title: Prolonged neurophysiologic effects of levetiracetam after oral administration in humans.
abstract: OBJECTIVE
  To determine whether neurophysiological effects of levetiracetam (LEV) outlast its serum half-life of approximately 7 h. Demonstration of prolonged effects would help to explain the efficacy of LEV at conventional dosing intervals that are longer than the serum half-life.
  
  
  METHODS
  Following an oral dose of LEV 3 g in 12 normal volunteers, we compared transcranial magnetic stimulation (TMS) measures of motor threshold (MT) and recruitment with LEV serum levels and subjective ratings of toxicity over 48 h. Subjects used a two-dimensional visual-analog scale to estimate the time course of any side effects.
  
  
  RESULTS
  LEV serum levels and subjective toxicity both peaked around 1 h after oral administration. MT elevation was delayed in comparison to peak serum levels and subjective toxicity. MT was maximally elevated at 6-9 h, and recruitment maximally reduced at 0.6-9 h. Changes in both measures had recovered by approximately 50% at 24 h. Despite the time difference between toxicity and TMS changes, toxicity estimates correlated with the maximum increase in MT.
  
  
  CONCLUSIONS
  There is a substantial time lag between LEV serum levels and TMS measures of neuronal effects, and a similar temporal dissociation between subjective toxicity and maximum TMS change. The time course of neurophysiological effects, as measured by TMS, may help to explain the sustained clinical efficacy of LEV despite a short peripheral half-life.
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. chipstein@earthlink.net
authors.forename: Charles M
authors.initials: CM
authors.lastname: Epstein
authors.forename: Lhys
authors.initials: L
authors.lastname: Girard-Siqueira
authors.forename: Joshua Andrew
authors.initials: JA
authors.lastname: Ehrenberg
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation
chemical_list: D000927:Anticonvulsants; D017661:Receptors, Presynaptic; D000077287:Levetiracetam; D010889:Piracetam