Prolonged neurophysiologic effects of levetiracetam after oral administration in humans

Purpose: 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.
Conclusion: 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.     

An open study of repetitive transcranial magnetic stimulation in treatment-resistant depression with Parkinson's disease.

OBJECTIVE: Major depression is a common concomitant of chronic central nervous system disorders, notably Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) has been investigated as a potential treatment for depression in PD and for the movement disorder of PD, but comprehensive testing in multiple areas of performance has seldom been carried out within a single study. We studied the effect of left dorsolateral prefrontal rTMS on several different functional domains. METHODS: Fourteen PD patients with treatment-resistant depression entered an open, 10-day inpatient study of 10-Hz rTMS, undergoing extensive psychiatric, neuropsychological, and motor testing from baseline to 6 weeks after treatment. Motor testing included a defined "off" state. RESULTS: rTMS was well tolerated. Highly significant improvement in depression scores was seen 3 days and 3-6 weeks after treatment. Improvement was also found in anxiety, movement scores (especially in the off state), and some neuropsychological measures. We found no evidence of increased risk from rTMS in this population. CONCLUSIONS: Further controlled trials of rTMS in PD appear worthwhile, and should include a defined "off" state. SIGNIFICANCE: TMS may be beneficial for depressed PD patients in multiple functional domains.     

Physiological and behavioral effects of methamphetamine in a mouse model of endotoxemia: a preliminary study

We investigated the effects of methamphetamine (METH) on core body temperature (Tb) and motor activity (MA) with or without exposure to a peripheral immune challenge. Mice were exposed to an escalating METH treatment and then to a METH treatment known to cause neurotoxicity (binge METH treatment). This was followed by a challenge with lipopolysaccharide (LPS). Three days later, METH and saline-treated control groups were challenged with an acute test dose of METH (METH test). Animals exposed to the escalating METH treatment exhibited a significant increase in Tb only after the initial exposure to METH (Day 1) and following the METH test (Day 7). The hyperthermic effect produced by the METH test (Day 7) was reduced in mice previously exposed to combined exposure to binge METH and LPS treatments. The escalating METH treatment produced MA sensitization to the METH test. Animals treated with the binge METH, LPS injection or both treatments combined prevented MA sensitization to the METH test. These findings suggest that induction of peripheral endotoxemia in animals with a history of METH reduced the hyperthermic response to a subsequent challenge with METH.