Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution
Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution
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DOI：
10.1016/s0008-6363(97)00142-9
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发表时间：
1997-10-01
影响因子：
10.8
通讯作者：
Unger, EF
中科院分区：
文献类型：
--
作者：
Lazarous, DF;Shou, M;Unger, EF
目的：我们已经证明，通过左心房或冠状动脉内途径给药时，碱性成纤维细胞生长因子（bFGF/FGF-2）可增强进行性冠状动脉闭塞犬模型中的心肌侧枝发育；然而，我们发现静脉注射 bFGF 在同一模型中无效。关于静脉注射 bFGF 的命运和功效的数据有限。我们假设肺首过摄取可能会限制静脉注射后心肌 bFGF 的可用性。我们假设通过楔形 Swan Ganz 导管的远端端口输送 bFGF 可能会通过限制 bFGF 暴露于有限数量的肺部结合位点来避免这个问题。本研究评估了静脉推注、Swan Ganz、左心房、冠状动脉内和心包递送后 I-125 标记的 bFGF 的不同区域摄取。方法：使用杂种狗。用 I-125 单碘化的人重组 bFGF 与冷 bFGF 混合至比活性为 0.03 mu Ci/mu g。通过静脉内、左心房、Swan Ganz、冠状动脉内或心包途径注射每只动物约100μg/kg。 15分钟或150分钟后狗被杀死。收获心脏、肺、肝脏、脾脏和肾脏并评估 I-125 活性。还进行了免疫组织化学和药代动力学研究。结果：冠状动脉内、静脉内和左心房分娩后，bFGF 的血清半衰期相当（50 分钟）；然而，在药效学方面存在显着差异。冠状动脉内给药后，从心脏回收总bFGF剂量的3-5%，肽免疫定位于细胞外基质和血管内皮。相比之下，左心房给药后，仅 1.3% 的注射 bFGF 定位于心脏，静脉或 Swan Ganz 给药后恢复了 0.5%，心包给药导致大量心脏 bFGF 给药，150 分钟时存在 19%，心肌摄取与 Swan Ganz 和静脉给药相似，表明给药剂量并未使可用的肺组织饱和。 结论：这些数据预测了冠状动脉内、左心房和心包内 bFGF 对心肌血管生成的功效，以及静脉推注和 Swan Ganz 给药后缺乏功效。 (C) 1997 Elsevier Science B.V.
Objective: We have shown that basic fibroblast growth factor (bFGF/FGF-2) enhances myocardial collateral development in a canine model of progressive coronary occlusion when delivered via the left atrial or intracoronary routes; however, we have found intravenous bFGF ineffective in the same model. Data on the fate and efficacy of intravenous bFGF are limited. We hypothesized that first pass lung uptake might limit myocardial bFGF availability after intravenous injection. We postulated that delivery of bFGF through the distal port of a wedged Swan Ganz catheter might circumvent this problem by restricting exposure of bFGF to a limited number of pulmonary binding sites. This study evaluated differential regional uptake of I-125 labeled bFGF following bolus intravenous, Swan Ganz, left atrial, intracoronary, and pericardial delivery. Methods: Mongrel dogs were used. Human recombinant bFGF, monoiodinated with I-125, was mixed with cold bFGF to a specific activity of 0.03 mu Ci/mu g. Approximately 100 mu g/kg was injected per animal by the intravenous, left atrial, Swan Ganz, intracoronary, or pericardial route. Dogs were killed 15 min or 150 min later. The heart, lungs, Liver, spleen, and kidneys were harvested and I-125 activity was assessed. Immunohistochemical and pharmacokinetic studies were also performed. Results: Serum half life of bFGF was comparable after intracoronary, intravenous and left atrial delivery (50 min); however, there were significant differences with regard to pharmacodynamics. After intracoronary administration, 3-5% of the total bFGF dose was recovered from the heart, with the peptide immunolocalized to the extracellular matrix and vascular endothelium. In contrast, only 1.3% of the injected bFGF was localized to the he;ut after left atrial administration, and 0.5% was recovered after intravenous or Swan Ganz delivery, Pericardial administration resulted in substantial cardiac bFGF delivery 19% was present at 150 min, Myocardial uptake was similar with Swan Ganz and intravenous delivery, suggesting that the administered dose did not saturate available pulmonary binding sites, Conclusions: These data predict efficacy of intracoronary, left atrial, and pericardial bFGF for myocardial angiogenesis, and a lack of efficacy after bolus intravenous and Swan Ganz administration. (C) 1997 Elsevier Science B.V.