Eptifibatide as Treatment for Acute Pain Episodes in Sickle Cell Disease

描述(申请人提供)：镰状细胞病(SCD)是一种高凝状态和慢性炎症状态。尽管有大量的高凝状态和慢性炎症的实验室证据，但这些变化在SCD发病机制中的作用仍不确定。SCD患者在非危象、稳定期表现为血小板和凝血活性升高。此外，有证据表明，当SCD患者经历急性疼痛发作时，与非危象、稳定状态相比，血小板和凝血活性进一步增加。已知的强效炎症介质CD40配体(CD40L)一旦暴露在血小板表面并在血小板激活后释放到血浆中，就会增加白细胞的增殖、内皮黏附和促凝血活性。我们最近发现SCD患者血浆中CD40L水平显著高于未受影响的健康个体，而这些患者的血小板中CD40L水平显著低于未受影响的健康个体。此外，与无危象、稳定状态的患者相比，有急性疼痛发作的SCD患者的血浆CD40L水平进一步升高。急性疼痛发作是SCD最常见的临床表现，并在很大程度上导致这些患者的生活如此不可预测。尽管对SCD的病理生理学有了更好的了解，但对急性疼痛发作的治疗仍然不够，主要是阿片类止痛药。北卡罗来纳大学的镰刀细胞计划提供了大量密切关注的患者群体，在这些患者中，我们将能够详细研究血小板激活和慢性炎症在SCD发病机制中的作用。我们试图验证的总体假设是，血小板活化增加和由此产生的炎症反应是SCD病理生理学的重要因素。我们认为，通过减少血小板聚集、炎症和血栓形成介质的释放，我们将影响SCD相关并发症的临床进程。我们建议通过实现以下具体目标来验证这一假设：a)我们将评估1IIb23拮抗剂eptifiatide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，以评估依替非那肽对这些患者急性疼痛发作的影响。B)在急性疼痛发作期间，我们将评估依替菲肽对体内血小板功能、血小板-白细胞聚集性、凝血活性、内皮活性和炎症标志物的影响。在我们拟议的工作结束时，我们将对血小板激活和炎症在SCD发病机制中的作用有一个更好的理解。如果数据支持依替非那肽安全有效的假设，我们计划进行足够有力的研究，以更明确地评估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。这些目标的实现将为患有这种慢性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)的治疗仅限于止痛剂、温和的水合作用，偶尔还需补充氧气。由于这些患者表现出慢性炎症和激活的凝血功能，我们建议对糖蛋白IIb/IIIa抑制剂爱替菲拉肽进行研究，以确定其在急性疼痛发作中的安全性和有效性。如果这种药物被发现是安全有效的，它将导致为急性疼痛发作期间的镰状细胞病患者开发新的治疗方案。

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.