Experimental and clinical studies show that the probucol derivative AGI-1067 prevents vascular growth.
AGI-1067 is a derivative of probucol that is a promising new development for the treatment of restenosis and possibly atherosclerosis. In monkeys fed a high-fat diet for 1 year, AGI-1067 prevented the development of atherosclerosis. In these monkeys, AGI-1067 lowered plasma levels of low-density lipoprotein (LDL)-cholesterol and, in contrast to probucol, was capable of increasing high-density lipoprotein (HDL)-cholesterol levels. Although AGI1067 did not have marked lipid-lowering effects in two transgenic mouse models (the LDL-receptor-deficient and apolipoprotein-E-deficient models) fed a high-fat chow, it decreased the atherosclerotic lesion area in the aorta. In a mouse model of acute inflammation, the mRNA for the pro-inflammatory vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 was upregulated and this was inhibited by AGI-1067. AGI-1067 inhibited the TNF-alpha induction of redox-sensitive inflammatory proteins, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 and Eselectin, in cell culture. In addition, AGI-1067 is an antioxidant. In the Canadian Antioxidant Restenosis Trial (CART-1) of AGI-1067 in percutaneous coronary interventions, AGI-1067 had no effect on LDL-cholesterol but lowered HDL-cholesterol. At 6 months follow up, the lumen area of the percutaneous coronary interventions segments was greater in patients treated with AGI1067 than in untreated patients. Restenosis rates were 37.5% in the placebo group and 26% in the AGI-1067 group. The lumen area of reference segments was reduced in the placebo group but increased with the higher doses of AGI1067. Unlike probucol, AGI-1067 did not alter QTc interval.
Doggrell
Sheila A
SA
Doggrell Biomedical Communications, 47 Caronia Crescent, Lynfield, Auckland, New Zealand. s_doggrell@yahoo.com
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D023903:Coronary Restenosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D011341:Probucol / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D000975:Antioxidants; C471047:succinobucol; D011341:Probucol