Several polypeptide growth factors have 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 or peripheral vascular disease. 1) We conducted a Phase I clinical trial of basic fibroblast growth factor (bFGF)in 25 pts randomized to a single dose of bFGF or placebo (in a 2:1 ratio), infused into a coronary artery over 1 minute. Consecutive cohorts received 3,10, 30 and 100 mcg/kg bFGF. bFGF caused an acute 5-18% decrease in MAP that was well-tolerated and independent of dose and an increase in epicardial coronary diameter (2.0 +/- 0.5 to 2.2 +/- 0.5 mm, P<.02). We concluded that IC bFGF at doses of 3-30 mcg/kg is generally well tolerated in pts with coronary disease and stable angina. Higher doses were associated with unacceptable side effects. 2) We also assessed the safety of intra- arterial bFGF in patients with intermittent claudication, and studied its effects on calf bloodflow. A double-blind, placebo-controlled, dose-escalation trial was conducted in claudication patients with ankle/brachial systolic index <0.8. Patients were randomly assigned to placebo (n=6), 10 mcg/kg of bFGF n=4), 30 mcg/kg of bFGF once (n=5) and 30 mcg/kg of bFGF twice (n=4). The study drug was infused into the femoral artery of the ischemic leg. Intra arterial bFGF was well tolerated. bFGF (30mcg/Kg) significantly improved calf bloodflow at 1 month by 66 +/- 26% (mean +/- SEM), and at 6 months by 153 +/- 51% (n=9, P=0.002). The magnitude of increase in calf blood flow was greater in patients receiving 2 doses of bFGF compared to 1 dose of 30 mcg/kg. Flow did not change significantly in the placebo group. bFGF- treated patients reported subjective improvement in symptoms of claudication, in contrast to placebo patients. In patients with intermittent claudication, 2 intra-arterial doses of 30 mcg/kg bFGF are safe. Based on these experiences we have proposed 2 phase I/II trials a) in the coronary circulation of CAD patients and b) in the peripheral circulation in PVD patients to evaluate the efficacy of bFGF in promoting angiogenesis. 3) Currently, we are planning a study to evaluate the potency of an adenovirus vector for VEGF (Ad GV VEGF) by direct intramuscular injection in patients with PVD.4) We are also planning to perform a study using GMCSF as a stimulator of endothelial progenitor cells in patients with PVD. - angiogenesis, basic fibroblast growth factor, vascular endothelial growth factor - Human Subjects
