PROPRANOLOL AS ANTI-ADHESIVE THERAPY IN SCD

普萘洛尔作为 SCD 的抗粘连治疗

• 批准号: 7797698
• 负责人: LAURA M. DE CASTRO
• 金额: $ 19.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797698
• 关键词: ADRB2 gene; Adenylate Cyclase; Adhesions; Adhesives; Adrenergic Receptor; Adverse effects; Animal Model; Biological Assay; Biological Markers; Blood Pressure; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical effectiveness; Cross-Over Studies; Data; Development; Disease; Dose; Effectiveness; Electrocardiogram; Endothelial Cells; Epinephrine; Erythrocytes; FDA approved; Frequencies; Functional disorder; Genes; Genetic Polymorphism; Genotype; Goals; Heart Rate; Hemoglobin SS; Hospitalization; In Vitro; Laboratories; Laminin; Leukocytes; Measurement; Measures; Medical History; Methods; Morbidity - disease rate; Multicenter Studies; Outcome; Pain; Patients; Pharmaceutical Preparations; Phase; Physiological; Placebos; Play; Prevention therapy; Process; Production; Propranolol; Proteins; Randomized; Receptor Gene; Recruitment Activity; Role; Safety; Sickle Cell; Sickle Cell Anemia; Testing; Up-Regulation; Vascular Endothelium; Work; adhesion receptor; base; clinically significant; cytokine; design; disability; drug efficacy; improved; in vitro Assay; in vivo; mortality; novel strategies; phase 1 study; phase 2 study; phase 3 study; prevent; public health relevance; response; success; therapy development; treatment duration

DESCRIPTION (provided by applicant): Vaso-occlusion (VOC) and its clinical manifestation, pain, are the hallmarks of sickle cell disease (SCD) 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 (SS RBCs) plays a major role in the vaso-occlusive process, but no anti-adhesive therapy for SCD is yet available or in clinical trial. We have described how SS RBC adhesion results from activation of RBC adhesion receptors via the 22-adrenergic receptor, a response not seen in normal RBCs. Physiologic concentrations of epinephrine increase adhesion of SS RBCs as well as their ability to stimulate leukocyte adhesion, which then leads to cytokine production and stimulation of pro-adhesive molecules by endothelial cells. We have recently further shown that propranolol inhibits epinephrine- induced SS RBC adhesion both in vitro and in vivo in an animal model. Moreover, we recently demonstrated that a single dose of propranolol given to SCD patients reduces 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 SCD treatment-the use of an already FDA- approved drug, propranolol, as the first anti-adhesive therapy for SCD. We therefore propose to study the efficacy of chronic propranolol therapy in reducing SS RBC adhesion to vascular endothelium. Study Objectives: Perform a phase II propranolol vs placebo crossover study to evaluate whether chronic propranolol therapy can safely reduce the adhesion of SS RBCs to endothelial cells and thereby improve markers of endothelial cell activation and dysfunction. Methods: Up to 40 patients recruited from the Duke Sickle Cell Center will complete this study over 2 years. Subjects will be treated with a 40 mg twice daily dose of propranolol or placebo for a total of 6 weeks and then be switched to the other therapy. Patient clinical and medical histories will be obtained. Laboratory tests and EKG will be performed at baseline and periodically during the drug treatment period and after a 2-week washout period. In vitro adhesion studies and measurement of biomarkers will be performed at baseline, during the 6 weeks of treatment and at the end of the washout period to evaluate the effect of propranolol on SS RBC adhesion and endothelial dysfunction. Summary: Overall, a combination of clinical and laboratory parameters will be used to measure the efficacy of chronic propranolol therapy in reducing SS RBC adhesion, with the long term goal of gathering data sufficient to support the development of a large scale, randomized, multicenter study to determine the efficacy of propranolol in reducing the frequency of vaso-occlusion in SCD. PUBLIC HEALTH RELEVANCE: 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（由申请人提供）：血管封闭（VOC）及其临床表现，疼痛是镰状细胞疾病（SCD）的标志，是SCD患者住院的主要原因，以及短期和长期残疾的原因。主要含有血红蛋白S（SS RBC）的红细胞的粘附在血管 - 占地过程中起主要作用，但尚无针对SCD的抗粘附疗法或在临床试验中。我们已经描述了SS RBC粘附如何通过22-肾上腺素能受体激活RBC粘附受体，这在正常RBC中未见。肾上腺素的生理浓度增加了SS RBC的粘附及其刺激白细胞粘附的能力，然后导致细胞因子产生并刺激内皮细胞对促粘附分子的刺激。最近，我们进一步表明，普萘洛尔在动物模型中抑制体外和体内肾上腺素诱导的SS RBC粘附。此外，我们最近证明，给予SCD患者的单剂量降低了体外测量的RBC粘附力，而基线的血压和心率显着变化。这一发现使SCD治疗是一种完全新颖的方法 - 使用已批准的药物Propranolol作为SCD的第一种抗粘附疗法。因此，我们建议研究慢性普萘洛尔治疗在减少SS RBC粘附对血管内皮的粘附方面的疗效。研究目标：执行II期普萘洛尔与安慰剂跨界研究，以评估慢性普萘洛尔治疗是否可以安全地减少SS RBC对内皮细胞的粘附，从而改善内皮细胞激活和功能障碍的标记。方法：从杜克镰刀中心招募的多达40名患者将在2年内完成这项研究。受试者将用40 mg的每日两次剂量的普萘洛尔或安慰剂治疗6周，然后切换到另一种疗法。将获得患者临床和病史。实验室测试和心电图将在基线和在药物治疗期间以及2周的冲洗期间进行定期进行。体外粘附研究和生物标志物的测量将在基线，治疗的6周和冲洗期结束时进行评估，以评估普萘洛尔对SS RBC粘附和内皮功能障碍的影响。总结：总体而言，将使用临床和实验室参数的组合来衡量慢性普萘洛尔治疗在降低SS RBC粘附方面的疗效，并长期目标是收集足以支持大规模，随机，多中心研究以确定Propranolol在降低Propranolol在降低vaso-cocc的频率上的效率的数据。 公共卫生相关性：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。因此，我们建议在II期单一中心临床研究中检验这一假设。