Abstracts

Several commonly-used anticonvulsants, including levetiracetam (LEV), are known to have a half-life in the human bloodstream which is shorter than their typical dosing interval. Their sustained efficacy without intermittent toxicity is not fully understood. Pharmacodynamic changes in the brain are generally suspected to persist longer than blood levels, but the time course of neurological effects has never been measured comprehensively in humans. We used transcranial magnetic stimulation (TMS) to compare LEV blood levels, pharmacodynamic effects, and subjective estimates of toxicity., Subjects were normal, medication-free volunteers aged 19-52 who had no history of any renal or CNS disorder, including epileptic seizures in themselves or first-degree relatives. Following an oral load of LEV 3 gm, blood levels and sequential TMS measures were taken over 48 hours. Subjects used a two-dimensional visual-analog scale to estimate the time course of any side effects they observed. Measures of motor threshold (MT) and recruitment at 150% MT were made from the right first dorsal interosseous muscle while stimulating at a fixed point over the left motor cortex., LEV blood levels peaked between 1 and 2 hours after oral administration. MT was maximally elevated beyond 3 hours, and recruitment maximally reduced beyond 5 hours. Changes in recruitment appeared to persist past 24 hours. Subjective toxicity was greatest within an hour of LEV administration, close to the time of peak blood levels. Despite the time lag between toxicity and TMS changes, toxicity estimates correlated significantly with the maximum increase in MT (p [lt] .05, Spearman)., There appears to be a substantial time lag between LEV blood levels and TMS measures of neuronal effects, and a similar temporal dissociation between subjective toxicity and maximum neurophysiological change. The time course of TMS changes may help to explain sustained clinical efficacy despite a short peripheral half-life.[figure1], (Supported by UCB Pharma.)