BACKGROUND: We assessed the feasibility of administering a neuroprotective drug, vigabatrin (VGB; gamma-vinyl-gamma-aminobutyric acid) with multimodality monitoring, including cerebral microdialysis, in severe head injury patients, to measure surrogate endpoints and blood-brain barrier (BBB) penetration. METHODS:Patients (n = 20) were randomised to VGB (0.5 g twice-daily, enteric) or control. ICP, ABP, CPP and cerebrovascularpressure reactivity index (PRx) were monitored. Microdialysate glucose, lactate, pyruvate, glutamate, glycerol, amino acids, VGB and GABA were analysed. RESULTS: Preliminary evaluation of results (five VGB-treated patients) showed that VGB levels rose in brain microdialysates, followed by a modest increase in GABA. VGB and GABA increased more in abnormal brain than in sites further from lesions, and were higher after multiple VGB doses. Highest VGB and GABA microdialysate levels were 75 and 4 μmol/L respectively. Microdialysate glucose and glycerol sometimes decreased, and glutamate and tyrosine sometimes increased, following VBG administration; causation unproven. VGB did not overtly affect ICP, ABP, CPP, PRx, or microdialysate lactate, pyruvate and lactate/pyruvate ratio. CONCLUSION: Multimodality monitoring, including cerebral microdialysis, is feasible for studying surrogate endpoints following drug administration. VGB crosses the BBB, leading to modest increases in extracellular GABA. Further analyses are ongoing. Microdialysis may assist the development of neuroprotective agents by determining penetration into extracellular fluid of the brain.
RCT Entities:
BACKGROUND: We assessed the feasibility of administering a neuroprotective drug, vigabatrin (VGB; gamma-vinyl-gamma-aminobutyric acid) with multimodality monitoring, including cerebral microdialysis, in severe head injurypatients, to measure surrogate endpoints and blood-brain barrier (BBB) penetration. METHODS:Patients (n = 20) were randomised to VGB (0.5 g twice-daily, enteric) or control. ICP, ABP, CPP and cerebrovascular pressure reactivity index (PRx) were monitored. Microdialysate glucose, lactate, pyruvate, glutamate, glycerol, amino acids, VGB and GABA were analysed. RESULTS: Preliminary evaluation of results (five VGB-treated patients) showed that VGB levels rose in brain microdialysates, followed by a modest increase in GABA. VGB and GABA increased more in abnormal brain than in sites further from lesions, and were higher after multiple VGB doses. Highest VGB and GABA microdialysate levels were 75 and 4 μmol/L respectively. Microdialysate glucose and glycerol sometimes decreased, and glutamate and tyrosine sometimes increased, following VBG administration; causation unproven. VGB did not overtly affect ICP, ABP, CPP, PRx, or microdialysate lactate, pyruvate and lactate/pyruvate ratio. CONCLUSION: Multimodality monitoring, including cerebral microdialysis, is feasible for studying surrogate endpoints following drug administration. VGB crosses the BBB, leading to modest increases in extracellular GABA. Further analyses are ongoing. Microdialysis may assist the development of neuroprotective agents by determining penetration into extracellular fluid of the brain.
Authors: Richard J Shannon; Keri L H Carpenter; Mathew R Guilfoyle; Adel Helmy; Peter J Hutchinson Journal: J Pharmacokinet Pharmacodyn Date: 2013-03-07 Impact factor: 2.745
Authors: Richard J Shannon; Ivan Timofeev; Jürgens Nortje; Peter J Hutchinson; Keri L H Carpenter Journal: Br J Clin Pharmacol Date: 2014-11 Impact factor: 4.335