Treatment of sickle cell acute pain episodes with intravenous gammagblobulin

描述（由申请人提供）：镰状细胞病是世界上最常见的血红蛋白病，在美国，约1/360的非洲裔美国人和1/1200的拉丁美洲人患病。小血管闭塞或血管闭塞是导致这种疾病的临床并发症的主要病理学。血管闭塞最常见的表现是急性疼痛发作（危象），这通常需要住院治疗和使用麻醉剂，从而对受影响的个体造成经济、社会和心理损失。护理标准不足，没有针对持续急性疼痛发作的特定疗法。小鼠模型已经表明，粘附于血管内皮的白细胞在血管闭塞中起着至关重要的作用，可能是通过它们随后与镰状红细胞的相互作用。进一步的研究表明，静脉注射丙种球蛋白（IVIG）无论是在诱导血管闭塞之前还是之后，都能迅速、显著地减少白细胞与内皮细胞的粘附以及随后的红细胞相互作用，从而显著提高存活率。基于这项工作，我计划通过进行一项随机、双盲、安慰剂对照、剂量递增的I-II期试验来发展我作为临床研究者的技能，以研究单剂量IVIG与生理盐水安慰剂相比对因无并发症急性疼痛发作而入院的镰状细胞性贫血患者的安全性和有效性。共入组52例受试者。我假设IVIG能迅速减少血管阻塞，从而减少疼痛评分、麻醉剂使用和住院时间。我还将通过测量参与白细胞粘附于内皮细胞和红细胞-白细胞相互作用的粘附受体、微循环血流和溶血的血清标志物来研究IVIG对镰状细胞病患者的生理作用。本试验的完成，沿着进一步的生物统计学和转化科学课程的正式培训、研究研讨会以及经验丰富的临床研究者的指导，将使我成为一名专注于转化工作的独立临床研究者。它也将允许我在培训期结束前提交NIH申请，将该试验扩展到III期试验或在I-II期试验中测试新鉴定的干扰血管闭塞分子机制的药物。 (End摘要）

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)