RESUMEN
In the design of 1-phenylbenzimidazoles as model cyclooxygenase (COX) inhibitors, docking to a series of crystallographic COX structures was performed to evaluate their potential for high-affinity binding and to reproduce the interaction profile of well-known COX inhibitors. The effect of ligand-specific induced fit on the calculations was also studied. To quantitatively compare the pattern of interactions of model compounds to the profile of several cocrystallized COX inhibitors, a geometric parameter, denominated ligand-receptor contact distance (LRCD), was developed. The interaction profile of several model complexes showed similarity to the profile of COX complexes with inhibitors such as iodosuprofen, iodoindomethacin, diclofenac, and flurbiprofen. Shaping of high-affinity binding sites upon ligand-specific induced fit mostly determined both the affinity and the binding mode of the ligands in the docking calculations. The results suggest potential of 1-phenylbenzimidazole derivatives as COX inhibitors on the basis of their predicted affinity and interaction profile to COX enzymes. The analyses also provided insights into the role of induced fit in COX enzymes. While inhibitors produce different local structural changes at the COX ligand binding site, induced fit allows inhibitors in diverse chemical classes to share characteristic interaction patterns that ensure key contacts to be achieved. Different interaction patterns may also be associated with different inhibitory mechanisms.
Asunto(s)
Bencimidazoles/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Cristalografía por Rayos X , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Bases de Datos de Proteínas , Indometacina/química , Indometacina/farmacología , Ligandos , Simulación del Acoplamiento Molecular , Prostaglandina-Endoperóxido Sintasas/química , TermodinámicaRESUMEN
The primary strategy to avoid mother-to-child transmission of human immunodeficiency virus (HIV) through breastfeeding is administration of highly active antiretroviral therapy (HAART) to HIV-positive pregnant women. Because significant changes in the pharmacokinetics of antiretroviral (ARV) drugs occur during pregnancy, quantifying HAART and the viral load in breast milk in this population is essential. Here, we developed an analytical assay for the simultaneous quantification of four ARV drugs in breast milk using ultra-performance liquid chromatography coupled to tandem mass spectrometry. We validated this method following Mexican and international guidelines. ARV drugs. We extracted the ARV drugs from 200 µL samples of breast milk and detected these drugs in a triple quadrupole mass spectrometer with positive electrospray ionization. The validated concentration ranges (ng/mL) for zidovudine, lamivudine, lopinavir, and ritonavir were 12.5-750, 50-2500, 100-5000 and 5 to 250, respectively. Additionally, the absolute recovery percentages (and matrix effects) were 91.4 (8.39), 88.78 (28.75), 91.38 (11.77) and 89.78 (12.37), respectively. We determined that ARV drugs are stable for 24 h at 8°C and 24°C for 15 days at -80°C. This methodology had the capacity for simultaneous detection; separation; and accurate, precise quantification of ARV drugs in human breast milk samples according to Mexican standard laws and United States Food and Drug Administration guidelines.
Asunto(s)
Fármacos Anti-VIH/análisis , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Leche Humana/química , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/normas , Lactancia Materna , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Calostro/química , Femenino , Infecciones por VIH/prevención & control , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Lamivudine/análisis , Lopinavir/análisis , Embarazo , Complicaciones Infecciosas del Embarazo/metabolismo , Estándares de Referencia , Reproducibilidad de los Resultados , Ritonavir/análisis , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normas , Adulto Joven , Zidovudina/análisisRESUMEN
Treatment with 17-ß estradiol and progesterone improves the performance of ovariectomized rats in an autoshaping learning task, representing cognitive improvement. To test whether this is attributable to genomic mechanisms, the antiestrogen ICI 182 780 or antiprogesterone RU486 was injected into ovariectomized animals primed previously with estrogen or progesterone, respectively. Compared with the vehicle control, each hormone administered alone produced an elevated expression of choline acetyltransferase and TrkA, along with an improvement in performance on the behavioral test. E2+ICI reverted the increase in these two proteins. However, RU alone elicited higher ChAT expression. With this exception, there was a clear linear regression between the number of conditioned responses and the level of ChAT and TrkA in the basal forebrain. The results suggest that TrkA may be more important than ChAT for regulating autoshaping learning tasks, and that genomic mechanisms in the basal forebrain could possibly underlie hormonal improvement of cognition.
Asunto(s)
Colina O-Acetiltransferasa/metabolismo , Cognición/efectos de los fármacos , Receptor trkA/metabolismo , Animales , Colina O-Acetiltransferasa/genética , Estradiol/metabolismo , Estradiol/farmacología , Femenino , Fulvestrant/metabolismo , Fulvestrant/farmacología , Aprendizaje/efectos de los fármacos , Mifepristona/metabolismo , Mifepristona/farmacología , Ovariectomía , Progesterona/metabolismo , Progesterona/farmacología , Ratas , Ratas Sprague-Dawley , Receptor trkA/genéticaRESUMEN
Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11ß-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.