Development of Dietary Quercetin to Treat Muscle Wasting Disorders

项目总结：恶病质，体重的无意损失，是常见的慢性疾病， 相关治疗。恶病质与身体功能降低、对药物耐受性降低有关。 治疗和死亡率增加。此外，恶病质的诊断与持续时间加倍一致。 与非恶病质患者相比，住院时间和4，000美元/例的额外费用。恶病质一直是 据报道，化疗治疗后，包括肌肉质量损失和疲劳，这有助于 生活质量下降。此外，伴有恶病质的瘦体重减少会损害化疗治疗 耐受性，并可能加剧功能衰退，导致功能依赖性和累积健康 护理费用。单一和联合化疗剂，如5氟尿嘧啶（5 FU）和FOLFIRINOX， 已被证明直接破坏荷瘤小鼠的骨骼肌质量和功能。此外，5 FU和 动物和人体FOLFIRINOX给药诱导与骨骼肌相关的体重减轻 质量损失和线粒体功能破坏，是研究恶病质的理想模型。目前的情况， 尽管我们对恶病质的理解有所提高， 肌肉萎缩的潜在机制槲皮素是一种天然多酚，存在于各种水果中， 蔬菜，已被公认为其抗炎特性和增加线粒体的能力， 生物起源我们已经收集了令人信服的数据，支持进一步研究槲皮素作为一种代理， 预防/治疗恶病质：1）我们报道槲皮素可以减少癌症诱导的恶病质; 2）我们表明， 槲皮素可以减轻化疗引起的身体疲劳; 3）我们报道了槲皮素 可以通过增加线粒体生物合成来提高身体表现; 4）我们发现槲皮素 可以减少许多疾病模型中的炎症。然而，槲皮素尚未被开发为 预防或治疗恶病质的药剂。我们的长期目标是将这种膳食化合物推向人类 临床试验作为一种创新的药物，以预防/治疗恶病质。在第一阶段SBIR项目中，我们将严格 检验饮食槲皮素将改善癌症和化疗诱导的恶病质的假设， 从而导致改善的治疗结果。本研究的目的有三：1）评价槲皮素的 对改善癌症和化疗诱导的恶病质的作用，2）建立有效的血浆， 肌肉水平和槲皮素的给药间隔，和3）进行亚慢性口服毒性筛选， 小鼠中的槲皮素。我们建议的第一阶段SBIR研究的成功将进一步发展槲皮素 作为预防/治疗恶病质的新药剂。后续的第二阶段SBIR计划将在这些最初的基础上扩展 研究：1）使用其他恶病质模型完成槲皮素的疗效研究; 2）完成 先进的药物毒理学研究小鼠。第二阶段的总体目标是将AcePre FDA预研究新药包装的LLC。

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.