Efficacy and Mechanisms of GLN Dipeptide in the SICU

描述(由申请人提供)： 相对谷氨酰胺(Gln)缺乏可能导致外科重症监护病房(SICU)患者的发病率和死亡率。在危重病期间，免疫系统、肠粘膜和其他组织对谷氨酰胺的利用超过内源性产量，血浆谷氨酰胺浓度下降，这可能导致细胞功能障碍，增加医院感染的风险和死亡率。传统的不含谷氨酰胺的肠外营养(PN)对SICU的预后影响有限，并且不能修复谷氨酰胺缺乏。我们最近的试验数据显示，添加谷氨酰胺二肽的PN减少了SICU患者的医院感染并改善了临床结果。其受益过程尚不清楚，但动物和人类数据表明，Gln治疗与a)上调血液和组织中的细胞保护分子[例如，GSH、特异性热休克蛋白(HSPs)和Gln]；以及b)改善上皮屏障防御和免疫细胞数量和功能有关。L-Gln的性质限制了在溶液中的供应，但Gln二肽丙氨酰-Gln(AG)在PN(AG-PN)中具有稳定性和溶解性。基于我们的试点数据，我们提出了一项多中心、双盲、随机、对照的III期试验，以检验AG-PN改善心脏、血管或结肠手术后需要PN的SICU患者的临床结果的假设。受试者将接受标准的不含谷氨酰胺的PN或等热量、等氮的AG-PN，直到建立肠内喂养。具体目的1是确定AG-PN是否能降低住院死亡率、医院感染和其他重要的发病率指标。具体目标2是在目标1受试者中获得新的、与机械相关的观察数据，以了解AG-PN a)是否增加了一系列血液中GSH、HSP-70和-27以及Gln的水平；b)减少了血清中细菌产物鞭毛蛋白和脂多糖的存在以及对这些介质的获得性免疫反应；以及c)改善了先天/获得性免疫的关键指标。这项研究旨在描述一种主要的新营养支持策略在高危SICU患者中的临床益处

DESCRIPTION (provided by applicant): Relative glutamine (GLN) deficiency may contribute to morbidity and mortality in surgical intensive care unit (SICU) patients. During critical illness, GLN utilization by the immune system, gut mucosa and other tissues exceeds endogenous production and plasma GLN concentrations decrease, which may contribute to cellular dysfunction and increase nosocomial infection risk and mortality. Conventional GLN-free parenteral nutrition (PN) has a limited impact on SICU outcomes and does not repair the GLN deficit. Our recent pilot data show that GLN dipeptide-supplemented PN decreases nosocomial infections and improves clinical outcomes in SICU patients. The process of benefit is poorly understood, but animal and human data suggest that GLN treatment correlates with a) up-regulation of cytoprotective molecules in blood and tissues [e.g, GSH, specific heat shock proteins (HSPs) and GLN]; and b) improved epithelial barrier defenses and immune cell number and function. Properties of L-GLN limit provision in solution, but the GLN dipeptide alanyl-GLN (AG) confers stability and solubility in PN (AG-PN). We propose a multicenter, double-blind, randomized, controlled phase III trial based on our pilot data to test the hypothesis that AG-PN improves clinical outcomes in SICU patients requiring PN after cardiac, vascular or colonic operations. Subjects will receive either standard GLN-free PN or isocaloric, isonitrogenous, AG-PN until enteral feeds are established. Specific Aim 1 is to determine whether AG-PN decreases hospital mortality, nosocomial infection and other important indices of morbidity. Specific Aim 2 is to obtain novel, mechanistically relevant observational data in the Aim 1 subjects on whether AG-PN a) increases serial blood levels of GSH, HSP-70 and -27, and GLN; b) decreases the presence in serum of the bacterial products flagellin and LPS and the adaptive immune response to these mediators; and c) improves key indices of innate/adaptive immunity. This study is designed to delineate the clinical benefit of a major new nutrition support strategy in high-risk SICU patients