Drotrecogin-Alpha: A Review

Bradley J. Phillips

摘要

Drotrecogin-alpha is a recombinant form of human activated protein C used to treat severe sepsis. In this article we are reviewing all aspects of this compound. General Information Drotrecogin-alpha is a recombinant form of human activated protein C used to treat severe sepsis. (Severe sepsis is defined as sepsis associated with acute organ dysfunction.) Drotrecogin-alpha has anti-inflammatory, antithrombotic, and profibrinolytic properties. Indications for Use Drotrecogin-α is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (as determined by APACHE II scores) Drotrecogin-alpha should only be ordered by a Critical Care Medicine Attending Physician with approval from a second Critical Care Medicine Attending Physician (our institution). The Drotrecogin alpha-activated criteria for use sheet must be completed and placed in the patient chart prior to ordering Drotrecogin-alpha can only be administered in an Intensive Care Unit (ICU), or a patient awaiting transfer to an ICU. Pharmacology The specific mechanisms by which drotrecogin-alpha (activated protein C) exerts its effect on survival in patients with severe sepsis is not completely understood. In vitro data suggest that activated protein C exerts an antithrombotic effect by inhibiting factors Va and VIIIa, and that it has indirect profibrinolytic activity by inhibiting plasminogen activator-inhibitor-1 (PAI-1). In vitro data also suggest that activated protein C may exert an anti-inflammatory effect by inhibiting tumor necrosis factor production, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium. Pharmacokinetics Peak concentrations of drotrecogin-alpha are seen 2 hours after starting the infusion. Plasma concentrations of drotrecogin-alpha fall to undetectable levels 2 hours after stopping the infusion. Inactivation of drotrecogin-alpha is through endogenous plasma protease inhibitors. No dose adjustment is needed in elderly patients, or in patients with renal or hepatic dysfunction. Precautions The following patients are at an increased risk for bleeding complications due to drotrecogin-alpha therapy, and a careful risk/benefit assessment should be made prior to initiating therapy. Therapeutic Heparin (>15 units/kg/hr) Platelet count <30,000/mm3 Recent (within 6 weeks) gastrointestinal bleeding Recent administration (within 3 days) of thrombolytic therapy Recent administration (within 7 days) of oral anticoagulants or GP IIb/IIIa inhibitors Recent administration (within 7 days) of >650mg/day of aspirin or other platelet inhibitors Recent (within 3 months) ischemic stroke Known or suspected intracranial AV malformation or aneurysm Known bleeding diathesis except for acute coagulopathy related to sepsis Chronic severe hepatic disease HIV infection in association with a last known CD4 count of <50/mm3 Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location Because drotrecogin-alpha is a therapeutic protein, there exists a potential for immunogenicity. Antibodies against drotrecogin have been observed. There is insufficient data at this time to quantify the risk, but extreme caution should be exercised if a patient has previously received drotrecogin-alpha. Contraindications The following patients should not receive drotrecogin-alpha: Active internal bleeding Recent (within 3 months) hemorrhagic stroke Recent (within 2 months) intracranial/intraspinal surgery/severe head trauma Trauma patients with an increased risk of life threatening bleeding Presence of an epidural catheter Known or suspected intracranial neoplasm or mass lesion Known hypersensitivity to drotrecogin alpha-activated or any component Acute pancreatitis without a proven source of infection Pregnancy Advance directive or patient, f

机译：Drotrecogin-alpha是用于治疗严重脓毒症的人类活化蛋白C的重组形式。在本文中，我们正在审查该化合物的所有方面。一般信息Drotrecogin-alpha是用于治疗严重脓毒症的人类活化蛋白C的重组形式。（严重脓毒症定义为与急性器官功能障碍相关的脓毒症。）Drotrecogin-alpha具有抗炎，抗血栓形成和纤溶蛋白的特性。 Drotrecogin-α的使用适应症可降低患有严重败血症（与急性器官功能障碍相关的败血症）且具有高死亡风险（由APACHE II评分确定）的成年患者的死亡率，Drotrecogin-α只能通过以下方式订购经第二位重症医学主治医师（我们机构）批准的重症医学主治医师。在订购Drotrecogin-alpha之前，必须先完成Drotrecogin alpha激活的使用表并放置在患者图表中，然后才能在重症监护病房（ICU）或等待转移至ICU的患者中进行治疗。药理学drotrecogin-α（活化蛋白C）通过其对严重脓毒症患者生存发挥作用的具体机制尚未完全了解。体外数据表明，活化的蛋白C通过抑制因子Va和VIIIa发挥抗血栓形成作用，并通过抑制纤溶酶原激活物抑制剂1（PAI-1）具有间接纤溶活性。体外数据还表明，活化的蛋白C可通过抑制肿瘤坏死因子的产生，阻断白细胞与选择素的粘附以及限制凝血酶诱导的微血管内皮内的炎症反应来发挥抗炎作用。药代动力学在开始输注2小时后，可以看到drotrecogin-α的峰值浓度。停止输注2小时后，drotrecogin-α的血浆浓度降至无法检测的水平。 drotrecogin-α的灭活是通过内源性血浆蛋白酶抑制剂实现的。老年患者或肾或肝功能不全的患者无需调整剂量。注意事项由于drotrecogin-α治疗，下列患者的出血并发症风险较高，在开始治疗前应仔细评估风险/获益。治疗性肝素（> 15单位/ kg / hr）血小板计数<30,000 / mm3最近（6周内）胃肠道出血最近溶栓治疗（3天之内）最近口服抗凝剂或GP IIb / IIIa的（7天之内）抑制剂最近服用（7天之内）> 650mg /天的阿司匹林或其他血小板抑制剂近期（3个月之内）缺血性中风已知或怀疑颅内AV畸形或动脉瘤除与败血症相关的急性凝血病外，已知出血性血液透析慢性重症肝病HIV最后一次已知的CD4计数小于50 / mm3的感染出血构成重大危害或由于其位置而特别难以控制的其他任何疾病因为drotrecogin-α是一种治疗性蛋白质，因此具有免疫原性的潜力。已经观察到针对drotrecogin的抗体。目前尚无足够的数据来量化风险，但是如果患者以前接受过drotrecogin-alpha，则应格外小心。禁忌症以下患者不应该接受drotrecogin-alpha的治疗：活动性内出血近期（3个月内）出血性中风近期（2个月内）颅内/脊柱内手术/严重头部创伤创伤生命危险性出血风险增加的患者存在硬膜外导管已知或疑似颅内肿瘤或肿块病变已知对drotrecoginα激活或任何成分的超敏反应没有明确感染源的急性胰腺炎怀孕提前指示或患者，f

Drotrecogin-Alpha: A Review

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