Phase 11 Study of Propranolol as Anti-Adhesive Therapy in SCD

普萘洛尔作为 SCD 抗粘连疗法的 11 期研究

• 批准号: 8115021
• 负责人: LAURA M. DE CASTRO
• 金额: $ 13.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115021
• 关键词: ADRB2 gene; Adenylate Cyclase; Adhesions; Adhesives; Adrenergic Receptor; Animal Model; Behavior; Biological Assay; Blood Circulation; Blood Pressure; Cell Adhesion; Characteristics; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical effectiveness; Data; Development; Disease; Dose; Effectiveness; Endothelial Cells; Endothelium; Epinephrine; Erythrocytes; FDA approved; Genes; Genetic Polymorphism; Genotype; Goals; Heart Rate; Hospitalization; In Vitro; Instruction; Laboratories; Laminin; Measurement; Measures; Methodology; Microcirculation; Morbidity - disease rate; Multicenter Studies; Outcome; Pain; Patients; Pharmaceutical Preparations; Phase; Physiological; Play; Prevention therapy; Process; Propranolol; Proteins; Randomized; Receptor Gene; Role; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Testing; Up-Regulation; Vascular Endothelium; Work; adhesion receptor; base; design; disability; drug efficacy; improved; in vivo; mortality; novel; novel strategies; open label; phase 1 study; phase 2 study; phase 3 study; prevent; response; success; therapy development

DESCRIPTION (provided by applicant): Vaso-occlusion (VOC) and its clinical manifestation, pain, are the hallmark of sickle cell disease (SCO) and are the main causes of hospitalization and both short- and long-term disability in patients with SCD. Adhesion of red cells containing primarily hemoglobin S (SSRBCs) plays a major role in the vasoocclusive process, but no anti-adhesive therapy for SCO is yet available or even in clinical trial. We have discovered that sickle red blood cell (SSRBC) adhesion results from activation of RBC adhesion receptors via the ¿2- adrenergic receptor, a response not seen in normal RBCs. Physiologic doses of epinephrine increase adhesion of SSRBCs, which then leads to stimulation of pro-adhesive molecules by endothelial cells. We have recently shown that propranolol inhibits epinephrine-induced SSRBC adhesion both in vitro and in an animal model and that a single dose of propranolol given to SCO patients can reduce RBC adhesion measured in vitro, without significant changes of blood pressure and heart rate from baseline. This discovery makes possible an entirely novel approach to SCO treatment-the use of an FDA-approved drug, propranolol, as the first anti-adhesive therapy for SCD. Here we are proposing to study the efficacy of chronic propranolol therapy in reducing sickle red blood cell adhesion to vascular endothelium. This will be a phase II open-label study to find out whether chronic propranolol therapy can safely reduce the adhesion of~ SSRBCs to the endothelium and thus improve in vivo SSRBC circulatory characteristics in the microvasculature. Forty patients will be studied. Subjects will be treated with a twice a day dose of 40 mg of propranolol for a total of 6 weeks during which their clinical data will be collected. In vitro and in vivo adhesion studies will be performed to evaluate the drug effect on SSRBC adhesion. Overall, a clinical and laboratory parameters will be used to measure the efficacy and safety of chronic propranolol therapy, in reducing SSRBC adhesion, with the long-term goal of gathering data supporting the development of a large scale, randomized, multicenter study to determine the efficacy of propranolol in reducing VOC in SCD. RELEVANCE (See instructions): Development of therapies to treat or prevent vaso-occlusion in sickle cell disease is paramount to reducing the disease's morbidity and mortality. Our preliminary data suggest that propranolol, an inexpensive and widely available drug, might be safe and useful for this purpose. Thus, we propose to test this hypothesis in a Phase II single center clinical study.

描述（由适用提供）：血管封闭（VOC）及其临床表现，疼痛，是镰状细胞疾病（SCO）的标志，是SCD患者的住院和短期和长期残疾的主要原因。含有原发性血红蛋白S（SSRBC）的红细胞的粘附在血管隔离过程中起主要作用，但在SCO中尚无抗粘附疗法，甚至在临床试验中仍可使用。我们发现，镰状红细胞（SSRBC）粘合剂通过RBC粘附受体通过«2-肾上腺素受体激活而产生，这是正常RBC中未见的反应。肾上腺素的生理剂量增加了SSRBC的粘附性，从而导致内皮细胞刺激促粘附分子。我们最近表明，普萘洛尔在体外和动物模型中抑制肾上腺素诱导的SSRBC粘合剂，并且给SCO患者的单剂量丙糖醇可降低体外测量的RBC粘合剂，而无需大量的血压和心脏从基线的心率变化。这一发现使SCO治疗是一种完全新颖的方法 - 使用FDA批准的药物Propranolol作为SCD的第一种抗粘附疗法。在这里，我们提议研究慢性普萘洛尔治疗在减少镰状红细胞粘合剂对血管森林的粘附方面的有效性。这将是一项II期开放标签研究，以找出慢性普萘洛尔治疗是否可以安全地降低〜SSRBC对内皮的粘附，从而改善微堡体内体内SSRBC循环特征。将研究40名患者。受试者每天将接受两次40毫克母酚的两次治疗，总共6周，在此期间将收集其临床数据。将进行体外和体内粘附研究，以评估药物对SSRBC粘附的影响。总体而言，将使用临床和实验室参数来衡量慢性普萘洛尔治疗的效率和安全性，在降低SSRBC粘附方面，其长期目标是收集数据支持大规模，随机，多中心研究的发展，以确定在SCD中降低voc的效率。相关性（请参阅说明）：开发治疗或预防镰状细胞疾病中血管牙合的疗法对于降低疾病的发病率和死亡率至关重要。我们的初步数据表明，普遍是一种廉价且可广泛使用的药物，对于此目的而言可能是安全且有用的。这，我们建议在II期单一中心临床研究中检验这一假设。