LIPITOR TO PREVENT AVASCULAR NECROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

立普妥预防系统性红斑狼疮的血管坏死

• 批准号: 7605699
• 负责人: HOWARD M BELMONT
• 金额: $ 0.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605699
• 关键词: Accidents; Adrenal Cortex Hormones; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Avascular necrosis of bone; Biological Markers; Blood Vessels; Bone Marrow; Bone necrosis; Buffaloes; Cell Adhesion Molecules; Cholesterol; Clinical; Compartment syndromes; Computer Retrieval of Information on Scientific Projects Database; Coronary Arteriosclerosis; Cushingoid facies; Cushingoid habitus; Deposition; Development; Disease; Dose; Double-Blind Method; E-Selectin; Endothelial Cells; Enzymes; Event; Exhibits; Family; Fatty acid glycerol esters; Flare; Frequencies; Funding; Grant; Head; High Density Lipoproteins; Hilar; Human; Hydroxymethylglutaryl-CoA reductase; Incidence; Inflammatory Response; Injury; Institution; Intercellular adhesion molecule 1; LDL Cholesterol Lipoproteins; Lipids; Lipomatosis; Lupus; Marrow; Measures; Microcirculation; Myocardial Infarction; Nature; Necrosis; Nitric Oxide; Patients; Placebos; Rate; Recruitment Activity; Reporting; Research; Research Personnel; Resources; Risk; Selectins; Serologic tests; Serum; Source; Steroids; Study of serum; Systemic Lupus Erythematosus; Time; Transcriptional Activation; Triglycerides; United States National Institutes of Health; Up-Regulation; Vascular Cell Adhesion Molecule-1; atorvastatin; base; blood lipid; bone; cholesterol biosynthesis; cysteine rich protein; femoral artery; human subject; indexing; inhibitor/antagonist; instrument; lipid biosynthesis; lipid metabolism; low density lipoprotein inhibitor; member; prevent; randomized placebo controlled trial; trial comparing

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The investigators have previously reported that vascular injury in systemic lupus erythematosus (SLE) is characterized by endothelial cell activation and the up-regulation of the adhesion molecules ICAM-1, VCAM-1, and E-selectin. They have also reported that exacerbated SLE is accompanied by increased levels of nitric oxide on the basis of up-regulated endothelial cell iNOS and by increased circulating endothelial cells (CEC) expressing ICAM-1 and iNOS. The endothelial injury typical of SLE flares may serve as an inciting event, which predisposes to the accelerated atherosclerosis that is associated with the disorder as well as disrupt the microcirculation (e.g., end artery of the femoral head) to predispose to avascular necrosis of bone (AVN). As a result, these patients exhibit rates of myocardial infarction and cerdbrovascular accident that are up to 50-fold higher than in those without SLE. The risk of developing avascular necrosis is 10-40 times greater than other patients on corticosteroids. Therefore, the increased frequency of coronary artery disease (CAD) and AVN observed in patients with SLE may be unified by the underlying vascular injury that distinguishes the disease. In a previous study the investigators observed that AVN is multifocal in nature and associated with high-dose steroid treatment of active disease, which is consistent with the hypothesis that AVN in SLE results from the co-occurrence of interosseous vascular injury and a bone compartment syndrome from excess lipid deposition (i.e., osseous lipomatosis akin to the Cushingoid habitus, moon face, buffalo hump, and hilar lipomatosis that can accompany high-dose steroid treatment). Increased adipogenesis and abnormal lipid metabolism has been shown to be associated with corticosteroid-induced osteonecrosis of bone in animal models, and there is increasing evidence to suggest that the relationship between fatty marrow content and AVN applies to humans. Atorvastatin is a member of the statin family of inhibitors of the highly regulated rate-limiting enzyme in the biosynthesis of cholesterol, HMG-CoA reductase, which lower the serum levels of blood lipids including cholesterol and LDL while maintaining HDL levels. The reduction in marrow fat conversion associated with statins in animal models reduces the development of AVN, but this benefit has yet to be established in human subjects. This study hypothesizes that atorvastatin, by preventing bone marrow fat accumulation, will reduce the incidence of AVN in steroid-treated lupus patients. Ninety SLE patients with active disease requiring steroid treatment will be recruited into a four-month double-blind randomized placebo-controlled trial comparing atorvastatin versus placebo to prevent AVN. The study will determine if atorvastatin is effective in lowering serum lipid levels (e.g., cholesterol, triglyceride, LDL) in SLE patients; if atorvastatin inhibits endothelial cell activation in active SLE by measuring soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin) and CEC; and if atorvastatin has an anti-inflammatory effect in active SLE that reduces biological markers of the inflammatory response (ESR, CRP, and SAA) and reduces disease activity assessed by serology (C3, C4, anti-dsDNA) or clinical instrument (Systemic Lupus Erythematosus Activity Index [SLEDAI]).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 研究人员先前已经报道说，全身性红斑狼疮（SLE）的血管损伤的特征是内皮细胞激活和粘附分子ICAM-1，VCAM-1和E-选择素的上调。他们还报道说，恶化的SLE在上调的内皮细胞iNOS和表达ICAM-1和iNOS的循环内皮细胞（CEC）的基础上伴随着一氧化氮水平的升高。 SLE耀斑的典型内皮损伤可能是煽动性事件，易于与该疾病相关的加速动脉粥样硬化，并破坏微循环（例如，股骨头的最终动脉）到倾向于骨骼易感性的骨（AVN）。结果，这些患者表现出心肌梗死和CERDRESDRASDRASDERASDARSED ISCALT的发生率，其比没有SLE的患者高出50倍。在皮质类固醇中，患血管坏死的风险是其他患者的10-40倍。因此，在SLE患者中观察到的冠状动脉疾病（CAD）和AVN的频率增加可能是通过区分疾病的潜在血管损伤统一的。 In a previous study the investigators observed that AVN is multifocal in nature and associated with high-dose steroid treatment of active disease, which is consistent with the hypothesis that AVN in SLE results from the co-occurrence of interosseous vascular injury and a bone compartment syndrome from excess lipid deposition (i.e., osseous lipomatosis akin to the Cushingoid habitus, moon face, buffalo hump, and hilar可以伴有大剂量类固醇治疗的脂肪瘤病）。 在动物模型中，脂肪生成增加和异常脂质代谢与皮质类固醇诱导的骨骼的骨坏死有关，并且有越来越多的证据表明，脂肪骨髓含量和AVN之间的关系适用于人类。 Atorvastatin是胆固醇，HMG-COA还原酶的生物合成中高度调节速率限制酶抑制剂的他汀类药物家族的成员，该酶的血清脂质水平降低了包括胆固醇和LDL的血清水平，同时保持HDL水平。与他汀类药物相关的骨髓脂肪转化的减少减少了AVN的发展，但这种好处尚未在人类受试者中确定。 这项研究假设，通过预防骨髓脂肪的积累，阿托伐他汀将减少类固醇治疗的狼疮患者中AVN的发生率。 需要类固醇治疗的九十名患有活性疾病的SLE患者将被招募到一个四个月的双盲随机安慰剂对照试验中，以比较阿托伐他汀与安慰剂，以防止AVN。 该研究将确定阿托伐他汀在SLE患者中是否有效降低血清脂质水平（例如胆固醇，甘油三酸酯，LDL）；如果Atorvastatin通过测量可溶性粘附分子（SICAM-1，SVCAM-1，SE-塞克蛋白）和CEC来抑制活性SLE中的内皮细胞活化；如果Atorvastatin在活性SLE中具有抗炎作用，以减少炎症反应（ESR，CRP和SAA）的生物学标志物，并减少通过血清学（C3，C4，抗DSDNA）或临床仪器（全身性红斑lupus filesiac Erythematosus Activation Intex Intex [Sleseex）评估的疾病活性。