Omega-3 fatty acid supplementation in HbSS Disease

补充 Omega-3 脂肪酸治疗 HbSS 疾病

• 批准号: 7813843
• 负责人: MARIE J. STUART
• 金额: $ 46.97万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813843
• 关键词: 2 year old; Acids; Adhesions; Adult; Age; Age-Months; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Arts; Ascaridil; Biological Availability; Biological Markers; Blood; Blood Platelets; Brain; CD59 Antigen; Cell Adhesion Inhibition; Cell Survival; Cell membrane; Cells; Cellular Membrane; Child; Childhood; Clinical; Clinical Trials; Collaborations; Companions; Data; Dinoprostone; Disease; Dissection; Documentation; Double-Blind Method; Drops; Eicosanoids; Elements; Endothelium; Erythrocytes; Evaluation; Event; Fatty Acids; Fibrin fragment D; Functional disorder; Future; Generations; Haptoglobins; Hemoglobin; Hemoglobin concentration result; Hemolysis; Hemostatic Agents; Hemostatic function; Individual; Infant; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Lecithin; Leukocytes; Leukotriene B4; Life; Lipids; Measurement; Measures; Mediating; Membrane; Membrane Lipids; Methodology; Monitor; Mononuclear Leukocytes; N-3 polyunsaturated fatty acid; Neurocognition; Nitric Oxide; Nitrites; Omega-3 Fatty Acids; Oral; Oxidants; Pain; Pain-Free; Pathway interactions; Patient Care; Patients; Phase; Phase II Clinical Trials; Phosphatidylethanolamine; Phosphatidylserines; Physiological; Pilot Projects; Placebo Control; Placebos; Plasma; Platelet Activation; Population; Principal Investigator; Production; Prothrombin; Randomized; Reperfusion Injury; Reporting; Resistance; Resolution; Reticulocyte count; Role; Selectins; Series; Sickle Cell; Sickle Cell Anemia; Sphingomyelins; Supplementation; Syndrome; Testing; Thrombin; Thromboplastin; Time; Translational Research; Vasodilation; Vision; Whole Blood; age group; aged; clinical care; cohort; cytokine; early onset; experience; follow-up; hydroxyurea; in vivo; leukocyte activation; lipid mediator; lipoxin A4; monocyte; novel; oxidant stress; phosphatidylethanolamine; placebo controlled study; pre-clinical; prevent; programs; response; skills; stressor; transcription factor; urinary; vaso-occlusive pain

We note that endothelial activation occurs in HbSS by age 2 years, and that markers such as sVCAM-1 and sE-selectin correlate with LDH, a marker of intravascular hemolysis (r=0.6, p<0.000001, n=79) and not with F cell levels (r=o.18, p=0.1). Clinical evidence of microvessel disease and silent CNS infarction in the young child with HbSS also suggests that endothelial dysfunction begins early in life, making us acutely aware that modulating hemolysis and inflammation are at the forefront of sickle cell patient care. Besides the use of Hydroxyurea (HU), many other interventional therapies have not fulfilled early promise. The n-3 fatty acids, eicosapentaenoic (EPA; 20:5) and docosahexaenoic (DMA; 22:6) acids have pleiotropic effects protecting erythrocytes from hemolysis induced by oxidative stressors; modulating ischemia-reperfusion injury by the production of a novel series of potent metabolites, the Resolvins and Protectins which stop the clock on inflammation (Serhan, Ann Rev Immunol 2007;25:101-137); inhibiting the proinflammatory transcription factor NF-icB, and platelet and monocyte activation; and decreasing thrombin production. A report, in 2001, of 10 adults with various SCO syndromes treated with n-3 supplementation showed a 50% reduction in pain. The less than rigorous documentation of pain, emphasis on platelet inhibition, and inclusion of individuals with high baseline Hbs prevented the emergence of other non-hemostatic observations. A recent report demonstrates a deficiency in n-3 fatty acids in the membranes of the cellular elements of blood in HbSS, with a correlation between RBC membrane n-3 and Hb. This report, the short time it takes for n-3 supplements to replenish n-3 in cell membranes, the known pleiotropic effects of these relatively non-toxic physiologic fatty acids, and the transformation in vivo of EPA and DHA into potent anti-inflammatory metabolites, has led us to the rational decision that a clinical trial of n- 3 supplementation should be performed in HbSS. We will conduct (Aims I & II), a double-blind, placebo-controlled Phase II Trial to test whether oral daily supplementation with EPA (45mg/kgm) and DHA (37mg/kgm) for 6 months versus placebo will effect pain parameters (primary endpoint). We will, in addition (secondary endpoints) assess the effects of n-3 supplementation on various red cell parameters (hemolysis, response to oxidant stress, dense cell and PS+ cohorts, adhesion, NO bioavailability and flow-mediated vasodilation); white cell parameters (inflammatory and antiinflammatory products of AA, DHA and EPA, including LKTs, and novel Resolvins and Protectins in collaboration with Dr. Serhan); various endothelial and platelet activation markers, and thrombin generation. We hypothesize that n-3 PUFAs will decrease vasocclusion-induced pain, dependent on a combination of effects on hemolysis, adhesion, inhibition of cell activation and production of anti-inflammatory modulators. In Aim III, we will evaluate RBC membrane fatty acid profiles in HbSS disease (ages 6 months to 12 years) to pinpoint the temporal sequence at which this n-3 deficiency occurs such that a follow-up EPA/DHA supplementation study in this vulnerable childhood population can be conducted at a later date. The study is thus translational in its true sense, including a direct intervention with potential to modify clinical care, while simultaneously providing a mechanistic evaluation of the effects of n-3 in HbSS using state-ofthe- art methodologies, and a team whose skills have been honed by previous CSCC Clinical Trial experience.

我们注意到HbSS患者在2岁时出现内皮细胞活化，并且标志物如sVCAM-1和sE-选择素 与血管内溶血的标志物LDH相关（r=0.6，p<0.000001，n=79），而与F细胞水平无关（r= 0.18， p=0.1）。HbSS患儿微血管疾病和无症状CNS梗死的临床证据也表明， 内皮功能障碍在生命早期就开始了，这使我们敏锐地意识到调节溶血和 炎症是镰状细胞病患者护理的最前沿。除了使用羟基脲（HU），许多其他 介入治疗尚未实现早期的承诺。n-3脂肪酸，二十碳五烯酸（EPA; 20：5）和 二十二碳六烯酸（DMA; 22：6）具有多效性作用，可保护红细胞免于由 氧化应激;通过产生一系列新的有效代谢物调节缺血再灌注损伤， 阻止炎症时钟的消退素和保护素（Serhan，Ann Rev Immunol 2007;25：101-137）;抑制 促炎性转录因子NF-κ B、血小板和单核细胞活化以及凝血酶减少 生产2001年的一份报告显示，10名患有各种SCO综合征的成年人接受n-3补充剂治疗后， 减少疼痛。不太严格的疼痛记录，强调血小板抑制，并纳入 具有高基线血红蛋白的个体防止了其他非止血观察结果的出现。最近的一份报告 证明HbSS中血液细胞成分的膜中n-3脂肪酸缺乏， 红细胞膜n-3与血红蛋白之间的关系。这份报告，短的时间内，它需要的n-3补充，以补充n-3在细胞 这些相对无毒的生理性脂肪酸的已知多效性作用，以及 体内的EPA和DHA转化为有效的抗炎代谢产物，使我们做出了合理的决定， HbSS中应进行3次补充。我们将进行（目标I和II），一个双盲、安慰剂对照阶段 II试验，以测试是否口服每日补充EPA（45 mg/kgm）和DHA（37 mg/kgm）6个月与 安慰剂将影响疼痛参数（主要终点）。此外，我们将（次要终点）评估n-3的影响 补充对各种红细胞参数（溶血、对氧化应激的反应、致密细胞和PS+群组， 粘附、NO生物利用度和流动介导的血管舒张）;白色细胞参数（炎性和炎性 AA、DHA和EPA的产品，包括LKT，以及新的Resolvins和Protectins合作 Serhan博士）;各种内皮和血小板活化标志物，以及凝血酶生成。我们假设n-3 PUFA将减少血管闭塞引起的疼痛，这取决于对溶血，粘附， 抑制细胞活化和产生抗炎调节剂。在目标III中，我们将评估红细胞膜 HbSS疾病（年龄6个月至12岁）中的脂肪酸谱，以确定这种n-3 因此，在这一脆弱的儿童人群中进行的后续EPA/DHA补充研究可以 在稍后的日期进行。因此，这项研究是真正意义上的翻译，包括有可能直接干预， 修改临床护理，同时使用状态评估方法对n-3在HbSS中的作用进行机制评估。 艺术方法，以及一个团队，其技能已经通过以前的CSCC临床试验经验磨练。