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.

血管闭塞发作在镰状细胞性贫血 (SCA) 患者中很常见，会导致疼痛和慢性器官损伤。 SCA 的特点是存在致密、脱水的镰状红细胞 (SS RBC)，这些细胞流变学异常，在血管闭塞期间被选择性捕获。防止细胞脱水的策略将提供重要的治疗选择，可能减少血管闭塞发作。 SS RBC 脱水是由两个阳离子转运系统介导的阳离子消耗造成的，即镰状细胞诱导的 (SI) 泄漏途径和 KCI 协同转运蛋白 (KCC)。该中心之前的工作表明，双嘧达莫在体外抑制 Na、K 和 Ca 的 SI 通量。在 SCA 动物模型中，增加细胞镁含量可抑制 KCC 活性并增加细胞水合作用。一项针对 SCA 患者的小型临床研究表明，补充镁可以增加细胞镁含量，降低 KCC 活性并改善红细胞水合作用。这项研究将检验以下假设：接受双嘧达莫或镁治疗的 SCA 患者中 SS RBC 脱水会显着减少。假设同时接受两种药物治疗的患者对致密细胞形成具有累加的、可能是协同的作用。将对 48 名年龄 12 岁的 SCA 患者进行前瞻性、随机、交叉、重复测量设计 和年纪大了。患者将从辛辛那提综合镰状细胞中心和底特律韦恩州立大学镰状细胞项目招募。这种设计将允许有效比较三种治疗方案；单独使用双嘧达莫、单独使用镁或两者的组合。我们预计患者能够很好地耐受这些疗法。主要结果指标包括通过自动细胞计数和邻苯二甲酸盐密度梯度评估的致密细胞数量、细胞阳离子含量、细胞体积和血红蛋白浓度。使用辛辛那提首创的生物素标记技术，将对每个治疗组的六名患者进行红细胞存活率和致密细胞形成率的测量，并将脱落 阐明了 SS RBC 脱水的机制以及双嘧达莫和镁对其的假设抑制作用。