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.

项目总结