The clinical success of antioxidant-based therapies has been extremely limited.22 Several studies have explored the potential contribution that supplementation with antioxidant-based natural vitamins, such as vitamin C or vitamin E, might play in reducing cardiovascular risk, with inconsistent results. In primary prevention studies, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial followed subjects on supplemental vitamin E or vitamin C for 3 years. Supplementation with vitamin C or vitamin E did not reduce the progression of atherosclerosis compared to placebo. Instead, vitamin E appeared to produce a small disease-promoting effect. A recent examination of the combined data from secondary prevention trials treating over 81 000 patients with vitamin E concluded that vitamin E therapy produced no significant reduction in coronary events. Similar results were observed using vitamin E in combination with other antioxidants where the combination of antioxidant therapies had no significant effect in reducing coronary events or in some cases actually worsened outcomes.22
Probucol 11 is a synthetic, highly lipophilic, phenolic antioxidant capable of interfering with both one- and two-electron oxidations.22 Probucol demonstrated potent antiatherogenic properties in animal studies and was effective in lowering plasma LDLc levels in animals and in hypercholesterolemic patients. Probucol reduces atherogenesis at least in part by reducing LDL oxidation. In clinical trials, patients with mean baseline LDLc levels of 166 mg dL _ 1 treated with probucol at 500 mg b.i.d. for up to 24 months, attained a modest 24-26% reduction in LDLc but their HDLc was also lowered by 21%. This response was accompanied by an approximate 14% decrease in intima media thickness (IMT) and a corresponding 14% reduction in coronary events.55 These results confirm the potential of novel antioxidant-based therapies as CHD treatments. Unfortunately, serious concerns remain about the safety of chronic dosing with high doses of probucol since both the parent drug and its metabolites have been associated with QTc prolongation and fatal arrhythmia.
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