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1.
Reprod Toxicol ; 28(4): 443-55, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19631735

RESUMEN

Belimumab is a fully human monoclonal antibody antagonist for soluble B-lymphocyte stimulator, and is a potential therapeutic for various autoimmune disorders. To support clinical use, belimumab was administered intravenously to pregnant cynomolgus monkeys every 2 weeks throughout gestation at dosages of 5 and 150 mg/kg. Fetuses were delivered by C-section on Gestation Day 150 from one-half of the mothers, and evaluated for teratologic effects (external, visceral, skeletal, and heart), pharmacodynamics (PD) and toxicokinetics (TK). Remaining mothers delivered their infants naturally, enabling extensive assessment of PD and TK during a 1-year postnatal period. Effects attributed to belimumab were limited to the expected pharmacology, primarily decreased numbers of B-lymphocytes in peripheral blood of mothers and infants, and in fetal lymphoid tissues. Infants demonstrated full recovery upon cessation of exposure. In conclusion, belimumab was well tolerated at pharmacologically active dose levels in pregnant cynomolgus monkeys and their infants after exposure throughout pregnancy.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Factor Activador de Células B/inmunología , Feto/efectos de los fármacos , Macaca fascicularis/embriología , Macaca fascicularis/crecimiento & desarrollo , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Área Bajo la Curva , Linfocitos B/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Inmunosupresores/inmunología , Inmunosupresores/farmacología , Activación de Linfocitos/efectos de los fármacos , Intercambio Materno-Fetal/efectos de los fármacos , Intercambio Materno-Fetal/inmunología , Tasa de Depuración Metabólica , Embarazo , Factores de Tiempo
2.
Birth Defects Res B Dev Reprod Toxicol ; 86(2): 117-30, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19278014

RESUMEN

BACKGROUND: Natalizumab is a humanized monoclonal immunoglobulin G4 antibody to human alpha4 integrin that binds to the alpha4 subunit of alpha4beta1 and alpha4beta7 integrins, where it blocks the interaction of these integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands appear to be involved in mammalian fetal development, it is possible that natalizumab may interfere with these processes. METHODS: The effects of natalizumab on fetal development were assessed in cynomolgus monkeys at doses of 0, 3, 10, and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70. Pregnancies were terminated by Cesarean section at GD 100. RESULTS: Natalizumab treatment was not associated with increased abortions. All fetuses were alive. No external, visceral, or skeletal abnormalities were seen that were considered to be related to treatment with natalizumab. No histopathological findings were seen in the heart, a target organ of developmental toxicity with a small molecule inhibitor of alpha4 integrin. At dose levels > or = 10 mg/kg, hematological and/or lymphoid effects were observed in some fetuses, consisting of slight thymic atropy, increased extramedullary hematopoiesis in the spleen with a corresponding decrease in the liver, increases in WBC and nucleated RBC, decreases in RBC parameters, and decreases in lymphoid CD20 staining. CONCLUSION: Natalizumab had no abortifacient or teratogenic effects, but was associated with changes in fetal hematopoiesis and leukocyte trafficking.


Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Anticuerpos Monoclonales/toxicidad , Quimiotaxis de Leucocito/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Feto/efectos de los fármacos , Hematopoyesis Extramedular/efectos de los fármacos , Integrina alfa4/inmunología , Macaca fascicularis/embriología , Animales , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/inmunología , Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Formación de Anticuerpos , Atrofia , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Feto/anomalías , Activación de Linfocitos/efectos de los fármacos , Subgrupos Linfocitarios/efectos de los fármacos , Natalizumab , Organogénesis/efectos de los fármacos , Embarazo , Distribución Aleatoria , Timo/efectos de los fármacos , Timo/embriología , Timo/patología
3.
J Comp Neurol ; 367(1): 70-89, 1996 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-8867284

RESUMEN

Bilateral enucleation was performed at different fetal ages during corticogenesis, and the brains were prepared for histological examination. Early-enucleated fetuses (operated prior to embryonic day 77) showed morphological changes at the level of the thalamus and the cortex. In the thalamus, there was a loss of lamination and a decrease in size of the lateral geniculate nucleus. There was a decrease in the size of the inferior pulvinar, but there was no change in the lateral pulvinar. The border of striate cortex was as sharp in the enucleates as it was in the normal monkeys. In three of the four early enucleates, we observed an interdigitation of striate and extrastriate cortex. In three of the early enucleates, we observed a small island of nonstriate cortex near the striate border that was surrounded entirely by striate cortex. Enucleation led to an age-related reduction of striate cortex. This reduction was greater in the operculum than in the calcarine fissure. The reduction of striate cortex was accompanied by an increase in the dimensions of extrastriate visual cortex, so that the overall dimensions of the neocortex remained invariant. The extrastriate cortex in the enucleated animals presented a uniform cytoarchitecture and was indistinguishable from area 18 in the normal animal. There were changes in the gyral pattern that were restricted mainly to the cortex on the operculum. A deepening of minor dimples as well as the induction of a variable number of supplementary sulci led to an increase in the convolution of the occipital lobe. These results are discussed with respect to the specification of cortical areas. They demonstrate that the reduction in striate cortex was not accompanied by an equivalent reduction in the neocortex; rather, there was a border shift, and a large volume of cortex that was destined to become striate cortex appears to be cytoarchitectonically normal extrastriate cortex.


Asunto(s)
Macaca fascicularis/embriología , Macaca fascicularis/crecimiento & desarrollo , Plasticidad Neuronal , Tálamo/fisiología , Corteza Visual/fisiología , Envejecimiento/fisiología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Enucleación del Ojo , Feto/fisiología , Corteza Visual/embriología , Corteza Visual/crecimiento & desarrollo
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