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Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris
E F Unger1, L Goncalves, S E Epstein
1Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20852-1428, USA. ungere@cber.fda.gov
Insights
Basic fibroblast growth factor (bFGF) showed good tolerability in stable angina patients at doses up to 30 microg/kg. This initial human trial found bFGF generally safe, with some hypotension and bradycardia at higher doses.
Area of Science:
- Cardiovascular Medicine
- Regenerative Medicine
- Clinical Pharmacology
Background:
- Basic fibroblast growth factor (bFGF) promotes angiogenesis and collateral development in animal models of coronary artery disease.
- Parenteral administration of bFGF in humans for cardiovascular indications was previously unevaluated.
Purpose of the Study:
- To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single intracoronary basic fibroblast growth factor (bFGF) injections in patients with stable angina.
- To establish the maximum tolerated dose and characterize the safety profile of bFGF in this patient population.
Main Methods:
- A Phase 1, randomized, dose-escalation trial involving 25 subjects with coronary artery disease and stable angina.
- Subjects received a single intracoronary injection of bFGF (3-100 microg/kg) or placebo in a 2:1 ratio.
- Safety, tolerability, pharmacokinetic parameters (clearance, half-life), and pharmacodynamic effects (hypotension, bradycardia, coronary artery diameter) were monitored.
Main Results:
- bFGF was generally well tolerated at doses up to 30 microg/kg.
- Plasma clearance was 20 +/- 2 ml/kg/min with an elimination half-life of 85 +/- 11 minutes.
- Acute dose-unrelated hypotension occurred in approximately 10% of subjects. Sustained hypotension, bradycardia, transient thrombocytopenia, and proteinuria were observed at higher doses (30-100 microg/kg).
- bFGF demonstrated coronary artery vasodilation (7.4 +/- 2.5% increase in diameter, p <0.02). No signs of systemic angiogenesis were detected.
Conclusions:
- Intracoronary bFGF at doses of 3 to 30 microg/kg is generally well tolerated in patients with stable angina.
- Higher doses (30-100 microg/kg) were associated with adverse events including hypotension and bradycardia.
- Further investigation into the therapeutic potential and safety of lower-dose bFGF in cardiovascular disease is warranted.
Abstract:
We sought to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of basic fibroblast growth factor (bFGF), administered as a single intracoronary injection, to subjects with stable angina pectoris secondary to coronary artery disease. bFGF, an angiogenic growth factor, has been shown to enhance collateral development in animal models of progressive coronary occlusion. To our knowledge, this study represents the initial introduction of parenteral bFGF into humans. This was a phase 1, randomized, dose-escalation trial of bFGF in 25 subjects with coronary artery disease and stable angina. Subjects were randomized 2:1 to a single dose of bFGF or placebo, injected into the left main coronary artery. bFGF doses ranged from 3 to 100 microg/kg, increasing in half-log increments. bFGF was generally well tolerated at doses of 3 to 30 microg/kg. Plasma clearance was 20 +/- 2 ml/kg/min, with an elimination half-life of 85 +/- 11 minutes. bFGF caused acute hypotension ( approximately 10%) that did not appear to be dose-related through the dose range studied. Of the 9 subjects who received 30 to 100 microg/kg bFGF, 2 had sustained hypotension, mild to moderate in severity, lasting 1 to 3 days, and 3 subjects developed bradycardia hours to days after bFGF administration. bFGF dilated epicardial coronary arteries (7.4 +/- 2.5% mean diameter increase, p <0.02). Transient mild thrombocytopenia and proteinuria were observed in some subjects in the 30-microg/kg cohort. No subject had signs suggesting systemic angiogenesis. Thus, intracoronary bFGF, at doses of 3 to 30 microg/kg, was generally well tolerated in subjects with stable angina.