Disufenton sodium
NXY-059 is the disulfonyl derivative of the neuroprotective spintrap phenylbutynitrone or "PBN". It was under development at the drug company AstraZeneca. A 2005 phase-3 clinical trial[1] [2] reported some efficacy in the acute treatment of ischemia injury due to stroke. However, a 2006 attempt to repeat this trial indicated no significant activity, resulting in AstraZeneca terminating the development programme.[3] Interestingly, PBN and its derivatives hydrolyze in vitro to form MNP-OH ( AKA, NtBHA ) and its parent spin-trap MNP. Such pharmacologically-active "contaminants" are known to be responsible for some of the actions of PBN itself.[4]
Putative mechanism of action
Beginning in the late 1970's Harry Demopoulos and his coworkers at New York University reported[5] that Free radicals, especially Reactive oxygen species, play a key role in the progression of brain injury due to ischemia from stroke. They likewise reported that much of this process occurs outside the brain at the the level of the blood vessel lining or endothelium. They and subsequent researchers enlarged upon and extended these two key discoveries and the general role of free radicals in the ischemic cascade.
NXY-059 was expected to be a practical application of this work. First, both NXY-059, its parent PBN and their hydrolysis product MNT are very powerful scavengers of free radicals. Unlike most antioxidants, this does not involve the further production of a reactive free radical. So they are particularly effective in terminating radical chain reactions. Likewise, unlike PBN and its derivatives, most reducing antioxidants can act as pro-oxidants. Finally, the negatively-charged sulfate groups of NXY-059 limits penetration of the drug into the brain, resulting in a low volume of distribution and a primary site of action at the level of the vascular endothelium.
Unfortunately, while this rationale appeared to be confirmed in small trials with both animals and humans, it failed to produce evidence of efficacy in large-scale Phase III clinical trials, leading to the termination of the development of the drug.
References
External links
- Initial report on "Free Radicals in Cerebral Ischaemia", with links to later citing articles.
Review Articles
Oxidants, antioxidants and the ischemic brain [1]
NXY-059: Review of Neuroprotective Potential for Acute Stroke [2]