THE EFFECT OF PROBUCOL ON LOW-DENSITY-LIPOPROTEIN OXIDATION AND FEMORAL ATHEROSCLEROSIS

The Probucol Quantitative Regression Swedish Trial (PQRST) investigate d the effect of the lipid lowering and antioxidant drug probucol on th e development of atherosclerosis in humans. 303 hypercholesterolemic p atients were randomized to receive either probucol or placebo, in comb ination with dietary advice and cholestyramine for a three-year period . Probucol was not found to effect progression/regression of femoral a therosclerosis significantly as assessed by quantitative arteriography . To evaluate the effectiveness of probucol as an antioxidant during t he study period, detailed analyses were performed on 42 of the randomi zed patients. During the trial, probucol-treated patients (n = 26) had 15% lower total cholesterol (P < 0.01) and 35% lower high density lip oprotein (HDL) cholesterol (P < 0.0001) compared with controls (n = 16 ). Low density lipoprotein (LDL) from probucol treated individuals was more resistant to oxidation by Cu2+ as determined by the lag phase fo r the formation of conjugated dienes (220 +/- 8 vs. 82 +/- 7 mm (mean +/- S.E)), showed a 13 times lower formation of lipid peroxides, a 97% reduction in macrophage degradation and close to 90% less decrease in LDL receptor binding following oxidation as compared with controls (P < 0.001 for all differences). The results demonstrate that although p robucol provided a significant protection against Cu2+-induced oxidati ve modification of LDL, it lacked effect on the development of femoral atherosclerosis. The relevance of these observations for the proposed role of lipid oxidation in atherosclerosis is discussed.