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      Tratamento da forma neovascular de degeneração macular relacionada à idade com drogas antiangiogênicas Translated title: Treatment of neovascular age-related macular degeneration with antiangiogenic drugs

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          Abstract

          Degeneração macular relacionada à idade (DRMI) é a principal causa de cegueira no mundo ocidental. Várias formas clínicas foram reconhecidas, e membrana neovascular coroideana (MNSR) representa manifestação importante passível de tratamento. O tratamento de MNSR tem sido um foco importante de pesquisa nas últimas décadas e a primeira terapia estabelecida baseada em evidência foi a fotocoagulação a laser, que reduziu o risco de perda visual em lesões extrafoveais. No fim da década de 90 a terapia fotodinâmica foi estabelecida como método eficiente de tratamento de MNSR predominantemente clássicas e ocultas. Terapias adicionais como a translocação macular, cirurgia submacular, e protrombose mediada por indocianina verde estão atualmente em investigação em ensaios clínicos em larga escala. A biologia molecular permitiu recentemente uma melhor compreensão da patogênese da DMRI e o fator de crescimento vascular endotelial foi reconhecido como um mediador-chave na angiogênese da formação de MNSR. Portanto, a abordagem farmacológica surge como opção terapêutica no tratamento da MNSR. O primeiro agente terapêutico aprovado pelo FDA é o aptâmero pegaptanib sódio (Macugen®), que inativa a isoforma fundamental para a angiogênese intra-ocular: VEGF165. Outros inativadores de VEGF como ranibizumab RhuFab V2 (Lucentis®) e bevacizumab (Avastin®) estão em avaliação em estudos clínicos. Resultados impressionantes de bevacizumab intravítreo foram liberados recentemente. Adicionalmente, o derivado de esteróides acetato de anecortave, assim como o corticosteróide acetato de triancinolona têm sido propostos como métodos no tratamento de DMRI-neovascular. Este artigo apresenta os princípios e resultados iniciais na terapia antiangiogênica farmacológica da MNSR na DMRI.

          Translated abstract

          Age-related macular degeneration (ARMD) remains a leading cause of blindness in the western world. Several clinical forms of the disease are recognized, whereas choroidal neovascularization (CNV) represents an important manifestation suitable for treatment. The treatment of CNV has been a major focus of research in the past decades, and the first evidence-based established therapy was laser photocoagulation, which reduces the risk of visual loss in extrafoveal lesions. In the late 90's photodynamic therapy has been established as an efficient method for the treatment of predominantly classic and occult CNV. Additional therapies such as macular translocation, submacular surgery, and indocyanine-mediated prothrombosis are currently under investigation in large-scale clinical trials. Molecular biology has recently provided a better comprehension of the pathogenesis of ARMD, and vascular endothelial growth factor (VEGF) was recognized as key mediator in the angiogenesis of CNV-formation. Therefore, the pharmacological approach rose as a key research area to treat CNV. The first FDA-approved agent for CNV-therapy is aptamer pegaptanib sodium (Macugen®), which inactivates the key angiogenic isoform VEGF165. Additional VEGF-blockers such as ranibizumab RhuFab V2 (Lucentis®) and bevacizumab (Avastin®) are under evaluation in major clinical studies. Impressive results of intravitreal bevacizumab were released recently. Moreover, the steroid-derived anecortave acetate as well as the corticosteroid triamcinolone acetate have been proposed as methods for treatment of wet-ARMD. This paper presents the rationale and principles of the pharmacologic antiangiogenic therapy for CNV in ARMD.

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          Angiogenesis in cancer and other diseases.

          Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.
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            Pegaptanib for neovascular age-related macular degeneration.

            Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration. We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks. In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Among the adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic injury to the lens (in 0.7 percent), and retinal detachment (in 0.6 percent) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1 percent of patients. Pegaptanib appears to be an effective therapy for neovascular age-related macular degeneration. Its long-term safety is not known. Copyright 2004 Massachusetts Medical Society.
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              Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

              Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.
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                Author and article information

                Journal
                abo
                Arquivos Brasileiros de Oftalmologia
                Arq. Bras. Oftalmol.
                Conselho Brasileiro de Oftalmologia (São Paulo, SP, Brazil )
                0004-2749
                1678-2925
                October 2006
                : 69
                : 5
                : 756-765
                Affiliations
                [01] orgnameHospital Regional São José orgdiv1Departamento de Retina orgdiv2Serviço de Oftalmologia
                [02] Florianópolis SC orgnameInstituto de Olhos Florianópolis orgdiv1Centro Oftalmológico Brasil
                [07] Marburg orgnamePhillips-University orgdiv1Hospital de Olhos orgdiv2Departamento de Oftalmologia Alemanha
                [08] Philadelphia PA orgnameWills Eye Hospital orgdiv1Retina Service USA
                [03] orgnameHospital Regional São José orgdiv1Departamento de Retina orgdiv2Serviço de Oftalmologia
                [04] Florianópolis SC orgnameInstituto de Olhos Florianópolis orgdiv1Centro Oftalmológico Brasil
                [05] orgnameHospital Regional São José orgdiv1Departamento de Retina orgdiv2Serviço de Oftalmologia
                [06] Florianópolis SC orgnameInstituto de Olhos Florianópolis orgdiv1Centro Oftalmológico Brasil
                Article
                S0004-27492006000500027 S0004-2749(06)06900527
                78dc284c-3fe1-4d75-bec2-c270059b931c

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                Figures: 0, Tables: 0, Equations: 0, References: 77, Pages: 10
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                Fator de crescimento do endotélio vascular,Inibidores de angiogênese,Macular degeneration,Retinal neovascularization,Vascular endothelial growth factor,Angiogenesis inhibitors,Degeneração macular,Neovascularização retiniana

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