Pharmaconutrients as Therapies for Critical Illness: Zinc in Severe Sepsis

描述(申请人提供)：该奖项允许Stapleton博士成为一名独立研究员，对患有脓毒症的危重患者的营养和药物营养素进行翻译研究，脓毒症是一种在危重疾病中常见的综合征，对公共健康有巨大影响。斯台普顿博士受过流行病学方面的培训，但为了确立自己在危重疾病的营养和药物营养治疗方面的专家领导地位，她正在寻求更多的药代动力学和转化研究方面的培训。通过一个有凝聚力的正规课程计划、杰出专家的直接指导以及执行她提议的项目的实践经验，该奖项将帮助她实现将新的营养干预措施转化为临床应用的职业目标。这项建议的总体目标是调查严重脓毒症患者的药理行为，并进行锌的I期剂量发现研究。锌在脓毒症中的生物学基础很强。锌缺乏几乎存在于所有危重病人中，并与死亡率增加和器官衰竭有关。健康志愿者补充锌可以恢复正常的免疫功能，包括使淋巴细胞计数正常化，减少炎症细胞因子的产生，恢复中性粒细胞的吞噬活性，减少感染的发生率。补充剂还可以减少小鼠脓毒症的器官衰竭和死亡，而且有证据表明，补充剂可能会提高存活率，这是对危重患者使用包括锌在内的几种抗氧化剂鸡尾酒的小型临床试验。目的1是一项在严重脓毒症患者中静脉注射锌的I期剂量发现研究，以确定用于未来试验的剂量。终点是血浆锌水平以及包括呕吐和腹泻在内的安全性和耐受性参数的正常化。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通过研究严重脓毒症患者锌的半衰期显著低于健康对照组的假说，明确锌在严重脓毒症患者中的药代动力学，并确定锌的给药间隔。目的3研究锌对严重脓毒症患者炎症、免疫和氧化防御的影响，为今后临床试验提供生物标志物。由于佛蒙特州肺脏中心提供了丰富的转化研究资源，这是斯台普顿博士在脓毒症危重患者的药代动力学、剂量发现研究和转化研究方面获得杰出经验的绝佳机会。 公共卫生相关性：败血症是危重疾病中的一种常见综合征，对公共健康有巨大影响，迫切需要新的治疗方法。锌是一种新的潜在疗法，本研究是一种创新的方法，建立了一种研究危重患者营养输送的新范式。它严格地通过定义药代动力学和进行I期剂量发现研究，同时使用获得的血液样本调查锌的生物影响，以获得将为未来临床试验的进行提供信息的信息。

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. PUBLIC HEALTH RELEVANCE: Sepsis is a common syndrome in critical illness, has a tremendous public health impact, and new therapies are urgently needed. Zinc is a novel potential therapy, and this research is an innovative approach that establishes a new paradigm of investigating nutrient delivery to critically ill patients. It rigorously progresses through defining the pharmacokinetics and conducting a phase I dose-finding study, while investigating zinc's biologic impact using obtained blood samples, to obtain information that will inform the conduct of future clinical trials.