ObjectiveTo assess the effect of atorvastatin on lipopolysaccharide(LPS)-inducedTNF-α production in RAW264.7 macrophages. MethodsRAW264.7 macrophageswere treated in different LPS concentrations oratdifferent time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-αmRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HOactivity was assayed. ResultsLPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate inregulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin onTNF-α expression and production in LPS-stimulated macrophages. ConclusionAtorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways,suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

阿托伐他汀逆转动脉僵硬度多中心、开放临床研究

目的:探讨阿托伐他汀对心血管疾病患者动脉僵硬度的影响.方法:67例心血管疾病患者,其中男性28例,女性39例,平均年龄(62.42±9.41)岁(范围35～80岁).受检者3例为单纯高脂血症,3例为单纯糖尿病患者,5例为单纯冠心病患者,56例为高血压合并冠心病或糖尿病患者.观察服用阿托伐他汀10 mg治疗4周、12周和24周时血脂水平及动脉僵硬度的改善状况.动脉僵硬度的评价应用脉搏波速度测定系统(pulse wave velocity,PWV)和血压脉搏测量装置.颈动脉-股动脉PWV(C-F PWV)、颈动脉-桡动脉PWV(C-R PWV)和心-踝血管指数(cardio-ankle vascular index,CAVI)作为反映动脉僵硬度改变的指标.结果:阿托伐他汀治疗前与治疗后4周、12周、24周相比总胆固醇水平明显降低[分别为(5.12±1.18) mmol/L,(4.05±0.82) mmol/L,(4.18±0.80) mmol/L和(4.27±1.00) mmol/L,与基线相比,均为P<0.01];低密度脂蛋白胆固醇水平在治疗后显著下降[分别为(2.95±0.92) mmol/L,(2.11±0.64) mmol/L,(1.24±0.24) mmol/L,(1.28±0.29) mmol/L,与基线相比,均为P<0.01];高密度脂蛋白胆固醇水平在治疗12周后明显增加,并持续至24周[分别为(1.33±0.40) mmol/L,(1.24±0.29) mmol/L,(2.22±0.72) mmol/L,(2.31±0.83) mmol/L,与基线相比,均为P<0.01].C-F PWV治疗后显著下降[分别为(12.33±2.54) m/s,(11.43±2.46) m/s,(11.18±2.05) m/s,(11.14±1.77) m/s,与基线相比,均为P<0.01];C-R PWV治疗12周后明显降低并持续到24周[分别为(10.07±1.89) m/s,(9.71±1.39) m/s,(9.62±1.41) m/s,(9.52±1.33) m/s,与基线相比,均为P<0.01].CAVI在治疗前后无显著差异.结论:阿托伐他汀治疗可有效降低胆固醇水平,并对改善心血管疾病患者动脉僵硬度有益,对动脉结构的改变需更长期的治疗.

In addition to its lipid-lowering effect, atorvastatin exerts anti-inflammatory and antioxidant effects as well. In this study, we hypothesized that atorvastatin could protect against cerebral isch-emia/reperfusion injury. The middle cerebral artery ischemia/reperfusion model was established, and atorvastatin, 6.5 mg/kg, was administered by gavage. We found that, after cerebral ischemia/reperfusion injury, levels of the inflammation-related factors E-selectin and myeloperoxidase were upregulated, the oxidative stress-related marker malondialdehyde was increased, and super-oxide dismutase activity was decreased in the ischemic cerebral cortex. Atorvastatin pretreatment signiifcantly inhibited these changes. Our ifndings indicate that atorvastatin protects against ce-rebral ischemia/reperfusion injury through anti-inlfammatory and antioxidant effects.

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are stil unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cel ular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cel signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebel um and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebel um. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as wel as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed fol owing atorvastatin treatment.

阿托伐他汀钙片致过敏性休克1例

病例:患者,男,58岁,既往体健.因"尿酸高"在家自服丙磺舒0.5g,每日2次;碳酸氢钠1g,每日2次.近日查体时发现血脂偏高,医生遂给予阿托伐他汀钙片(北京嘉林药业股份有限公司生产,批号:090507 )10mg口服,每日1次.

新型HMG-CoA还原酶抑制剂匹伐他汀治疗高脂血症研究进展

他汀类药物作为3-羟-3甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,可以有效预防心脑血管疾病的发生.它对糖尿病、冠心病、血脂障碍和高胆固醇血症病人的心血管都有良好的保护作用,可以预防心肌梗死、中风和外周动脉栓塞等的发生[1-3].目前临床广泛应用的他汀类药物主要有3代,分别是第一代的洛伐他汀(lovastatin) [4]、普伐他汀(pravastatin)[5]和辛伐他汀(simvastatin)[6],第二代的氟伐他汀(fluvastatin) [7]和第三代的西立伐他汀(cerivastatin) [8]、阿托伐他汀(atorvastatin)[9]等.

他汀类药物治疗骨质疏松症的研究进展

他汀类药物(statins)是近20年公认为降低血浆低密度脂蛋白(LDL)和血浆胆固醇(CH)的有效药物,因为该药疗效显著,不良反应小,耐受性好,受到临床应用的重视和好评.目前国际上常用的他汀类药物至少有8种,包括洛伐他汀(1ovastatin)、普伐他汀(pravastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、西立伐他汀(cerivastatin)、贝伐他汀(bervastatin)及尼伐他汀(niavastatin).近年来发现以辛伐他汀为主的他汀类药物可促进骨形成、减少骨折发生率、恢复骨骼微结构、增加骨骼强度等优点,但其确切的机制尚不清楚.

正确认识他汀类药物的临床疗效和安全性

他汀类药物又称HMG-CoA还原酶.抑制剂.首个品种洛伐他汀(lovastatin)于1987年9月1日获美国食品药品监督管理局(FDA)批准上市.尔后,普伐他汀(pravastatin)、辛伐他汀(sitmvasta-血)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)等品种相继上市,使调脂治疗进入一个新的时期.

阿托伐他汀对糖尿病大鼠肾小管间质树突状细胞的影响

近期的炎件反应学说认为,肾小管间质浸润的炎性细胞及炎性免疫反应是糖尿病肾病肾小管间质损伤的主要原因,浸润的炎性细胞包括树突状细胞(DC),其浸润肾组织的过程与P选择素有关[1].本实验通过建立糖尿病大鼠模型,观察DC与肾小管间质损伤的关系,并探讨阿托伐他汀抗炎护肾的可能机制.

A sensitive, accurate and selective liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed and validated for the simultaneous quantitation of atorvastatin (AT) and its equipotent hydroxyl metabolites, 2-hydroxy atorvastatin (2-AT) and 4-hydroxy atorvastatin (4-AT), in human plasma. Electrospray ionization (ESI) interface in negative ion mode was selected to improve the selectivity and the sensitivity required for this application. Additionally, a solid phase extraction (SPE) step was performed to reduce any ion-suppression and/or enhancement effects. The separation of all compounds was achieved in less than 6 min using a C18 reverse-phase fused-cores column and a mobile phase, composed of a mixture of 0.005%formic acid in water:acetonitrile:methanol (35:25:40, v/v/v), in isocratic mode at a flow rate of 0.6 mL/min. The method has lower limit of quantitation (LLOQ) of 0.050 ng/mL for all analytes. The method has shown tremendous reproducibility, with intra-and inter-day precision less than 6.6%, and intra- and inter-day accuracy within 74.3% of nominal values, for all analytes, and has proved to be highly reliable for the analysis of clinical samples.

Objective:To observe the effect of atorvastatin combined with ezetimibe on the levels of urine protein, PCT, serum lipid, and hs-CRP in patients with acute coronary syndrome (ACS). Methods:A total of 90 ACS patients who were admitted in our hospital were included in the study and randomized into A, B, and C groups with 30 cases in each group. The patients in A group were given atorvastatin (20 mg/d, a maintenance dose), the patients in B group were given atorvastatin (40 mg/d, a load dose), while the patients in C group were given atorvastatin in a load dose combined with ezetimibe (10 mg/d). The changes of 24 h UMA, PCT, serum lipid, and hs-CRP after two-week treatment in the three groups were observed, and the adverse reactions in the three groups were observed.Results:The improvements of urine protein, PCT, and serum hs-CRP concentration after treatment in B and C groups were significantly superior to those in A group (P<0.05). The improvements of urine protein, PCT, and serum hs-CRP concentration after treatment in C group were significantly superior to those in A and B groups (P<0.05). The levels of TC and LDL-C after treatment in B and C groups were significantly reduced when compared with those before treatment (P<0.05). The levels of TC and LDL-C after treatment in group A were not statistically different from those before treatment (P>0.05). No obviously adverse reactions occurred in the three groups.Conclusions:Atorvastatin in a load dose combined with ezetimibe can significantly adjust the levels of UMA, PCT, and serum lipid in ACS patients, reduce the concentrations of inflammatory factors, and play an active role in the treatment of ACS.