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1.
Invest Ophthalmol Vis Sci ; 49(2): 662-70, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18235012

RESUMO

PURPOSE: To investigate the effect of the combined treatment of photodynamic therapy and specific VEGF165 inhibition with pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Lexington, MA) on ocular neovascularization. METHODS: Photodynamic therapy's (PDT's) effects on the integrity of pegaptanib sodium were analyzed by HPLC, a VEGF165-binding assay, and a VEGF165-induced tissue factor gene expression assay. The effects of mono- or combined treatment on vessel growth and regression were determined in a murine corneal neovascularization model. The effects of combined treatment on vessel growth were also determined in a murine choroidal neovascularization model. RESULTS: PDT did not affect the chemical composition of pegaptanib sodium nor the efficacy of pegaptanib sodium in the inhibition of VEGF165 binding to Flt-1 and VEGF165-induced gene expression. In an animal model of effects on existing ocular neovascular lesions (corneal neovascularization), PDT monotherapy yielded an initial regression of these vessels, but there followed a rapid regrowth. In contrast, pegaptanib sodium monotherapy yielded little regression but potently abrogated further vessel growth. The combination of pegaptanib sodium and PDT resulted in the regression of the neovascular lesions, as observed with PDT alone, but also prevented significant vessel regrowth, leading to a significantly greater reduction in lesion size than did each monotherapy. In addition, there was a significantly greater effect of the combination of pegaptanib sodium and PDT on lesion size in choroidal neovascularization than with each monotherapy. Pretreatment with pegaptanib sodium appeared to decrease the efficacy of PDT-induced vessel regression in corneal neovascularization, and as such the enhanced efficacy over monotherapy when the agents were delivered simultaneously was not observed. CONCLUSIONS: Although the combined simultaneous treatment of ocular neovascularization with PDT and pegaptanib sodium may provide a more effective approach for the regression and overall treatment of CNV associated with AMD, the order of addition of these treatments may play a role in achieving optimal efficacy.


Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Neovascularização da Córnea/tratamento farmacológico , Modelos Animais de Doenças , Fotoquimioterapia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Cromatografia Líquida de Alta Pressão , Córnea/irrigação sanguínea , Neovascularização da Córnea/metabolismo , Neovascularização da Córnea/patologia , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , RNA Mensageiro/metabolismo , Tromboplastina/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Verteporfina
2.
Circulation ; 113(19): 2278-84, 2006 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-16682612

RESUMO

BACKGROUND: Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. METHODS AND RESULTS: We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 microg/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. CONCLUSIONS: The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.


Assuntos
Plaquetas/química , Calgranulina B/genética , Doença da Artéria Coronariana/genética , Perfilação da Expressão Gênica , Infarto do Miocárdio/genética , RNA Mensageiro/análise , Doença Aguda , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/sangue , Antígenos de Diferenciação de Linfócitos T/genética , Biomarcadores/sangue , Calgranulina B/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C , Masculino , Megacariócitos/química , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Transcrição Gênica
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