Eptifibatide as Treatment for Acute Pain Episodes in Sickle Cell Disease

描述（由申请人提供）：镰状细胞病（SCD）被认为是一种高凝状态和慢性炎症状态。尽管高凝状态和慢性炎症有丰富的实验室证据，但这些变化对SCD发病机制的贡献仍不确定。SCD患者在非危象、稳定状态下表现出血小板和凝血活化增加。此外，有证据表明，与非危象、稳态相比，当SCD患者经历急性疼痛发作时，血小板和凝血活化甚至进一步增加。已知有效的炎症介质CD 40配体（CD 40 L）一旦暴露于血小板表面并在血小板活化后释放到血浆中，就会增加白细胞增殖、内皮细胞增殖和促凝血活性。我们最近发现，相对于未受影响的健康个体，SCD患者血浆中的CD 40 L水平显著较高，而这些患者血小板中的CD 40 L水平显著降低。此外，与处于非危象、稳定状态的患者相比，具有急性疼痛发作的SCD患者的CD 40 L的血浆水平进一步升高。急性疼痛发作是SCD最常见的临床表现，并且是使这些患者的生活如此不可预测的主要原因。尽管对SCD的病理生理学有了更好的理解，但对急性疼痛发作的治疗仍然不足，主要包括阿片类镇痛药。该项目提供了大量密切关注的患者群体，我们将能够详细研究血小板活化和慢性炎症对SCD发病机制的贡献。我们试图检验的总体假设是，血小板活化增加和由此产生的炎症反应是SCD病理生理学的重要贡献者。我们相信，通过减少血小板聚集，以及炎症和血栓形成介质的释放，我们将影响SCD相关并发症的临床过程。我们建议通过实现以下具体目标来检验这一假设：a）我们将评估1 IIb 23拮抗剂依替巴肽在SCD患者急性疼痛发作期间的安全性。此外，我们将进行一项探索性研究，以评估依替巴肽对这些患者急性疼痛发作的影响。B）我们将评价在急性疼痛发作期间依替巴肽对体内血小板功能、血小板-白细胞聚集体、凝血活化、内皮活化和炎性标志物的影响。在我们提出的工作的结论，我们将有一个更好的了解血小板活化和炎症的作用，SCD的发病机制。如果数据支持依替巴肽安全有效的假设，我们计划进行充分的研究，以更明确地评价抗血小板药物治疗和/或预防SCD急性疼痛发作的安全性和有效性。这些目标的实现应该为患有这种慢性疾病的患者提供更多的治疗选择。公共卫生相关性：镰状细胞病患者的急性疼痛发作（或血管闭塞性疼痛危象）的治疗仅限于镇痛药、温和水合作用和偶尔补充氧气。由于这些患者表现出慢性炎症和活化凝血的证据，我们提出了一项研究的糖蛋白IIb/IIIa抑制剂，eptifibatide，以确定其在急性疼痛发作的安全性和有效性。如果这种药物被发现是安全有效的，它将导致镰状细胞病患者在急性疼痛发作期间的新治疗选择的发展。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) has been referred to both as a hypercoagulable and chronic inflammatory state. Despite the abundant laboratory evidence of hypercoagulability and chronic inflammation, the contribution of these changes to the pathogenesis of SCD remains uncertain. Patients with SCD exhibit increased platelet and coagulation activation in the non-crisis, steady state. In addition, there is evidence that platelet and coagulation activation increase even further when SCD patients experience an acute pain episode compared to the non- crisis, steady state. The potent inflammatory mediator, CD40 ligand (CD40L), is known to increase leukocyte proliferation, endothelial adhesiveness and procoagulant activity, once it is exposed on the platelet surface and released into plasma following platelet activation. We recently showed that levels of CD40L are markedly higher in the plasma of SCD patients and significantly reduced in the platelets of these patients relative to unaffected, healthy individuals. In addition, plasma levels of CD40L are increased further in SCD patients with acute pain episodes compared to patients in their non-crisis, steady states. Acute pain episodes represent the most common clinical manifestation of SCD, and are largely responsible for making the lives of these patients so unpredictable. Despite an improved understanding of the pathophysiology of SCD, the treatment of acute pain episodes remains inadequate, consisting mainly of opioid analgesics. The UNC Sickle Cell Program offers a large and closely followed patient population in whom we will be able to study in detail, the contribution of platelet activation and chronic inflammation to the pathogenesis of SCD. The overall hypothesis that we seek to test is that increased platelet activation and the resultant inflammatory responses are important contributors to the pathophysiology of SCD. We believe that by decreasing platelet aggregation, and the release of mediators of inflammation and thrombosis, we will affect the clinical course of SCD-related complications. We propose to test this hypothesis by carrying out the following specific aims: a) We will evaluate the safety of the 1IIb23 antagonist, eptifibatide in SCD patients during an acute pain episode. Furthermore, we will perform an exploratory study to evaluate the effect of eptifibatide on acute pain episodes in these patients. b) We will evaluate the effect of eptifibatide on in vivo platelet function, platelet-leukocyte aggregates, coagulation activation, endothelial activation and inflammatory markers during an acute pain episode. At the conclusion of our proposed work, we will have an improved understanding of the contribution of platelet activation and inflammation to the pathogenesis of SCD. If the data support the hypothesis that eptifibatide is safe and effective, we plan on carrying out adequately powered studies to more definitively evaluate the safety and efficacy of antiplatelet agents for the treatment and/or prevention of acute pain episodes in SCD. Accomplishment of these goals should allow more treatment options for patients with this chronic disease. PUBLIC HEALTH RELEVANCE: The treatment of acute pain episodes (or vaso-occlusive pain crises) in patients with sickle cell disease is limited to analgesics, gentle hydration and occasionally, supplemental oxygen. As these patients manifest evidence of chronic inflammation and activated blood coagulation, we have proposed a study of the glycoprotein IIb/IIIa inhibitor, eptifibatide, to determine its safety and effectiveness in acute pain episodes. If this agent is found to be safe and effective, it will lead to the development of new treatment options for sickle cell disease patients during acute pain episodes.