Development of Dietary Quercetin to Treat Muscle Wasting Disorders

开发膳食槲皮素治疗肌肉萎缩疾病

基本信息

批准号：
10081511
负责人：
Brandon VanderVeen
金额：
$ 30万
依托单位：
ACEPRE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081511
关键词：
Animals Anti-Inflammatory Agents Automobile Driving Behavioral Biochemical Biogenesis Biological Availability Body Weight Body Weight decreased Cachexia Cancer Patient Cessation of life Chemotherapy-Oncologic Procedure Chronic Disease Chronic Kidney Failure Chronic Obstructive Airway Disease Clinical Trials Data Dependence Development Diagnosis Diet Disease Disease model Dose Drug Kinetics FDA approved Fatigue Fluorouracil Goals Health Care Costs Heart failure Human Impairment Inflammation Investigation Investigational Drugs Length of Stay Link Malignant Neoplasms Mitochondria Modeling Mus Muscle Muscle Weakness Muscle function Muscular Atrophy New Agents Oral Outcome Pathologic Patients Pharmacologic Substance Phase Physical Function Physical Performance Physiological Plasma Positioning Attribute Property Quality of life Quercetin Reporting Skeletal Muscle Small Business Innovation Research Grant Testing Thinness Time Tissues Toxic effect Toxicology Wasting Syndrome cancer cachexia cancer therapy chemotherapeutic agent chemotherapy cost disease heterogeneity effective therapy efficacy study follow-up fruits and vegetables improved innovation mitochondrial dysfunction mortality muscle form neuromuscular physical inactivity polyphenol prevent programs screening success therapy outcome tumor wasting

项目摘要

PROJECT SUMMARY: Cachexia, the unintentional loss of body weight, is prevalent in chronic diseases and associated treatments. Cachexia is associated with reduced physical function, decreased tolerance for treatment, and increased mortality. Moreover, a cachexia diagnosis is consistent with a doubling in duration of hospital stay and an additional cost of $4,000/case compared to non-cachectic patients. Cachexia has been reported following chemotherapy treatment including muscle mass loss and fatigue which contribute to reduced quality of life. Furthermore, the loss of lean mass with cachexia impairs chemotherapy treatment tolerance and can exacerbate functional decrements leading to functional dependencies and accrued health care cost. Single and combined chemotherapeutic agents such as 5 fluorouracil (5FU) and FOLFIRINOX have been shown to directly disrupt skeletal muscle mass and function in tumor-bearing mice. Additionally, 5FU and FOLFIRINOX administration in animals and humans induces body weight loss associated with skeletal muscle mass loss and disrupted mitochondrial function, representing as an ideal model to study cachexia. Currently, there are no approved therapies for cachexia despite the improvements in our understanding of the mechanisms underlying muscle wasting. Quercetin, a natural polyphenol found in various fruits and vegetables, has been recognized for its anti-inflammatory properties and its ability to increase mitochondrial biogenesis. We have collected convincing data that support further investigation of Quercetin as an agent to prevent/treat cachexia: 1) we reported that Quercetin can reduce cancer-induced cachexia; 2) we showed that Quercetin can reduce the physical fatigue that is associated with chemotherapy; 3) we reported that Quercetin can increase physical performance by increasing mitochondrial biogenesis; and 4) we showed that Quercetin can reduce inflammation in a number of disease models. However, Quercetin has not yet been developed as an agent to prevent or treat cachexia. Our long-term goal is to move this dietary compound towards human clinical trials as an innovative agent to prevent/treat cachexia. In this Phase I SBIR project we will rigorously test the hypothesis that dietary Quercetin will ameliorate the cancer and chemotherapy-induced cachexia and thereby result in improved therapeutic outcomes. Three specific aims are proposed: 1) evaluate Quercetin’s effects on ameliorating cancer and chemotherapy-induced cachexia, 2) establish the effective plasma and muscle levels and dosing interval for Quercetin, and 3) perform a subchronic oral toxicity screening of Quercetin in mice. The success of our proposed phase I SBIR study will further the development of Quercetin as a new agent to prevent/treat cachexia. A follow-up Phase II SBIR program will expand on these initial studies to: 1) complete efficacy studies of Quercetin using additional models of cachexia; and 2) complete advanced pharmaceutical toxicology studies in mice. The overall goal of Phase II will be to position AcePre LLC for an FDA Pre-Investigational New Drug package.

项目摘要：恶病质，即体重无意减轻，在慢性疾病和相关治疗中很常见。恶病质与身体功能下降、治疗耐受性降低和死亡率增加有关。此外，恶病质诊断与病程加倍有关。据报道，与非恶病质患者相比，化疗后的恶病质患者的住院时间缩短了，并且增加了 4,000 美元/例的费用，其中包括肌肉质量损失和疲劳，从而导致生活质量下降。此外，恶病质引起的瘦体重损失会损害化疗治疗的耐受性，并可能加剧功能减退，导致功能依赖性和增加医疗费用，单用和联合化疗药物如 5 氟尿嘧啶 (5FU) 和 FOLFIRINOX 已被证明会直接破坏骨骼肌。此外，在动物和人类中施用 5FU 和 FOLFIRINOX 会导致与骨骼肌质量损失相关的体重减轻。线粒体功能受损，是研究恶病质的理想模型，尽管我们对肌肉萎缩机制的了解有所提高，但槲皮素（一种存在于各种水果和蔬菜中的天然多酚）已得到认可。因其抗炎特性及其增加线粒体生物发生的能力，我们收集了令人信服的数据，支持进一步研究槲皮素作为预防/治疗恶病质的药物：1) 我们报道槲皮素可以减少癌症诱发的情况。恶病质；2) 我们证明槲皮素可以减轻与化疗相关的身体疲劳；3) 我们报道槲皮素可以通过增加线粒体生物合成来提高身体机能；4) 我们证明槲皮素可以减少多种疾病模型中的炎症。然而，槲皮素尚未被开发为预防或治疗恶病质的药物，我们的长期目标是将这种膳食化合物作为预防/治疗恶病质的创新药物进行人体临床试验。在第一阶段 SBIR 项目中，我们将严格测试膳食槲皮素将改善癌症和化疗引起的恶病质，从而改善治疗结果的假设：1）评估槲皮素对改善癌症和化疗引起的恶病质的作用， 2) 确定槲皮素的有效血浆和肌肉水平以及给药间隔，以及 3) 在小鼠中进行槲皮素的亚慢性毒性口服筛查我们提议的成功。 I 期 SBIR 研究将进一步开发槲皮素作为预防/治疗恶病质的新药物。后续的 II 期 SBIR 计划将扩展这些初步研究，以：1）使用其他恶病质模型完成槲皮素的功效研究； 2) 在小鼠中完成先进的药物毒理学研究第二阶段的总体目标是将 AcePre LLC 定位为 FDA 预研究新药包。