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，导致疼痛和慢性器官损伤。SCA的特征在于存在致密、脱水的镰状红细胞（SS RBC），其是流变学异常的并且在血管闭塞期间被选择性地捕获。防止细胞脱水的策略将提供重要的治疗选择，可能会减少血管阻塞发作。SS RBC脱水是由两个阳离子转运系统介导的阳离子耗竭引起的， (SI)泄漏途径和KCl协同转运蛋白（KCC）。本中心以前的工作表明，双嘧达莫抑制钠，钾和钙的SI通量在体外。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。在SCA患者中进行的一项小型临床研究表明，补充镁可增加细胞镁，降低KCC活性并改善红细胞水合作用。本研究将检验这样一个假设，即在用潘生丁或镁治疗的SCA患者中，SS RBC脱水将显著减少。在同时接受两种药物治疗的患者中，假设对致密细胞形成有相加作用，可能是协同作用。将在48例年龄12岁的SCA患者中进行前瞻性、随机、交叉、重复测量设计 年纪也更大了患者将从辛辛那提综合镰状细胞中心和底特律州立大学韦恩的镰状细胞项目招募。这种设计将允许三种治疗方案的有效比较;单用双嘧达莫，单用镁或两者的组合。我们预计这些治疗将被患者很好地耐受。主要结局指标包括通过自动细胞计数和邻苯二甲酸酯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，并将脱落 光的机制SS红细胞脱水和其假定的抑制双嘧达莫和镁。