Dissertation Defense: Eric Witherspoon
Candidate: Eric Witherspoon
Major: Pharmacology & Physiology
Advisor: Patrick Forcelli, Ph.D.
Pharmacological and Toxicological Characterizations of New-Generation Antiseizure Drugs in Neonatal Rodents: An Update and Assessment of Efficacy and Safety
Epilepsy is a serious neurological brain condition, characterized by spontaneous and reoccurring seizures. Despite the fact that there are many available antiseizure medications (ASMs), many individuals do not achieve adequate seizure control with current medications. The treatment of seizures during critical periods of brain development (e.g., during pregnancy or early in life) is further complicated by the fact that many ASMs induce adverse neurotoxic effects. Thus, for infants and young children, as well as pregnant women with epilepsy, the treatment of seizures presents unique challenges. Antiseizure medications are typically screened for efficacy in adult animal models, and clinical trials rarely directly evaluate ASMs in either young populations or in pregnancy. As a result, there is an urgent need to identify and examine newer generation medications for the treatment and management of seizures during early life and pregnancy. Several newer-generation ASMs may be promising drugs for controlling excessive neuronal activity, given their unique pharmacological profiles for modulating both excitatory and inhibitory neurotransmission. Moreover, since several newer-generation ASMs have mechanistic profiles that mimic ASM that are generally regarded safe, they may offer additional therapeutic options for managing seizures during periods of vulnerable brain development. The overarching objective of my dissertation was to assess the efficacy and safety of newer generation ASMs for treatment and management of seizures. Using neonatal rats as a model, I evaluated the efficacy of cannabidiol to protect against seizures; the efficacy and potential for drug toxicity of padsevonil and cenobamate; and the potential neurotoxicity profile of three voltage gated sodium channel blockers that are increasing in clinical use (rufinamide, zonisamide and lacosamide).
My work indicates that these drugs all display more promising safety profiles than first generation compounds such as phenobarbital and phenytoin. While many ASMs remain to examine, my work expands the current understanding of the efficacy and safety od rugs for the treatment of epilepsy and fills what was previously a clear gap in our preclinical knowledge of this class of drugs.