Alanyl-glutamine supplementation of standard treatment for C. difficile infection

补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法

• 批准号: 9887011
• 负责人: Cirle Alcantara Warren
• 金额: $ 80.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9887011
• 关键词: Adult; Aftercare; Age; Animals; Antibiotic Therapy; Antibiotics; Apoptosis; Body Weight decreased; CASP8 gene; Cell Line; Cell Proliferation; Cells; Cessation of life; Child; Clinical Trials; Clostridium difficile; Comparative Effectiveness Research; Data; Death Rate; Diarrhea; Dipeptides; Disease; Dose; Double-Blind Method; Ensure; Epidemiology; Gastroenterology; Geriatrics; Glutamine; Growth; Histopathology; Human; Immunocompromised Host; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestinal Secretions; Intestines; Lead; Mediating; Monoclonal Antibodies; Mus; Nosocomial Infections; Oral; Oryctolagus cuniculus; Outcome Study; Pathogenesis; Patients; Performance; Persons; Pharmacology; Phase II Clinical Trials; Pilot Projects; Placebos; Population; Production; Public Health; Publishing; Randomized; Rattus; Reaction; Recovery; Recurrence; Recurrent disease; Relapse; Research Personnel; Research Proposals; Safety; Supplementation; Testing; Time; Tissues; Toxin; Treatment outcome; Vancomycin; Virulence Factors; Work; aged; antibiotic-associated diarrhea; antimicrobial; base; cell motility; cost; double-blind placebo controlled trial; dysbiosis; gut microbiota; healthcare-associated infections; human disease; human old age (65+); improved; improved outcome; in vivo; inflammatory disease of the intestine; innovation; intestinal barrier; intestinal epithelium; metabolic profile; metabolomics; microbiome; microbiota; mortality; mouse model; novel; novel strategies; nutritional supplementation; parenteral administration; prevent; primary outcome; rho; secondary outcome; standard care; standard of care

PROJECT SUMMARY C. difficile is the leading cause of antibiotic-associated diarrhea and nosocomial infection. Antibiotic treatment is the standard approach in managing C. difficile infection (CDI) and is associated with high recurrence rates of up to 65% depending on the number of previous disease. Alanyl-glutamine prevents C. difficile toxin-induced impairment of cell migration and proliferation in intestinal cell lines, secretion and histopathology in animal ileal tissues, and increased apoptosis in vitro and in vivo. We have shown that in the mouse model of CDI, alanyl- glutamine supplementation significantly reduced diarrhea, weight loss, histopathology, relapse and deaths in vancomycin-treated mice. A small pilot study in human suggests that alanyl-glutamine may prevent recurrent disease up to 6 months after CDI treatment. We hypothesize that supplementation with alanyl-glutamine will improve outcomes of treatment of CDI in humans. To prove this hypothesis, we plan to conduct a randomized, double-blinded, placebo-controlled trial. The specific aims of this project are 3-fold. First, we shall determine the optimal dose of oral alanyl-glutamine on preventing recurrence and deaths in patients treated with standard anti-C.difficile agents. Secondly, we shall demonstrate the safety of oral alanyl- glutamine supplementation. And thirdly, we shall test the effect of alanyl-glutamine on intestinal inflammation, barrier function and gut flora in patients undergoing standard treatment for CDI. This research proposal will allow for a rigorous, safe and productive performance of the clinical trial to prove the benefit of alanyl-glutamine in human disease, potentially introducing a novel approach to treatment of CDI.

项目概要 艰难梭菌是抗生素相关性腹泻和医院感染的主要原因。抗生素治疗是 管理艰难梭菌感染 (CDI) 的标准方法，并且与以下疾病的高复发率相关： 至 65%，具体取决于先前疾病的数量。丙氨酰谷氨酰胺可预防艰难梭菌毒素诱导的 动物回肠肠细胞系细胞迁移和增殖、分泌和组织病理学受损 组织，并增加体外和体内的细胞凋亡。我们已经证明，在 CDI 小鼠模型中，丙氨酰- 补充谷氨酰胺可显着减少腹泻、体重减轻、组织病理学、复发和死亡 万古霉素治疗的小鼠。一项针对人类的小型试点研究表明丙氨酰谷氨酰胺可以预防复发 CDI 治疗后长达 6 个月的疾病。我们假设补充丙氨酰谷氨酰胺将 改善人类 CDI 的治疗结果。为了证明这个假设，我们计划进行 随机、双盲、安慰剂对照试验。该项目的具体目标有三个。首先，我们要 确定口服丙氨酰谷氨酰胺预防患者复发和死亡的最佳剂量 用标准抗艰难梭菌药物治疗。其次，我们将证明口服丙氨酰的安全性 补充谷氨酰胺。第三，我们要测试丙氨酰谷氨酰胺对肠道的影响 接受 CDI 标准治疗的患者的炎症、屏障功能和肠道菌群。这 研究提案将允许临床试验进行严格、安全和富有成效的执行，以证明 丙氨酰谷氨酰胺对人类疾病的益处，可能会引入一种治疗 CDI 的新方法。