Water-Soluble Progesterone
Analogues Are Effective,
Injectable Treatments in Animal Models of Traumatic Brain Injury
- Publication date
- Publisher
Abstract
After more than 30 years of research and 30 failed clinical
trials
with as many different treatments, progesterone is the first agent
to demonstrate robust clinical efficacy as a treatment for traumatic
brain injuries. It is currently being investigated in two, independent
phase III clinical trials in hospital settings; however, it presents
a formidable solubility challenge that has so far prevented the identification
of a formulation that would be suitable for emergency field response
use or battlefield situations. Accordingly, we have designed and tested
a novel series of water-soluble analogues that address this critical
need. We report here the synthesis of C-20 oxime conjugates of progesterone
as therapeutic agents for traumatic brain injuries with comparable
efficacy in animal models of traumatic brain injury and improved solubility
and pharmacokinetic profiles. Pharmacodynamic analysis reveals that
a nonprogesterone steroidal analogue may be primarily responsible
for the observed activity