Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids

The Oxford Cholesterol Study is a randomized placebo-controlledtrial designed primarily to assess the effects of simvastatinon blood cholesterol levels and side-effects in preparationfor a large, long-term trial of the effects of cholesterol-loweringdrug therapy on mortality. At present there is only limitedevidence from randomized comparisons of the effects of HMG-CoAreductase inhibitors, such as simvastatin, on thrombogenic,as distinct from atherogenic, pathways in coronary heart disease.The present sub-study was carried out to assess the effectsof simvastatin on a range of haemostatic variables, as wellas on free fatty acids and on lipoprotein fractions not studiedin detail previously. At an average of about 2 years after starting study treatment,non-fasting blood samples were obtained from a sequential sampleof 162 participants who had been randomly allocated to receive40 mg (54 patients) or 20 mg (57 patients) daily simvastatinor matching placebo treatment (51 patients). Only patients whoreported taking their study treatment and who were not knownto be diabetic or to be taking some other lipid lowering treatmentwere to be included. The principal comparisons were to be ofthose allocated simvastatin (i.e. 20 and 40 mg doses combined)vs those allocated placebo. Among patients allocated simvastatin, marginally significantlower factor VII antigen levels (12·10%±6·08of standard; 2P<0·05) and non-significantly lowerfactor VII coagulant activity (8·24%±4·99of standard) and fibrinogen concentrations (0·10±0·08g.l^–1) were observed. In contrast, plasminogen activatorinhibitor activity was significantly higher (2·62±1·03IU; 2P<0·01) among patients allocated simvastatin.No significant differences were seen in the other haemostaticfactors studied (e.g. prothrombin fragment 1·2, factorXII and C$$$ inhibitor). Total free fatty acid concentrationwas marginally significantly reduced (2P=0·02) with simvastatin,but none of the reductions in individual free fatty acids wassignificant. Lipoprotein fractions were only measured amongpatients allocated 40 mg daily simvastatin or placebo. Comparedwith placebo, simvastatin produced significant decreases notonly in LDL cholesterol (1·74±0·15 mmol.1^–1;2P<0·0001) but also in VLDL cholesterol (0·28±0·08mmol.1^–1; 2P<0·001) and IDL cholesterol (0·17±0·03mmol.1^–1; 2P<0·0001). There were also lowertriglyceride levels associated with LDL (0·07±0·01mmol.1^–1; 2P<0·0001), IDL (0·03±0·01mmol.1^–1; 2P<0·01) and VLDL (0·27±0·14;2P=0·05). The effects of simvastatin on haemostatic variables appear tobe far less marked than its lipid effects. Given the associationsof haemostatic factors with coronary heart disease incidence,larger randomized comparisons of the HMG-CoA re1ductase inhibitors(and of the newer fibrates, which may produce greater effects)are needed to provide more reliable estimates of the extentto which they influence these variables.     

Endothelial dysfunction in streptozotocin-diabetic rats is not reversed by dietary probucol or simvastatin supplementation

Summary Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i. v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1 % w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01 % w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300 ± 5 μm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats. 8-epi-prostaglandin (PG)F₂α, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF₂α in aorta and liver of diabetic rats but increased 8-epi-PGF₂α content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC₅₀ diabetic 6.763 ± 0.172 vs control 7.541 ± 0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat. [Diabetologia (1998) 41: 157–164] Received: 4 August 1997 and in revised form: 29 September 1997     

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in Type IIa hypercholesterolemia

Summary Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL₂ 17%; HDL₃ 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.     

自噬对高胆固醇饮食大鼠下颌骨结构改变的影响研究

目的    探讨自噬对高胆固醇饮食大鼠下颌骨结构改变的影响及辛伐他汀的治疗效果。方法　将30只SD大鼠随机分为正常饮食组（NC组）10只、高胆固醇组20只;喂养24周后,高胆固醇组再随机分成两组,每组10只,一组继续喂养高胆固醇饲料（HC组）,另一组在高胆固醇饲料中加入5 mg/kg辛伐他汀（HC+SIM组）。喂养32周后,取大鼠空腹血进行生化检测;处死大鼠后对下颌骨进行骨组织形态分析;实时荧光定量PCR（qRT-PCR）及免疫组织化学染色检测各组自噬相关基因Lc3及p62的mRNA和蛋白表达水平。结果　（1）3组总胆固醇和低密度脂蛋白水平总的比较,差异均有统计学意义（F值分别为21.539、16.596,均P < 0.05）;其中NC组和HC+SIM组总胆固醇和低密度脂蛋白水平均低于HC组（均P < 0.05）,而NC组和HC+SIM组组间比较,差异无统计学意义（P > 0.05）。（2）与NC组比较,HC组大鼠骨体积分数、骨小梁厚度、骨小梁数目明显下降,而骨小梁间隔增加,Lc3及p62 mRNA表达水平明显升高,差异均有统计学意义（均P < 0.05）;与HC组比较,HC+SIM组骨体积分数、骨小梁厚度、骨小梁数目均明显升高,骨小梁间隔减小,p62 mRNA和蛋白表达水平明显下降,差异均有统计学意义（均P < 0.05）;而NC组和HC+SIM组这些指标组间比较,差异均无统计学意义（均P > 0.05）。结论    自噬可能参与调控高胆固醇饮食大鼠下颌骨结构的改变,辛伐他汀能够改善高胆固醇饮食导致的大鼠下颌骨微结构的破坏     

������͡��ʵ������ֲ����Χ����Ӧ���о�

目的探讨辛伐他汀在种植体周围炎骨缺损区应用对种植体骨再结合的影响。方法本研究于2011年6月至2012年2月在哈尔滨医科大学动物实验中心完成。选取4只成年杂种犬,全麻下拔除双侧第一、二、三前磨牙,即刻植入种植体24颗,植入12周确定骨结合后,丝线栓结法建立实验性动物口腔种植体周围炎模型。随机进行分组治疗。(1)空白组(6颗种植体):单纯去除种植体周围炎性肉芽组织,骨缺损区不填入任何材料;(2)实验组(9颗种植体):去除种植体周围炎性肉芽组织,骨缺损区填入骨粉+生物膜+局部注射辛伐他汀(3.0 mg/kg·d);(3)对照组(9颗种植体):去除种植体周围炎性肉芽组织,骨缺损周围填入骨粉+生物膜+局部注射等量空白溶剂。3组术后龈缘内均应用盐酸米诺环素软膏2周(1次/周),实验组和对照组局部注射5 d(1次/d)。术后16周处死动物,行大体观察、缺损区重建骨量测量、电镜观测。结果局部注射辛伐他汀实验组骨重建区骨密度较对照组高,实验组骨重建区骨再结合强度较对照组高,差异有统计学意义(P<0.05)。结论局部注射辛伐他汀可促进骨生长。     

依折麦布辛伐他汀片对兔腹主动脉粥样硬化斑块逆转作用的实验研究

目的：观察腹主动脉粥样斑块内炎性巨噬细胞和平滑肌细胞的表达情况,以探索依折麦布联合他汀类药物在逆转动脉斑块中的作用及机制。方法选取24只健康雄性新西兰大耳白兔,随机分为对照组（n＝8）和高胆固醇血症组（n＝16）。对照组给予普通饲料,喂养12周。高胆固醇血症组喂饲致动脉粥样硬化饲料（由普通颗粒饲料＋15g/L胆固醇＋100g/L猪油＋150g/L蛋黄粉组成）2周后行腹主动脉内膜球囊拉伤术,术后再随机分为模型亚组和依折麦布辛伐他汀（ES）亚组（给予5/10mg/（kg·d）每组8只,两亚组均继续喂饲致动脉粥样硬化饲料10周。喂养第12周时活杀动物,取腹主动脉进行石蜡切片。检测不同时间点脂质和脂蛋白,应用光学显微镜观察动脉粥样硬化进程,采用免疫组化方法分析巨噬细胞和平滑肌细胞在斑块处的表达。结果 ES亚组的血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）浓度明显低于模型亚组（P＜0.01）。病理检测显示两亚组及ES亚组斑块直径、斑块厚度和动脉内/中膜厚度经单因素方差分析,差异有统计学意义（P＜0.05）。免疫组化检测结果示ES亚组血管壁中巨噬细胞的表达量较模型亚组显著减少（P＜0.05）,而平滑肌细胞的表达量较模型亚组显著增多（P＜0.01）。结论 ES可能通过减少细胞外脂质的沉积,减少内膜和中膜巨噬细胞的数量和胆固醇的含量,增加胶原和平滑肌细胞面积,从而起到逆转斑块的作用。     

辛伐他汀联合环磷腺苷治疗心衰的疗效及对相关血清因子的影响

目的：探讨辛伐他汀联合环磷腺苷治疗冠心病慢性心力衰竭（CHF）的临床疗效及对相关血清因子水平的影响。方法：选择我院2011年1月-2012年1月收治的78例冠心病CHF患者,采用数字表法随机均分为辛伐他汀组和联合用药组,辛伐他汀组在常规对症治疗基础上再给予辛伐他汀治疗,联合用药组再在辛伐他汀组基础上加用环磷腺苷,比较两组临床疗效及治疗前后心功能指标和血清因子水平变化。结果：联合用药组总有效率为92.31％,显著高于辛伐他汀组的71.79％（P＜0.05）;与治疗前及辛伐他汀组治疗后比较,联合用药组治疗后左室射血分数[LVEF,（33.54±3.34）％、（43.41±3.23）％比（55.21±3.45）％]和二尖瓣舒张早期/晚期峰值血流速度[E/A,（0.63±0.11）、（0.70±0.15）比（1.01±0.21）]显著增加,脑钠肽[BNP,（536.74±21.41）ng/ml、（117.23±11.57）ng/ml比（78.20±10.92）ng/ml]和C反应蛋白质[CRP,（24.00±2.34）mg/L、（17.01±1.09）mg/L比（8.28±0.81）mg/L]水平显著降低,P＜0.05-＜0.01。结论：辛伐他汀联合环磷腺苷治疗冠心病慢性心力衰竭疗效显著,可明显改善患者心功能及血清因子水平,具有较好的临床应用价值。     

Statins and Contrast-induced Acute Kidney Injury with Coronary Angiography

BackgroundContrast-induced acute kidney injury is an adverse outcome resulting from radiocontrast medium exposure during coronary angiography and percutaneous coronary intervention.MethodsA systematic search was conducted to retrieve studies that investigated the impact of statin exposure before coronary angiography or percutaneous coronary intervention on the development of contrast-induced acute kidney injury. The primary outcome was the development of contrast-induced acute kidney injury. We separately analyzed statin/placebo comparisons and high-/low-dose statin comparisons.ResultsFifteen randomized controlled trials met inclusion criteria: 11 studies with statin-naïve subjects, 2 studies with chronic statin users, and 2 studies with unspecified prior statin exposure. Statin exposure reduced the risk of contrast-induced acute kidney injury relative to placebo (relative risk [RR] 0.63, P = .01) with a nonsignificant reduction in the need for hemodialysis (RR 0.25, P = .08). This benefit was also observed in high-dose versus low-dose statin trials (RR 0.46, P = .004), in statin-naïve patients (RR 0.53, P <.0001), and with all studied statins. Higher statin exposure reduced contrast-induced acute kidney injury in patients with acute coronary syndromes compared with placebo or low-dose statins (RR 0.49, P <.00001), with no significant benefit among patients undergoing elective procedures (RR 0.86, P = .50). Subgroup analyses confirmed the benefit of statins in patients with diabetes, chronic kidney disease, congestive heart failure, and those receiving >140 mL of contrast dye.ConclusionStatin therapy is effective at reducing the risk of contrast-induced acute kidney injury. It should thus be considered, at least on a short-term basis, for patients at increased risk of this complication.     

缺氧诱导因子（HIF）-1α介导的辛伐他汀抗大鼠心肌细胞凋亡作用

目的：观察原代心肌细胞模拟缺血／再灌注（I／R）对缺氧诱导因子（HIF-1α）表达的影响以及HIF-1α在辛伐他汀心肌细胞保护中的作用。方法：原代培养心肌细胞,采用Western blot检测HIF-1α在心肌细胞中的表达水平,采用HEPES缓冲液在低氧（10ml／L）条件下培养心肌细胞2h（模拟缺血组,ISC组）,然后以含有100ml／L新生牛血清的DMEM培养液在常规细胞培养箱中继续培养细胞6h（缺血／再灌注组,I／R组）,辛伐他汀预处理（SIM）组是用2μmol／L辛伐他汀预处理心肌细胞后再进行I／R处理。以这种方法模拟细胞在缺血时缺乏血清、糖和氧供的培养条件,再灌注时恢复血清、糖及正常供氧供的条件。接着,运用表达HIF-1α的腺病毒载体在原代心肌细胞中的过表达HIF-1α,采用Western blot检测PARP降解程度方法检测对照腺病毒（AdC）组、对照腺病毒感染细胞进行I／R处理（AdCIR）组、对照腺病毒感染细胞采用2μmol／L辛伐他汀预处理后进行I／R处理（AdCIRS）组和Ad-HIF-1α感染细胞后采用2μmol／L辛伐他汀预处理后进行I／R处理（AdHIRS）组心肌细胞的凋亡程度。结果：模拟I／R诱导HIF-1α表达,原代心肌细胞模拟缺血2hHIF-1α表达是对照组的（3．4±0．8）倍（P〈0．05）;而模拟缺血2h／再灌注6h组HIF-1α达是对照组的（8．9±1．5）倍（P〈0．05）。辛伐他汀抑制I／R诱导的HIF-1α表达增高。采用表达HIF-1α的腺病毒过表达HIF-1α消了辛伐他汀抑制PARP蛋白降解产物的作用。结论：证明I／R可以诱导HIF-1α表达升高,而辛伐他汀可以显著抑制HIF-1表达的升高;辛伐他汀对HIF-1α表达的抑制是其心肌保护作用的机制之一。     

Efficacy of Subgingivally Delivered Simvastatin in the Treatment of Patients With Type 2 Diabetes and Chronic Periodontitis: A Randomized Double‐Masked Controlled Clinical Trial

Background: Simvastatin (SMV) is a specific competitive inhibitor of 3‐hydroxy‐2‐methyl‐glutaryl coenzyme A reductase. Recently, it has been reported that statins promote bone formation. The present study is designed to investigate the effectiveness of 1.2% SMV in an indigenously prepared, biodegradable, controlled‐release gel as an adjunct to scaling and root planing (SRP) in the treatment of patients with type 2 diabetes and chronic periodontitis (CP). Methods: Thirty‐eight patients were categorized into two treatment groups: SRP plus 1.2% SMV and SRP plus placebo. Clinical parameters were recorded at baseline before SRP and at 3, 6, and 9 months; they included modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). At baseline and after 6 and 9 months, radiologic assessment of intrabony defect (IBD) fill was done using computer‐aided software. Results: Mean PD reduction and mean CAL gain were found to be greater in the SMV group than the placebo group at 3, 6, and 9 months. Furthermore, significantly greater mean percentage of bone fill was found in the SMV group (32.64% ± 12.90%) compared to the placebo group (4.22% ± 9.75%) after 9 months. Conclusion: There was a greater decrease in mSBI and PD and more CAL gain with significant IBD fill at sites treated with SRP plus locally delivered SMV in patients with type 2 diabetes and CP.