RISK FACTORS FOR PHENYTOIN TOXICITY

该职业发展奖是由一位即将完成流行病学博士学位的博士级临床药剂师申请的，他完全致力于作为一名独立的、联邦资助的老年药物流行病学学术研究者的职业生涯。候选人将使用经过验证的“80%研究/ 20%临床”的职业模式，这将提供临床研究问题的来源以及进行以患者为导向的研究的基础设施。我们制定了一个三阶段的职业发展计划，专门解决候选人背景方面的差距。除了将作为“核心课程”的研究项目外，职业发展计划将进一步发展他对衰老的关注，并提供分子和遗传流行病学的课堂和实验室培训，目的是使他能够与实验室科学家进行知识和有效的合作。在奖励的后期阶段，候选人将发展更多的研究思路，进行试点研究，并申请联邦研究（如R01）资助。正式的职业咨询程序是职业发展计划的一个组成部分。本提案的研究部分是对严重神经系统苯妥英毒性的危险因素进行研究，多个数据来源表明，苯妥英毒性是严重药物不良反应的主要原因之一，特别是在老年人中。该研究将检查治疗和患者特异性因素，包括年龄和表达细胞色素P450酶同种异构体CYP2C19和CYP2C9的基因多态性，这两种异构体负责苯妥英代谢。研究设计是一项病例对照研究，嵌套在我们的卫生系统内因癫痫发作障碍而就诊的患者人群中。在我国卫生系统的三家主要医院进行同步监测将用于确定潜在病例，对照从我国卫生系统内因癫痫发作而服用苯妥英的患者中随机选择。这一职业发展奖项将使候选人能够完成技能和经验的发展，他将需要发展成为一个独立的学术研究者在衰老的药物流行病学。

This career development award is being sought by a doctoral-level clinical pharmacist nearing the completion of his PhD in Epidemiology who is fully committed to a career as an independent, federally-funded academic investigator in the pharmacoepidemiology of aging. The Candidate will use the proven "80% research / 20% clinical" career model, which will provide a source of clinical research questions as well as the infrastructure to conduct patient-oriented research. A three-phase career development plan has been formulated specifically to address gaps in the Candidate's background. In addition to the research project that will serve as the "core curriculum," the career development plan will further develop his focus on aging, and provide classroom and laboratory training in molecular and genetic epidemiology with the objective of enabling him to collaborative knowledgeably and effectively with laboratory scientists. In the latter phase of the award, the Candidate will develop additional research ideas, perform pilot studies, and apply for federal research (e.g., R01) funding. A formal career advisory process is an integral component of the career development plan. The research component of this proposal is a study of risk factors for severe neurologic phenytoin toxicity, which has been shown in multiple data sources to be one of the leading causes of serious adverse drug reactions, particularly in the elderly. The study will examine therapy- and patient-specific factors, including age and polymorphisms in the genes that express cytochrome P450 enzyme isoforms CYP2C19 and CYP2C9, which are responsible for phenytoin metabolism. The study design is a case-control study that is nested within the population of patients seen for seizure disorders within our health system. Concurrent surveillance in the three major hospitals in our health system will be used to identify potential cases, with controls being randomly selected from patients prescribed phenytoin for seizure disorders within our health system. This career development award will enable the Candidate to complete the development of the skills and experience that he will need to evolve into an independent academic investigator in the pharmacoepidemiology of aging.