Pharmacologic prevention of both restenosis and atherosclerosis progression: AGI-1067, probucol, statins, folic acid and other therapies.
OBJECTIVE
In this article, the authors intend to provide an update on clinical trials of pharmacologic prevention of restenosis after percutaneous coronary interventions, placed in the perspective of the use of orally administered therapy for the prevention of atherosclerosis progression and clinical events.


RESULTS
AGI-1067, the mono-succinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed v-protectants. It has strong antioxidant properties equipotent to those of probucol and antiinflammatory properties. It inhibits gene expression of VCAM-1 and MCP-1 and has been effective at preventing atherosclerosis in all tested animal models including the non-human primate. In the Canadian Antioxidant Restenosis Trial (CART) 1, AGI-1067 and probucol improved lumen dimensions at the site of percutaneous coronary intervention. AGI-1067 also improved luminal dimensions of non-intervened coronary reference segments in the Canadian Antioxidant Restenosis Trial, which suggests a direct antiatherosclerosis effect. Probucol reduced post-percutaneous coronary intervention restenosis and progression of carotid atherosclerosis in other clinical trials. Although statins reduce atherosclerotic events, they do not appear to have a significant effect on restenosis. The failure of folate therapy to protect against restenosis in the Folate After Coronary Intervention Trial (FACIT) occurred despite significant reductions in homocysteine levels.


CONCLUSIONS
Prevention of both post-percutaneous coronary intervention restenosis and atherosclerosis progression with a pharmacologic agent such as AGI-1067 may be an attractive treatment paradigm. Two important trials that test the antioxidant/antiinflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial 2, which assesses its value for the reduction of both atherosclerosis progression and post-percutaneous coronary interventions restenosis, and the Aggressive Reduction of Inflammation Stops Events (ARISE) trial which is evaluating its effects on cardiovascular events.
Tardif
Jean-Claude
JC
Montreal Heart Institute, 5000 Belanger Street, Montreal, PQ, H1T 1C8, Canada. tardifjc@icm.umontreal.ca
Grégoire
Jean
J
Lavoie
Marc-André
MA
L'Allier
Philippe L
PL
D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000517:prevention & control*; D023903:Coronary Restenosis / Q000188:drug therapy / Q000517:prevention & control*; D005492:Folic Acid / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D011341:Probucol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use; D062367:ortho-Aminobenzoates / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014815:Vitamins; D062367:ortho-Aminobenzoates; D005492:Folic Acid; C012293:tranilast; C471047:succinobucol; D011341:Probucol; D020123:Sirolimus