The Effects of Antiepileptic Drugs on Serologic Indices of Vascular Risk

说明(申请人提供)：抗癫痫药物(AEDs)是美国最常用的药物类别之一。一些最常用的AEDs对细胞色素P450酶系统有很大影响，可能会导致广泛和有害的代谢影响，如血清胆固醇和C反应蛋白(CRP)的升高。这可能与数百万人的健康在临床上高度相关，因为多条证据表明，癫痫患者患心脑血管疾病的几率更高。这项研究培训资助提案的教育目标是让申请者发展必要的技能和专业知识，以设计和执行对抗癫痫药物代谢影响的独立调查。这项建议的研究目标是确定诱导细胞色素P450酶系统活性的AEDs是否会导致某些血清学指标(致动脉粥样硬化脂类，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：我们将检验这样一种假设，即随机服用苯妥英钠(PHT)的急性蛛网膜下腔出血患者的血清CRP和致动脉粥样硬化脂类显著升高，而那些随机接受药物治疗或服用非诱导剂左乙拉西坦(Lev)的患者，这些指标将没有变化。那些随机服用丙戊酸盐(VPA)的患者，肝酶抑制剂将会降低致动脉粥样硬化的胆固醇。目的II：我们将测试这样一种假设，即改用非诱导性AED的PHT或卡马西平(CBZ)的患者在6周后血清CRP和致动脉粥样硬化脂类显著降低，并且这些降低将持续6个月。这项工作将在杰斐逊综合癫痫中心和杰斐逊神经科学医院进行，杰斐逊综合癫痫中心是一个拥有大量患者和临床研究的老牌项目，杰斐逊神经科学医院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：该项目将研究某些癫痫药物是否可能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，以及是否将患者切换到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.