Dipyridamole/Magnesium to Improve Sickle Cell Hydration

在镰状细胞性贫血(SCA)患者中，血管闭塞发作很常见，导致疼痛和慢性器官损害。SCA的特征是存在致密的脱水镰状红细胞(SS RBC)，这些红细胞在血液流变学上异常，在血管闭塞时被选择性地捕获。预防细胞脱水的策略将提供重要的治疗选择，可能减少血管闭塞事件。SS红细胞脱水是由两种阳离子转运系统介导的阳离子耗竭引起的，镰刀诱导的 (Si)泄漏途径和KCI协同转运体(KCC)。该中心以前的工作表明，双嘧达莫在体外可以抑制钠、钾和钙的SI流量。在SCA动物模型中，增加细胞镁抑制KCC活性并增加细胞水合作用。对SCA患者的一项小型临床研究表明，补充镁可增加细胞镁含量，降低KCC活性，并改善红细胞水合作用。这项研究将验证这样一个假设，即服用双嘧达莫或镁的SCA患者将显著减少SS红细胞脱水。在同时使用两种药物治疗的患者中，假设有一种附加的，可能是协同的对致密细胞形成的影响。这项前瞻性、随机化、交叉、重复测量设计将在48名12岁的SCA患者中进行。 而且年纪也更大。患者将从辛辛那提综合镰刀细胞中心和底特律韦恩州立大学的镰刀细胞计划中招募。这一设计将允许对三种治疗方案进行有效的比较：单用双嘧达莫、单用镁或两者结合。我们预计这些疗法将被患者很好地耐受。主要结果指标包括致密细胞的数量，通过自动细胞计数和邻苯二甲酸盐密度梯度评估，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，将在每个治疗组的6名患者中测量红细胞存活率和致密细胞形成率，并将 阐明SS红细胞脱水的机制以及双嘧达莫和镁对其假定的抑制作用。

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.