کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9891231 | 1540398 | 2005 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A functional radioreceptor assay of alpha-V-beta-3 (αvβ3) inhibitors in plasma: Application as an ex vivo pharmacodynamic model
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کلمات کلیدی
bFGFRGDαvβ3RRAEchistatinAUC - AUCArginine-Glycine-Aspartic Acid - آرژینین-گلیسین-اسیدپارشی اسیدAngiogenesis - آنژیوژنزBinding - الزام آورIntegrin - اینتگرینRadioreceptor assay - تست رادیوتراپیpharmacodynamic - فارماکودینامیکbasic fibroblast growth factor - فاکتور رشد فیبروبلاست پایهarea under the curve - منطقه تحت منحنیPlasma - پلاسما
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Development of αvβ3-integrin inhibitors has been hampered by a lack of pharmacodynamic endpoints to identify doses that inhibit αvβ3 in vivo. To address this need, we developed an αvβ3 radioreceptor assay (RRA) that could be performed in 100% plasma. The RRA was based on 125I-echistatin binding to plate-immobilized αvβ3. Small molecule αvβ3 inhibitors efficiently competed echistatin binding to αvβ3 when the assay was carried out in buffer. However, when carried out in 100% plasma, the RRA revealed a 45 to > 3000-fold loss in compound potencies. The losses in potency reflected, in part, the high plasma protein binding by the compounds examined. The RRA was adapted as an ex vivo pharmacodynamic model. Echistatin binding was measured in the presence of plasma harvested at timed intervals from rats dosed with select compounds. Using this pharmacodynamic model, compound and dose selection was optimized for further testing in models of corneal angiogenesis. Moderate anti-angiogenic activity was achieved when rats were dosed sufficient to achieve sustained (> 50%) plasma inhibition through the trough interval. Thus, the RRA provided a simple technique to rank order compound potency in plasma, and could find general use as an ex vivo pharmacodynamic assay to select compounds and doses for preclinical and clinical proof-of-principle studies.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Biochemical and Biophysical Methods - Volume 65, Issues 2â3, 31 December 2005, Pages 107-120
Journal: Journal of Biochemical and Biophysical Methods - Volume 65, Issues 2â3, 31 December 2005, Pages 107-120
نویسندگان
Margery A. Chaikin, Júan José Marugan, Gerald W. De Vries, Peter Baciu, Jeffrey Edelman, Ming Ni, Bruce E. Tomczuk, Wenxi Pan, Zihong Guo, Beth Anaclerio, Kristi Leonard, Stephen H. Eisennagel, Christopher J. Molloy, Carl L. Manthey,