Pharmaconutrients as Therapies for Critical Illness: Zinc in Severe Sepsis

药用营养素治疗危重疾病：锌治疗严重脓毒症

• 批准号: 8499405
• 负责人: Renee D Stapleton
• 金额: $ 15.65万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499405
• 关键词: Acute Lung Injury; Acute respiratory failure; Address; Antioxidants; Award; Behavior; Biological; Biological Markers; Blood specimen; Body Weight; Cessation of life; Child; Clinical Trials; Critical Illness; Development; Diarrhea; Dose; Drug Kinetics; Elements; Epidemiology; Evaluation; Excretory function; Future; Goals; Guanine; Half-Life; Human; IL8 gene; Immunity; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Intervention; Intravenous; Kinetics; Knowledge; Laboratories; Lead; Leukocytes; Lung; Lymphocyte Count; Malondialdehyde; Measurement; Measures; Mechanical ventilation; Mentors; Metabolism; Micronutrients; Modeling; Multiple Organ Failure; Mus; Natural Immunity; Nutrient; Organ failure; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Plasma; Play; Production; Public Health; Quality of life; Randomized; Research Personnel; Resources; Safety; Sepsis; Serum; Serum zinc level result; Supplementation; Survivors; Syndrome; TNF gene; Testing; Therapeutic Agents; Therapeutic Studies; Time; Toxic effect; Training; Translating; Translational Research; Vermont; Vomiting; Work; Zinc; Zinc deficiency; activated Protein C; adaptive immunity; career; clinical application; cytokine; experience; healthy volunteer; immune function; improved; innovation; insight; monocyte; mortality; neutrophil; novel; novel therapeutics; nutrition; programs; septic; skills

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.

描述（由申请人提供）：该奖项允许Stapleton博士成为一名独立的研究者，从事有关败血症患者的营养和药物营养和药物的转化研究，这是一种在危重疾病中常见的综合征，并具有巨大的公共卫生影响。 Stapleton博士接受了流行病学的培训，但为了确立自己的营养和药物营养素疗法专家，在危重疾病方面，她正在寻求在药代动力学和转化研究方面的额外培训。通过一项正式课程，杰出专家的直接指导以及进行拟议项目的实践经验的凝聚力计划，该奖项将有助于她实现将新颖的营养干预措施转化为临床应用的职业目标。该提案的总体目的是研究药理行为，并对严重败血症患者进行锌的I期剂量调查研究。败血症中锌的生物原理很强。几乎所有重症患者都存在锌缺乏症，并且与死亡率和器官衰竭的增加有关。健康志愿者中补充锌可以恢复正常的免疫功能，包括使淋巴细胞计数归一化，炎症细胞因子产生降低，恢复中性粒细胞的吞噬活性以及降低感染发生率。补充剂还减少了鼠类败血症的器官衰竭和死亡，并且有一些抗氧化鸡尾酒的小临床试验的证据，包括重病人类中补充的锌可以提高生存率。 AIM 1是对严重败血症患者的静脉锌的I期剂量调查研究，以鉴定在以后的试验中使用剂量。终点是血浆锌水平的归一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应用程序的临床试验应用。 AIM 2定义了严重败血症患者的锌的药代动力学与健康对照组相比，并通过研究了以下假设，即严重败血症患者的锌的半衰期明显低于健康对照组中的锌的半衰期。 AIM 3通过选定的实验室测量进行了锌对严重败血症患者的炎症，免疫力和氧化剂防御的影响，这将洞悉生物学标志物，以在将来的临床试验中使用。鉴于佛蒙特州肺中心提供的翻译研究资源丰富，这是斯塔普尔顿博士在药代动力学，剂量调查研究和败血症患者中的转化研究方面获得出色经验的极好机会。