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1.
Arch Dis Child ; 109(3): 222-226, 2024 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-38041668

RESUMEN

OBJECTIVE: The objective of this study was to understand caregiver perspectives and experiences relating to the treatment of paediatric community-acquired pneumonia (CAP). DESIGN, SETTING AND PATIENTS: This was a phenomenological qualitative study involving interviews with caregivers of young children in Hamilton, Ontario. Caregivers were asked open-ended questions relating to germ theory, pneumonia and the role of antibiotic treatment. The principles of conventional content analysis guided the coding and synthesis of the transcribed interviews. RESULTS: Eleven caregivers were interviewed. Many knew that antibiotics were not effective against all types of infections and stated that there was an increased risk of developing resistance with frequent use. However, there were misconceptions that probiotics effectively mitigated antibiotic side effects, and few were familiar with the potential long-term consequences of antibiotic use in children.There was variability in the perceived severity of paediatric CAP. Some participants thought that antibiotic treatment would accelerate recovery and prevent caregivers from feeling helpless. However, others also thought it was inappropriate for physicians to prescribe antibiotics solely to make the caregiver feel better. Many caregivers also felt strongly that clinical follow-up and discussions on treatment risks/benefits would be desirable to counteract feelings of helplessness that result from being sent home without a prescription. CONCLUSION: Recognising that parents may have misperceptions about antibiotic use for CAP (and may seek antibiotics without strong rationale) can inform clinicians' efforts to better educate and support caregivers in the emergency department. Care strategies informed by caregiver experiences can improve parent-provider communication and reduce antibiotic misuse.


Asunto(s)
Programas de Optimización del Uso de los Antimicrobianos , Neumonía , Niño , Humanos , Preescolar , Cuidadores , Neumonía/tratamiento farmacológico , Antibacterianos/uso terapéutico , Padres , Investigación Cualitativa
2.
ACS Med Chem Lett ; 10(1): 80-85, 2019 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-30655951

RESUMEN

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

3.
Anal Biochem ; 399(2): 284-92, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20018163

RESUMEN

Vanin-1 is a pantetheinase that catalyzes the hydrolysis of pantetheine to produce pantothenic acid (vitamin B5) and cysteamine. Reported here is a highly sensitive fluorescent assay using a novel fluorescently labeled pantothenate derivative. The assay has been used for characterization of a soluble version of human vanin-1 recombinant protein, identification and characterization of hits from high-throughput screening (HTS), and quantification of vanin pantothenase activity in cell lines and tissues. Under optimized assay conditions, we quantified vanin pantothenase activity in tissue lysate and found low activity in lung and liver but high activity in kidney. We demonstrated that the purified recombinant vanin-1 consisting of the extracellular portion without the glycosylphosphatidylinositol (GPI) linker was highly active with an apparent K(m) of 28 microM for pantothenate-7-amino-4-methylcoumarin (pantothenate-AMC), which was converted to pantothenic acid and AMC based on liquid chromatography-mass spectrometry (LC-MS) analysis. The assay also performed well in a 384-well microplate format under initial rate conditions (10% conversion) with a signal-to-background ratio (S/B) of 7 and a Z factor of 0.75. Preliminary screening of a library of 1280 pharmaceutically active compounds identified inhibitors with novel chemical scaffolds. This assay will be a powerful tool for target validation and drug lead identification and characterization.


Asunto(s)
Amidohidrolasas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Inhibidores Enzimáticos/química , Espectrometría de Masas/métodos , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/genética , Secuencia de Aminoácidos , Animales , Línea Celular , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes/química , Proteínas Ligadas a GPI , Ensayos Analíticos de Alto Rendimiento , Humanos , Riñón/enzimología , Ratones , Datos de Secuencia Molecular , Ácido Pantoténico/química , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrofotometría Ultravioleta
4.
J Am Chem Soc ; 130(20): 6324-5, 2008 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-18444611

RESUMEN

Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15N and variable temperature experiments; mass spectrometry included TOF-ESI-MSn and FT-MSn experiments. Chemical degradation followed by chiral HPLC- and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.


Asunto(s)
Cianobacterias/química , Depsipéptidos/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Depsipéptidos/aislamiento & purificación , Depsipéptidos/farmacología , Cromatografía de Gases y Espectrometría de Masas , Células HL-60 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Resonancia Magnética Nuclear Biomolecular , Espectrometría de Masa por Ionización de Electrospray
5.
J Am Soc Mass Spectrom ; 18(9): 1612-6, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17629494

RESUMEN

An automated, routine method to obtain sub-ppm accurate mass data on a benchtop electrospray ionization time-of-flight (ESI-TOF) mass spectrometer is described. Standards in the mass range 114 to 734 Da were analyzed over a 5-day period to demonstrate intra- and interday precision and mean mass accuracy less than 1 ppm. One hundred drug discovery pharmaceutical compounds were used to demonstrate an absolute average mass accuracy of 0.47 +/- 0.31 ppm. This is in contrast to previous reports of accurate mass analysis using time-of-flight mass spectrometry (TOFMS) technology that operates within 3 to 5 ppm. The same 100 samples were also analyzed using Fourier transform mass spectrometry (FTMS) technology and yielded comparable results to the TOFMS analysis.


Asunto(s)
Microquímica/métodos , Nanotecnología/métodos , Preparaciones Farmacéuticas/análisis , Preparaciones Farmacéuticas/química , Robótica/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Diseño de Fármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
6.
Bioorg Med Chem ; 15(13): 4396-405, 2007 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-17490884

RESUMEN

The design, synthesis, and biological evaluation of beta-keto sulfones as 11beta-HSD1 inhibitors and the mechanism of inhibition are described here. This class of compounds is not active against 11beta-HSD2 and therefore may have therapeutic potential for metabolic syndrome and type 2 diabetes.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cetonas/síntesis química , Cetonas/farmacología , Sulfonas/síntesis química , Sulfonas/farmacología , Alquilación , Animales , Células CHO , Cricetinae , Cricetulus , Electroquímica , Indicadores y Reactivos , Solventes , Relación Estructura-Actividad
7.
Comb Chem High Throughput Screen ; 8(6): 459-66, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16178805

RESUMEN

Integrity profiling of HTS hits is valuable for verification of the hit identity and purity. This provides early discovery researchers with more confident SAR theories. Methodology for integrity profiling of HTS hits must be high throughput, consume little material, and selectively provide structure-based data. Analytical techniques that can be utilized for integrity profiling methods are reviewed for their appropriateness in sample preparation, component separation, detection, purity quantitation, identity confirmation, and follow-up.


Asunto(s)
Cromatografía Liquida/métodos , Técnicas Químicas Combinatorias , Espectrometría de Masas/métodos , Dispersión de Radiación , Espectrofotometría Ultravioleta , Relación Estructura-Actividad
8.
Anal Biochem ; 343(1): 143-51, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16018870

RESUMEN

A novel fluorescent assay to continuously monitor fatty acid amide hydrolase (FAAH) activity that is simple, sensitive, and amenable to high-throughput screening (HTS) of compound libraries is described in this article. Stable Chinese hamster ovary (CHO) cell lines expressing either human FAAH or an inactive mutant, FAAH-S241A, were established. Arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA), a novel fluorogenic substrate for FAAH, was designed and synthesized. FAAH catalyzes the hydrolysis of AAMCA to generate arachidonic acid and a highly fluorescent 7-amino, 4-methyl coumarin (AMC). The assay was done at 25 degrees C by incubating whole cell or microsomal preparations from FAAH-expressing cells with AAMCA. Release of AMC was monitored continuously using a fluorometer. Microsomal FAAH catalyzed the hydrolysis of AAMCA with an apparent K(m) of 0.48muM and V(max) of 58pmolmin(-1)mgprotein(-1). The assay is specific for FAAH given that microsomes prepared from cells expressing FAAH-S241A or vector alone had no significant activity against AAMCA. Furthermore, the activity was inhibited by URB-597, an FAAH-specific inhibitor, in a concentration-dependent manner with an IC(50) of 33.5nM. The assay was optimized for HTS and had a Z' value ranging from 0.7 to 0.9. The assay is also compatible with ex vivo analysis of FAAH activity.


Asunto(s)
Amidohidrolasas/química , Ácidos Araquidónicos/química , Bioensayo/métodos , Cumarinas/química , Colorantes Fluorescentes/química , Microsomas/enzimología , Amidohidrolasas/genética , Animales , Ácidos Araquidónicos/síntesis química , Benzamidas/farmacología , Células CHO , Carbamatos/farmacología , Cumarinas/síntesis química , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Fluorescencia , Colorantes Fluorescentes/síntesis química , Humanos
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