Developing natural compound emodin as a therapy for alcoholic cardiomyopathy

项目摘要：酒精性心肌病(ACM)是酒精所致心脏的最常见形式 损坏。酒精剂量依赖性地诱导ACM，以心肌进行性减少为特征 收缩能力和脑室扩张，最终导致心力衰竭。在细胞水平上，慢性酒精 消耗会导致心肌细胞死亡、心脏炎症和心脏纤维化。目前没有 FDA批准的ACM治疗方法。该项目的长期目标是推进大黄素，一种小分子 具有抗炎、抗细胞凋亡和抗纤维化活性的天然化合物，用于预防ACM或 治疗。我们已经在基础科学和早期发现方面产生了大量的背景数据 支持大黄素作为治疗急性心肌梗塞的新疗法的阶段包括：1)转化生长因子β信号转导是主要的基础 酒精诱导的心脏纤维化的机制，ACM发病的关键组成部分，2) 大黄素是多种细胞中转化生长因子β典型和非典型信号转导的有效抑制剂 大黄素在小鼠模型中的药代动力学(PK)和良好的安全性已被检测，4)在非 口服毒性剂量的大黄素有效地改善与阿霉素相关的心脏纤维化和功能障碍 病理与ACM相似。此外，我们的初步数据表明，大黄素可以减弱酒精诱导的 心肌细胞活力丧失和心脏成纤维细胞活化。我们建议进一步测试中央 假设大黄素可以被开发为一种安全有效的ACM预防和/或治疗药物。 在第一阶段的STTR应用中，我们建议检查大黄素在慢性阻塞性肺疾病中的PK、安全性和有效性。 建立饮酒啮齿动物模型，并在猪体内进行PK和毒性研究 目标。SA1.检测饮酒是否影响大黄素代谢，并评价其安全性和有效性 大黄素改善小鼠ACM模型的实验研究。SA2.考察大黄素的PK、安全性和有效性 在预防和治疗环境中减少酒精喂养大鼠的心脏纤维化和心功能障碍。 在猪身上进行大黄素的PK和安全性研究，找到可能达到有效的安全剂量范围 血液大黄素浓度。在第一阶段申请的资助期结束时，我们会 可能使大黄素进入药物开发的下一个阶段：使IND成为可能的临床前研究。里程碑 对于去或不去的决定包括：1)如果大黄素不会夸大酒精诱导的小鼠和大鼠的毒性， 尤其是肝脏毒性；2)大黄素是否对小鼠和大鼠的ACM有显著的改善作用；以及 3)如果在猪身上确定了适当的安全剂量，可以推算到人类身上。如果对上述问题的回答 有三个问题是肯定的，决定进一步推进大黄素的开发进程，以及 将提交第二阶段申请，以执行IND启用的临床前研究，包括1)安全性和 GLP环境下猪ACM模型的药效研究2)大黄素的处方和cGMP制造 人用胶囊。

Project Summary: Alcoholic Cardiomyopathy (ACM) is the most prevalent form of ethanol-induced heart damage. Alcohol dose-dependently induces ACM, characterized by progressive reduction in myocardial contractility and ventricular dilatation, culminating in heart failure. At the cellular level, chronic alcohol consumption results in cardiomyocyte death, cardiac inflammation, and cardiac fibrosis. There are currently no FDA-approved therapies for ACM. The long-term goal of this project is to advance emodin, a small molecule natural compound with anti-inflammatory, anti-apoptotic, and anti-fibrotic activities, for ACM prevention or treatment. We have generated a robust body of background data in the basic science and early discovery phase that supports emodin as a novel therapy for ACM including: 1) TGFβ signaling is the primary underlying mechanism responsible for alcohol-induced cardiac fibrosis, a key component of ACM pathogenesis, 2) Emodin is an effective inhibitor of TGFβ canonical and non-canonical signaling in multiple cell types, 3) The pharmacokinetics (PK) and excellent safety of emodin have been examined in murine models, and 4) At non- toxic oral doses, emodin effectively ameliorates cardiac fibrosis and dysfunction associated with doxorubicin, a pathology similar to ACM. Furthermore, our preliminary data illustrates that emodin attenuates alcohol-induced loss of cardiomyocyte viability and activation of cardiac fibroblasts. We propose to further test the central hypothesis that emodin can be developed as a safe and effective preventive and/or therapeutic agent for ACM. In this Phase 1 STTR application, we propose to examine the PK, safety, and efficacy of emodin in chronic alcohol consumption rodent models and perform a PK and toxicity study in pigs in the following three specific aims. SA1. To test if alcohol consumption influences emodin metabolism and evaluate the safety and efficacy of emodin in ameliorating ACM in mouse models. SA2. To examine the PK, safety, and efficacy of emodin in reducing cardiac fibrosis and cardiac dysfunction in alcohol-fed rats in both prevention and treatment settings. SA3.To perform a PK and safety study of emodin in pigs and find a safe dose range that may achieve effective blood emodin concentrations. By the end of the funding period of this STTR Phase 1 application, we will possibly move emodin towards the next phase of drug development: IND-enabling preclinical study. Milestones for a Go/no-go decision include: 1) if emodin does not exaggerate alcohol-induced toxicities in mice and rats, particularly liver toxicity; 2) if there is significant efficacy of emodin in ameliorating ACM in mice and rats; and 3) if an appropriate safe dose is identified in pigs that can be extrapolated to humans. If answers to the above three questions are positive, the decision will be made to further the development process of emodin, and a Phase II application will be submitted to perform an IND-enabling preclinical study, including 1) safety and efficacy studies in pig ACM models in a GLP setting, and 2) formulation and cGMP manufacturing of emodin capsule for human use.