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

项目摘要 标签外药物广泛用于儿科患者的临床护理， 心血管亚专科超过75%的心血管疾病儿童至少接受一次治疗， 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 多种标签外治疗，包括抗抑郁药（76%的处方药），β受体阻滞剂（97%）， 肾上腺素能药物（85%）和钙通道阻滞剂（96%）。由于儿童CHD人群 在临床前和临床研究中代表性不足，从业者通常依赖经验数据或成人数据， 指导标签外处方选择和/或外推给药方案。因此，心血管药物 对新生儿、婴儿和儿童标签外给药，很少考虑心肌不成熟。的确， 许多心血管药物已被证明会产生不同的年龄依赖性结果，和/或 不良反应。迫切需要一种生理学驱动的方法来告知和优化年龄- 适当的治疗冠心病患者，特别是在新生儿-青少年时期，当心肌 经历了快速的适应性变化。 在拟议的应用中，我们将测试心肌不成熟干扰心脏药物的假设， 反应性，如离子通道表达，钙处理和多巴胺/肾上腺素能药物靶点， 不发达。使用创新技术，包括大型动物模型和人类心脏组织， 在手术过程中，电压和细胞内钙的光学映射，计算模型，和转录组学 和蛋白质组学分析，我们将解决以下目标：1）确定在何种程度上，产后 发育改变了心肌的转录组学、蛋白质组学和解剖学特征。2)探讨 在新生儿-幼年心脏中对标签外抗心律失常药物和正性肌力药物的药效学反应， 心肺转流术（CPB）。3)评价心肌不成熟对临床的影响 冠心病患者对药物治疗的反应性。本研究通过以下方式实现PAR-20 - 300的目标： 使用高度转化的心脏模型建立发育药效学数据， 数学建模方法。结果将通过提供以下信息为CHD患者的临床护理决策提供信息： 关于抗心律失常药和正性肌力药的安全性、有效性和效力的证据。此外，方法和 本研究中的模型可扩展到儿科心脏病学中使用的其他药物治疗。完成这项工作 将增强我们对CHD背景下出生后心脏发育的理解， 适合年龄和疾病的定制药物疗法。

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.