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1.
Biomed Chromatogr ; : e4928, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32567713

RESUMO

A practical, sensitive and robust ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method is developed and validated to quantify lacosamide in human plasma. A simple one-step protein precipitation was employed to extract lacosamide and labeled lacosamide-13C, D3 as an internal standard from 150 µL plasma. The extracts were analyzed on Eclipse Plus C18 (50 × 2.1 mm, 1.8 µm) column using 0.1 % formic acid in water and methanol: acetonitrile (50:50, v/v) under gradient conditions. Quantification was executed on LCMS-8040 using electrospray ionization source operated in positive ionization and multiple reaction monitoring mode. The method showed good linearity from 0.02-20 µg/mL, which was adequate to cover lacosamide concentration assayed in formulations with different strengths. The bioanalytical assay was fully validated as per current regulatory guidelines. The intra-batch and inter-batch precision values of lacosamide were ≤ 4.6 %. Lacosamide was found to be stable at different storage conditions. The extraction recoveries and IS-normalized matrix factors for lacosamide ranged from 97.17-99.68 % and 0.973-1.012, respectively. The validated method was successfully applied to a pharmacokinetic study with three lacosamide formulations (50 mg, 100 mg and 200 mg) in 36 healthy subjects. The assay reliability was ascertained by reanalysis of 81 subject samples.

3.
Int J Nanomedicine ; 15: 573-585, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158209

RESUMO

Introduction: A comparative study of Putranjiva roxburghii Wall. seed extract and developed silver nanoparticles (PJSNPs) for improving bioavailability that enhance their anti-cancer activity against HCT-116 (colon carcinoma), PANC-1 (pancreatic carcinoma), MDA-MB 231 (breast carcinoma) cell lines was performed. Materials and Methods: The green synthesis of PJSNPs (Putranjiva silver nanoparticles) was performed using PJ (Putranjiva) extract, and characterization of synthesized nanoparticles was accomplished through UV-Vis spectrum, X-ray diffraction (XRD), transmission electron microscopy, energy-dispersive X-ray spectroscopy (TEM-EDAX), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and Raman spectroscopy. Results: The results revealed that PJSNPs are homogeneous, spherical in shape, ~8±2 nm in size, and negatively charged with a zeta potential of about -26.71 mV. The cytotoxicity pattern observed was AgNO3 > PJSNPs > PJ extract. The morphological changes of the cells were observed by flow cytometry and also by the DNA ladder pattern on gel electrophoresis, which indicated that the process of cell death occurred via the apoptosis mechanism and PJSNPs were exerting late-stage apoptosis in all the tested cell lines. The small size and negative value of zeta potential could be the factors responsible for greater bioavailability and thus increased uptake by the tumor cells. Conclusion: The MTT assay and morphological changes observed by various methods indicate that the novel PJSNPs are a better anticancer agent than PJ extract. All the above properties make biologically synthesized PJSNPs an important target in the field of anti-cancer drug discovery.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Nanopartículas Metálicas/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Euphorbiaceae/química , Células HCT116 , Humanos , Células MCF-7 , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sementes/química , Prata/química , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
4.
Int J Hyperthermia ; 37(1): 263-272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180481

RESUMO

Introduction: HIV infection is associated with increased treatment-related toxicity and worse outcomes in locally advanced cervical cancer patients (LACC), especially in resource-constrained settings. Local control (LC) in a phase III randomized, controlled trial investigating modulated electro-hyperthermia (mEHT) on LACC patients in South Africa (ethics registration: M120477/M190295), was significantly higher in participants randomized to receive chemoradiotherapy (CRT) with mEHT compared to CRT alone (stratum: HIV status, accounting for age and stage). This analysis investigates whether mEHT adds to the toxicity profile of CRT in HIV-positive LACC participants.Methods: Inclusion criteria: signed informed consent; International Federation of Gynecology and Obstetrics stages IIB to IIIB squamous cell carcinoma of the cervix; HIV-positive patients: CD4 count >200 cell/µL/on antiretroviral treatment for >6 months; eligible for CRT with radical intent. Recruitment: January 2014 to November 2017 (ClinicalTrials.gov: NCT03332069). Acute toxicity (evaluated using CTCAE v4 criteria) and quality of life (according to EORTC forms) in 206 participants randomized for treatment were evaluated alongside the LC results to determine safety and efficacy in HIV-positive participants.Results: Compliance to mEHT treatment was high (97% completed ≥8 treatments) with no significant differences in CRT-related toxicity between treatment groups or between HIV-positive and -negative participants. Adverse events attributed to mEHT were minor, even in obese patients, and did not affect CRT compliance. Participants treated with mEHT reported improved fatigue, pain, emotional and cognitive functioning.Conclusion: mEHT did not cause unexpected CRT-related toxicities and is a safe treatment modality for HIV-positive patients, with minor limitations regarding body weight, even in a low-resource setting.

5.
Vasc Endovascular Surg ; 54(2): 135-140, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31769352

RESUMO

PURPOSE: Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis (USAT) appears to provide promising results for the management of acute submassive pulmonary embolisms (ASMPEs) at tertiary care centers. This study assessed outcome measures at a community-based hospital systems and compared results to known studies. MATERIALS AND METHODS: This is a single-center, retrospective study assessing clinical outcomes of the EkoSonic Endovascular System intervention for ASMPEs performed by three surgical 3 subspecialties (interventional radiology, interventional cardiology, and vascular surgery) part of a pulmonary embolism response team (PERT). We reviewed 146 PERT activations from June 2013 to December 2017. Eighty-three patients with ASMPEs underwent USAT. RESULTS: Our study showed greater differences (P = .01) between baseline and follow-up pulmonary artery systolic pressures (20.9 ± 9.8 mm Hg [n = 14]) compared to the ULTIMA study (12.3 ± 10 mm Hg [n = 30]). Our length-of-stay measures were shorter (6.1 ± 5.1 [n = 83]; P = .0001) compared to the SEATTLE II study (8.8 ± 5.0 [n = 150]). Preprocedure transthoracic echocardiograms (TTEs) were performed for 54 (65%) of 83 patients. Postprocedure TTEs at 48 hours was performed for 52 (62%) of 83 patients. Use of TTEs before and after intervention did not change outcomes. Intracranial hemorrhage was not observed in our patient population. There was no difference in outcomes between the three subspecialties in our study. CONCLUSIONS: Use of USAT in a community-based hospital PERT has similar outcomes to tertiary care centers. Furthermore, similar outcomes were observed between the three subspecialties suggesting development of a comprehensive care team for management of ASMPEs.


Assuntos
Cateterismo Periférico , Fibrinolíticos/administração & dosagem , Hospitais Comunitários , Embolia Pulmonar/terapia , Terapia Trombolítica/métodos , Terapia por Ultrassom , Doença Aguda , Adulto , Idoso , Cardiologistas , Cateterismo Periférico/efeitos adversos , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Infusões Intra-Arteriais , Masculino , Michigan , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/fisiopatologia , Radiologistas , Estudos Retrospectivos , Especialização , Cirurgiões , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Terapia por Ultrassom/efeitos adversos
6.
Mol Biol Rep ; 47(1): 533-544, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724125

RESUMO

In the present investigation, we report cloning, expression, purification and characterization of a novel Bleomycin Resistance Dioxygenase (BRPD). His-tagged fusion protein was purified to homogeneity using Ni-NTA affinity chromatography, yielding 1.2 mg of BRPD with specific activity of 6.25 U mg-1 from 600 ml of E. coli culture. Purified enzyme was a dimer with molecular weight ~ 26 kDa in SDS-PAGE and ~ 73 kDa in native PAGE analysis. The protein catalyzed breakdown of hydrocarbon substrates, including catechol and hydroquinone, in the presence of metal ions, as characterized via spectrophotometric analysis of the enzymatic reactions. Bleomycin binding was proven using the EMSA gel retardation assay, and the putative bleomycin binding site was further determined by in silico analysis. Molecular dynamic simulations revealed that BRPD attains octahedral configuration in the presence of Fe2+ ion, forming six co-ordinate complexes to degrade hydroquinone-like molecules. In contrary, in the presence of Zn2+ ion BRPD adopts tetrahedral configuration, which enables degradation of catechol-like molecules.

7.
Biomed Chromatogr ; 34(1): e4708, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630419

RESUMO

A rapid, simple and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed to quantify fenoprofen, a nonsteroidal anti-inflammatory drug in human plasma for a pharmacokinetic study in healthy subjects. Owing to high levels of protein binding, protein precipitation followed by solid-phase extraction was employed for the extraction of fenoprofen and fenoprofen-d3 (used as internal standard) from 200 µL human plasma. Separation was performed on a BEH C18 (50 × 2.1 mm, 1.7 µm) column using methanol-0.2% acetic acid in water (75:25, v/v) under isocratic elution. Electrospray ionization was operated in the negative mode for sample ionization. Ion transitions used for quantification in the selected reaction monitoring mode were m/z 241/197 and m/z 244/200 for fenoprofen and fenoprofen-d3, respectively. Under the optimized conditions, fenoprofen showed excellent linearity in the concentration range 0.02-20 µg/mL (r2 ≥ 0.9996), adequate sensitivity, favorable accuracy (96.4-103.7%) and precision (percentage coefficient of variation ≤4.3) with negligible matrix effect. The validated method was successfully applied to a pharmacokinetic study of fenoprofen in healthy subjects. The significant features of the method include higher sensitivity, small plasma volume for processing and a short analysis time.


Assuntos
Fenoprofeno/sangue , Fenoprofeno/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Fenoprofeno/química , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Sensors (Basel) ; 19(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835479

RESUMO

Aptamers are synthetic bio-receptors of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) origin selected by the systematic evolution of ligands (SELEX) process that bind a broad range of target analytes with high affinity and specificity. So far, electrochemical biosensors have come up as a simple and sensitive method to utilize aptamers as a bio-recognition element. Numerous aptamer based sensors have been developed for clinical diagnostics, food, and environmental monitoring and several other applications are under development. Aptasensors are capable of extending the limits of current analytical techniques in clinical diagnostics, food, and environmental sample analysis. However, the potential applications of aptamer based electrochemical biosensors are unlimited; current applications are observed in the areas of food toxins, clinical biomarkers, and pesticide detection. This review attempts to enumerate the most representative examples of research progress in aptamer based electrochemical biosensing principles that have been developed in recent years. Additionally, this account will discuss various current developments on aptamer-based sensors toward heavy metal detection, for various cardiac biomarkers, antibiotics detection, and also on how the aptamers can be deployed to couple with antibody-based assays as a hybrid sensing platform. Aptamers can be used in various applications, however, this account will focus on the recent advancements made toward food, environmental, and clinical diagnostic application. This review paper compares various electrochemical aptamer based sensor detection strategies that have been applied so far and used as a state of the art. As illustrated in the literature, aptamers have been utilized extensively for environmental, cancer biomarker, biomedical application, and antibiotic detection and thus have been extensively discussed in this article.


Assuntos
Técnicas Biossensoriais/métodos , Monitoramento Ambiental , Análise de Alimentos , Patologia Molecular , Anticorpos/isolamento & purificação , Aptâmeros de Nucleotídeos/química , Biomarcadores/análise , Humanos , Ligantes , Técnica de Seleção de Aptâmeros/métodos
9.
J Genet ; 982019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31819017

RESUMO

A study was conducted to examine the genetic divergence and to determine the genetic loci and genes associated with natural variation of grain zinc (Zn) concentration among 28 landraces, improved varieties and advanced breeding lines of rice using candidate gene specific primers. Field evaluation of the experimental material was conducted in randomized block design with three replications and Zn content in unpolished grains of the entries was determined by addition of nitric acid and perchloric acid (1:3) following the procedure of diacid digestion method. Statistical analysis revealed the exploitable extent of variability with respect to grain Zn concentration among the entries. Eighteen entries were selected from the two extremes of grain Zn distribution range and subjected to molecular profiling using a panel of 14 candidate genes specific 12 reported and 14 designed primer pairs. Only eight (OsZIP1-1, OsZIP3a, OsZIP4a, OsZIP5-3, OsZIP7-2, OsZIP8b, OsNRAMP7 and OsNAAT1) reported and eight (OsZIP3K, OsZIP4K, OsZIP5K, OsZIP7K, OsNRAMP7K, OsNAAT1K, OsNACK and OsYSL14K) designed primers generated polymorphic amplified products showing sequence length variation due to targeted amplification of candidate genes specific genomic regions. Ample genetic differentiation and divergence were revealed among the entries, which were accommodated into similarity coefficient-based six clusters, remarkably consistent with grain Zn concentration of the entries. Hierarchical classification pattern of entries was almost completely corroborated by principal co-ordinate analysis based spatial distribution pattern of their genetic profiles. Molecular analysis based on candidate genes specific primers appeared to be an efficient approach for the elucidation of genetic differentiation and divergence in relation to variation of grain Zn concentration among entries. Hence, these markers can be effectively and efficiently utilized for grain Zn concentration related discrimination of rice genotypes and selection of parental genotypes for grain Zn biofortification. Microsatellites were detected within the candidate genes and amplicons, thereby providing a basis to deduce that the repeat sequence length variation in candidate genes may be a role player in the differential grain Zn accumulation in rice varieties. Single marker analysis established the association of OsNACK, OsZIP1-1, OsNRAMP7 and OsNRAMP7K with grain Zn concentration. Thus, these four markers can be effectively used in marker-assisted selection programme for grain Zn biofortification in rice.

10.
Front Pharmacol ; 10: 1186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680964

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by circumscribed, red, thickened plaques with overlying silvery white scales. It is associated with the release of pro-inflammatory mediators that lead to the development of edema and distress. Here we show the anti-inflammatory and anti-psoriatic efficacies of a neutraceutical sea buckthorn oil (SBKT) derived from the fruit pulp of Hippophae rhamnoides. Chemical analysis of the SBKT showed the presence of 16 major saturated, mono-, and polyunsaturated fatty acids components, imparting significant nutritional values. Efficacy of the SBKT in modulating psoriasis and associated inflammation was first tested in vitro using human monocytic (THP-1) cells. SBKT induced cytotoxicity at a dose of ≥25 µl/ml. Treatment of the lipopolysaccharide-stimulated THP-1 cells with SBKT subdued the enhanced release of intracellular reactive nitrogen species and expression of NF-κB protein, in a concentration-dependent manner. This was accompanied by a reduction in the release of downstream pro-inflammatory cytokines: Interleukin-1ß and interleukin-6. Tumor necrosis factor-α released in the stimulated THP-1 cells were also inhibited by SBKT dose of 5 µl/ml. In vivo oral and topical treatment with SBKT in the Carrageenan-stimulated paw edema model, showed a significant decrease in paw volume and edema. In the 12-O tetradecanoyl phorbol 13-acetate (TPA) stimulated CD-1 mice psoriasis-like model, concurrent oral and tropical SBKT treatments substantially reduced ear edema and ear biopsy weights. Histopathologically, significant reduction in ear epidermal thickness and skin lesion scores was observed in the SBKT-treated animals. In conclusion, SBKT showed anti-inflammatory and anti-psoriasis-like efficacies in healing chemical-induced inflammation and psoriasis. The possible mode of action of SBKT was found through inhibition of reactive nitrogen species, and downregulation of NF-κB protein and pro-inflammatory cytokines. Thus, the present data suggest that Sea buckthorn oil can be used as an anti-inflammatory and anti-psoriatic nutraceutical.

11.
Digit Health ; 5: 2055207619879349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632685

RESUMO

Objective: Critical care capabilities needed for the management of septic patients, such as continuous vital sign monitoring, are largely unavailable in most emergency departments (EDs) in low- and middle-income country (LMIC) settings. This study aimed to assess the feasibility and accuracy of using a wireless wearable biosensor device for continuous vital sign monitoring in ED patients with suspected sepsis in an LMIC setting. Methods: This was a prospective observational study of pediatric (≥2 mon) and adult patients with suspected sepsis at the Kigali University Teaching Hospital ED. Heart rate, respiratory rate and temperature measurements were continuously recorded using a wearable biosensor device for the duration of the patients' ED course and compared to intermittent manually collected vital signs. Results: A total of 42 patients had sufficient data for analysis. Mean duration of monitoring was 32.8 h per patient. Biosensor measurements were strongly correlated with manual measurements for heart rate (r = 0.87, p < 0.001) and respiratory rate (r = 0.75, p < 0.001), although were less strong for temperature (r = 0.61, p < 0.001). Mean (SD) differences between biosensor and manual measurements were 1.2 (11.4) beats/min, 2.5 (5.5) breaths/min and 1.4 (1.0)°C. Technical or practical feasibility issues occurred in 12 patients (28.6%) although were minor and included biosensor detachment, connectivity problems, removal for a radiologic study or exam, and patient/parent desire to remove the device. Conclusions: Wearable biosensor devices can be feasibly implemented and provide accurate continuous heart rate and respiratory rate monitoring in acutely ill pediatric and adult ED patients with sepsis in an LMIC setting.

12.
ACS Omega ; 4(14): 15862-15872, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31592456

RESUMO

A new class of blue light-emitting bowl-shaped mesogens with the thiacalix[4]arene core appended with 1,3,4-thiadiazole derivatives having peripheral alkoxy side chains have been synthesized and well characterized. The liquid crystalline behavior of present synthesized derivatives was examined by optical polarizing microscopy, differential scanning calorimetry, and X-ray diffraction studies. It was observed that these thiacalix[4]arene derivatives were capable of stabilizing the observed Colh phase with a higher temperature range. The cone-shaped thiacalix[4]arene-based liquid crystals with peripheral alkoxy side chains able to pack into the columns with enriched intermolecular interactions and thermal behavior. All derivatives showed blue luminescence in solution, solid thin-film, and gelation state. The hexagonal columnar phase and emissive nature of thiadiazole-based thiacalixarene compounds having xerogel behavior make them favorable in the application of emissive electronic display devices. The electrochemical properties of these thiacalixarene-based compounds demonstrate the effect of alkyl side chain on the highest occupied molecular orbital-lowest unoccupied molecular orbital energy levels and also exhibited lower electron band gaps. The electroluminescence behavior of the compound 10c was examined as emissive layers in the fabrication of organic light-emitting diodes.

13.
Chem Commun (Camb) ; 55(85): 12789-12792, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31593194

RESUMO

We report the utility of water-soluble corroles and also protein-coated nanoparticles (NPs) of lipophilic corroles as potent candidates for sonodynamic therapy (SDT), through the detection and quantification of the singlet oxygen that is produced by the ultrasonic irradiation of their aqueous solutions. Preliminary results on a cancer cell line provide evidence for the true utility of the NPs for SDT.

14.
J Genet Eng Biotechnol ; 17(1): 6, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31659568

RESUMO

BACKGROUND: Studying expression of genes by direct sequencing and analysis of metatranscriptomes at a particular time and space can disclose structural and functional insights about microbial communities. The present study reports comparative analysis of metatranscriptome from two distinct soil ecosystems referred as M1 (agriculture soil) and O1 (organic soil). RESULTS: Analysis of sequencing reads revealed Proteobacteria as major dominant phyla in both soil types. The order of the top 3 abundant phyla in M1 sample was Proteobacteria > Ascomycota > Firmicutes, whereas in sample O1, the order was Proteobacteria > Cyanobacteria > Actinobacteria. Analysis of differentially expressed genes demonstrated high expression of transcripts related to copper-binding proteins, proteins involved in electron carrier activity, DNA integration, endonuclease activity, MFS transportation, and other uncharacterized proteins in M1 compared to O1. Of the particular interests, several transcripts related to nitrification, ammonification, stress response, and alternate carbon fixation pathways were highly expressed in M1. In-depth analysis of the sequencing data revealed that transcripts of archaeal origin had high expression in M1 compared to O1 indicating the active role of Archaea in metal- and pesticide-contaminated environment. In addition, transcripts encoding 4-hydroxyphenylpyruvate dioxygenase, glyoxalase/bleomycin resistance protein/dioxygenase, metapyrocatechase, and ring hydroxylating dioxygenases of aromatic hydrocarbon degradation pathways had high expression in M1. Altogether, this study provided important insights about the transcripts and pathways upregulating in the presence of pesticides and herbicides. CONCLUSION: Altogether, this study claims a high expression of microbial transcripts in two ecosystems with a wide range of functions. It further provided clue about several molecular markers which could be a strong indicator of metal and pesticide contamination in soils. Interestingly, our study revealed that Archaea are playing a significant role in nitrification process as compared to bacteria in metal- and pesticide-contaminated soil. In particular, high expression of transcripts related to aromatic hydrocarbon degradation in M1 soil indicates their important role in biodegradation of pollutants, and therefore, further investigation is needed.

15.
Cancer Chemother Pharmacol ; 84(6): 1157-1166, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31482228

RESUMO

Cancer caused by fundamental defects in cell cycle regulation leads to uncontrolled growth of cells. In spite of the treatment with chemotherapeutic agents of varying nature, multiple resistance mechanisms are identified in cancer cells. Similarly, numerous variations, which decrease the metabolism of chemotherapeutics agents and thereby increasing the toxicity of anticancer drugs have been identified. 5-Fluorouracil (5-FU) is an anticancer drug widely used to treat many cancers in the human body. Its broad targeting range is based upon its capacity to act as a uracil analogue, thereby disrupting RNA and DNA synthesis. Dihydropyrimidine dehydrogenase (DPD) is an enzyme majorly involved in the metabolism of pyrimidines in the human body and has the same metabolising effect on 5-FU, a pyrimidine analogue. Multiple mutations in the DPD gene have been linked to 5-FU toxicity and inadequate dosages. DPD inhibitors have also been used to inhibit excessive degradation of 5-FU for meeting appropriate dosage requirements. This article focusses on the role of dihydropyrimidine dehydrogenase in the metabolism of the anticancer drug 5-FU and other associated drugs.

16.
J Pharm Biomed Anal ; 175: 112790, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31362250

RESUMO

Optimization of extraction and chromatographic conditions is essential for the simultaneous analysis of drugs having different physico-chemical properties, especially for in vivo applications. The present work describes concurrent estimation of metformin (MET) and three sodium-glucose co-transporter 2 (SGLT-2) inhibitors namely canagliflozin (CANA), dapagliflozin (DAPA) and empagliflozin (EMPA) in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample clean-up was optimized using ion-pair solid-phase extraction with sodium lauryl sulphate on Strata-X extraction cartridges. Consistent recoveries were obtained by critically optimizing parameters such as washing and elution solvents during extraction. The extraction recovery ranged from 79 to 88% for all the analytes. Chromatographic separation were accomplished on a Cyano (150 × 4.6 mm, 5 µm) column within 5.0 min using acetonitrile and 10 mM ammonium formate buffer (75:25, v/v) as the mobile phase. The resolution factors between MET-EMPA, MET-DAPA, MET-CANA, DAPA-EMPA and CANA-DAPA were 4.92, 5.85, 7.13, 1.01 and 1.44, respectively. Calibration curves were linear in the concentration range of 2.00-2000, 3.00-3000, 0.20-200 and 1.50-1500 ng/mL for MET, CANA, DAPA and EMPA, respectively. Mass spectrometric analysis was performed using a polarity switching approach to achieve high sensitivity in multiple reaction monitoring mode. The method was validated using current regulatory guidelines and applied to study the pharmacokinetics of fixed-dose formulations of MET and SGLT-2 inhibitors in healthy subjects.


Assuntos
Metformina/química , Plasma/química , Inibidores do Transportador 2 de Sódio-Glicose/química , Compostos Benzidrílicos/química , Calibragem , Canagliflozina/química , Cromatografia Líquida/métodos , Glucosídeos/química , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
17.
PLoS One ; 14(6): e0217894, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216321

RESUMO

BACKGROUND: The global burden of cervical cancer remains high with the highest morbidity and mortality rates reported in developing countries. Hyperthermia as a chemo- and radiosensitiser has shown to improve treatment outcomes. This is an analysis of the local control results at six months post-treatment of patients enrolled in an ongoing study investigating the effects of the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for the treatment of HIV-positive and -negative cervical cancer patients in a low-resource setting. METHODS: This ongoing Phase III randomised controlled trial, conducted at a state hospital in Johannesburg, South Africa, was registered with the appropriate ethics committee. After signing an informed consent, participants with FIGO stages IIB to IIIB squamous cell carcinoma of the cervix were randomised to receive chemoradiotherapy with/without mEHT using a secure online random-sampling tool (stratum: HIV status) accounting for age and stage. Reporting physicians were blind to treatment allocation. HIV-positive participants on antiretroviral treatment, or with a CD4 count >200cell/µL were included. mEHT was administered 2/weekly immediately before external beam radiation. The primary end point is local disease control (LDC) and secondary endpoints are toxicity; quality of life analysis; and two year survival. We report on six month LDC, including nodes visualised in the radiation field on 18F-FDG PET/CT (censored for six month survival), and six month local disease free survival (LDFS) (based on intention to treat). Trial status: Recruitment closed (ClinicalTrials.gov: NCT03332069). RESULTS: 271 participants were recruited between January 2014 and November 2017, of which 210 were randomised for trial and 202 were available for analysis at six months post-treatment (mEHT: n = 101; Control: n = 101). Six month LDFS was higher in the mEHT Group (n = 39[38.6%]), than in the Control Group (n = 20[19.8%]); p = 0.003). LDC was also higher in the mEHT Group (n = 40[45.5%]) than the Control Group (n = 20[24.1%]); (p = 0.003). CONCLUSION: Our results show that mEHT is effective as a chemo-radiosensitiser for cervical cancer, even in high risk a patients and resource-constrained settings.


Assuntos
Quimiorradioterapia , Hipertermia Induzida/métodos , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , HIV/patogenicidade , Soropositividade para HIV/virologia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
18.
J Phys Condens Matter ; 31(39): 395802, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31195375

RESUMO

Spintronic functionality in ferromagnetic materials is a next-generation technique, to be used in data storage, high-frequency communications, and logic devices with minimum energy consumption. Ultra-low energy consumption in high-speed logic devices can be envisioned by inducing ferromagnetic behavior into room temperature multiferroic materials. However, there is a scarcity of room temperature multiferroic materials which have a definite spin degree of freedom. To fully exploit these technological challenges, we introduce the induced ferromagnetism in bismuth ferrite (BiFeO3, BFO) by doping transition metal (Cr, Ni, Co) elements. Our investigation initiates with the experimental study on chemically synthesized BiFe(1-x)M x O3 samples where x = 0.0625 (6.25%) and M = Cr, Ni and Co. Experimental findings are verified by theoretical simulation using density functional theory (DFT + U) and gauge including projector augmented wave (GIPAW) based calculation. All the experimental studies are done at room temperature while the theoretical verification using DFT is carried to understand the underlying mechanism behind the magnetic behavior of doped BiFeO3. It is done by optimizing the structural parameters comparable to the room temperature values. Microstructural and magnetic properties are studied using x-ray diffraction (XRD), transmission electron microscopy (TEM) and Vibrating sample magnetometer (VSM). All these experimental studies confirm the structural changes and induced ferromagnetism with doping. X-ray photoelectron spectroscopy (XPS) verified the reason behind this ferromagnetic property on the basis of oxygen vacancy content. Electron paramagnetic resonance (EPR) spectroscopy shows the tuning of Δg values due to enhanced magnetization. The density of states (DOS) calculations were performed on BFO (band-gap 1.89 eV) after structural optimization using DFT + U method, confirm our experimental findings. Magnetic moment values change drastically with doping elements (M), i.e. almost negligible for BFO (antiferromagnetic) to maximum (2.85 µ B/f.u.) for Ni-doped sample. We also compute the EPR g-tensor using GIPAW method to confirm the tuning of Δg values due to enhanced magnetization. These results can highlight the impact and importance of suitable transition element doping to induce the room temperature ferromagnetism in BiFeO3.

19.
Front Microbiol ; 10: 966, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134015

RESUMO

Magnaporthe oryzae is one of the fungal pathogens of rice which results in heavy yield losses worldwide. Understanding the genomic structure of M. oryzae is essential for appropriate deployment of the blast resistance in rice crop improvement programs. In this study we sequenced two M. oryzae isolates, RML-29 (avirulent) and RP-2421 (highly virulent) and performed comparative study along with three publically available genomes of 70-15, P131, and Y34. We identified several candidate effectors (>600) and isolate specific sequences from RML-29 and RP-2421, while a core set of 10013 single copy orthologs were found among the isolates. Pan-genome analysis showed extensive presence and absence variations (PAVs). We identified isolate-specific genes across 12 isolates using the pan-genome information. Repeat analysis was separately performed for each of the 15 isolates. This analysis revealed ∼25 times higher copy number of short interspersed nuclear elements (SINE) in virulent than avirulent isolate. We conclude that the extensive PAVs and occurrence of SINE throughout the genome could be one of the major mechanisms by which pathogenic variability is emerging in M. oryzae isolates. The knowledge gained in this comparative genome study can provide understandings about the fungal genome variations in different hosts and environmental conditions, and it will provide resources to effectively manage this important disease of rice.

20.
J Maxillofac Oral Surg ; 18(2): 224-228, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30996542

RESUMO

Aim: To highlight the spontaneous regeneration of mandibular segmental defects in young and pediatric cases and to review the literature of this unusual and rare phenomenon. Methodology: Two case reports of a 17-year old male and a 8-month-old infant has been presented who underwent resection of mandible for benign tumors. These two cases have been compared with the existing literature of 61 cases published till date. Inference: Spontaneous regeneration of mandible as a viable reconstructive option is not practically feasible. The consistency and predictability of the phenomenon is questionable. Bone grafting should probably be done immediately in all cases, even in young patients if a delay would interfere with quality of life. In infants and small children though, we propose that immediate reconstruction may be avoided to allow some regeneration at the defect site. If it does not occur, secondary reconstruction may then be considered.

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