Biologic risk factors of clinical digoxin toxicity

地高辛临床毒性的生物学危险因素

• 批准号: 7071787
• 负责人: KEVIN HAYNES
• 金额: $ 7.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071787
• 关键词: P glycoprotein; atorvastatin; clinical research; digoxin; drug adverse effect; drug interactions; genetic polymorphism; genetic susceptibility; human old age (65+); human subject; multidrug resistance; paroxetine; pharmacogenetics; postdoctoral investigator; verapamil

DESCRIPTION (provided by applicant): Digoxin toxicity is a common and important cause of adverse drug events in the elderly US population. The serum and central nervous system (CMS) concentrations of digoxin are affected by p-glycoprotein (P-gp), which regulates gastrointestinal absorption, renal elimination, and CMS penetration of digoxin. The variability in P-gp activity caused by either genetic mutation or concomitant medications has not been studied in a population receiving digoxin clinically. Advancing knowledge of the role of P-gp in clinical digoxin toxicity will assist in elucidating the etiology of toxicity, which may ultimately lead to interventions to reduce the risk of digoxin toxicity. The primary aim of the proposed case-control study is to examine the relationship, in an elderly patient population, between clinical digoxin toxicity and genotypic differences in the multi-drug resistance-1 (MDR1) gene which encodes P-gp. The second aim is to characterize the effect of concomitant drug therapy with P-gp inhibition activity. In addition to improving the safety of digoxin, the - Pharmacoepidemiology study will foster career development in a promising young investigator. The results may advance the safety of several therapeutic agents through understanding the biology of P-gp.

描述（由申请方提供）：地高辛毒性是美国老年人群中药物不良事件的常见和重要原因。地高辛的血清和中枢神经系统（CMS）浓度受P-糖蛋白（P-gp）的影响，P-糖蛋白调节地高辛的胃肠道吸收、肾脏消除和CMS渗透。尚未在临床接受地高辛的人群中研究基因突变或合并用药引起的P-gp活性变异性。深入了解P-gp在地高辛临床毒性中的作用将有助于阐明毒性的病因，这可能最终导致干预措施，以降低地高辛毒性的风险。拟定病例对照研究的主要目的是在老年患者人群中检查地高辛临床毒性与编码P-gp的多药耐药1（MDR 1）基因的基因型差异之间的关系。第二个目的是描述伴随药物治疗对P-gp抑制活性的影响。除了提高地高辛的安全性外，药物流行病学研究还将促进有前途的年轻研究者的职业发展。通过对P-gp生物学特性的了解，这些结果可能会提高几种治疗药物的安全性。