The Effects of Antiepileptic Drugs on Serologic Indices of Vascular Risk

描述（由申请人提供）：抗癫痫药物（aed）是美国最常用的药物类别之一，一些最常用的aed对细胞色素P450酶系统有很大影响，这可能导致广泛和有害的代谢作用，如血清胆固醇和c反应蛋白（CRP）升高。这可能在临床上与数百万人的健康高度相关，因为多项证据表明，癫痫患者患心脑血管疾病的比例更高。本研究培训资助计划的教育目标是培养申请人设计和执行aed代谢效应独立调查所需的技能和专业知识。本提案的研究目的是确定AEDs诱导细胞色素P450酶系统活性是否会导致某些血清学指标（动脉粥样硬化脂质，CRP）的变化，从而增加心肌和脑缺血的风险。这将通过两个具体目标进行调查。目的1：我们将检验急性蛛网膜下腔出血患者随机接受苯妥英（PHT）治疗的血清CRP和致动脉粥样硬化性脂质的显著升高，而随机接受无药物治疗或非诱导药物左乙西坦（LEV）治疗的患者在这些指标上没有变化的假设。那些随机服用丙戊酸酯（VPA）（一种肝酶抑制剂）的患者会经历致动脉粥样硬化胆固醇的降低。目的II：我们将检验假设，服用PHT或卡马西平（CBZ）的患者在切换到非诱导性AED后，6周后血清CRP和致动脉粥样硬化性脂质显著降低，并且这种降低将持续6个月。这项工作将在杰弗逊综合癫痫中心（Jefferson Comprehensive Epilepsy Center）和杰弗逊神经科学医院（Jefferson Hospital for Neuroscience）进行，前者是一个拥有大量患者和临床研究的成熟项目，后者是美国最繁忙的急性蛛网膜下腔出血治疗中心之一。相关性：该项目将检查某些癫痫药物是否会提高胆固醇和其他血液成分的水平，从而增加心脏病发作和中风的风险，以及是否将患者转换为不同的癫痫药物可能会迅速逆转这些变化。

DESCRIPTION (provided by applicant): Antiepileptic drugs (AEDs) are among the most-prescribed drug classes in the U.S. Some of the most commonly-used AEDs have large effects upon the cytochrome P450 enzyme system, which may result in wide-ranging and detrimental metabolic effects such as elevations in serum cholesterol and C-reactive protein (CRP). This may be highly clinically relevant to the health of millions of people, as multiple lines of evidence suggest that patients with epilepsy suffer from higher rates of cardiovascular and cerebrovascular disease. The educational goal of this research training grant proposal is for the applicant to develop the skills and expertise necessary to design and perform independent investigations into the metabolic effects of AEDs. The research goal of this proposal is to determine whether AEDs which induce the activity of the cytochrome P450 enzyme system produce changes in certain serologic indices (atherogenic lipids, CRP), which would be expected to increase the risk of myocardial and cerebral ischemia. This will be investigated through two specific aims. Aim 1: We will test the hypothesis that patients with acute subarachnoid hemorrhage randomized to phenytoin (PHT) will experience significant increases in serum CRP and atherogenic lipids, while those randomized to no drug treatment or to levetiracetam (LEV), a non-inducing agent, will experience no change in these measures. Those randomized to valproate (VPA), an inhibitor of hepatic enzymes, will experience a decrease in atherogenic cholesterol. Aim II: We will test the hypothesis that patients taking PHT or carbamazepine (CBZ) who are switched to a non-inducing AED will experience significant reductions in serum CRP and atherogenic lipids after 6 weeks, and that these reductions will persist for 6 months. The work will be performed at the Jefferson Comprehensive Epilepsy Center, an established program with a large volume of patients and clinical research, and the Jefferson Hospital for Neuroscience, which is among the busiest centers in the country for the treatment of acute subarachnoid hemorrhage. Relevance: This project will examine whether certain seizure medications might raise levels of cholesterol and other blood components which could increase the risk of heart attacks and strokes, and whether switching patients to different seizure medications might rapidly reverse those changes.