Pharmacogenetics and Antithrombotic Therapy

描述（由申请人提供）： 我们的长期目标是预防血栓性事件导致的死亡和残疾。 最近，我们一直在研究如何管理和剂量Warfarin治疗， 如何预防房颤患者中风一个主要 开处方进行Warfarin治疗的问题是，它的治疗指数狭窄， 和“特异质”反应合谋，使其启动旷日持久， 危险了 这项研究的重点是遗传和临床因素如何影响 可以用来预测这种反应。 这两年的主要目标 建议是构建，验证和使用华法林剂量算法， 开始治疗。 第二个目标是验证范例 遗传药理学知识可以降低 处方药 本研究有四个目的：1。为了构建一个基于基因的， 指导华法林诱导的华法林给药算法。发展 算法，我们将使用临床数据和遗传样本，我们有 从298名长期服用华法林的患者中获得。 我们建议 完成我们对这些标本的单核苷酸多态性的基因分型 细胞色素P450 2C 9基因的单核苷酸多态性（SNP）。 我们将测试假设1： 华法林给药算法将解释至少30%的方差， 治疗剂量2.为了验证基于基因的华法林剂量算法 在250名患者的独立样本中。我们将测试假设2： 给药算法将解释至少30%的治疗差异， 验证样本中的华法林剂量。3.使用基于基因的华法林 开始华法林治疗的50例患者的剂量。我们会用基因- 在50例患者的初步研究中，基于算法启动华法林治疗。 我们将检验假设3：与华法林治疗的历史对照组相比， 根据经验开始，使用基于遗传的华法林剂量的参与者将 更快地开出治疗剂量。4.将基因和 临床因素与血浆游离华法林水平。使用高 高效液相色谱法，我们将测量水平的2 华法林的对映异构体和检验假设4：S-华法林的清除率 在2C 9 SNP的存在下显著降低。

DESCRIPTION (provided by applicant): Our long-term goal is to prevent death and disability from thrombotic events. Recently, we have been studying how to manage and dose Warfarin therapy and how to prevent stroke in patients who have atrial fibrillation. A major problem with prescribing Warfarin therapy is that its narrow therapeutic index and "idiosyncratic" response conspire to make its initiation protracted and dangerous. The proposed study focuses on how genetic and clinical factors can be used to predict this response. The primary objective of this 2-year proposal is to construct, validate, and use a warfarin-dosing algorithm for initiation of therapy. The secondary objective is to validate the paradigm that knowledge of pharmacogenetics can decrease the toxicity of commonly prescribed drugs. The study has 4 aims: 1. To construct a genetic-based, warfarin-dosing algorithm that will guide warfarin induction. To develop the algorithm, we will use clinical data and genetic specimens that we have obtained from 298 patients taking chronic warfarin therapy. We propose to complete our genotyping of these specimens for single nucieotide polymorphisms (SNPs) of the cytochrome P450 2C9 gene. We will test Hypothesis 1: The warfarin dosing algorithm will explain at least 30% of the variance in the therapeutic dose. 2. To validate the genetic-based, warfarin-dosing algorithm in an independent sample of 250 patients. We will test Hypothesis 2: The dosing algorithm will explain at least 30% of the variance in the therapeutic warfarin dose in the validation sample. 3. To use genetic-based warfarin dosing in 50 patients beginning warfarin therapy. We will use the genetic- based algorithm to initiate warfarin therapy in a pilot study of 50 patients. We will test Hypothesis 3: As compared to historic controls whose warfarin is initiated empirically, participants who use genetic-based warfarin dosing will be prescribed their therapeutic dose sooner. 4. To correlate genetic and clinical factors with the plasma level of free warfarin. Using high performance liquid chromatography, we will measure the levels of the 2 enantiomers of warfarin and test Hypothesis 4: Clearance of S-warfarin will be significantly decreased in the presence of 2C9 SNPs.