Dipyridamole/Magnesium to Improve Sickle Cell Hydration

双嘧达莫/镁改善镰状细胞水合作用

• 批准号: 6782210
• 负责人: KAREN A KALINYAK
• 金额: $ 18.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6782210
• 关键词: adolescence (12-20); adult human (21+); blood vessel occlusion; cell morphology; cell water; clinical trials; cooperative study; dipyridamole; drug screening /evaluation; human subject; human therapy evaluation; magnesium ion; patient oriented research; sickle cell anemia; sickle cell crisis; sickling inhibitor

Vaso-occlusivc episodesare common among patients with sickle cell anemia (SCA), causing pain and chronic organ damage. SCA is characterized by the presence of dense, dehydrated sickle red blood cells (SS RBC), which are rheologically abnormal and are selectively trapped during vaso-occlusion. Strategies to prevent cellular dehydration would offer important therapeutic options that might decrease vaso-occlusive episodes. SS RBC dehydration results from cation depletion mediated by two cation transport systems, a sickling-induced (SI) leak pathway and the KCI cotransporter (KCC). Previous work at this Center has shown that di-pyridamole inhibits the SI fluxes of Na, K and Ca in vitro. Increasing cellular magnesium inhibits KCC activity and increases cellular hydration in animal models of SCA. A small clinical study in SCA patients demonstrated that Mg supplementation increased cellular Mg, reduced KCC activity and improved red cell hydration. This study will test the hypothesis that significant reduction in SS RBC dehydration will be seen in patients with SCA treated with either dipyridamole or magnesium. An additive, and possibly synergistic, effect on dense cell formation is hypothesized in patients treated simultaneously with both agents. A prospective, randomized, crossover, repeated measures design will be conducted among 48 patients with SCA, ages 12 years and older. Patients will be recruited from the Cincinnati Comprehensive Sickle Cell Center and the Sickle Cell Program at Wayne State University in Detroit. This design will allow for efficient comparison of the three treatment options; dipyridamole alone, magnesium alone or a combination of both. We anticipate that these therapies will be well tolerated by the patients. Primary outcome measures include the number of dense cells, assessed by automated cell counting and phthalate density gradients, cellular cation content, cell volume and hemoglobin concentrations. Using the biotin label technique pioneered in Cincinnati, measurements of red cell survival and rate of dense cell formation will be made in six patients in each treatment group, and will shed light on the mechanisms underlying SS RBC dehydration and its postulated inhibition by dipyridamole and Mg.

在镰状细胞贫血（SCA）患者中常见的血管 - occlusivc发作，导致疼痛和慢性器官损伤。 SCA的特征在于存在致密的镰状红细胞（SS RBC），它们在流变学上异常，在血管酸凝聚过程中被选择性地捕获。防止细胞脱水的策略将提供重要的治疗选择，从而减少血管成核的发作。 SS RBC脱水是由两种阳离子传输系统介导的阳离子耗竭，这是一种可恶的诱导的 （SI）泄漏途径和KCI共转运蛋白（KCC）。该中心的先前工作表明，Di-Pyridamole在体外抑制Na，K和Ca的Si通量。在SCA动物模型中，增加细胞镁会抑制KCC活性并增加细胞水合。一项针对SCA患者的小型临床研究表明，补充毫克的细胞MG增加，KCC活性降低并改善了红细胞水合。这项研究将检验以下假设：在用二吡啶胺或镁治疗的SCA患者中，SS RBC脱水的显着降低。假设在与两种药物同时治疗的患者中，假设对密集细胞形成的添加剂且可能是协同作用的影响。在48名SCA患者中，将进行一项前瞻性，随机，跨界，重复措施设计 又年龄较大。将在底特律韦恩州立大学的辛辛那提综合细胞中心和镰状细胞计划中招募患者。这种设计将有效地比较三种治疗方案；单独的二吡啶胺，单独使用镁或两者的组合。我们预计患者可以很好地耐受这些疗法。主要结局指标包括通过自动细胞计数和邻苯二甲酸盐密度梯度，细胞阳离子含量，细胞体积和血红蛋白浓度评估的致密细胞数量。使用辛辛那提（Cincinnati）率先使用的生物素标记技术，将在每个治疗组的六名患者中对红细胞存活和致密细胞形成速率进行测量，并将脱落 对SS RBC脱水的基础机制及其二吡啶胺和MG抑制作用的灯光。