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1.
BMC Vet Res ; 16(1): 75, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131830

RESUMO

BACKGROUND: The intestinal epithelial barrier, which works as the first line of defense between the luminal environment and the host, once destroyed, it will cause serious inflammation or other intestinal diseases. Tight junctions (TJs) play a vital role to maintain the integrity of the epithelial barrier. Lipopolysaccharide (LPS), one of the most important inflammatory factors will downregulate specific TJ proteins including Occludin and Claudin-1 and impair integrity of the epithelial barrier. Betaine has excellent anti-inflammatory activity but whether betaine has any effect on TJ proteins, particularly on LPS-induced dysfunction of epithelial barriers remains unknown. The purpose of this study is to explore the pharmacological effect of betaine on improving intestinal barrier function represented by TJ proteins. Intestinal porcine epithelial cells (IPEC-J2) were used as an in vitro model. RESULTS: The results demonstrated that betaine enhanced the expression of TJ proteins while LPS (1 µg/mL) downregulates the expression of these proteins. Furthermore, betaine attenuates LPS-induced decreases of TJ proteins both shown by Western blot (WB) and Reverse transcription-polymerase chain reaction (RT-PCR). The immunofluorescent images consistently revealed that LPS induced the disruption of TJ protein Claudin-1 and reduced its expression while betaine could reverse these alterations. Similar protective role of betaine on intestinal barrier function was observed by transepithelial electrical resistance (TEER) approach. CONCLUSION: In conclusion, our research demonstrated that betaine attenuated LPS-induced downregulation of Occludin and Claudin-1 and restored the intestinal barrier function.

2.
J Neural Eng ; 17(2): 026001, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32000145

RESUMO

OBJECTIVES: With the rapid development of EEG-based wearable healthcare devices and brain-computer interfaces, reliable and user-friendly EEG sensors for EEG recording, especially at forehead sites, are highly desirable and challenging. However, existing EEG sensors cannot meet the requirements, since wet electrodes require tedious setup and conductive pastes or gels, and most dry electrodes show unacceptable high contact impedance. In addition, the existing electrodes cannot absorb sweat effectively; sweat would cause cross-interferences, and even short circuits, between adjacent electrodes, especially in the moving scenarios, or a hot and humid environment. To resolve these problems, a novel printable flexible Ag/AgCl dry electrode array was developed for EEG acquisition at forehead sites, mainly consisting of screen printing the Ag/AgCl coating, conductive sweat-absorbable sponges and flexible tines. APPROACH: A systematic method was also established to evaluate the flexible dry electrode array. MAIN RESULTS: The experimental results show the flexible dry electrode array has reproducible electrode potential, relatively low electrode-skin impedance, and good stability. Moreover, the EEG signals can be effectively captured with a high quality that is comparable to that of wet electrodes. SIGNIFICANCE: All the results confirmed the feasibility of forehead EEG recording in real-world scenarios using the proposed flexible dry electrode array, with a rapid and facile operation as well as the advantages of self-application, user-friendliness and wearer comfort.

3.
Brain Imaging Behav ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31903526

RESUMO

Using resting-state functional magnetic resonance imaging and graph theory approaches to investigate the topological characteristics of functional networks and their potential correlations with clinical information in patients with systemic lupus erythematosus (SLE). A total of 41 patients and 35 volunteers were consecutively recruited. Detailed clinical data of all participants were recorded. All participants underwent a resting-state functional magnetic resonance imaging examination. Functional networks were constructed by a Pearson correlation matrix of 116 brain regions. The topological properties were analyzed by graph theory. Parametric tests were used to compare the topological properties between the groups. Partial correlation analysis was used to identify relationships between the abnormal topological properties and the clinical data. The nodal network metrics were abnormal in the SLE patients compared to the controls. Decreased nodal efficiency was identified in the right insula, bilateral putamen, and bilateral Heschl's gyrus in the SLE patients. Decreased degree centrality was also found in the right amygdala and bilateral Heschl's gyrus. In addition, the SLE patients showed decreased network functional connectivity (FC) between several regions, particularly between the basal ganglia and the cerebellum. Moreover, FC values between the right putamen and vermis 6 were positively correlated with Mini-Mental State Examination scores. The nodal efficiency and the degree centrality values in the left Heschl's gyrus were both positively correlated with the course of the disease. The topological structure of the functional network was apparently abnormal in SLE patients. FC values between the right putamen and vermis 6 may serve as a neuroimaging marker for evaluating the progressive cognitive decline in SLE patients. Decreased synergy between the basal ganglia region and the cerebellum in the extrapyramidal system may be one cause of cognitive dysfunction in SLE patients.

4.
Bioorg Med Chem ; 28(2): 115258, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31864776

RESUMO

Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced binding interactions, metabolic stability, and reduced toxicity. In this study, based on the intermediate derivatization methods, we synthesized 13 new fluorine-containing proguanil derivatives, and found that 7a,7d and 8e had much lower IC50 than proguanil in 5 human cancerous cell lines. The results of clonogenic and scratch wound healing assays revealed that the inhibitory effects of derivatives 7a,7d and 8e on proliferation and migration of human cancer cell lines were much better than proguanil as well. Mechanistic study based on representative derivative 7a indicated that this compound up-regulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. In conclusion, these new fluorine-containing derivatives show potential for the development of cancer chemotherapeutic drugs.

5.
Bioanalysis ; 11(21): 1967-1980, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31829056

RESUMO

Aim: Advancements in RNA interference therapeutics have triggered development of improved bioanalytical methods for oligonucleotide metabolite profiling and high-throughput quantification in biological matrices. Results & methodology: HPLC coupled with high-resolution mass spectrometry (LC-HRMS) methods were developed to investigate the metabolism of a REVERSIR™ molecule in vivo. Plasma and tissue samples were extracted using solid-phase extraction followed by LC-HRMS analysis for metabolite profiling and quantification. The method was qualified from 10 to 5000 ng/ml (plasma) and 100 to 50000 ng/g (liver and kidney). In rat liver, intra and interday accuracy ranged from 80.9 to 118.5% and 88.4 to 111.9%, respectively, with acceptable precision (<20% CV). Conclusion: The LC-HRMS method can be applied for metabolite profiling and quantification of oligonucleotides in biological matrices.

6.
Exp Ther Med ; 18(4): 3037-3045, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31555387

RESUMO

NF-κB activating protein (NKAP) is a highly conserved protein involved in transcriptional repression, immune cell development, maturation, acquisition of functional competency and maintenance of hematopoiesis. In the present study, the function of NKAP in the progress of Ewing sarcoma (ES) was investigated. It was identified that NKAP is highly expressed in ES cells when compared with human mesenchymal stem cells (MSCs). NKAP was knocked-down in human ES cell lines A673 and RD-ES using small interfering (si)RNA transfection. The effectiveness of transfection was then verified using reverse transcription-quantitative PCR and western blot analysis to determine mRNA and protein levels, respectively. The results of the proliferation assays indicated that the knockdown of NKAP inhibited the proliferation and clonogenic abilities of human ES cells. Transwell assays further indicated that cell invasion and migration were significantly inhibited by NKAP knockdown, which may be mediated by downregulation of matrix metalloproteinase (MMP)-9 activity. Gain-of-function analysis also demonstrated the positive role NKAP played in the proliferation, invasion and migration of ES cells. Cell apoptosis was evaluated by flow cytometry, which identified that apoptotic cells were significantly increased when NKAP was silenced. In addition, downregulation of NKAP increased the levels of Bax and cleaved caspase 3, but decreased Bcl2 levels, which suggested that the mitochondrial apoptosis pathway was activated. To explore the action mechanism of NKAP, the status of the AKT signaling pathway in NKAP-silenced A673 and RD-ES cells was investigated. Results indicated that NKAP knockdown led to decreased phosphorylation of AKT and expression of cyclin D1, a down-stream effector of the AKT signaling pathway, suggesting inactivation of the AKT signaling pathway. In conclusion, the present study revealed that NKAP promoted the proliferation, migration and invasion of ES cells, at least partly, through the AKT signaling pathway, providing new approaches for the therapeutic application of NKAP in ES.

7.
Magn Reson Imaging ; 63: 267-273, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31445117

RESUMO

PURPOSE: To examine the feasibility of MR diffusion kurtosis imaging (DKI) for characterizing nonalcoholic fatty liver disease (NAFLD) and diagnosing nonalcoholic steatohepatitis (NASH). METHODS: Thirty-two rabbits on high fat diet with different severities of NAFLD were imaged at 3 T MR including diffusion weighted imaging (DWI) and DKI using b values of 0, 400, 800 s/mm2 with 15 diffusion directions at each b value. Apparent diffusion coefficient (ADC) was derived from the linear exponential DWI model. Mean diffusion (MD) and mean kurtosis (MK) were derived from the quadratic exponential model of DKI. Correlations between MR parameters and hepatic pathology determined by the NAFLD activity scoring system were analyzed by Spearman rank correlation analysis. Receiver operating characteristic analyses were applied to determine the cutoff values of MD, MK as well as ADC in distinguishing NASH from non-NASH. The diagnostic efficacies of MD and MK in detecting NASH were compared with that of ADC. RESULTS: Values for ADC and MD significantly decreased as the severity of NAFLD increased (ρ = -0.529, -0.904, respectively; P < 0.05). MK values significantly increased as the severity of NAFLD increased (ρ = 0.761; P < 0.05). In addition, both MD and MK values were significantly different between borderline NASH and NASH groups (MD: 1.729 ±â€¯0.144 vs. 1.458 ±â€¯0.240[×10-3 mm2/s]; MK: 1.096 ±â€¯0.079 vs. 1.237 ±â€¯0.180; P < 0.05). Moreover, there was a significantly higher area under the curve (AUC) for both MD (0.955) and MK (0.905), as compared to ADC (0.736). CONCLUSION: Diffusion kurtosis imaging was feasible for stratifying NAFLD, and more accurately discriminated NASH from non-NASH when compared with DWI.

8.
Drug Metab Dispos ; 47(10): 1183-1194, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31270142

RESUMO

Small interfering RNAs (siRNAs) represent a new class of medicines that are smaller (∼16,000 Da) than biologic therapeutics (>150,000 Da) but much larger than small molecules (<900 Da). Current regulatory guidance on drug-drug interactions (DDIs) from the European Medicines Agency, Food and Drug Administration, and Pharmaceutical and Medical Devices Agency provides no recommendations for oligonucleotide therapeutics including siRNAs; therefore, small molecule guidance documents have historically been applied. Over ∼10 years, in vitro DDI investigations with siRNAs conjugated to a triantennary N-acetylgalactosamine [(GalNAc)-siRNA] ligand have been conducted during nonclinical drug development to elucidate the potential clinical DDI liability. GalNAc siRNAs were evaluated as substrates, inhibitors, or inducers of major cytochrome P450s (P450s) and as substrates and inhibitors of transporters. Aggregate analysis of these data demonstrates a low potential for DDI against P450s. Zero of five, 10, and seven are inducers, time-dependent inhibitors, or substrates, respectively, and nine of 12 do not inhibit any P450 isoform evaluated. Three GalNAc siRNAs inhibited CYP2C8 at supratherapeutic concentrations, and one mildly inhibited CYP2B6. The lowest K i value of 28 µM is >3000-fold above the therapeutic clinical C max at steady state, and importantly no clinical inhibition was projected. Of four GalNAc siRNAs tested none were substrates for transporters and one caused inhibition of P-glycoprotein, calculated not to be clinically relevant. The pharmacological basis for DDIs, including consideration of the target and/or off-target profiles for GalNAc siRNAs, should be made as part of the overall DDI risk assessment. If modulation of the target protein does not interfere with P450s or transporters, then in vitro or clinical investigations into the DDI potential of the GalNAc siRNAs are not warranted. SIGNIFICANCE STATEMENT: Recommendations for evaluating DDI potential of small molecule drugs are well established; however, guidance for novel modalities, particularly oligonucleotide-based therapeutics are lacking. Given the paucity of published data in this field, in vitro DDI investigations are often conducted. The aggregate analysis of GalNAc-siRNA data reviewed herein demonstrates that, like new biological entities, these oligonucleotide-based therapeutic drugs are unlikely to result in DDIs; therefore, it is recommended that the need for in vitro or clinical investigations similarly be determined on a case-by-case basis. Given the mechanism of siRNA action, special consideration should be made in cases where there may be a pharmacological basis for DDIs.

9.
Alzheimers Dement (N Y) ; 5: 254-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304231

RESUMO

Introduction: Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. Methods: Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face-name pairs. Results: Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face-name pairs at day 7 and day 14, relative to baseline. Discussion: Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.

10.
Int J Phytoremediation ; 21(7): 683-692, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30924369

RESUMO

A pot experiment was conducted to explore the plant-assisted degradation efficiency of di-(2-ethylhexyl) phthalate (DEHP) and pyrene. Three plant species: Ceylon spinach, sunflower, and leaf mustard were cultivated in co-contaminated soils under three contamination levels: control (T0), 20 mg kg-1 (T20), and 50 mg kg-1 (T50). The results showed that a higher DEHP and pyrene degradation efficiency was observed evidently in planted cases, increasing from 42 to 53-59% (T0), 61 to 65-76% (T20) and 52 to 68-78% (T50) for DEHP, and from 22 to 30-49% (T0), 58 to 62-72% (T20), and 54 to 57-70% (T50) for pyrene. Under T20 contamination level, soil phospholipid fatty-acid analysis depicted the increased microbial biomass in rhizosphere, especially the arbuscular mycorrhizal fungus that is effective for the degradation of organic pollutants. The study also revealed that the activities of dehydrogenase, acid phosphomonoesterase, urease, and phenol oxidase negatively correlated with pollutant concentration. In general, the removal rate of DEHP and pyrene was highest in the soil planted with leaf mustard for each contamination level considered. For soils at T20 level, sunflower and leaf mustard appeared as interesting phytoremediation plants due to the improved removal rates of organic pollutants and the soil microbial activity.


Assuntos
Dietilexilftalato/análise , Microbiota , Poluentes do Solo , Biodegradação Ambiental , Ácidos Ftálicos , Pirenos , Solo , Microbiologia do Solo
11.
Nucleic Acids Res ; 47(7): 3306-3320, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30820542

RESUMO

For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2'-F-monomer metabolites was low and transient in rats and humans. In vitro, 2'-F-nucleoside 5'-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2'-F-nucleosides, typically not attained in vivo. No apparent functional impact on mitochondria and no significant accumulation of 2'-F-monomers were observed after weekly administration of two GalNAc-siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2'-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc-siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.


Assuntos
Acetilgalactosamina/efeitos adversos , Acetilgalactosamina/química , Desoxirribonucleotídeos/efeitos adversos , Desoxirribonucleotídeos/química , Flúor/química , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/química , Animais , Feminino , Flúor/efeitos adversos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
12.
Food Funct ; 10(2): 1235-1242, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30747184

RESUMO

Inflammation caused by either intrinsic or extrinsic toxins results in intestinal barrier dysfunction, contributing to inflammatory bowel disease (IBD) and other diseases. Vitamin A is a widely used food supplement although its mechanistic effect on intestinal structures is largely unknown. The goal of this study was to explore the mechanism by investigating the influence of vitamin A on the intestinal barrier function, represented by tight junctions. IPEC-J2 cells were differentiated on transwell inserts and used as a model of intestinal barrier permeability. Transepithelial electrical resistance (TEER) was used as an indicator of monolayer integrity and paracellular permeability. Western blot and the reverse transcriptase-polymerase chain reaction were used to assess the protein and mRNA expression of tight junction proteins. Immunofluorescence microscopy was used to evaluate the localization and expression of tight junctions. Differentiated cells were treated with a vehicle control (Ctrl), inflammatory stimulus (1 µg mL-1 LPS), LPS co-treatment with 0.1 µmol L-1 Vitamin A (1 µg mL-1 LPS + 0.1 µmol L-1 VA) and 0.1 µmol L-1 Vitamin A. LPS significantly decreased TEER by 24 hours, continuing this effect to 48 hours after application. Vitamin A alleviated the LPS-induced decrease of TEER from 12 hours to 48 hours, while Vitamin A alone enhanced TEER, indicating that Vitamin A attenuated LPS-induced intestinal epithelium permeability. Mechanistically, different concentrations of Vitamin A (0-20 µmol L-1) enhanced tight junction protein markers including Zo-1, Occludin and Claudin-1 both at protein and mRNA levels with an optimized dose of 0.1 µmol L-1. Immunofluorescence results demonstrated that majority of Zo-1 and Claudin-1 is located at the tight junctions, as we expected. LPS reduced the expression of these proteins and Vitamin A reversed LPS-reduced expression of these proteins, consistent with the results of western blot. In conclusion, Vitamin A improves the intestinal barrier function and reverses LPS-induced intestinal barrier damage via enhancing the expression of tight junction proteins.


Assuntos
Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/citologia , Lipopolissacarídeos/toxicidade , Proteínas de Junções Íntimas/metabolismo , Vitamina A/farmacologia , Animais , Linhagem Celular , Suínos , Proteínas de Junções Íntimas/genética
13.
Environ Sci Pollut Res Int ; 26(20): 20030-20039, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29705900

RESUMO

A pot experiment and a leaching experiment were conducted to investigate the effects of earthworms and pig manure on heavy metals (Cd, Pb, and Zn) immobility, in vitro bioaccessibility and leachability under simulated acid rain (SAR). Results showed manure significantly increased soil organic carbon (SOC), dissolved organic carbon (DOC), available phosphorus (AP), total N, total P and pH, and decreased CaCl2-extractable metals and total heavy metals in water and SAR leachate. The addition of earthworms significantly increased AP (from 0.38 to 1.7 mg kg-1), and a downward trend in CaCl2-extractable and total leaching loss of heavy metals were observed. The combined earthworm and manure treatment decreased CaCl2-extractable Zn, Cd, and Pb. For Na4P2O7-extractable metals, Cd and Pb were decreased with increasing manure application rate. Application of earthworm alone did not contribute to the remediation of heavy metal polluted soils. Considering the effects on heavy metal immobilization and cost, the application of 6% manure was an alternative approach for treating contaminated soils. These findings provide valuable information for risk management during immobilization of heavy metals in contaminated soils.


Assuntos
Esterco , Metais Pesados/farmacocinética , Oligoquetos , Poluentes do Solo/farmacocinética , Chuva Ácida , Animais , Disponibilidade Biológica , Carbono/análise , Recuperação e Remediação Ambiental/métodos , Metais Pesados/química , Fósforo/farmacocinética , Solo/química , Poluentes do Solo/química , Suínos
14.
Acta Radiol ; 60(3): 382-387, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29863413

RESUMO

BACKGROUND: Few studies have reported on the use of intravoxel incoherent motion (IVIM) for renal tumors. PURPOSE: To investigate the value of IVIM for distinguishing renal tumors. MATERIAL AND METHODS: Thirty-one patients with clear cell renal cell carcinomas (CCRCCs), 13 patients with renal angiomyolipomas with minimal fat (RAMFs), eight patients with chromophobe renal cell carcinomas (ChRCCs), and ten patients with papillary renal cell carcinomas (PRCCs) were examined. The tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f) were calculated. RESULTS: The D and f values were highest for CCRCCs, lowest for PRCCs, and intermediate for ChRCCs and RAMFs ( P < 0.05). The D values of CCRCCs differed significantly from those of ChRCCs and PRCCs ( P < 0.05). The D* values were highest for RAMFs, lowest for ChRCCs, and intermediate for CCRCCs and PRCCs ( P < 0.05). Statistically significant differences were observed between the D* values of CCRCCs and RAMFs ( P < 0.05). The D* values of the CCRCCs differed significantly from the D* values of the ChRCCs ( P < 0.05). Using the D and f values of 1.10 and 0.41, respectively, as the threshold values for differentiating CCRCCs from RAMFs, ChRCCs, and PRCCs, the best results had sensitivities of 81.0% and 66.8% and specificities of 85.7% and 81.0%, respectively. Using the D* value of 0.038 as the threshold value for differentiating RAMFs from CCRCCs, ChRCCs, and PRCCs, the best result obtained had a sensitivity of 90.5% and specificity of 76.2%. CONCLUSION: IVIM may provide information for differentiating renal tumor types.


Assuntos
Angiomiolipoma/diagnóstico por imagem , Carcinoma Papilar/diagnóstico por imagem , Carcinoma de Células Renais/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Renais/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Sensibilidade e Especificidade
15.
Am J Cardiol ; 122(9): 1496-1505, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217371

RESUMO

Two post hoc analyses in self-identified black and white patients with hypertension evaluated the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the fixed-dose combination of AZL-M with chlorthalidone (AZL-M/CLD) versus the ARB olmesartan (OLM) and the OLM fixed-dose combination with hydrochlorothiazide (OLM/HCTZ). One analysis pooled 1,610 patients from two 6-week randomized controlled trials to compare once daily AZL-M 40 mg, AZL-M 80 mg, OLM 40 mg, and placebo. The second analysis included 1,020 patients from a 12-week randomized controlled trial to compare once daily AZL-M/CLD 40/25 mg, AZL-M/CLD 80/25 mg, and OLM/HCTZ 40/25 mg. Efficacy end points were 24-hour mean ambulatory and clinic systolic and diastolic blood pressure (SPB/DBP) and the percentage of patients achieving clinic SBP/DBP targets. Treatment with AZL-M 80 mg lowered mean clinic SBP by 12.5 mm Hg (p <0.01 vs OLM), treatment with AZL-M/CLD 40 mg/25 mg lowered mean ambulatory SBP by 31.0 mm Hg and mean clinic SBP by 39.3 mm Hg (both p <0.05 vs OLM/HCTZ), and treatment with AZL-M/CLD 80 mg/25 mg lowered mean ambulatory SBP by 34.4 mm Hg (p <0.01 vs OLM/HCTZ) and mean clinic SBP by 39.2 mm Hg (p <0.05 vs OLM/HCTZ). Target BP goals were achieved more frequently with AZL-M versus OLM and with AZL-M/CLD versus OLM/HCTZ. In conclusion, in both black and white patients, BP was lowered more effectively with AZL-M versus OLM and with AZL-M/CLD versus OLM/HCTZ. The AZL-M/CLD 40 mg/25 mg combination resulted in a statistically significant reduction in BP in both black and white patients.


Assuntos
Afro-Americanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Benzimidazóis/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Hipertensão/tratamento farmacológico , Imidazóis/administração & dosagem , Oxidiazóis/administração & dosagem , Tetrazóis/administração & dosagem , Idoso , Clortalidona/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Hidroclorotiazida/administração & dosagem , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia
16.
Cancer Chemother Pharmacol ; 82(5): 803-814, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30128949

RESUMO

PURPOSE: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib. METHODS: After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. RESULTS: Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0-816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0-35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. CONCLUSIONS: Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/urina , Compostos de Boro/sangue , Compostos de Boro/urina , Fezes/química , Glicina/análogos & derivados , Neoplasias/metabolismo , Administração Oral , Antineoplásicos/administração & dosagem , Área Sob a Curva , Biotransformação , Compostos de Boro/administração & dosagem , Radioisótopos de Carbono , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/urina , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Neoplasias/tratamento farmacológico
17.
Case Rep Radiol ; 2018: 4602352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854535

RESUMO

We report a case of 50-year-old man with a severe acute ischemic stroke followed by intracerebral hemorrhage and brain abscess due to systemic infection. His initial intracranial radiographic findings were normal but three days later MRI scan of the brain revealed well-defined rounded cystic lesion on the T2-weighted and T1-weighted images in the right basal ganglia; the lesion presented an area of diffusion restriction on DWI; lately the lesion was confirmed to be an early stage of cerebral abscess. A week later the patient was noted to have worsening neurological status and left extremity weakness, and emergency brain CT scan revealed massive intracerebral hemorrhage in the right occipital lobe; he underwent intracranial hematoma evacuation surgery. The hematoma was removed successfully, and the systemic infections were treated with antibiotics.

18.
Transl Neurodegener ; 7: 10, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719719

RESUMO

Background: Brain consists of plenty of complicated cytoarchitecture. Gaussian-model based diffusion tensor imaging (DTI) is far from satisfactory interpretation of the structural complexity. Diffusion kurtosis imaging (DKI) is a tool to determine brain non-Gaussian diffusion properties. We investigated the network properties of DKI parameters in the whole brain using graph theory and further detected the alterations of the DKI networks in Alzheimer's disease (AD). Methods: Magnetic resonance DKI scanning was performed on 21 AD patients and 19 controls. Brain networks were constructed by the correlation matrices of 90 regions and analyzed through graph theoretical approaches. Results: We found small world characteristics of DKI networks not only in the normal subjects but also in the AD patients; Grey matter networks of AD patients tended to be a less optimized network. Moreover, the divergent small world network features were shown in the AD white matter networks, which demonstrated increased shortest paths and decreased global efficiency with fiber tractography but decreased shortest paths and increased global efficiency with other DKI metrics. In addition, AD patients showed reduced nodal centrality predominantly in the default mode network areas. Finally, the DKI networks were more closely associated with cognitive impairment than the DTI networks. Conclusions: Our results suggest that DKI might be superior to DTI and could serve as a novel approach to understand the pathogenic mechanisms in neurodegenerative diseases.

19.
Clin Hypertens ; 24: 2, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29445520

RESUMO

Background: This was a phase 3, randomized, double-blind, placebo-controlled study. Methods: Adult Korean patients with essential hypertension and a baseline mean sitting clinic systolic blood pressure (scSBP) ≥150 and ≤180 mmHg were randomized to 6-week treatment with placebo (n = 65), azilsartan medoxomil (AZL-M) 40 mg (n = 132), or AZL-M 80 mg (n = 131). The primary endpoint was the change from baseline to week 6 in trough scSBP. Results: The least-squares mean (standard error) change from baseline in trough scSBP in the placebo, AZL-M 40-mg, and 80-mg groups at week 6 were - 8.8 (2.00), - 22.1 (1.41), and - 23.7 (1.40) mmHg, respectively (p < 0.001 for AZL-M 40 and 80 mg vs placebo). No clinically meaningful heterogeneity in efficacy was observed between subgroups (age, sex, diabetes status) and the overall population. Treatments were well tolerated and adverse events were similar between groups. Conclusions: Results of this study confirm a positive benefit-risk profile of AZL-M for essential hypertension in Korean adults. Trial registration: Clinicaltrial.gov; identifier number: NCT02203916. Registered July 28, 2014 (retrospectively registered).

20.
Acta Radiol ; 59(1): 114-120, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28467098

RESUMO

Background Cases of primary renal lymphoma (PRL) are quite rare and are often mistaken for renal cell carcinoma. Purpose To determine the multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) characteristics of PRL. Materials and Methods Twenty-three patients with PRL were identified by CT and MRI, and their tumor characteristics were assessed. Results Tumors exhibited single or multifocal nodules (n = 19) and diffuse renal enlargement (n = 4). Twenty-two tumors exhibited an infiltrative appearance. There was no evidence of calcification in any of the cases. Twenty-one tumors displaced or wrapped around abdominal vessels rather than encasing them. Enlarged retroperitoneal nodes were observed in three cases. Neither extension into the venous system nor distant metastasis was found. Tumor enhancement was of low attenuation compared with that of normal renal cortex and medulla ( P < 0.05). PRL was isointense on T1-weighted imaging, slightly hypointense on T2-weighted imaging and hyperintense on diffusion-weighted imaging. Twenty-two patients exhibited biopsy-confirmed PRN. There were four, 12, and seven cases of low-grade, intermediate-grade, and high-grade tumors, respectively. Patient were followed up over 16 to 166 months. Six patients died within three years and five patients died within five years. Conclusion Infiltrative appearance and tumor displacement or extension around abdominal vessels rather than vessel encasement are common findings on CT or MRI imaging and may suggest a diagnosis of PRL.


Assuntos
Neoplasias Renais/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Tomografia Computadorizada Multidetectores/métodos , Adulto , Idoso , Feminino , Humanos , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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