RESUMEN
BACKGROUND: Vitamin D analogs and calcimimetics are used to manage secondary hyperparathyroidism (SHPT) in dialysis patients. DP001 is an oral vitamin D analog that suppresses parathyroid hormone (PTH) in uremic rats, osteopenic women, and hemodialysis patients. The safety and effectiveness of DP001 suppressing PTH in dialysis patients previously managed with active vitamin D with or without a calcimimetic are presented. METHODS: A multicenter, randomized, double-blind study compared DP001 to placebo in hemodialysis patients with serum-intact PTH (iPTH) ≥300 pg/ml. The primary efficacy endpoint was the proportion of patients achieving 2 consecutive ≥30% decreases in iPTH levels during the 12 weeks of treatment. Calcium, phosphorus, calcium × phosphorus product and safety were also evaluated. The responses to DP001 were compared in patients previously treated with both active vitamin D and a calcimimetic to those previously on active vitamin D alone. RESULTS: Sixty-two patients were randomized (n = 34 DP001; n = 28 placebo). At week 12, 78% of all DP001-treated patients and 7% of all placebo-treated patients achieved the primary endpoint (p < 0.0001); iPTH fell 45% in the DP001 group and increased 37% in the placebo group. No patient exceeded the safety threshold of 2 consecutively corrected serum calcium levels ≥11.0 mg/dl. Patients previously on cinacalcet plus active vitamin D also responded to DP001 (n = 10) resulting in a 55% decrease in iPTH, while those on placebo (n = 9) increased by 70%. CONCLUSION: DP001 safely and effectively suppressed iPTH in hemodialysis patients with SHPT that were previously managed with active vitamin D alone or with a calcimimetic (www.clinicaltrials.gov, NCT01922843).
Asunto(s)
Calcitriol/análogos & derivados , Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/terapia , Diálisis Renal , Adulto , Anciano , Calcitriol/uso terapéutico , Calcio/metabolismo , Método Doble Ciego , Femenino , Humanos , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/metabolismo , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/metabolismo , Fósforo/metabolismo , Resultado del TratamientoRESUMEN
Neural precursor cell expressed, developmentally down-regulated 9 (Nedd9, Casl, Hef1, p105cas, Ef1) is a scaffolding protein that assembles complexes involved in regulating cell adhesion, migration, division, and survival. Nedd9 is found very early in the developing embryonic nervous system. A highly conserved complex retinoic acid response element (RARE) is located 485 base pairs (bp) upstream of exon 2B in the promoter of the Nedd9 gene. Mice transgenic for a 5.2 kilobase (kb) region of the 2B Nedd9 promoter containing the RARE upstream of a lacZ reporter gene [Nedd9(RARE)-lacZ] show a large subset of the normal endogenous Nedd9 expression including that in the caudal hindbrain neuroepithelium, spinal cord, dorsal root ganglia (drg) and migrating neural crest (ncc). However, the transgenic mice do not recapitulate the native Nedd9 expression pattern in presumptive rhombomeres (pr) 3 and 5 of the early hindbrain, the base of the neuroepithelium in the midbrain, nor the forebrain telencephalon. Thus, the 5.2 kb region containing the intact RARE drives a large subset of Nedd9 expression, with additional sequences outside of this region needed to define the full complement of expression. When the 5.2 kb construct is modified (eight point mutations) to eliminate responsiveness of the RARE to all-trans retinoic acid (atRA) [Nedd9(mutRARE)-lacZ], virtually all ß-galactosidase (ß-gal, lacZ) expression is lost. Exposure of Nedd9(RARE)-lacZ transgenic embryos to excess atRA at embryonic day 8.0 (E8.0) leads to rostral ectopic transgene expression within 6 h whereas the Nedd9(mutRARE)-lacZ mutant does not show this effect. Thus the RARE upstream of the Nedd9 2B promoter is necessary for much of the endogenous gene expression during early development as well as ectopic expression in response to atRA.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica/genética , Tretinoina/administración & dosificación , Animales , Embrión de Mamíferos , Ratones , Ratones Transgénicos , Regiones Promotoras GenéticasRESUMEN
The vitamin A metabolite, all-trans retinoic acid (atRA), is a regulator of nervous system development. Using a subtracted cDNA library constructed from neuroblastoma cells, the atRA-responsive gene calmin (Clmn) was identified (Merrill et al. [2004] Biol Chem 385:605-614). The Clmn transcript is detected very early in rat embryonic development and is sensitive to retinoid status. In vitamin A-deficient embryos, Clmn mRNA is dramatically down-regulated in the neuroepithelium adjacent to the somites, and this expression can be rescued with the addition of atRA. In embryonic day 18.5 embryos, CLMN is detected in regions where newly differentiated neurons are found, including the neural retina and the cortical plate; and in the adult brain, CLMN is most highly expressed in the neuron cell bodies of the hippocampus, cerebellum, and olfactory bulb. Thus, Clmn is sensitive to retinoid status during early gestational stages, and its expression is relegated to postmitotic neuronal cells in the adult rat brain.