RESUMEN
CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment.
Asunto(s)
Hormona de Crecimiento Humana/uso terapéutico , Hipopituitarismo/terapia , Lípidos/sangre , Proteínas Recombinantes/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Adulto , Anciano , Composición Corporal/efectos de los fármacos , Método Doble Ciego , Ecocardiografía , Ejercicio Físico/fisiología , Femenino , Hormona de Crecimiento Humana/deficiencia , Humanos , Hipopituitarismo/sangre , Hipopituitarismo/fisiopatología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/efectos de los fármacos , Resistencia Física/efectos de los fármacosRESUMEN
Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta.
Asunto(s)
Compuestos Azo/síntesis química , Compuestos Azo/farmacología , Receptor beta de Estrógeno/agonistas , Fluorenos/química , Fluorenos/farmacología , Animales , Compuestos Azo/química , Compuestos Azo/farmacocinética , Receptor beta de Estrógeno/metabolismo , Fluorenos/síntesis química , Fluorenos/farmacocinética , Humanos , Ligandos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
Asunto(s)
Oxatiinas/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Animales , Sitios de Unión , Unión Competitiva , Línea Celular , Cristalografía por Rayos X , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Tamaño de los Órganos/efectos de los fármacos , Oxatiinas/química , Oxatiinas/farmacología , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Activación Transcripcional , Útero/efectos de los fármacosRESUMEN
A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
Asunto(s)
Flavonoides/química , Flavonoides/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Femenino , Humanos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Útero/metabolismoRESUMEN
A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.