ERYTHROPOEITIN PHYSIOLOGY AND PHARMACOLOGY IN INFANTS

多次红细胞输注用于早产 婴儿作为贫血的治疗方法是昂贵的，而且他们有患贫血的风险 血液传播感染和其他与输血有关的并发症。这个 项目1的长期目标是制定有效的战略 优化应用重组人促红细胞生成素(r-HuEPO) 治疗早产儿贫血。实现这一目标是 重要和及时，因为r-HuEPO仍然是一种不断发展的临床 在如何、何时和为谁治疗方面没有明确的共识 在这些患者中使用。我们的目标将通过执行来实现 促红细胞生成素的机械性药代动力学(PK)和药效学(PD) 用灵敏准确的示踪剂在羊和人身上进行的研究 方法论。实现对红细胞生成的最大刺激依赖于 部分是基于到目前为止对EPO的全面理解 难以捉摸的体内新陈代谢，部分依赖于 全面了解EPO迄今难以捉摸的体内代谢 以及其复杂的PK和PD行为。因为血浆促红细胞生成素浓度 贫血的早产儿比贫血的早产儿要少 成年人，促红细胞生成素分泌不足被认为是主要原因 这些新生儿不可避免地发生贫血的潜在机制 并作为r-HuEPO治疗的正当理由。基于直接的动物和 间接的人类数据，我们认为EPO的产生不足并不是 关于直接的动物和间接的人类数据，我们建议 EPO生产不足不是主要机制，而是另一个机制 机制可能更重要。这种猜测的基础是一个 不断扩大的数据表明促红细胞生成素在体内发生处置 主要是通过一个可饱和的、受体介导的过程。作为一个整体 假设我们推测EPO在体内的PK和PD是由 EPO受体(EPO-R‘s)的数量和亲和力 在体内可扩展的红系祖细胞池上。这 假设与观察到的EPO PK行为是一致的 非线型，早产儿促红细胞生成素排除量是对照组的3到4倍 婴儿比成年人多，而且红骨髓占了3-4倍 幼儿每公斤体重的体积比成年人大。因为 他们的灵敏度和准确性，PK方法利用标签 EPO示踪剂非常适合于研究EPO的非线性 并用于直接测量其内源生产率。在……里面 解决了我们的建议的三个目标，125I-r-HuEPO和生物素化r-EPO- HuEPO和生物素化r-HuEPO(Bio-EPO)将作为示踪剂给予 在对绵羊进行的基于高级系统分析的PK和PD研究中 和人类。在目标1中，基于分析的PK方法和 帕金森病研究分别在绵羊和人类身上进行。在目标1中， 使r-HuEPO保持其PK行为的生物素化方法和 将开发和验证在示踪剂数量中测量Bio-EPO。在……里面 AIMS#2和#3,125I-r-HuEPO示踪方法将首先应用于 用绵羊进行活体实验，以确定扰动对 红细胞生成(即通过骨髓消融和静脉切除法诱导 贫血和r-HuEPO治疗)对EPO的PK、PD和产生率的影响。什么时候 Bio-EP作为示踪剂可用，将进行类似的研究 在人类婴儿和成人研究小组中。对EPO主键的了解 而PD将允许更优化地使用r-HuEPO，从而导致 通常通过以下方式恢复的多次红细胞输注减少 早产儿。

The many red blood cells (RBC) transfusions administered to preterm infants as treatment for anemia are expensive and pace them at risk for blood-borne infections and other transfusion related complications. The long-term objectives of Project #1 is to develop effective strategies for optimally administering recombinant human erythropoietin (r-HuEPO) in the treatment of anemia of prematurity. Achieving this goal is important and timely because r-HuEPO remains an evolving clinical therapy without a clear consensus of how, when and for whom it should be used in these patients. Our objective will be accomplished by performed mechanistically based EPO pharmacokinetic (PK) and pharmacodynamic (PD) studies in sheep and human subjects using sensitive and accurate tracer methodologies. Achieving maximal stimulation for erythropoiesis relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and its complex PK and PD behaviors. Because plasma EPO concentrations in anemic preterm infants are reduced relative to those in anemic adults, inadequate EPO production has been suggested as a primary underlying mechanism for the anemia these neonates inevitably develop and as justification for r-HuEPO treatment. Based on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary mechanism, but that other mechanisms may be more important. The basis for this speculation is an expanding body of data indicating that EPO's in vivo disposition occurs primarily via a saturable, receptor-mediated process. As an overall hypothesis we speculate that EPO's in vivo PK and PD are determined by the number and affinity of EPO receptors (EPO-R's) located predominantly on the body's expandable pool of erythroid progenitor cells. This hypothesis is consistent with the observation that EPO's PK behavior is non-linear, that EPO elimination is 3 to 4 times greater in premature infants than adults, and that the red marrow occupies a 3- to 4-fold greater volume per kg body weight in young children than adults. Because of their sensitivity and accuracy, PK methodologies utilizing labeled EPO tracers are ideally suited for investigating EPO's non-linear behavior and for directly measuring its endogenous production rate. In addressing our proposal's three aims, 125I-r-HuEPO and biotinylated r- HuEPO and biotinylated r-HuEPO (Bio-EPO) will be administered as tracers in advanced system analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for biotinylating r-HuEPO retaining its PK behavior and for measuring Bio-EPo in tracer amounts will be developed and validated. In Aims #2 and #3, 125I-r-HuEPO tracer methodology will first be applied in vivo experiments in sheep to determine the effect of perturbations in erythropoiesis (i.e., by bone marrow ablation and by phlebotomy-induced anemia and r-HuEPO treatment) on EPO's PK, PD, and production rate. When Bio-EP becomes available as a tracer, similar studies will be conducted in human infant and adult study groups. Knowledge gained about EPO's PK and PD will permit more optimal use of r-HuEPO thus leading to a reduction in the multiple RBC transfusions typically recovered by preterm infants.