpensive, simple-operation and environmentally-friendly process for the removal of the cyanotoxins that show the major impact on drinking water: microcystins (MC-LR and MC-RR), cylindrospermopsin (CYN), anatoxin-a (ATX) and saxitoxin (STX). The performance of the system was evaluated under ambient conditions and circumneutral pH (pH0 = 5) using relevant cyanotoxin concentrations (100-500 µg L-1). The nature of the cyanotoxins determined their reactivity towards CWPO, which decreased in the following order: MC-RR > CYN > MC-LR ≫ ATX > STX. In this sense, microcystins and CYN were completely removed in short reaction times (1-1.5 h) with a low catalyst concentration (0.2 g L-1) and the stoichiometric amount of H2O2 (2-2.6 mg L-1), while only 60-80% conversion was achieved with ATX and STX in 5 h. In these cases, an intensification of the operating conditions (1 g L-1 catalyst and up to 30 mg H2O2 L-1) was required to remove both toxins in 1 h. The impact of the main components of freshwaters i.e. natural organic matter (NOM) and several inorganic ions (HCO3-, HPO42-, SO42-) on the performance of the process was also investigated. Although the former led to a partial inhibition of the reaction due to HO· scavenging and catalyst coating, the latter did not show any remarkably effect, and the versatility of the process was finally confirmed in a real surface water. To further demonstrate the effectiveness of the catalytic system, the toxicity of both the initial cyanotoxins and the resulting CWPO effluents was measured with the brine shrimp Artemia salina. Remarkably, all CWPO effluents were non-toxic at the end of the treatment.


Assuntos
Água Potável , Microcistinas , Toxinas Bacterianas , Peróxido de Hidrogênio , Peróxidos , Saxitoxina , Tropanos , Uracila/análogos & derivados
17.
Food Chem Toxicol ; 132: 110664, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279043

RESUMO

Cylindrospermopsin (CYN) is a potent cyanotoxin recognized as an emerging human threat due to its cytotoxicity and potential carcinogenicity. Although the genotoxicity of CYN has been extensively studied in vitro, limited data are available on its in vivo genotoxicity. The aim of this study was to evaluate the in vivo genotoxicity of pure CYN (7.5-75 µg/kg body weight) after oral exposure of rats through a combined assay of the micronucleus test (MN) in bone marrow, and the standard and modified comet assay in stomach, liver and blood. Also, histopathological changes in stomach and liver were evaluated. Positive results in the MN test were observed in bone marrow in the exposed rats at all the tested concentrations. However, the comet assay revealed that CYN did not induce DNA strand breaks nor oxidative DNA damage in any of the tissues investigated. Finally, histopathological changes were observed in stomach and liver (7.5-75 µg/kg) in intoxicated rats. These results could indicate that CYN is able to induce irritation in stomach before its biotransformation in rats orally exposed, and genotoxicity in bone marrow.


Assuntos
Toxinas Bacterianas/toxicidade , Ensaio Cometa , Testes para Micronúcleos , Mutagênicos/toxicidade , Uracila/análogos & derivados , Animais , Medula Óssea/efeitos dos fármacos , Dano ao DNA , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Uracila/toxicidade
18.
Se Pu ; 37(7): 723-728, 2019 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-31271011

RESUMO

A method was developed for the determination of cylindrospermopsin (CYN), nodularin (NOD), microcystin-RR (MC-RR), microcystin-YR (MC-YR) and microcystin-LR (MC-LR) in freshwater fish by dispersive solid phase extraction-liquid chromatography-tandem mass spectrometry (DSPE-LC-MS/MS). The analytes were extracted from fish tissues with acetonitrile-water-formic acid (89:10:1, v/v/v), and purified by DSPE using C18 as the adsorbent. The separation of analytes was performed on an Agilent ZORBAX Eclipse XDB C18 column with the gradient elution of acetonitrile and water as mobile phases. Qualitative analysis was performed using the multiple reaction monitoring (MRM) mode. The analytes were quantified by matrix-matched external standard curves. The chromatographic and MS parameters were optimized. Major factors affecting the extraction and cleanup efficiencies including the type of extraction solvent and cleanup sorbent were investigated. The linear correlation coefficients (R2) of the five target compounds were no less than 0.9954. The limits of detection (LODs, S/N=3) and limits of quantification (LOQs, S/N=10) of the five target compounds were 5-10 µg/kg and 15-40 µg/kg, respectively. The spiked recoveries of the five target compounds ranged from 62.3% to 101.2%. The developed method is simple, rapid, accurate, sensitive, and is suitable for the determination of cylindrospermopsin, nodularin and microcystins in freshwater fish.


Assuntos
Toxinas Bacterianas/análise , Peixes , Contaminação de Alimentos/análise , Microcistinas/análise , Peptídeos Cíclicos/análise , Uracila/análogos & derivados , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Água Doce , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Uracila/análise
19.
Anticancer Res ; 39(7): 3967-3969, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262929

RESUMO

BACKGROUND/AIM: The aim of this report was to evaluate the onset of grade≥3 neutropenia during the first-cycle in patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil and its relationship with clinical parameters of interest, such as overall survival (OS). PATIENTS AND METHODS: We performed a retrospective analysis of all consecutive patients with mCRC, treated with trifluridine/tipiracil in third or later treatment lines in mCRC, at our Medical Oncology Unit between July 2017 and December 2018. We evaluated 15 patients. RESULTS: Median age was 63 years (range: 46-80 years). Trifluridine/tipiracil was used in third-line treatment in 10 patients (66.7%). The only serious adverse events were grade 3 (26.7%) and grade 4 (13.3%) neutropenia. Median follow-up time (FUT) was 53 months (range=17-91 months). At the last FUT, 5 patients (33.3%) were deceased. Median OS was 5 months (range=1-15 months). At the univariate analysis, the onset of grade ≥3 neutropenia at the first cycle showed a statistically positive impact on OS (p=0.046). CONCLUSION: The onset of grade ≥3 neutropenia at the first-cycle is associated with longer median OS compared to no onset of neutropenia also in real-life.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Trifluridina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Análise de Sobrevida , Uracila/análogos & derivados
20.
Am J Health Syst Pharm ; 76(6): 339-348, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361848

RESUMO

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, and place in therapy of trifluridine-tipiracil are reviewed. SUMMARY: Trifluridine-tipiracil is an oral antineoplastic agent consisting of trifluridine (a trifluorothymidine, a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor), at a molar ratio of 1:0.5. Tipiracil blocks the degradation of trifluridine by thymidine phosphorylase, which improves the bioavailability of trifluridine and allows for oral administration. A Phase III study comparing trifluridine-tipiracil versus placebo in metastatic colorectal cancer (mCRC) patients refractory to or intolerant of standard therapy (n = 800) showed a benefit in overall survival (the primary endpoint) and progression-free survival compared with placebo. The most common grade ≥ 3 adverse events in trifluridine-tipiracil groups in Phase II and III trials were neutropenia, anemia, and leukopenia. The recommended dose of trifluridine-tipiracil is 35 mg/m2 twice a day after meals in a 28-day cycle comprising 2 weeks of 5 days of treatment and 2 days of rest (days 1-5 and 8-12 [every] 28 days), followed by 2 weeks of rest. Trifluridine-tipiracil is approved for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor biological therapy and, if RAS wild-type, an antiepidermal growth factor receptor therapy. CONCLUSION: Trifluridine-tipiracil is a new treatment option for patients with mCRC who have received at least 2 prior lines of standard chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an antiepidermal growth factor receptor antibody in patients with KRAS wild-type tumors). Ongoing trials are investigating trifluridine/tipiracil in combination with other anticancer agents for mCRC and its use in other malignancies, such as metastatic gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/farmacologia , Trifluridina/farmacologia , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Intervalo Livre de Progressão , Pirrolidinas/uso terapêutico , Timidina Fosforilase/antagonistas & inibidores , Timidina Fosforilase/metabolismo , Trifluridina/uso terapêutico , Uracila/farmacologia , Uracila/uso terapêutico
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