阿托伐他汀对糖尿病大鼠视网膜核因子-κB表达的影响

目的 探讨他汀类药物对糖尿病大鼠视网膜核因子(NF)-κB表达的影响及其可能机制.方法 雄性SD大鼠60只,随机抽40只腹腔注射链脲佐菌素65 mg/kg建立糖尿病模型,余20只为正常对照组.成模大鼠随机分成两组,糖尿病非药物干预组及阿托伐他汀干预组.干预组予阿托伐他汀(2 mg·kg-1·d-1)灌胃,对照组及糖尿病非药物干预组给予等量饮用水.大鼠分别于3,6个月时按比例处死.取一眼视网膜组织抽提RNA,另一眼固定后做免疫组织化学观察.RT-PCR法扩增NF-κB基因,比较3组大鼠的NF-κB mRNA表达差异.免疫组织化学法观察NF-κB蛋白表达差异.结果 PCR结果示糖尿病大鼠视网膜NF-κB mRNA表达较正常大鼠明显增高(P＜0.05),药物干预的大鼠,NF-κB mRNA表达比糖尿病非药物干预组明显减少(P＜0.05).免疫组织化学结果示视网膜上,NF-κB主要分布在血管层,糖尿病大鼠视网膜中NF-κB阳性的细胞比正常组明显增多(P＜0.05),且着色较深.阿托伐他汀干预组NF-κB阳性的细胞比糖尿病大鼠明显减少(P＜0.05),且着色较浅.结论 阿托伐他汀能降低糖尿病大鼠视网膜中NF-κB mRNA及NF-κB蛋白质的表达,减缓视网膜病变进展.     

阿托伐他汀对糖尿病大鼠心肌组织NF-κB表达影响的研究

60只雄性大鼠,20只为对照组,余用链脲佐菌素(STZ)制备2型糖尿病大鼠模型。成模后,随机分成两组,糖尿病非药物干预组及阿托伐他汀干预组。干预组予阿托伐他汀(2mg/kg/day)灌胃,对照组及糖尿病非药物干预组予等量饮用水灌胃。3个月处死大鼠。取一部分心肌组织抽提RNA,另一部分心肌组织固定后做免疫组织化学观察。应用RT-PCR方法扩增NF-κB基因,比较3组大鼠的NF-κB在基因水平上的表达差异,RT-PCR方法检测心肌组织中NF-κB的mRNA表达水平,免疫组织化检测其蛋白表达。结果:糖尿病大鼠心肌组织中NF-κB在mRNA表达及蛋白表达比正常大鼠明显增高(P<0.05),给药3月NF-κB的mRNA表达及蛋白表达比糖尿病非药物干预组明显减少(P<0.05)。结论:阿托伐他汀能降低糖尿病大鼠心肌组织中NF-κB mRNA及NF-κB蛋白质的表达,减缓心肌组织病变进展。     

阿托伐他汀对家兔动脉粥样硬化斑块中基质金属蛋白酶的影响

目的探讨阿托伐他汀对家兔腹主动脉粥样硬化斑块基质金属蛋白酶(MMP)2和MMP9表达及活性的影响。方法18只体重2kg左右雄性新西兰兔随机分为对照组和高胆固醇血症组,后者喂饲高胆固醇饲料2周后行腹主动脉内膜球囊拉伤术,术后再随机分为模型组和阿托伐他汀组(给予阿托伐他汀5 mg·kg-1·d-1)每组6只,两组均继续喂饲高胆固醇饲料4周。采用免疫组化、明胶酶谱法和逆转录多聚酶链反应(RT-PCR)检测腹主动脉粥样硬化斑块MMP2和MMP9的表达及活性。结果阿托伐他汀组的腹主动脉内膜厚度较模型组显著减薄[(0．49±0．072)对(0．66±0．08)mm,P<0．05)],并且泡沫细胞的数量较模型组显著减少;免疫组化检测结果示阿托伐他汀组血管壁中MMP2的表达量显著较模型组减少;RT-PCR提示阿托伐他汀组的MMPs／GAPDH的mRNA表达较模型组显著降低,分别为MMP2(3．58±0．62对12．74±1．01)和MMP9(4．4±1．07对10．21±4．32),均为P<0．05;明胶酶谱法显示,阿托伐他汀组血管壁MMP9和MMP2的活性亦较模型组显著降低,分别为(40535±7841)对(57345±9320)du／mg和(55744±3430)对(80888±5435)du／mg,均为P<0．05。结论阿托伐他汀可能通过抑制动脉粥样硬化斑块内MMP2和MMP9的表达和活性,而抑制动脉粥样硬化病变的形成,起到稳定斑块的作用。     

阿托伐他汀对糖尿病心肌病患者血清基质金属蛋白酶-2及转化生长因子-α水平的影响

目的观察基质金属蛋白酶(MMP)-2及转化生长因子(TGF)-α与糖尿病心肌病(DCM)发病的关系以及阿托伐他汀对其水平的影响。方法将60例DCM患者随机分为常规治疗组(30例)和阿托伐他汀组(30例),两组治疗过程中均严格控制血糖,常规治疗组予以利尿剂、血管紧张素Ⅱ转化酶抑制剂(ACEI)、血管紧张素Ⅱ受体拮抗剂(ARB)、洋地黄及硝酸酯类等药物常规治疗;阿托伐他汀组在常规治疗基础上加用阿托伐他汀(20 mg/d)治疗。另外选择40名同期健康体检者作对照组。分别于入院后24 h内和治疗第8周测定血清MMP-2和TGF-α水平,并行心脏彩超检查。结果 DCM患者血清MMP-2和TGF-α水平〔(222.67±14.15)μg/L,(75.50±10.82)ng/L〕明显高于健康对照组〔(113.25±7.35)μg/L,(26.83±5.12)ng/L〕(P0.01);血清MMP-2和TGF-α水平随心功能程度的恶化而逐渐升高(P0.05);经8 w治疗后,常规治疗组和阿托伐他汀组患者心功能均得到显著的改善,血清MMP-2和TGF-α水平均明显下降,但阿托伐他汀组更为明显(P0.05)。结论血清MMP-2和TGF-α可以作为判断DCM严重程度的指标;在常规治疗的基础上加用阿托伐他汀能有效降低DCM患者血清MMP-2和TGF-α水平,改善心室重构及心功能。     

阿托伐他汀对急性脑梗死患者血清MMP-9的影响

脑梗死(cerebral Infarction,CI)主要是由于动脉粥样硬化斑块破裂,继发血栓形成所致.因此,研究动脉粥样硬化斑块破裂的发生机制及寻找稳定斑块的有效治疗措施对防治CI具有重要的临床意义.     

不同剂量阿托伐他汀对2型糖尿病患者体内炎症的影响

目的:探讨阿托伐他汀防治2型糖尿病并发动脉粥样硬化患者的可能机制。方法:用胶乳免疫增强比浊法测定2型糖尿病患者外周血中高敏C-反应蛋白(hs-CRP)水平、用酶联免疫吸附双抗体夹心法测定2型糖尿病患者外周血中白细胞介素6(IL-6)的水平,并观察不同剂量阿托伐他汀对它们的影响。结果:阿托伐他汀能显著降低2型糖尿病患者外周血中hs-CRP、IL-6的水平(P<0.05),增大剂量效果更显著(P<0.05),同时对肝功能及血肌酸磷酸激酶(CK)影响不大。结论:阿托伐他汀对2型糖尿病患者炎症有抗炎作用,且在一定范围内随着剂量的增加而加强,其抗炎作用可能是防治糖尿病并发动脉粥样硬化的机制之一。     

阿托伐他汀对心肌肥厚大鼠细胞外基质重塑的抑制作用

目的探讨阿托伐他汀对去甲肾上腺素诱导的心肌肥厚大鼠细胞外基质重塑的影响及其可能的机制.方法雄性SD大鼠随机分为三组(1)对照组,(2)去甲肾上腺素组[1.06 mg/(kg·d)×15 d],(3) 去甲肾上腺素+阿托伐他汀组[50 mg/(kg·d)×15 d].去甲肾上腺素ip,2次/d,15 d,建立心肌肥厚模型.应用超声心动图及病理学方法评价整体心肌肥厚及组织胶原表达.用逆转录-聚合酶链反应法(RT-PCR)及免疫组化检测细胞外基质调节因子-基质金属蛋白酶(MMP-9)及其生理性抑制剂(TIMP-1)和转化生长因子β1(TGF-β1)mRNA和蛋白表达.结果去甲肾上腺素组大鼠发生左心室肥厚及纤维化,胶原含量及MMP-9、TIMP-1和TGF-β-1蛋白、mRNA表达显著高于健康对照组(P<0.01).阿托伐他汀能减少心肌中总体胶原及Ⅰ、Ⅲ型胶原的合成及MMP-9、TGF-β-1表达(P<0.01).结论 MMP-9、TIMP-1和TGF-β-1与心肌肥厚大鼠的细胞外基质重塑有关.阿托伐他汀能有效防治心肌纤维化及细胞外基质重塑,这一效应与其降低心肌中高表达的MMP-9和TGF-β-1有关.     

阿托伐他汀对动脉粥样硬化兔肿瘤坏死因子α和组织因子水平的影响

目的 研究阿托伐他汀对动脉粥样硬化兔血浆和外周血单核细胞表达肿瘤坏死因子α和组织因子水平的影响.方法 采用高胆固醇饮食法建立动脉粥样硬化兔模型(n=12),随机给予阿托伐他汀或淀粉4周,同时6只兔以普通饲料喂养.12周后,取各组兔主动脉测定斑块内膜面积,分离外周血单核细胞培养24 h.采用酶联免疫吸附法检测血浆和细胞培养上清液中肿瘤坏死因子α及细胞膜组织因子水平.结果 阿托伐他汀能降低主动脉斑块面积百分数、血浆和外周血单核细胞肿瘤坏死因子α及组织因子水平(均P<0.01);主动脉斑块面积百分数、血浆及外周血单核细胞肿瘤坏死因子α和组织因子水平两两之间呈正相关(均P<0.01).结论 阿托伐他汀在降低胆固醇同时,还可通过降低肿瘤坏死因子α和组织因子水平发挥抗动脉粥样硬化作用.     

阿托发他汀对糖尿病大鼠外周血和肾组织核因子κB的影响

目的 探讨阿托伐他汀对链脲佐菌素诱导的糖尿病大鼠肾组织与外周血单个核细胞(PBMC)中核因子κB(NF-κB)活性的影响.方法 30只雄性SD大鼠分成对照组、糖尿病组和阿托伐他汀治疗组;酶联免疫吸附法(ELISA)测定各组大鼠PBMC中NF κB活性;免疫组化检测各组大鼠肾组织NF-κB、单核细胞趋化蛋白1(MCP-1).结果 糖尿病大鼠PBMC和肾小球中NF κB显著高于对照组(P＜0.01).与糖尿病大鼠相比,阿托伐他汀明显抑制NF-κB活化及MCP-1和纤黏连蛋白(FN)表达(P＜0.05),减少24 h尿蛋白排泄,改善肾功能及肾病理学损害.结论 NF-κB在糖尿病肾病发病中具有重要作用,抑制NF-κB的活化可能是他汀类药物发挥肾脏保护作用的机制之一.     

阿托伐他汀对慢性心力衰竭病人心功能及肿瘤坏死因子的影响

目的探讨慢性心力衰竭(CHF)病人肿瘤坏死因子(TNF-α)的变化及阿托伐他汀对其的干预作用。方法将70例CHF病人随机分为阿托伐他汀组和常规治疗组,采用放免法测定CHF病人TNF-α浓度、左室射血分数(LVEF)、左室舒张末内径(LVDd)。结果随着NYHA心功能分级的升高,TNF-α逐渐升高(P0.05);TNF-α与LVEF呈负相关,与LVDd呈正相关;阿托伐他汀组治疗后TNF-α水平显著降低(P0.05),LVEF显著提高(P0.05),LVDd显著降低(P0.05),与常规治疗组治疗后比较差异也有统计学意义(P0.05)。结论在常规治疗的基础上加用阿托伐他汀能进一步降低TNF-α水平,改善心功能。     

Effect of atorvastatin on endothelial function and inflammation in long-duration type 1 diabetic patients without coronary heart disease and arterial hypertension

Aim:  We evaluated the ability of atorvastatin, an HMG-CoA reductase inhibitor, to affect endothelial function and inflammation in long-duration (>10 years) type 1 diabetes mellitus (T1DM) patients without coronary heart disease (CHD) and arterial hypertension (AH).
Methods and Results:  We randomized 204 Caucasians with long-duration T1DM into either the atorvastatin 40 mg/day plus hypolipaemic diet group (n = 154) or the placebo plus hypolipaemic diet group (n = 50) for 6 months. Endothelium-dependent flow-mediated (FMD) and endothelium-independent flow-mediated vasodilatation, serum levels of plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF) and high sensitivity C-reactive protein (hs-CRP) were estimated before and after treatment. After 6 months of therapy, FMD was increased by 44% in the atorvastatin plus diet group compared with the placebo plus diet group. Treatment with atorvastatin led to a significant reduction in levels of PAI-1 and hs-CRP; however, the elevation of vWF level was observed. In the placebo plus diet group, we observed a significant reduction in levels of hs-CRP but not of vWF and PAI-1.
Conclusions:  Atorvastatin improves endothelial function and reduces some proinflammatory and prothrombotic markers of atherosclerosis in T1DM patients without CHD and AH. The surprising effect of atorvastatin on serum vWF levels in T1DM requires further study.     

Effect of rosuvastatin or atorvastatin on urinary albumin excretion and renal function in type 2 diabetic patients

The effect of rosuvastatin or atorvastatin on urinary albumin excretion (UAE) was determined in type 2 diabetic patients. A randomized, double-blind, parallel-group, response-based design compared rosuvastatin 10mg (titrated to 40 mg) with atorvastatin 10mg (titrated to 80 mg) in type 2 diabetic patients with dyslipidemia, with dose titration to an LDL-C target of <3.0 mmol/L. Overnight timed urine collections were obtained at baseline, 8 and 16 weeks to UAE. Glomerular filtration rate (GFR) was determined using the Modification of Diet in Renal Disease formula. Patients with paired, UAE collections of at least 8h duration were analyzed (n=344). No significant change from baseline in UAE was observed for either treatment group or between-treatment groups at 16 weeks, and median UAE for both treatment groups remained within normal limits (rosuvastatin 4.5 microg/min, atorvastatin 5.0 microg/min). A similar absence of change from baseline was observed for 51 patients with UAE above the normal range at study entry (>20 microg/min). No significant change in GFR from baseline after 16 weeks was observed for either treatment group. These data provide reassurance that type 2 diabetic patients can be treated with higher efficacy statins without clinically meaningful effects on urinary albumin excretion.     

Alternate-day dosing of atorvastatin: effects in treating type 2 diabetic patients with dyslipidaemia

Abstract An analysis is made of the effect of alternateday dosing of atorvastatin and standard once-daily dosing, based on mean low-density lipoprotein (LDL) reduction from baseline in type 2 diabetics. Forty-four type 2 diabetics were enrolled in the study. In compliance with American Diabetes Association (ADA) and National Cholesterol Education Program Expert Panel (NCEP-III) guidelines, LDL-C<100 mg/dl was chosen as the treatment target. Patients were assigned to 10 mg atorvastatin as an initial dose every day. The atorvastatin dose was doubled every 6 weeks if the patients failed to reach the treatment target. After achieving LDL<100 mg/dl, the patients were assigned to the corresponding atorvastatin dose every other day for 12 weeks. Thirty-three patients correctly completed the study. LDL-C decreased 39% after the every-day period and 23% after the alternate-day atorvastatin dosing period (p<0.05). The target LDL-C concentration of <100 mg/dl was maintained in 19 patients (57.6%) in the alternate-day period. None of the 33 patients showed elevations in liver enzymes or creatine kinase during the alternate-day dosing period. Alternate-day dosing of atorvastatin could be an effective and safe alternative to daily-dosing in some type 2 diabetic patients.     

Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients.

OBJECTIVES: The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND: Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS: Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS: Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.     

Effects of exercise on inflammation markers in type 2 diabetic subjects

Endothelial dysfunction and plasma markers of inflammation are significantly increased in type 2 diabetics. Several proinflammatory cytokines, acute-phase proteins, and cell adhesion molecules, such as C-reactive protein (CRP), interleukines (IL), and tumor necrosis factor alpha (TNF-α), seem to play a role in the low-grade systemic inflammation observed in these subjects. Lifestyle changes are necessary to prevent atherosclerosis and cardiovascular events. Physical exercise is known to reduce markers of inflammation by decreasing adipocytokine production and cytokine release from skeletal muscles, endothelial cells, and immune system and also improving antioxidant status. In type 2 diabetics, aerobic and resistance training have different effects on cytokine levels, and the differences in the modalities of exercise (type, duration, and intensity) and especially in the examined population could produce different results. Recent research showed that combined exercise has greater anti-inflammatory effects than aerobic or resistance exercise alone causing a deepest decrease in CRP, IL-6, IL-1β, TNF-α, leptin, and resistin and a higher increase in anti-inflammatory cytokines such as IL-4, IL-10, and adiponectin.     

Comparison of effects of pitavastatin and atorvastatin on glucose metabolism in type 2 diabetic patients with hypercholesterolemia

Aims/Introduction

The distinct effects of different statins on glycemic control have not been fully evaluated. In this open‐label, prospective, cross‐over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia.

Materials and Methods

A total of 28 Japanese type 2 diabetics with hypercholesterolemia treated with rosuvastatin (2.5 mg/day) for at least 8 weeks were recruited to this quasi‐randomized cross‐over study. At study entry, the patients assigned to sequence 1 received pitavastatin (2 mg/day) for 12 weeks in period 1 and atorvastatin (10 mg/day) for another 12 weeks in period 2, whereas patients assigned to sequence 2 received atorvastatin (10 mg/day) for 12 weeks in period 1 and pitavastatin (2 mg/day) for another 12 weeks in period 2. Blood samples were collected at three visits (baseline, after 12 and 24 weeks).

Results

Lipid control was similar in both statins. The difference in glycated hemoglobin between pitavastatin and atorvastatin treatments was −0.18 (95% confidence interval −0.34 to −0.02; P = 0.03). Compared with atorvastatin, pitavastatin treatment significantly lowered the levels of glycoalbumin, fasting glucose and homeostasis model assessment of insulin resistance.

Conclusions

Our results showed that treatment with pitavastatin had a more favorable outcome on glycemic control in patients with type 2 diabetes compared with atorvastatin. This trial was registered with UMIN (no. 000003554).     

阿托伐他汀对老年2型糖尿病并高脂血症患者降脂疗效观察

目的 观察阿托伐他汀对老年2型糖尿病合并高脂血症患者降脂的疗效. 方法 研究对象每晚睡前服用阿托伐他汀片10 mg,疗程为12个月.治疗前及治疗后3、6、9、12个月分别测定血总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、谷丙转氨酶、谷草转氨酶、血糖、肌酐及颈总动脉、髂总动脉、股动脉的内膜中层厚度(IMT).结果阿托伐他汀治疗1年后,患者TC和LDL-C显著降低[(5.11±0.94)mmol/L至(4.46±0.98)mmol/L和(3.01±0.78)mmol/L至(2.55±0.83)mmol/L,均P<0.01],不同检测时间点LDL-C均达到治疗标准(<2.59 mmol/L),但TC只有在9个月时降至标准以下(<4.04 mmol/L).颈总动脉、髂总动脉和股动脉的IMT均呈减少的趋势,但差异无统计学意义,谷丙转氨酶、谷草转氨酶和肌酐无明显变化. 结论 阿托伐他汀对老年2型糖尿病合并高脂血症患者有明显降脂效果,不良反应小,并且具有保护血管内膜的作用.     

阿托伐他汀对老年2型糖尿病患者颈动脉硬化的影响

目的探讨阿托伐他汀对老年2型糖尿病患者颈动脉硬化的影响。方法选择100例合并颈动脉硬化的老年2型糖尿病患者,随机分为对照组50例(仅控制血糖)和联合组50例(在控制血糖基础上,口服阿托伐他汀20mg/晚),疗程为12个月。测定治疗前后颈动脉硬化相关指标、血脂及高敏C反应蛋白(hs-CRP)。结果两组患者治疗前颈动脉内膜中层厚度(IMT)、斑块检出率、斑块Crouse积分及颈动脉内径无显著差异;与治疗前比较,对照组治疗12个月后颈动脉IMT、斑块检出率及Crouse积分明显增加(P<0.05),颈动脉内径、血脂及hs-CRP水平无明显变化;联合组治疗12个月后颈动脉IMT、斑块检出率、Crouse积分明显降低,颈动脉内径明显增加(P<0.05),治疗6个月、12个月后血清LDL-C、TG、TC、hs-CRP明显降低,HDL-C明显升高(P<0.05)。IMT、Crouse积分均与LDL-C、TG、TC、hs-CRP呈正相关,与HDL-C呈负相关(P<0.05)。结论在控制血糖的同时,联合应用阿托伐他汀,对延缓老年2型糖尿病患者颈动脉硬化进展有一定影响。