Effect of Probucol and/or Cilostazol on Carotid Intima Media Thickness in Patients with Coronary Heart Disease: A Randomized,Multicenter, Multinational Study

Aim: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time.Methods: Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints.Results: Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; −0.12 ± 0.36 mm vs. probucol; −0.11 ± 0.32 mm vs. combo; −0.16 ± 0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p = 0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions.Conclusion: Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.     

Effectiveness of probucol in reducing plasma low-density lipoprotein cholesterol oxidation in hypercholesterolemia

Oxidized low-density lipoprotein (LDL) interacts with macrophages to induce intracellular cholesterol ester accumulation and foam cell formation. Probucol is a lipid-lowering drug with a well-known antioxidant action. The thiobarbituric acid (TBA)-reacting substances were measured as an index of plasma and LDL lipid peroxidation in a group of hypercholesterolemic patients compared with a normolipidemic control group. The effect of probucol treatment on plasma and LDL lipid peroxidation in the hypercholesterolemic group was also evaluated. Twenty-five patients (10 men and 15 women) with total cholesterol levels greater than 6.5 mmol/liter were given probucol for 24 weeks. Lipid and apoprotein measurements were obtained at 0, 12 and 24 weeks. TBA-reacting substances were also measured in plasma and the LDL fraction. Twenty-five normolipidemic subjects matched for sex, age and body mass index underwent complete blood analysis for purposes of comparison at week 0. Plasma, LDL and high-density lipoprotein cholesterol, and plasma apoproteins A-I and B significantly decreased after 12 and 24 weeks of probucol treatment. Hypercholesterolemic subjects (men and women) had significantly higher TBA-reacting substances in plasma and LDL than control subjects had (p less than 0.05). The amount of TBA-reacting substances in plasma and LDL showed a very significant decrease after probucol treatment (40 and 44%, respectively, after 24 weeks; p less than 0.05). This reduction was not related to age, sex or body mass index, and was greater than the decrease in lipids. These results support a potential role for probucol as a coadjuvant drug in any lipid-lowering antiatherogenic therapy.     

Long-term treatment with probucol improves endothelial function in patients with coronary artery disease.

Recent studies have shown that endothelial function is impaired in patients with coronary artery disease (CAD). Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and may improve endothelial function. The aim of this study was to evaluate the effects of probucol on endothelial function in patients with CAD. We evaluated endothelial function, based on flow-mediated vasodilation during reactive hyperemia (FMD), and the intima-media thickness (IMT) of the common carotid artery using high resolution ultrasonography in patients either with (CAD group, n=26) or without CAD (Control group, n=12). We measured the serum cholesterol concentration, including the low-density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA). Measurements of FMD and serum cholesterol were repeated after 3 months of probucol (500 mg/day, n=9) or placebo (n=9) treatment in patients with CAD. The IMT was significantly greater (p < 0.001) and FMD was significantly lower (p < 0.001) in the CAD group than in the Control group. While the serum cholesterol concentration and plasma ADMA were similar in the two groups, the plasma homocyst(e)ine concentrations were higher in the CAD group than in the Control group (p < 0.01). After probucol therapy, FMD was significantly improved in the CAD group (p < 0.05). The serum LDL-cholesterol concentration did not significantly decrease after probucol treatment. Placebo treatment did not alter FMD or the serum cholesterol concentration. Our findings suggest that long-term treatment with probucol improves endothelial function in patients with CAD, an outcome independent of the LDL-cholesterol-lowering effects of probucol, and that homocyst(e)ine may be a better predictor of atherosclerosis than ADMA.     

Prognosis of hypercholesterolemic patients taking pravastatin for five years: the Chiba Lipid Intervention Program (CLIP) Study

The Chiba Lipid Intervention Program (CLIP) Study was designed to clarify the prognosis of Japanese hypercholesterolemic patients taking pravastatin for 5 years. Hypercholesterolemic patients (n = 2,529) with a total cholesterol level > or = 220 mg/dl and without histories of ischemic coronary heart disease and/or cerebral infarction were administered pravastatin (10-20 mg/day). Among them, 2,131 took pravastatin fully (Pravastatin-continued group), and 398 discontinued the treatment (Discontinued group). The baseline total cholesterol level was 264.3 +/- 34.7 mg/dl (mean +/- standard deviation). The mean reduction rates of total cholesterol and low-density lipoprotein (LDL) cholesterol were 18.0% and 27.2%, respectively. Mild and moderate adverse events occurred in 86 cases (3.6%). Serious adverse events were not observed. Death rates of the pravastatin-continued group and of the discontinued group were 2.6 and 16.0/1,000 persons/year, respectively. Cardiac events (fatal and nonfatal myocardial infarction, cardiac death, angina pectoris) in all, occurred in 35 patients (incidence rate = 2.77/1,000 persons/year). In the pravastatin continued group, 9 causes of fatal and nonfatal myocardial infarction occurred (0.84/1,000 persons/year), whereas in the discontinued group, 4 cases occurred (2.06/1,000 persons/ year). The risk ratio for cardiac events was correlated with the number of risks. In the low-risk group (< or = 1 risk), decreased rates of LDL-cholesterol were less in the cardiac event group than the non-cardiac event group (LDL-cholesterol; 16% vs 25%, p = 0.04). These results suggested the following; 1) Pravastatin maintained a cholesterol lowering effect long-term without serious complications. 2) Pravastatin administration might reduce the mortality rate and myocardial infarction. 3) The combination of multiple risks is a strong factor for a cardiac event in addition to hypercholesterolemia.     

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE)

Aims: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD).Methods: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n = 438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n = 438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients.Results: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport.Conclusion: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).     

普罗布考对高脂血症兔肝功能及胆汁酸受体表达的影响

目的观察普罗布考对高脂血症兔肝功能及肝脏胆汁酸受体(FXR)mRNA表达的影响。方法16只新西兰大白兔给予高脂饲料饲养8周后,随机分为:(1)高胆固醇组(n=8):继续饲以高脂饲料6周;(2)普罗布考组(n=8):在饲以高脂饲料的基础上给予1%普罗布考,共6周。正常饲料组(n=8):另选8只饲以普通饲料14周的兔为对照组。动态观察肝功能变化,实验结束后,采用半定量逆转录聚合酶链式反应(RT-PCR)法测定肝脏FXR mRNA的表达。结果①普罗布考治疗6周后,血清总胆固醇,低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)均明显下降;②普罗布考组谷丙转氨酶(ALT)(45.34±14.91)U/L及谷草转氨酶(AST)(49.68±15.84)U/L,较高胆固醇组[ALT(67.20±17.34)U/L,AST(81.36±22.97)U/L]均明显降低,P均<0.01;③与高胆固醇组比较,普罗布考组血清总胆汁酸(TBA)(46.11±18.58)mmol/L vs(56.34±20.67)mmol/L,总胆红素(T-BIL)均明显降低,为(3.04±1.06)mmol/L vs(5.34±1.38)mmol/L,P均<0.05;④肝脏FXR mRNA的表达明显增加,为0.86±0.05 vs 0.62±0.06,P=0.018。结论普罗布考具有护肝作用,其降低HDL-C可能与上调FXRmRNA的表达有关。     

Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statins

To investigate the association between Chlamydia pneumoniae (C. pneumoniae) infection and atherosclerosis, we compared the effect of lipid-lowering drugs on carotid intima-media thickness (IMT) between patients who were positive and negative for C. pneumoniae antibodies. A total of 165 asymptomatic hypercholesterolemic patients were randomized to probucol (500 mg per day, n = 82) or pravastatin (10 mg per day, n = 83) and followed for 2 years. The 2-year change of IMT in the common carotid artery was the primary endpoint, while mean IMT change and major cardiovascular events were secondary endpoints. C. pneumoniae antibodies (IgA and IgG) were measured by enzyme-linked immunosorbent assay. The 50 patients without C. pneumoniae antibodies showed significant reduction of IMT progression (-19%), while no significant change of IMT was noted in the 115 antibody-positive patients (-6%). Significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (P < 0.01 and 0.01, respectively). No significant differences in the reduction of serum total-cholesterol and LDL-cholesterol were found between antibody-positive and -negative patients. There was no significant difference of efficacy between probucol and pravastatin. These observations suggest that C. pneumoniae infection reduces the effect of lipid-lowering therapy on carotid atherosclerosis and that this organism may play a role in the progression of atherosclerosis.     

普罗布考对高脂血症患者血脂及血管内皮舒张功能的影响

目的　评价普罗布考降血脂的同时对高脂血症患者血管内皮舒张功能的影响。方法　采用自身对照和组间对照 ,将 5 2例原发性高脂血症患者分为两组 ,其中普罗布考组 (36例 ) ,服用普罗布考 0 .5 ,Bid;普伐他汀组 (16例 ) ,服用普伐他汀 10 mg,QN,疗程均为 4周。选择血脂正常的 2 0例健康者为空白对照组。采用高分辨率超声技术 ,对治疗前后血管内皮舒张功能进行检测。结果　 1高脂血症患者治疗前肱动脉血流介导的舒张功能 (FMD)明显低于正常对照组 [(4.6± 3.2 ) %比 (12 .8± 3.5 ) % ,P<0 .0 1],而对硝酸甘油的反应 (NMD)正常。 2普罗布考明显降低总胆固醇 (TC)、低密度脂蛋白胆固醇 (L DL - c)和高密度脂蛋白胆固醇 (HDL - c) ,三酰甘油变化不明显。 3普罗布考使 FMD明显增强 ,NMD无显著性改变。 4普罗布考降 TC及对 FMD的改善作用均不比普伐他汀差 (分别P<0 .0 1和 P<0 .0 5 )。 5 FMD的改善与 TC及 L DL - c无相关性。结论　普罗布考短期治疗即可显著降低血脂 ,并明显改善 FMD,可作为良好的保护内皮功能的药物 ,其改善 FMD的作用与降脂无关     

Effects of cholesterol-lowering treatments on oxidative modification of plasma intermediate density lipoprotein plus low density lipoprotein fraction in Type 2 diabetic patients

To investigate the normalization of enhanced oxidative modification of the lipoprotein such as increased lysophosphatidylcholine (LPC) and lipid hydroperoxide (LPO) contents in diabetic subjects, we studied the effect of cholesterol-lowering treatment on those parameters in 24 hypercholesterolemic Type 2 diabetic patients. Those patients were randomly assigned to two treatment groups, such as 12 patients treated with pravastatin 10 mg daily and 12 patients treated with probucol 500 mg daily for 8 weeks. Characteristics of the patients including age, gender, body mass index (BMI), smoking habit, modality of diabetic treatment and the glycemic control state were comparable between the two groups. LPC content in the lipoprotein fractions obtained from 24 patients with Type 2 diabetes mellitus was significantly higher than that of non-diabetic control subjects. The abnormality was improved to the control level after a significant improvement of serum cholesterol levels following 8 week-treatments with either probucol or pravastatin without any change in glycemic control (P < 0.025). Furthermore, increased LPO content in the lipoprotein fraction in those diabetics was also significantly (P < 0.0025) improved by the probucol treatment and tended to be improved by pravastatin treatment (P = 0.06). LPC contents in the lipoprotein fraction was positively correlated with LPO contents before cholesterol-lowering treatments (r = 0.41, P < 0.05). These results indicate that cholesterol-lowering treatments effectively reduce oxidative modification of the lipoprotein fraction containing intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) in hypercholesterolemic Type 2 diabetic patients.     

Effect of plasma cholesterol reduction by pravastatin on the functional properties of forearm arteries in hypercholesterolemic patients.

BACKGROUND AND AIM: Since functional properties in the vasculature of hypercholesterolemic subjects are impaired, a six-month pravastatin treatment (20 mg/die) was tested in an open design, on the impaired unstimulated forearm arterial compliance (Un-FAC(AUC)) of 14 asymptomatic type IIa familial hypercholesterolemic patients. In order to evaluate whether FAC(AUC) changes might be related to the extent of cholesterol reduction achieved, this evaluation was carried out in five severely hypercholesterolemic patients, undergoing LDL-apheresis. METHODS AND RESULTS: Arterial functional properties, i.e. FAC(AUC) responses to glyceryl trinitrate (GTN-FAC(AUC)) and acetylcholine (ACh-FAC(AUC), four patients) and the effects on rest and peak forearm blood flow and vascular resistance were evaluated on the non-dominant arm using plethysmographic methods, that also allow the direct assessment of the non-linear "compliance-blood pressure" curve. Selective LDL-apheresis was performed by using a dextran-sulphate column. Pravastatin effectively lowered plasma total (-16%, p = 0.002) and LDL cholesterol levels (-22%, p = 0.006 vs baseline). Rest and peak flow, basal and post ischemic vascular resistance were not affected as well as Un-FAC(AUC) and GTN-FAC(AUC). However, in the four hypercholesterolemic patients undergoing ACh infusion, there was an improvement in the ACh-FAC(AUC) of borderline statistical significativity (p = 0.056). LDL-apheresis reduced plasma total and LDL cholesterol levels by 55% and 59%, without affecting blood pressure. In this series of five patients Un-FAC(AUC) increased, the Un-FAC(AUC) rise being inversely related to the absolute reduction of plasma total (r = 0.92, p < 0.05) and LDL cholesterol (r = 0.89, p < 0.05) levels. CONCLUSIONS: In hypercholesterolemic patients a short-term hypocholesterolemic treatment with pravastatin, although able to improve the lipid profile, cannot alter significantly blood flow, vascular resistance, Un-FAC(AUC) and GTN-FAC(AUC). A possible selective improvement in the ACh-receptor-activated signal transduction pathway has been observed and the importance of a drastic reduction of cholesterol concentrations in order to affect the Un-FAC(AUC) is suggested.