Atherosclerosis - AGI-1067
Atherosclerosis is the biggest killer in the western world, being responsible for up to three-quarters of all deaths from stroke and heart attacks.
Atherosclerosis is the biggest killer in the western world, being responsible for up to three-quarters of all deaths from stroke and heart attacks.
It is a degenerative disease of the arteries, where fatty plaques form on the artery linings, impeding the normal flow of blood. Low density lipoproteins (LDLs) carry cholesterol to the arteries, and if these levels are too high, the plaques can all too easily form. There is a good correlation between high levels of LDL and incidence of atherosclerosis, strokes and heart attacks. The plaques appear to form when LDLs are activated by free radicals, which cause oxidation, so antioxidants may well have an effect in lowering the chances of atherosclerosis developing by reducing this oxidative stress.
Oxidative stress induces the localised expression of vascular cell adhesion molecule 1 (VCAM-1) in the endothelium, which triggers off the cascade that forms the plaques, so it would appear to be a good target for potential drug therapies to prevent atherosclerosis.
US biotech company AtheroGenics has been exploring the possibility, and the result is AGI-1067.1 It is the monosuccinate ester of probucol, an antioxidant drug that has been shown to reduce the incidence of restenosis, but which was removed from the market in the US because of significant side-effects. The new drug has better solubility in water and cell permeability, and is a potent inhibitor of VCAM-1, as well as monocyte chemo-attractant protein 1, which is involved in the formation of plaques.
In a multi-centre randomised, double blind, placebo-controlled trial, a total of 305 patients due to undergo angioplasty (with or without stenting) were given 70, 140 or 280mg of AGI-1067 once a day, placebo or probucol, for two weeks before and four weeks after their treatment.2 After six months, both AGI-1067 and probucol gave significant reductions in restenosis - 31% and 32% respectively, which indicates a direct effect on atherosclerosis. AGI-1067 had a beneficial effect after as little as two weeks' treatment.
The success of this trial has led to a Phase III study being initiated. Around 4,000 patients in about 180 cardiac centres around the world will be evaluated for at least 18 months.