Anat Biegon used to be Pharmos' CSO--very bright. The delay to administration has been the bane of most stroke and TBI drugs--Lord knows if you give a rat a neuroprotectant before occluding them, they do very well (often 80-90% protection).
That paper raised an intriguing hypothesis--that one needs to downregulate glutamate the first hour, and upregulate it afterwards. Since NMDA receptor inhibition was thought to be the lesser of dex's mechanisms (inflammatory cytokine inhibition (NFkappaB for example), and free radical scavenging were more salient), I hoped this was not a critical element, and the preclinical data predicted benefit out to six hours. The PhII and PhIII both had mean delays of around five hours, so this doesnt account for the discrepancy between trials. I asked them if there was a length of delay effect--they said they had broken it into 0-4 hour vs 5-6 hour categories, and found no effect. I'll bet there were no patients administered at one hour, few if any at 2 hrs. So--it may be that you have to give it in the ambulance for it to have an effect.
But it is the reason the CABG indication was appealing--you had absolute control over timing, everyone gets it as prophylaxis.
After all this, if a family member of mine had the option of dex after a TBI, I'd sure as hell say yes.
Harry
NeuroInvestment |
