BASIC FIBROBLAST GROWTH FACTOR AND MYOCARDIAL ANGIOGENESIS

几种多肽生长因子已被证实具有这种能力 诱导血管发育(血管生成)，总体上 项目目标是利用这种生长因子促进冠状动脉 缺血性心脏病患者的侧枝循环发育。我们有 研究表明，碱性成纤维细胞生长因子(BFGF)与血管 内皮生长因子，既有血管生成多肽生长因子， 给药后促进犬冠脉侧支循环发育 反复进入冠脉循环，或者，对于碱性成纤维细胞生长因子，当 每日注入全身动脉循环，共7次 几天。这些管理途径，尽管在 实验动物，在人类受试者身上是不实用的。多数 最近，我们发现，两个单剂量的碱性成纤维细胞生长因子被注射到 左冠状动脉主干增加犬冠脉侧支血流， 一种在人类受试者身上可行的养生法。狗受制于 导致冠状动脉左回旋支逐渐闭塞 随机接受碱性成纤维细胞生长因子100微克/公斤或赋形剂对照组 冠脉内给药一次或两次(每次给药间隔2天)。 在最大冠状动脉血管扩张期间评估侧支循环灌注 治疗后17天。接受治疗的狗的最大侧支血流 两个剂量的碱性成纤维细胞生长因子超过对照组的39%(P&lt；0.0005)。 根据这些和之前的一些调查，我们已经获得了 一种用于人体第一阶段研究的IND(研究新药)。 这是一项随机、双盲的安全性研究，采用典型剂量 将bFGF(或车辆)管理到 冠状循环。首批参与研究的患者是在 1995年7月。更多的临床前研究正在进行中，以评估 基因治疗影响冠状动脉血管生成的可能性。基因治疗 是管理的一个有吸引力的替代方案。 多肽生长因子。血管生成的持续局部表达 基因产物可导致部位特异性血管生成刺激 在接受一次冠状动脉内治疗后。

Several polypeptide growth factors have been identified with the ability to induce blood vessel development (angiogenesis), and the overall project goal is to utilize such growth factors to facilitate coronary collateral development in patients with ischemic heart disease. We have shown that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor, both angiogenic polypeptide growth factors, enhance coronary collateral development in dogs when administered repeatedly into the coronary circulation, or, in the case of bFGF, when administered daily into the systemic arterial circulation for seven days. These routes of administration, although acceptable in experimental animals, are not practical in human subjects. Most recently, we have shown that two single doses of bFGF administered into the left main coronary artery enhance coronary collateral flow in dogs, a regimen that would be feasible in human subjects. Dogs were subjected to gradual occlusion of the left circumflex coronary artery and randomized to receive bFGF 100 micrograms/kg or a vehicle control as an intracoronary bolus on one or two occasions (2 days between doses). Collateral perfusion was assessed during maximal coronary vasodilatation 17 days after treatment. Maximal collateral flow in dogs that received two doses of bFGF exceeded that of control dogs by 39% (P<0.0005). Based on these and a number of earlier investigations, we have obtained an IND (Investigational New Drug) for a Phase I study in human subjects. This is a randomized, double-blind safety study with a typical dose escalation format in which bFGF (or vehicle) is administered into the coronary circulation. The first patients entered into the study in July, 1995. Additional preclinical studies are underway to assess the potential of gene therapy to effect coronary angiogenesis. Gene therapy represents an attractive alternative to the administration of polypeptide growth factors. Sustained local expression of angiogenic gene products could result in site-specific angiogenic stimulation following a single intracoronary treatment.