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.

大约每 830 名非裔美国人中就有 1 人出生时患有 HbSC 疾病。这些患者有与镰状细胞性贫血相同的血管闭塞并发症——只是较少发生。 HbSC 疾病的临床描述比比皆是，并且对其独特的病理生理学有了深入的了解。尽管如此，已发表的治疗试验却很少。也许这就是人们错误地认为 HbSC 疾病是良性的或者其罕见性妨碍了结论性治疗试验的线索。我们认为： HbSC 疾病并发症通常需要紧急治疗；安全的预防性治疗可以预防随年龄增长而出现的疾病并发症；逆转这种疾病病理生理学的新方法已经存在；存在足够的患者来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，因为它使细胞内的 HbS 达到诱导临床上显着的 HbS 聚合和细胞镰状化的浓度。 K-CI 共转运在 HbSC 红细胞中高度表达，并决定其特征性的小红细胞增多和脱水。因此，HbSC 疾病代表了旨在预防 K-CI 共转运介导的细胞脱水的治疗的理想靶标。初步研究表明，羟基脲和镁会影响 HbSC 疾病中的红细胞水合作用。我们的假设是口服镁和羟基脲会增加细胞内镁，阻断 K-CI 共转运，防止细胞脱水，并减少聚合引起的血管闭塞并发症。据此，我们 提出了一项双盲、安慰剂对照试验，以检验羟基脲、吡酮酸镁和羟基脲+吡酮酸镁在降低 HbSC 疾病细胞密度方面的有效性。作为次要终点，由于该试验要求简短，我们将检查该治疗在预防镰状细胞病相关血管闭塞发作方面的有效性。其他次要终点包括 HbF 水平、F 细胞数量和血液学测量。羟基脲和镁的细胞作用应该有利于调节这种疾病的进程，这项研究的结果将为明确的疗效试验提供框架。