CORE--Inter Center Collaborative Clinical Research

CORE--跨中心协作临床研究

• 批准号: 6900243
• 负责人: Martin H. Steinberg
• 金额: $ 36万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-20 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900243
• 关键词: African American; biomedical facility; blood disorder chemotherapy; blood vessel occlusion; clinical research; clinical trials; cooperative study; erythrocytes; hemoglobin Ss; human subject; human therapy evaluation; hydroxyurea; ion transport; magnesium; patient oriented research; potassium chloride; sickle cell anemia

At birth, about 1 in 830 African Americans has HbSC disease. These patients have the same vasoocclusive complications as sickle cell anemia---only less often. Clinical descriptions of HbSC disease abound and substantial insights into its distinct pathophysiology have been gained. Nevertheless, few published trials of its treatment exist. Perhaps this is clue to the mistaken perception that HbSC disease is benign or that its rarity precludes conclusive therapeutic trials. We submit that: HbSC disease complications often merit acute treatment; a safe preventive treatment might forestall the disease complications that develop with age; novel means of reversing the pathophysiology of this disorder are available; sufficient patients exist to carry out a successful therapeutic trial. HbSC disease exhibits a characteristic erythrocyte dehydration compared with sickle cell trait or HbC trait erythrocytes. Cell dehydration plays a crucial role in the pathophysiology of HbSC disease because it allows for the intracellular HbS to reach concentrations that induce clinically significant HbS polymerization and cell sickling. K-CI cotransport is highly expressed in HbSC erythrocytes and determines their characteristic microcytosis and dehydration. Thus, HbSC disease represents the ideal target for therapies aimed at preventing K-CI cotransport mediated cell dehydration. Pilot studies showed that hydroxyurea and Mg affect erythrocyte hydration in HbSC disease. Our hypothesis is that oral Mg and hydroxyurea will increase intracellular Mg, block K-CI cotransport, prevent cell dehydration, and reduce polymerization-induced vasoocclusive complications. Accordingly, we propose a double-blinded, placebo-controlled trial to examine the effectiveness of hydroxyurea, magnesium pidolate and hydroxyurea + magnesium pidolate in reducing cell density in HbSC disease. As a secondary endpoint, because of the required brevity of this trial, we will examine the effectiveness of this treatment in preventing sickle cell disease-related vasoocclusive episodes. Other secondary endpoints include HbF level, F-cell numbers and hematologic measurements. The cellular effects of hydroxyurea and magnesium should modulate favorably the course of this disorder and the results of this study will provide the framework for a definitive efficacy trial.

出生时，大约有830名非裔美国人患有HBSC疾病。这些患者与镰状细胞贫血相同的血管闭合并发症 - 仅频率少。 HBSC疾病的临床描述充斥着对其独特的病理生理学的大量见解。然而，很少有关于其治疗的已发表试验。也许这是错误的看法，即HBSC疾病是良性的，或者它的稀有性排除了结论性的治疗试验。我们认为：HBSC疾病并发症通常值得急性治疗；安全的预防治疗可能会阻止随着年龄的增长而发展的疾病并发症。可以使用逆转这种疾病的病理生理学的新颖手段；有足够的患者进行成功的治疗试验。 HBSC疾病表现出特征性红细胞脱水 与镰状细胞性状或HBC性状性红细胞相比。细胞脱水在HBSC疾病的病理生理学中起着至关重要的作用，因为它允许细胞内HBS达到诱导临床意义的HBS聚合和细胞疾病的浓度。 K-CI共晶型在HBSC红细胞中高度表达，并确定其特征性微细胞增多和脱水。因此，HBSC疾病代表了旨在防止K-CI共转运介导的细胞脱水的理想靶标。试点研究表明，羟基脲和MG会影响HBSC疾病中的红细胞水合。我们的假设是，口服MG和羟基脲将增加细胞内MG，阻断K-CI共转运，防止细胞脱水，并减少聚合引起的血管含量并发症。因此，我们 提出了一项双盲，安慰剂对照的试验，以检查羟基脲，香镁镁和羟基酸镁 +少镁在降低HBSC疾病中细胞密度中的有效性。作为次要终点，由于这项试验所需的简洁性，我们将研究这种治疗方法在预防与镰状细胞相关的血管隔离事件方面的有效性。其他次要终点包括HBF水平，F细胞数量和血液学测量值。羟基脲和镁的细胞作用应有利地调节这种疾病的病程，这项研究的结果将为确定的功效试验提供框架。