AN ALTERNATIVE APPROACH TO HYDROXYUREA THERAPY IN SICKLE CELL DISEASE

羟基脲似乎是一种有前途的药物，用于预防 镰状细胞病（SCD）中的血管闭塞。 目前的想法是 羟基脲的临床益处是通过增加 Hb F浓度。因此，目前的治疗策略是使用 最大耐受剂量的羟基脲，以实现 最大Hb F反应。 然而，一些证据表明， 除Hb F本身增加以外的因素也是重要的。 我们 假设羟基脲的一个关键作用是显著降低 密集的镰状红细胞亚群。 因此，我们建议调查 是否可以将羟基脲剂量滴定至该终点 无血液毒性的显著临床益处通常 与最大剂量相关，因此导致风险改善：获益 比率、更好的患者依从性和更广泛的患者适用性 人口 我们进一步建议，这种治疗策略的特点的影响， 对SCD患者红细胞、白细胞和血液流变学特性的影响， 确定其在治疗几种重要的血管闭塞性 SCD的并发症：疼痛危象、肺动脉高压、肾性 功能不全和腿部溃疡 这些调查应提供一个 提高了对羟基脲在SCD中的生理作用的理解， 同时也为它的临床应用提供了新的见解。

Hydroxyurea appears to be a promising agent for the prevention of vascular occlusion in sickle cell disease (SCD). Current thinking holds that the clinical benefits of hydroxyurea are mediated by increases in Hb F concentration. Therefore, the current treatment strategy is to use maximally tolerated doses of hydroxyurea in order to achieve the maximimum Hb F response. However, several lines of evidence suggest that factors other than increased Hb F per se are also important. We hypothesize that a key effect of hydroxyurea is a marked reduction in the dense subpopulation of sickle RBC. We therefore propose to investigate whether titration of hydroxyurea dosage to this endpoint can achieve significant clinical benefits without the hematologic toxicity often associated with maximal doses, thus resulting in an improved risk:benefit ratio, better patient compliance and broader applicability to the patient population. We further propose to characterize the effects of this treatment strategy on a broad range of RBC, WBC and hemorheologic properties in SCD, and to determine its efficacy in treating several important vasoocclusive complications of SCD: painful crisis, pulmonary hypertension, renal insufficiency and leg ulcers. These investigations should provide an improved understanding of the physiologic effects of hydroxyurea in SCD, as well as give new insights into its clinical utility.