Monitoring gene changes during antiepileptic drug therapy to widen the safety window and reduce pharmacoresistance.
A novel and potentially effective way to decrease pharmacoresistance is to widen an antiepileptic drug's (AED) safety window by altering its efficacy-toxicity relationship to reduce the frequency or eliminate the occurrence of drug-induced toxicities. The first step in this process is to identify specific AED toxicities that are common, objective, reliable to assess, and exhibit both interpatient and interdrug variability. Next, one or more of the fundamental sources of biological variability (e.g., DNA, RNA, proteins, or metabolites) is selected for study. By identifying a relationship between variations in these fundamental sources and specific AED toxicities, one aims to identify pathways underlying the genesis of the toxicity (mechanisms) or biomarkers related to elevated risk for AED toxicity (predictors). These types of studies have many methodological challenges. However, if properly conducted, the resulting data could be used to design interventions that directly block the toxicity mechanisms or preselect individuals who are at high risk of developing these toxicities. Both approaches would conceivably widen the safety window of efficacious AEDs and reduce the incidence of pharmacoresistance. This article describes a general framework for this approach and provides an example of the methodology using differential gene expression measured using RNA-based microarray technology in children experiencing VPA-associated weight gain.
Glauser
Tracy A
TA
Comprehensive Epilepsy Program, Division of Neurology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA. Tracy.Glauser@cchmc.org
D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D046228:Microarray Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D016896:Treatment Outcome
D000927:Anticonvulsants