title: Add-on effect of probucol in atherosclerotic, cholesterol-fed rabbits treated with atorvastatin.
abstract: OBJECTIVE
  Lowering 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.
  
  
  RESULTS
  Atherosclerosis 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.
  
  
  CONCLUSIONS
  Probucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis.
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan; Division of Biological Chemistry, Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Keyamura
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Nagano
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kohashi
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Niimi
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nozako
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Yasufuku
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Imaizumi
authors.affiliation: Division of Biological Chemistry, Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Itabe
authors.affiliation: Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy*; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000009:adverse effects* / Q000097:blood; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D011341:Probucol / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D000924:Anticholesteremic Agents; D000975:Antioxidants; D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; D002097:C-Reactive Protein; D002784:Cholesterol; D000069059:Atorvastatin; D011341:Probucol