Off-label drugs in cardiology: evaluating age- and disease-appropriate therapies

心脏病学中的标签外药物：评估适合年龄和疾病的疗法

• 批准号: 10578746
• 负责人: Nikki Gillum Posnack
• 金额: $ 66.02万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578746
• 关键词: Address; Adolescent; Adrenergic Agents; Adrenergic Receptor; Adrenergic beta-Antagonists; Adult; Adverse effects; Affect; Age; Amiodarone; Anatomy; Animal Model; Animals; Anti-Arrhythmia Agents; Architecture; Arrhythmia; Biophysics; Calcium; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiology; Cardiopulmonary Bypass; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Child; Childhood; Clinical; Clinical Research; Computer Models; Congenital Abnormality; Data; Depressed mood; Development; Disease; Dopamine; Dose; Drug Design; Drug Prescriptions; Drug Targeting; Edema; Electrolytes; Electrophysiology (science); Environment; Epinephrine; Genetic Transcription; Goals; Heart; Heart failure; Human; Hypotension; Hypoxia; Infant; Inflammation; Ion Channel; Knowledge; Label; Lesion; Life; Live Birth; Low Cardiac Output; Maps; Measurement; Mechanics; Metabolic; Methods; Mind; Modeling; Muscle; Myocardial; Myocardium; Neonatal; Nodal; Operative Surgical Procedures; Optics; Outcome; Oxygen; Patients; Pediatric cardiology; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Physiology; Population; Postoperative Period; Process; Proteomics; Regimen; Reporting; Safety; System; Techniques; Testing; Tissue Procurements; Tissues; Underrepresented Populations; Work; age group; age related; cardiogenesis; channel blockers; clinical care; congenital heart disorder; drug efficacy; drug testing; esmolol; experience; fetus hypoxia; innovation; mathematical model; neonate; off-label drug; pediatric patients; postnatal; postnatal development; preclinical study; receptor density; repaired; response; therapy design; transcriptomics; voltage

Project Summary Off-label medications are widely used in the clinical care of pediatric patients, with disproportionate use in cardiovascular subspecialties. More than 75% of children with cardiovascular disease receive at least one off- label medication. Further, congenital heart disease (CHD) patients requiring surgical repair are likely to receive multiple off-label therapies, including antiarrhythmics (76% of prescribed medications), beta-blockers (97%), adrenergic agents (85%) and Ca2+ channel blockers (96%). Since pediatric CHD populations are underrepresented in preclinical and clinical studies, practitioners often rely on empirical data or adult data to guide off-label prescription choice and/or extrapolate dosing regimens. As a result, cardiovascular drugs are administered off-label to neonates, infants, and children with little consideration of myocardial immaturity. Indeed, many cardiovascular medications have been shown to exert variable age-dependent outcomes and/or undesirable adverse effects. A physiology-driven approach is urgently needed to inform and optimize age- appropriate therapies for CHD patients, particularly in the neonatal – adolescent period when the myocardium undergoes rapid adaptive changes. In the proposed application, we will test the hypothesis that myocardial immaturity perturbs cardiac drug responsiveness, as ion channel expression, calcium handling, and dopamine/adrenergic drug targets are underdeveloped. Using innovative techniques, including large animal models and human cardiac tissue procured during surgery, optical mapping of voltage and intracellular calcium, computational models, and transcriptomic and proteomic profiling, we will address the following aims: 1) Determine the extent to which postnatal development alters the transcriptomic, proteomic, and anatomical profile of the myocardium. 2) Investigate pharmacodynamic responses to off-label antiarrhythmic and inotropic drugs in neonatal – juvenile hearts, in the context of cardiopulmonary bypass (CPB). 3) Evaluate the impact of myocardial immaturity on clinical responsiveness to drug therapies in CHD patients. This study addresses the objectives of PAR-20-300 by establishing data on developmental pharmacodynamics using highly translational cardiac models and mathematical modeling approaches. Results will inform clinical care decisions for CHD patients by providing evidence on the safety, efficacy, and potency of antiarrhythmics and inotropes. Moreover, the methods and models within this study are scalable to other drug therapies used in pediatric cardiology. Completion of this work will enhance our understanding of postnatal cardiac development in the context of CHD, which can promote tailored pharmacotherapies that are age- and disease-appropriate.

项目摘要 标签外药物被广泛用于儿科患者的临床护理中，不成比例地使用 心血管亚专科。超过75％的心血管疾病儿童至少接受一个外 标签药物。此外，需要手术修复的先天性心脏病（CHD）患者可能会接受 多种标签疗法，包括抗心律失常（占处方药的76％），β受体阻滞剂（97％），， 肾上腺素（85％）和CA2+通道阻滞剂（96％）。由于小儿CHD种群是 从业人员在临床前和临床研究中的代表性不足，通常依靠经验数据或成人数据来 指导标签的处方选择和/或推断给药方案。结果，心血管药物是 对新生儿，婴儿和儿童进行了标签，几乎没有考虑心肌不成熟。的确， 许多心血管药物已显示出可变的年龄依赖性结果和/或 不良的不良影响。迫切需要采用生理驱动的方法来告知和优化年龄 冠心病患者的适当疗法，特别是在新生儿 - 青少年时期 经历快速自适应变化。 在拟议的应用中，我们将测试心肌不成熟性心脏药物的假设 反应性，因为离子通道表达，钙处理和多巴胺/肾上腺素药物靶标是 欠发达。使用创新技术，包括大型动物模型和人类心脏组织 在手术期间，电压和细胞内钙，计算模型和转录组的光学映射 和蛋白质组学分析，我们将解决以下目的：1）确定产后的程度 发育改变了心肌的转录组，蛋白质组学和解剖学特征。 2）调查 对新生儿 - 少年心脏中的标签外抗心律失常和肌力药物的药物学反应 心肺旁路（CPB）的上下文。 3）评估心肌不成熟对临床的影响 冠心病患者对药物疗法的反应。这项研究探讨了Par-20-300的目标 使用高度翻译的心脏模型和 数学建模方法。结果将通过提供的临床护理决定为临床护理决定提供信息 关于抗心律失常和肌力的安全性，效率和效力的证据。此外，方法和 本研究中的模型可扩展到小儿心脏病学中使用的其他药物疗法。完成这项工作 将在CHD的背景下增强我们对产后心脏发展的理解，这可以促进 适合年龄和疾病的量身定制的药物治疗。