Antioxidant Therapy to Reduce Inflammation in Sickle Cell Disease

减少镰状细胞病炎症的抗氧化疗法

• 批准号: 8037026
• 负责人: Bruce N Ames
• 金额: $ 17.55万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037026
• 关键词: Accident and Emergency department; Acute; Adhesions; Admission activity; Adverse effects; Affect; African American; Amino Acids; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Attitude; Biochemical; Blood; Blood Vessels; Blood flow; C-reactive protein; Cell Adhesion Molecules; Cell Death; Cell division; Cell membrane; Clinic Visits; Clinical; Clinical Trials; Clinics and Hospitals; Controlled Clinical Trials; Couples; Cushing Syndrome; Cysteine; Data; Development; Dexamethasone; Disease; Double-Blind Method; Emotional; Encapsulated; Endothelial Cells; Erythrocytes; Evaluation; Event; Fetal Hemoglobin; Frequencies; Generations; Glutathione; Glutathione Disulfide; Growth; Health; Health Care Costs; Health Personnel; Hemoglobin; Hemolysis; Hemolytic Anemia; Homocysteine; Homocystine; Hospitalization; Hospitals; Human; Hypoxia; Immunosuppression; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Institution; Interferon Type II; Interleukin-6; Interleukins; Interruption; Levocarnitine; Levocarnitine Acetyl; Life; Life Style; Lipids; Malondialdehyde; Measurable; Measurement; Measures; Morbidity - disease rate; National Center for Complementary and Alternative Medicine; Nature; Nitric Oxide; Opioid; Osteoporosis; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Pain; Paralysed; Participant; Patients; Pattern; Peripheral; Placebo Control; Plasma; Play; Polymers; Population; Predisposition; Preparation; Preventive; Quality of life; Quality-of-Life Assessment; Randomized; Recurrence; Recurrent pain; Reduced Glutathione; Reporting; Role; Safety; Sepsis; Serum; Sickle Cell Anemia; Sickle Hemoglobin; Source; Stroke; Symptoms; Thioctic Acid; Time; Tissues; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Viscosity; Visit; Work; acute chest syndrome; antioxidant therapy; base; cytokine; diaries; disability; experience; hydroxyurea; improved; monocyte; neoplastic; oxidation; polymerization; prevent; protein transport; sickling; vaso-occlusive pain

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is an inherited hemolytic anemia that affects more than 70,000 individuals in the US, primarily African-Americans, and millions more worldwide. The complications of SCD arise from vaso-occlusion resulting in interruption of blood flow to the tissues. Severe pain and damage in the affected tissue result in disability, repeated clinic visits and hospitalizations, along with significant health-care costs. A relatively inexpensive preventive therapy is especially important to this population, but there are few or no clinical trials to accomplish this. The currently available agents to prevent vaso-occlusion have several adverse effects associated with long-term therapy including adreno-cortical suppression, Cushing's syndrome, growth disturbances, osteoporosis, and immune suppression. and are not completely effective. Prior clinical experience and experimental observations suggest that anti-inflammatory therapy can effectively prevent vaso- occlusion, but there is a lack of potent and non-toxic agents that can be used on a long-term basis. A trial of anti-inflammatory therapy in SCD offers the great benefit of targeting a different pathophysiological mechanism than hydroxyurea, the current standard preventive therapy to reduce the frequency of vaso-occlusion in SCD. Hydroxyurea, an anti-neoplastic agent that interferes with cell division, induces fetal hemoglobin which antagonizes polymerization of the sickle hemoglobin in red blood cells. Because oxidant generation contributes to the development of inflammation in SCD, antioxidant therapy potentially offers a mechanism to reduce clinical symptoms. We administered 1-lipoic acid (LA) and acetyl-L-carnitine (ALCAR) - a potent antioxidant combination of two biochemicals with a known safety record - at our institution to 8 patients with SCD. The antioxidant therapy led to an improvement in the plasma glutathione redox status. The plasma concentration of serum C-reactive protein (CRP), a sensitive indicator of inflammation, was high at baseline in 4 subjects and returned to normal in 3 subjects after three weeks of antioxidant therapy. Plasma interleukin-6, another indicator of inflammation, also normalized after three weeks in the one subject with a high baseline level. Based upon these encouraging clinical results and our previous experimental observations, we hypothesize that LA/ALCAR will lower systemic inflammation in patients with SCD by reducing oxidative stress, which will result in a decrease in the frequency of vaso-occlusive pain episodes and improve their quality of life. We propose to conduct a randomized, double blind, placebo-controlled clinical trial of LA/ALCAR treatment for 6 months in 60 patients with SCD with five specific aims. We propose five specific aims to evaluate the impact of treatment on: (1) Average serum C-reactive protein value during the six months of treatment with LA/ALCAR; (2) Plasma concentrations of inflammatory cytokines, markers of endothelial activation, and monocyte activation; (3) Plasma and erythrocyte markers of oxidative stress; (4) Total number of vaso-occlusive episodes; and (5) Quality of life assessments. We expect that a decrease in inflammation in individuals with SCD would reduce the frequency of vaso-occlusive episodes. If this observation turns out to be true, it would provide valuable evidence for the role of inflammation in causing vaso-occlusion in humans with SCD.

描述（由申请人提供）：镰状细胞病（SCD）是一种遗传性溶血性贫血，在美国影响超过70，000人，主要是非洲裔美国人，在全球范围内影响数百万人。SCD的并发症由血管闭塞引起，导致流向组织的血流中断。受影响组织的严重疼痛和损伤导致残疾、反复就诊和住院，沿着巨额医疗费用。相对便宜的预防性治疗对这一人群尤其重要，但很少或根本没有临床试验来实现这一点。目前可用的预防血管闭塞的药物具有与长期治疗相关的几种不良反应，包括肾上腺皮质抑制、库欣综合征、生长障碍、骨质疏松症和免疫抑制。并且不是完全有效的。先前的临床经验和实验观察表明，抗炎治疗可以有效地预防血管闭塞，但缺乏可以长期使用的强效和无毒的药物。SCD中的抗炎治疗试验提供了靶向与羟基脲不同的病理生理机制的巨大益处，而羟基脲是目前降低SCD中血管闭塞频率的标准预防性治疗。羟基脲是一种干扰细胞分裂的抗肿瘤药物，可诱导胎儿血红蛋白，从而拮抗红细胞中镰状血红蛋白的聚合。由于氧化剂的产生有助于SCD炎症的发展，抗氧化剂治疗可能提供了一种减轻临床症状的机制。我们给予1-硫辛酸（LA）和乙酰-L-肉碱（ALCAR）-一种有效的抗氧化剂组合的两种生物化学物质与已知的安全记录-在我们的机构与SCD 8例患者。抗氧化治疗导致血浆谷胱甘肽氧化还原状态的改善。血清C-反应蛋白（CRP）的血浆浓度是一种敏感的炎症指标，在基线时4名受试者较高，在抗氧化治疗3周后3名受试者恢复正常。血浆白细胞介素-6，另一个炎症指标，在一个具有高基线水平的受试者中也在三周后恢复正常。基于这些令人鼓舞的临床结果和我们之前的实验观察，我们假设LA/ALCAR将通过减少氧化应激降低SCD患者的全身炎症，这将导致血管闭塞性疼痛发作频率降低并改善其生活质量。我们建议进行一项随机、双盲、安慰剂对照的临床试验，在60例SCD患者中进行为期6个月的LA/ALCAR治疗，有5个具体目标。我们提出了五个具体目标来评价治疗对以下方面的影响：（1）LA/ALCAR治疗6个月期间的平均血清C反应蛋白值;（2）炎症细胞因子、内皮活化标志物和单核细胞活化的血浆浓度;（3）氧化应激的血浆和红细胞标志物;（4）血管闭塞发作的总次数;（5）生活质量评估。我们预计，SCD患者炎症的减少将降低血管闭塞发作的频率。如果这一观察结果是正确的，它将为炎症在导致SCD患者血管闭塞中的作用提供有价值的证据。