The Effect of Cyclosporine on Isoprostane and Neuroprostane Production Following Severe Traumatic Brain Injury

Optimal design for translational clinical trials of neuroprotective treatments continues to be investigated. Defining a rationale approach to neuroprotective drug therapy for patients with traumatic brain injury (TBI) will require systematic determination of pharmacokinetic and pharmacodynamic endpoints associated with response. Lack of pharmacokinetic data to guide dosing for specific pharmacodynamic endpoints is one of several reasons for failure of investigational drugs to demonstrate benefit in this population. Cyclosporine (CsA) is a promising neuroprotective agent for acute TBI. Our research team has characterized the systemic pharmacokinetic profile of cyclosporine following TBI in humans and also gathered preliminary safety data. In the course of this study, isoprostane (IP) and neuroprostanes (NP) have demonstrated potential as biomarkers for response to CsA. This proposal is a "proof of concept" study to further investigate the PK/PD relationship between CsA and IP/NP production. The hypothesis of this investigation is that systemic administration of CsA will lower the concentration of IP and NP in the CSF of severe TBI patients. The specific aims are 1)To quantify IP and NP concentrations during the first eight hours following severe TBI; 2)To determine the effect of seventy-two hour continuous infusion CsA on IP and NP concentrations; 3)To determine concentration response profiles for CsA and IP/NP changes following acute severe TBI.