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: 7363635
• 负责人: Bruce N Ames
• 金额: $ 17.73万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7363635
• 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; Bacteria; Biochemical; Blood; 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; Immune; 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; Protein C; Quality of life; Quality-of-Life Assessment; Randomized; Recurrence; Recurrent pain; Reporting; Role; Safety; Sepsis; Serum; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Source; Stroke; Symptoms; Thioctic Acid; Time; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Vascular Endothelium; 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，主要是非裔美国人，在全世界有数百万人。SCD的并发症是由于血管阻塞导致血液流向组织的中断。受影响组织的剧烈疼痛和损伤会导致残疾、反复就诊和住院，同时还需要支付高昂的医疗费用。一种相对便宜的预防性治疗对这一人群尤为重要，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有几种与长期治疗相关的副作用，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。并不是完全有效的。以往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，但缺乏有效的、无毒的、可以长期使用的药物。一项抗炎治疗SCD的试验提供了与羟基脲不同的病理生理机制的巨大好处，羟基脲是目前减少SCD血管闭塞频率的标准预防治疗。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，从而对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，抗氧化治疗可能提供一种减轻临床症状的机制。我们给8名SCD患者服用了1-硫辛酸（LA）和乙酰-左旋肉碱（ALCAR），这是两种生物化学物质的有效抗氧化剂组合，具有已知的安全记录。抗氧化治疗可改善血浆谷胱甘肽氧化还原状态。血清c反应蛋白（CRP）是炎症的敏感指标，4例受试者血浆浓度在基线时较高，3例受试者在抗氧化治疗3周后恢复正常。血浆白细胞介素-6（另一种炎症指标）在一个基线水平较高的受试者中，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可以通过减少氧化应激来降低SCD患者的全身炎症，从而减少血管闭塞性疼痛发作的频率，提高他们的生活质量。我们建议在60例SCD患者中进行一项随机、双盲、安慰剂对照的LA/ALCAR治疗6个月的临床试验，有5个具体目标。我们提出了五个具体目标来评估治疗对：(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、内皮细胞活化标志物和单核细胞活化的血浆浓度；(3)血浆和红细胞氧化应激标志物；(4)血管闭塞发作总次数；(5)生活质量评估。我们期望SCD患者炎症的减少会减少血管闭塞发作的频率。如果这一观察结果被证明是正确的，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。