Treatment of sickle cell acute pain episodes with intravenous gammagblobulin

静脉注射丙种球蛋白治疗镰状细胞性急性疼痛发作

基本信息

批准号：
8547090
负责人：
Patricia Ann Shi
金额：
$ 12.62万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547090
关键词：
Acute Pain Address Adherence Adhesions Affect African American Biometry Blood Vessels Blood flow Blood specimen Cell Communication Clinical Clinical Investigator Disease Dose Double-Blind Method Economics Endothelium Enrollment Erythrocytes Functional disorder Hemoglobin Hemoglobinopathies Hemolysis Hospitalization Hospitals Individual Intravenous Intravenous Immunoglobulins Laboratories Latino Length Leukocytes Manuscripts Measures Mentorship Molecular Narcotics Nitric Oxide Normal saline Pain Pathology Patients Phase Phase III Clinical Trials Physiological Placebo Control Placebos Play Randomized Research Role Serum Markers Sickle Cell Sickle Cell Anemia Testing Training Translational Research United States United States National Institutes of Health Work abstracting adhesion receptor base bench to bedside experience mouse model peripheral blood psychologic receptor safety study skills social standard of care venule

项目摘要

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)

描述（由申请人提供）：镰状细胞疾病是世界上最常见的血红蛋白病，在*美国，在360名非裔美国人中约有1个，而1200个拉丁美洲人中有1个。小血管阻塞或血管封闭是导致该疾病临床并发症的主要病理。血管咬合最常见的表现是急性疼痛发作（危机），通常需要住院和麻醉性使用，从而对受苦的人造成了经济，社会和心理伤害。护理标准不足，没有针对急性疼痛发作的特定疗法。小鼠模型表明，遵守血管内皮的白细胞可能通过随后与镰状红细胞的相互作用来在血管肠结被方面起着至关重要的作用。我贡献的进一步工作表明，在迅速诱导血管凝集之前或之后，静脉注射γ（IVIG）迅速降低了白细胞粘附到内皮和随后的红细胞相互作用，从而降低了白细胞粘附，从而导致生存的显着增加。基于这项工作，我计划通过进行随机，双盲，安慰剂控制的，剂量 - 降低阶段L-LL试验来研究单一剂量的IVIG的安全性和功效，并与对镰状细胞贫血患者的正常盐水安慰剂的安全性和疗效相比，该剂量的安全性和功效。总共将注册52名受试者。我假设IVIG将迅速采取行动，以减少血管咬合，从而减少疼痛评分，麻醉性使用和住院时间。我还将通过测量与白细胞粘附于内皮和红细胞白细胞相互作用，微循环血流以及血液溶解的血清标志物相互作用的粘附受体和血液溶解的血清标记，来研究IVIG对镰状细胞疾病患者的生理影响。这项试验的完成，以及在生物统计学和转化科学课程，研究研讨会以及经验丰富的临床研究人员的指导方面的进一步正式培训，将使我成为一名专注于转化基准台上工作的独立临床研究者。它还将使我在培训期结束时提交NIH应用程序，以将该试验扩展到III期试验或测试，在L-LL期试验中，新鉴定的药物会干扰干扰血管封闭的分子机制。（抽象的结尾）