Pharmaconutrients as Therapies for Critical Illness: Zinc in Severe Sepsis

描述（由申请人提供）：该奖项允许斯台普顿博士成为一名独立的研究者，对脓毒症危重患者的营养和药物营养素进行转化研究，脓毒症是一种常见于危重疾病的综合征，对公共卫生有巨大的影响。斯台普顿博士接受过流行病学方面的培训，但为了使自己成为危重病营养和药物营养素治疗方面的专家领导者，她正在寻求药代动力学和转化研究方面的额外培训。通过正式课程的凝聚力计划，由杰出专家直接指导，以及进行她提出的项目的实践经验，该奖项将帮助她实现将新型营养干预转化为临床应用的职业目标。本提案的总体目标是研究锌在严重脓毒症患者中的药理学行为并进行I期剂量探索研究。锌在脓毒症中的生物学原理是强有力的。几乎所有重症患者都存在锌缺乏，并且与死亡率和器官衰竭增加有关。在健康志愿者中补充锌可恢复正常的免疫功能，包括使淋巴细胞计数正常化，减少炎性细胞因子的产生，恢复中性粒细胞的吞噬活性，并降低感染的发生率。补充剂还可以减少小鼠败血症中的器官衰竭和死亡，并且有证据表明，在重症患者中进行的一些小型抗氧化剂鸡尾酒（包括锌）临床试验表明，补充剂可以提高生存率。目的1是一项I期剂量探索研究，静脉注射锌在严重脓毒症患者中，以确定在未来试验中使用的剂量。终点是血浆锌水平的正常化以及安全性和耐受性参数，包括呕吐和腹泻。这项研究的结果将导致R01或U01应用于未来的临床试验。目的2定义了锌在严重脓毒症患者与健康对照相比的药代动力学，并通过研究锌在严重脓毒症患者中的半衰期显著低于健康对照的假设来确定锌的给药间隔。目的3：通过选择实验室测量，研究锌对严重脓毒症患者炎症、免疫和氧化防御的影响，这项工作将为未来的临床试验提供生物标志物。凭借佛蒙特肺中心提供的丰富转化研究资源，这是斯台普顿博士在脓毒症重症患者中获得药代动力学、剂量探索研究和转化研究方面杰出经验的绝佳机会。

DESCRIPTION (provided by applicant): This Award allows Dr. Stapleton to become an independent investigator performing translational research on nutrition and pharmaconutrients in critically ill patients with sepsis, a syndrome that is common in critical illness and has an enormous public health impact. Dr. Stapleton is trained in epidemiology, but to establish herself as an expert leader in nutrition and pharmaconutrient therapy in critical illness, she is seeking additional training in pharmacokinetics and translational research. Through a cohesive program of formal coursework, direct mentoring by outstanding experts, and practical experience conducting her proposed projects, this Award will help her achieve her career goals of translating novel nutrient interventions into clinical application. The overall objective of this proposal is to investigate the pharmacologic behavior and to perform a phase I dose-finding study of zinc in patients with severe sepsis. The biologic rationale for zinc in sepsis is strong. Zinc deficiency is present in nearly all critically ill patients and is associated with increased mortality and organ failure. Zinc supplementation in healthy volunteers restores normal immune function including normalizing lymphocyte count, decreasing inflammatory cytokine production, restoring phagocytic activity of neutrophils, and reducing incidence of infections. Supplementation also decreases organ failure and death in murine sepsis, and there is evidence from a few small clinical trials of antioxidant cocktails including zinc in critically ill humans that supplementation may improve survival. Aim 1 is a phase I dose-finding study of intravenous zinc in patients with severe sepsis to identify a dose for use in future trials. The endpoints are normalization of plasma zinc level and safety and tolerability parameters including vomiting and diarrhea. The results of this study will lead to R01 or U01 applications for future clinical trials. Aim 2 defines the pharmacokinetics of zinc in patients with severe sepsis compared to healthy controls and determines a dosing interval for zinc by investigating the hypothesis that the half-life of zinc in severe sepsis patients is significantly lower than in healthy controls. Aim 3 investigates the impact of zinc on inflammation, immunity, and oxidant defense in patients with severe sepsis through selected laboratory measurements, work which will provide insight into biologic markers for use in future clinical trials. With the rich resources in translational research provided by the Vermont Lung Center, this is an exceptional opportunity for Dr. Stapleton to gain outstanding experience in pharmacokinetics, dose-finding studies, and translational research in critically ill patients with sepsis.