Add-On Effect of Probucol in Atherosclerotic, Cholesterol-Fed Rabbits Treated with Atorvastatin

Abstract

ObjectiveLowering the blood concentration of low-density lipoprotein (LDL) cholesterol is the primary strategy employed in treating atherosclerotic disorders; however, most commonly prescribed statins prevent cardiovascular events in just 30% to 40% of treated patients. Therefore, additional treatment is required for patients in whom statins have been ineffective. In this study of atherosclerosis in rabbits, we examined the effect of probucol, a lipid-lowering drug with potent antioxidative effects, added to treatment with atorvastatin.Methods and ResultsAtherosclerosis was induced by feeding rabbits chow containing 0.5% cholesterol for 8 weeks. Probucol 0.1%, atorvastatin 0.001%, and atorvastatin 0.003% were administered solely or in combination for 6 weeks, beginning 2 weeks after the start of atherosclerosis induction. Atorvastatin decreased the plasma concentration of non-high-density lipoprotein cholesterol (non-HDLC) dose-dependently; atorvastatin 0.003% decreased the plasma concentration of non-HDLC by 25% and the area of atherosclerotic lesions by 21%. Probucol decreased the plasma concentration of non-HDLC to the same extent as atorvastatin (i.e., by 22%) and the area of atherosclerotic lesions by 41%. Probucol with 0.003% atorvastatin decreased the plasma concentration of non-HDLC by 38% and the area of atherosclerotic lesions by 61%. Co-administration of probucol with atorvastatin did not affect the antioxidative effects of probucol, which were not evident on treatment with atorvastatin alone, such as prevention of in vitro LDL-oxidation, increase in paraoxonase-1 activity of HDL, and decreases in plasma and plaque levels of oxidized-LDL in vivo.ConclusionsProbucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis.

Dietary Cholesterol Atherogenic Changes in Juvenile Rabbits

“…Our previous study on rabbits fed cholesterol under the same conditions as younger rabbits in the present study 4) showed a significant increase in plasma oxidized LDL levels and excessive accumulation of oxidized LDL in atherosclerotic plaques. Those results suggested that oxidative stress was associated with atherogenesis in these rabbits and that the extent of LDL oxidation in blood or accumulation of oxidized LDL in vascular tissue could change during a short juvenile period.…”

“…4) At the end of cholesterol feeding, the animals were euthanized by exsanguination under pentobarbital anesthesia, and their aortas were isolated. The ascending and thoracic aortic regions were dissected partly for histological analysis.…”

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

“…[51][52][53][54][55] Additonally, Keyamura et al and Lee et al reported that antioxidant coenzyme Q10 or probucol has an add-on effect on statin-conferred atheroprotection in CAD patients or cholesterol-fed experimental animals. 56,57 Conversely, several large-scale, double, placebo-controlled trials have shown that antioxidative vitamin adminstration does not necessarily reduce CAD risk in patients even with coadminstartion with simvastatin. [58][59][60] Much of this controversy probably results from shortages in experimental design of these studies.…”

Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin–Angiotensin System Blockade

“…Indeed, a recent animal study showed that a combination of probucol and atorvastatin produced a significantly greater reduction in area of the atherosclerotic lesion in high fat-fed rabbits than that of atorvastatin monotherapy. 20 To date, however, it is unclear whether the combination of probucol and statins has additional lipid-lowering and antiatherosclerotic effects compared with statin monotherapy in diabetic kidney disease because of the limited clinical use of probucol after the introduction of statins. Nevertheless, the additional LDL-C-lowering effect of probucol observed in the current study is noteworthy given the lack of an additional LDL-C-lowering effect of probucol compared with lovastatin monotherapy in a previous study conducted in patients with familial hypercholesterolemia.…”