Abstracts

Glutamate-mediated neuronal damage is one of the best-studied mechanisms of cell damage in traumatic brain injury (TBI). Despite positive effects of various anti-glutaminergic agents in animal models, none has shown significant neuroprotective effects in clinical studies, perhaps because their kinetics in the cerebral interstitial fluid and the dosages needed to reduce cerebral glutamate levels to potentially neuroprotective levels have not been known. Among its multiple biologic activities, topiramate (TPM) is a glutamate antagonist at non-NMDA, AMPA/kainate receptors. We used microdialysis as a novel technique to assess TPM pharmacokinetics/pharmacodynamics in patients with severe TBI, measuring cerebrospinal fluid and cerebral interstitial TPM concentrations as well as effects of TPM on cerebral glutamate release.
In this open-label study, 20 patients ([ge]16 yrs old) with severe TBI (Glasgow Coma Scale 3-10, excluding gunshot wounds and fixed dilated pupils) received one of two TPM treatment regimens via nasogastric tube every 12 hrs: 5.7 mg/kg TPM for 7 days (N=10) or 11.4 mg/kg TPM for 2 days followed by 5.7 mg/kg TPM for 5 days (N=10). Brain dialysate was collected using a microdialysis catheter inserted into the less injured brain hemisphere. TPM levels were measured in dialysate and CSF. Glasgow Outcome Score (GOS, 1 = no disability; 5=dead) was assessed at 3 mos.
TPM dialysate vs. plasma and CSF levels showed good penetration of the blood-brain-barrier. In patients receiving 5.7 mg/kg TPM, the decrease in glutamate levels vs. baseline was not statistically significant, although the decline was marked when compared to historical controls. With 11.4 mg/kg TPM during the first 48 hrs, the decrease in glutamate levels vs. baseline was statistically significant (P[lt]0.05). Mean GOS at 3 mos: 2.9 with 5.7 mg/kg TPM; 2.7 when 11.4 mg/kg TPM was administered during first 48 hrs. No serious adverse events attributable to TPM were observed; deaths (20%) were attributable to severe head injury.
Microdialysis can be successfully used to demonstrate drug penetration in brain tissue, control of targeted pathophysiological mechanisms, and effects on brain neurochemistry. Using this technique, TPM reduced glutamate levels to potentially neuroprotective effects in seemingly dose-related fashion in patients with severe TBI. Additional studies are needed, including trials that evaluate whether surrogate measures of antiglutaminergic and metabolic effects are predictive of clinical outcomes.
[Supported by: Johnson [amp] Johnson Pharmaceutical Research [amp] Development]