Treatment of sickle cell acute pain episodes with intravenous gammagblobulin

描述(申请人提供)：镰状细胞病是世界上最常见的血红蛋白疾病，在*美国，大约每360名非洲裔美国人和每1200名拉丁裔美国人中就有1人受到影响。小血管闭塞或血管闭塞是导致本病临床并发症的主要病理因素。血管闭塞最常见的表现是急性疼痛发作(危象)，通常需要住院和使用麻醉剂，从而给患者带来经济、社会和心理上的损失。护理标准不足，没有针对持续急性疼痛发作的具体治疗。小鼠模型表明，白细胞与血管内皮细胞的黏附可能通过随后与镰刀状红细胞的相互作用在血管闭塞中发挥关键作用。我参与的进一步工作表明，静脉注射丙种球蛋白(IVIG)在血管闭塞诱导之前或之后迅速而显著地减少白细胞与内皮细胞的黏附和随后的红细胞相互作用，导致存活率显著增加。在这项工作的基础上，我计划通过进行一项随机、双盲、安慰剂对照、剂量递增的L-11期试验来发展我的临床研究技能，以研究单剂量静脉注射免疫球蛋白与生理盐水安慰剂对入院并无并发症的急性疼痛发作的镰状细胞性贫血患者的安全性和有效性。共录取52个科目。我假设IVIG将迅速起作用，从而减少血管闭塞，从而减少疼痛评分、麻醉剂使用和住院时间。我还将通过检测参与白细胞与内皮细胞黏附和红细胞-白细胞相互作用的黏附受体、微循环血流量和血清溶血标志物来研究IVIG在镰状细胞病患者中的生理作用。完成这项试验，再加上生物统计学和转化科学课程的进一步正式培训，研究研讨会，以及经验丰富的临床研究人员的指导，将为我成为一名专注于转化床边工作的独立临床调查员做好准备。它还将允许我在培训期结束前提交一份美国国立卫生研究院的申请，将这项试验扩大到第三阶段试验，或者在L第二阶段试验中测试新发现的干扰血管闭塞分子机制的药物。(摘要结束)

DESCRIPTION (provided by applicant): Sickle cell disease is the most common hemoglobinopathy in the world, and, in the* United States, affects approximately 1 in 360 African Americans and 1 in 1200 Latinos. Small vessel occlusion, or vaso-occlusion, is the primary pathology leading to clinical complications of this disease. The most frequent manifestation of vaso-occlusion is the acute pain episode (crisis), which often requires hospitalization and narcotic use, thus exacting an economic, social, and psychological toll on afflicted individuals. Standard of care is inadequate, there being no specific therapies that target ongoing acute pain episodes. Mouse models have shown that leukocytes adherent to blood vessel endothelium play a crucial role in vaso-occlusion, probably through their subsequent interaction with sickle red blood cells. Further work, to which I contributed, has shown that intravenous gammaglobulin (IVIG) administered either prior to or after the induction of vaso-occlusion rapidly and dramatically reduces leukocyte adhesion to endothelium and subsequent red cell interactions, leading to a marked increase in survival. Based on this work , I plan to develop my skills as a clinical investigator by conducting a randomized, double-blind, placebo-controlled, dose-escalation Phase l-ll trial to study the safety and efficacy of a single dose of IVIG compared to normal saline placebo administered to patients with sickle cell anemia admitted to the hospital with an uncomplicated acute pain episode. A total of 52 subjects will be enrolled. I hypothesize that IVIG will act quickly to reduce vaso-occlusion and thus pain scores, narcotic use, and length of hospitalization. I will also investigate the physiological effects of IVIG in patients with sickle cell disease by measuring the adhesion receptors involved in leukocyte adherence to endothelium and red blood cell- leukocyte interactions, microcirculatory blood flow, and serum markers of hemolysis. Completion of this trial, along with further formal training in biostatistics and translational science coursework, research seminars, and the mentorship of experienced clinical investigators, will prepare me to become an independent clinical investigator focusing on translational bench-to-bedside work. It will also allow me to submit by the end of the training period an NIH application to expand this trial into a Phase III trial or to test, in Phase l-ll trials, newly identified agents that interfere with the molecular mechanism of vaso-occlusion. (End of Abstract)