Antioxidant Therapy to Reduce Inflammation in Sickle Cell Disease

减少镰状细胞病炎症的抗氧化疗法

基本信息

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
项目类别：
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

项目摘要

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）：镰状细胞疾病（SCD）是一种遗传性溶血性贫血，影响了美国70,000多人，主要是非裔美国人，在全球范围内影响了数百万。 SCD的并发症是由血管咬合引起的，导致血液流向组织。受影响组织的严重疼痛和损害导致残疾，反复的诊所就诊和住院以及大量的医疗保健费用。相对廉价的预防疗法对该人群尤其重要，但是完成这一目标的临床试验很少或没有。目前可预防血管咬合的药物具有与长期治疗有关的几种不良反应，包括腺皮质抑制，库欣综合征，生长障碍，骨质疏松症和免疫抑制作用。并且不完全有效。先前的临床经验和实验观察结果表明，抗炎疗法可以有效防止血管阻塞，但是缺乏长期使用的有效和无毒剂。 SCD中抗炎疗法的试验为靶向与羟基脲不同的病理生理机制的巨大好处，羟基脲是当前的标准预防疗法，以降低SCD中的血管酸性频率。羟基脲是一种干扰细胞分裂的抗塑性剂，诱导胎儿血红蛋白，可拮抗红细胞中镰状血红蛋白的聚合。由于氧化剂产生有助于SCD中炎症的发展，因此抗氧化剂治疗可能提供了减少临床症状的机制。我们在我们的机构向8例SCD患者提供了1-硫酸（LA）和乙酰基-L-肉碱（ALCAR） - 具有已知安全记录的两种生化记录的有效抗氧化剂组合。抗氧化剂疗法导致血浆谷胱甘肽氧化还原状况有所改善。血清C反应蛋白（CRP）的血浆浓度是一种敏感的炎症指标，在4名受试者的基线时很高，在抗氧化治疗三周后，在3名受试者中恢复了正常。血浆白介素-6是炎症的另一个指标，在三个星期的受试者中，基线水平较高后也标准化。基于这些令人鼓舞的临床结果和我们先前的实验观察结果，我们假设LA/ALCAR通过减少SCD患者的全身性炎症，通过减少氧化应激，这将导致血管结核性疼痛发作的频率降低并改善其生活质量。我们建议在60例SCD患者中进行6个月的LA/ALCAR治疗的随机，双盲，安慰剂对照试验，具有五个特定目标。我们提出了五个特定的目标，以评估治疗对：（1）在LA/Alcar治疗的六个月内，平均血清C反应蛋白值；（2）炎性细胞因子的血浆浓度，内皮活化的标志物和单核细胞激活；（3）氧化应激的血浆和红细胞标记；（4）血管占主导性发作的总数；（5）生活质量评估。我们预计SCD患者的炎症会减少会降低血管熟悉发作的频率。如果这一观察结果是正确的，它将为炎症在引起SCD的人类中引起血管肠结牙的作用提供宝贵的证据。