PHASE I/II STUDY OF SIMVASTATIN (ZOCOR) THERAPY IN SICKLE CELL DISEASE

描述（由申请人提供）： 与SCD相关的许多临床并发症主要归因于镰状动脉引起的血管损伤。 SCD的血管病变的特征在于由于缺氧、增加的切应力、镰状红细胞（RBC）的异常内皮粘附的影响而导致的内皮损伤，以及由再灌注损伤诱导的炎症。 越来越多的证据表明，这种血管病变也促进血管生成，激活凝血和血管调节紊乱。 因此，针对导致内皮损伤的途径的治疗可能会改善SCD中发生的进行性血管损伤。 3-羟基-3-甲基-戊二酰辅酶A（HMG-CoA）还原酶抑制剂，也称为他汀类药物，是胆固醇生物合成的有效抑制剂，已广泛用于治疗高胆固醇血症患者。 最近的临床和实验数据表明，他汀类药物调节其他病理生理过程，其中许多在SCD的血管病变中发挥重要作用。 辛伐他汀已被证明在人体中具有良好的耐受性和安全性，并且似乎在胆固醇正常的个体中具有显著的一氧化氮（NO）增强作用。 大量研究记录了他汀类药物的血管保护作用，以及显示NO供体在SCD中的治疗作用的初步数据，为研究他汀类药物在SCD中的潜在临床获益提供了令人信服的依据。 辛伐他汀已被广泛研究并上市用于其他患者人群，使其易于用于SCD患者的治疗。 然而，在开始随机对照试验以测试辛伐他汀的临床疗效之前，需要评估辛伐他汀在SCD中的生理作用、安全性和耐受性的数据。 调查人员提出了以下具体目标： 1.通过测定外周血内皮损伤标志物，确定口服辛伐他汀（Zocor）对SCD患者血管生理学的影响。 2.评估口服辛伐他汀治疗SCD患者的安全性和耐受性。

DESCRIPTION (provided by applicant): The numerous clinical complications associated with SCD are primarily attributable to sickle-induced vascular damage. The vasculopathy of SCD is characterized by endothelial injury due to the effects of hypoxia, increased shear stress, abnormal endothelial adherence of sickled red blood cells (RBCs), and inflammation induced by reperfusion injury. Growing evidence indicates that this vasculopathy also promotes angiogenesis, activation of coagulation, and disordered vasoregulation. Therapies targeted at the pathways contributing to endothelial injury may thus ameliorate the progressive vascular damage that occurs in SCD. The 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors, also known as statins, are potent inhibitors of cholesterol biosynthesis and have been used extensively to treat patients with hypercholesterolemia. Recent clinical and experimental data indicate that statins modulate yet other pathophysiologic processes, many of which play a major role in the vasculopathy of SCD. Simvastatin has been shown to be well tolerated and safe in humans and appears to have significant nitric oxide (NO) enhancing effects in normocholesterolemic individuals. Numerous studies documenting the vasculoprotective effects of statins, together with preliminary data showing the therapeutic role of NO donors in SCD, provide a compelling rationale to investigate the potential clinical benefit of statins in SCD. Simvastatin has been extensively studied and marketed for use in other patient populations, making it readily available for treatment in SCD patients. However, data assessing the physiologic effects, safety and tolerability of simvastatin in SCD are needed prior to initiating randomized controlled trials to test the clinical efficacy of simvastatin. The investigators propose the following specific aims: 1. To determine the effect of oral simvastatin (Zocor) on vascular physiology in SCD, as measured by peripheral blood markers of endothelial injury. 2. To assess the safety and tolerability of oral simvastatin in patients with SCD.