NOVEL THERAPIES FOR DOXORUBICIN CARDIOTOXICITY

阿霉素心脏毒性的新疗法

• 批准号: 7682644
• 负责人: John Anthony Bauer
• 金额: $ 8.5万
• 依托单位: NOVA-THER TECHNOLOGIES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2008-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682644
• 关键词: Antineoplastic Agents; Cardiac; Cardiac Myocytes; Cardiotoxicity; Chemicals; Clinical; Condition; Cytoprotection; Dose-Limiting; Doxorubicin; Drug Formulations; Evaluation; Functional disorder; In Vitro; Infusion procedures; Injury; Kinetics; Life; Pharmaceutical Preparations; Phase; Pilot Projects; Prevention approach; Rate; Research; Screening procedure; Solubility; Solutions; Testing; Therapeutic Uses; Toxic effect; base; clinical efficacy; commercial application; cost; cost effective; cytotoxicity; design; in vivo; mouse model; novel; prevent; research study; uptake

DESCRIPTION (provided by applicant): Doxorubicin (DOX) is an important anticancer drug with a wide array of therapeutic uses. Despite its very frequent clinical use, the utility of DOX is severely compromised by dose-limiting cardiotoxicities. While DOX cardiotoxicity has been known for many years, it remains a contemporary problem and therapies to prevent it have not been optimized. The only currently approved therapy (derazoxane) has only modest clinical value and may actually reduce the clinical efficacy of DOX as a tumoricidal agent. We propose to design, test, and optimize novel mechanism-based approaches for prevention of DOX induced cardiac injury and dysfunction that are effective, safe, and relatively cost-efficient. Phase 1 aims include in vitro screening assessments and in vivo pharmacological experiments of nine novel dual acting compounds (new chemical entities) and corresponding two component mixtures for mechanism- based cardioprotection. Studies include cardiomyocyte evaluations (cytoprotection from doxorubicin toxicity, uptake kinetics, cytotoxicities) and formulation strategies (solubilities, stabilities, pH-rate profiles) and pilot studies using relevant mouse models of DOX cardiotoxicity and DOX tumoricidal efficacy. PROPOSED COMMERCIAL APPLICATIONS: The perceived commercial product of this research includes a drug infusion solution used to prevent cardiotoxicity during doxorubixin therapy. The product will provide protection against this life-threatening condition without having negative effects on doxorubicin tumoricidal actions, and will be cost effective.

描述（由申请人提供）：阿霉素（DOX）是一种重要的抗癌药，具有广泛的治疗用途。尽管经常使用临床用途，但DOX的效用受到剂量限制的心脏毒性的严重损害。尽管DOX心脏毒性已经闻名了很多年，但它仍然是当代的问题和疗法以防止其优化。当前唯一的批准治疗（Derazoxane）仅具有适度的临床价值，实际上可能会降低DOX作为肿瘤剂的临床功效。我们建议设计，测试和优化基于新型机制的方法，以预防DOX诱导的心脏损伤和功能障碍，这些方法有效，安全且相对成本效益。第1阶段的目的包括九种新型双作用化合物（新化学实体）的体外筛查评估和体内药理实验，以及基于机制的心脏保护的两种组件混合物。研究包括心肌细胞评估（对阿霉素毒性，摄取动力学，细胞毒性的细胞保护作用）和配方策略（溶解度，稳定性，pH率谱），并使用相关的DOX心脏毒性小鼠模型和DOX肿瘤肿瘤功效的相关小鼠研究。 拟议的商业应用： 这项研究的商业产品包括一种药物输注溶液，用于预防多克苏蛋白治疗期间的心脏毒性。该产品将为这种威胁生命的状况提供保护，而不会对阿霉素肿瘤作用产生负面影响，并且具有成本效益。