The 22-center Pediatric Emergency Care Applied Research Network (PECARN) is in the early stages of planning for a Phase I/II clinical trial using PROG in brain-injured children. The continuing stream of positive results seem almost too good to be true―especially in light of the history of PS341 failures to find an effective neuroprotective
agent. Some investigators25,33 have expressed concern that many, if not most, preclinical animal studies in TBI lack direct, translation to clinical relevance because they fail to meet certain standards similar Inhibitors,research,lifescience,medical to the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations.34 While no one study may be able to meet all the STAIR recommendations, it is important to note that in the aggregate, the large Inhibitors,research,lifescience,medical number of studies
on PROG do, in fact, meet such criteria as: Dose-response studies Statistical power analyses to determine sample size(s) Comparison with other agents thought to be effective, their antagonists, or knockout technologies to elucidate mechanisms Histological and functional outcome measurements to examine short- and long-term effects Monitoring of relevant variables during surgery Studies in both males and females Studies in different, models and species Replication of effects across laboratories (These criteria are derived from recommendations proposed by Loane and .Fadcn.33 Inhibitors,research,lifescience,medical They arc similar to Inhibitors,research,lifescience,medical the STAIR recommendations for use in testing new drugs for the treatment, of stroke). Much of the growing
support for PROG as a potential treatment is likely based on its high safety profile and evidence of efficacy in animal and human testing, but, it, will be at least several more years before any conclusions concerning its Inhibitors,research,lifescience,medical neuroprotective benefits in largescale testing can be fully confirmed. Progesterone in stroke and neurodegenerative disorders Stroke has overlapping pathophysiological mechanisms with TBI, and the preclinical stroke data and recent, human studies in 1131 support a potential role for PROG in acute stroke. Recently we reported significant neuroprotective effects Tolmetin of acute post-injury administration of PROG in an adult rat model of permanent and transient (2 h) middle cerebral artery occlusion stroke.35-36 In different models of cerebral ischemia, PROG can significantly reduce the area of necrotic cell death and improve behavioral outcomes.37 Our findings corroborated other studies showing PROG to be neuroprotective following global ischemia in cats,38,39 and transient focal ischemia in rats.37,40 Several reviews and original research papers13,22,41-45 on the use of neurosteroids in stroke note favorable outcomes in reduction of infarct size leading to better functional status.42 Nevertheless, TBI and stroke are very different diseases, and there is no guarantee that PROG treatment will work in human stroke.