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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS058669-05
Application #
8298521
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
2008-07-01
Project End
2013-12-30
Budget Start
2012-07-01
Budget End
2013-12-30
Support Year
5
Fiscal Year
2012
Total Cost
$167,476
Indirect Cost
$11,396
Name
Thomas Jefferson University
Department
Neurology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Mintzer, Scott; Maio, Vittorio; Foley, Kathleen (2014) Use of antiepileptic drugs and lipid-lowering agents in the United States. Epilepsy Behav 34:105-8
Wang, Sophia Pan; Mintzer, Scott; Skidmore, Christopher T et al. (2013) Seizure recurrence and remission after switching antiepileptic drugs. Epilepsia 54:187-93
Mintzer, Scott (2010) Metabolic consequences of antiepileptic drugs. Curr Opin Neurol 23:164-9
Lopinto-Khoury, Carla; Mintzer, Scott (2010) Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol 12:300-8
Mintzer, Scott; Mattson, Richard T (2009) Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 50 Suppl 8:42-50