NXY-059
Encyclopedia
Disufenton sodium is the disulfonyl derivative of the neuroprotective spin trap
Spin trapping
Spin trapping in chemistry is an analytical technique employed in the detection and identification of short-lived free radicals. Spin trapping involves the addition of radical to a nitrone spin trap resulting in the formation of a spin adduct, a nitroxide-based persistent radical, that can be...

 phenylbutynitrone or "PBN". It was under development at the drug company AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...

. A 2005 phase-3 clinical trial called "SAINT-1" reported some efficacy in the acute treatment of ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

 injury due to stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

. However, a 2006 attempt to repeat this trial indicated no significant activity. After ruling out other causes, the authors tentatively attributed the positive results in the first trial to "chance". This was even though the probability of the SAINT-1 results happening by chance was roughly one in 25 for the main part of the SAINT-1 study, involving the Modified Rankin scale. It was also one chance in 200 for a parallel study looking at inhibition of hemorrhagic stroke from use of the "clot-buster" alteplase or "tPA".

AstraZeneca then terminated the development programme. PBN and its derivatives hydrolyze and oxidize in vitro to form respectively 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. Though AstraZeneca denies this, a similar process may account for the positive results in the first trial.

Putative mechanism of action

Beginning in the late 1970s Harry Demopoulos
Harry Demopoulos
Harry B. Demopoulos, MD is an pioneer in the medical aspects of free radicals, especially in the areas of ischaemic injury, the toxicity of anticancer drugs, and in spinal cord injury...

 and his coworkers at New York University
New York University
New York University is a private, nonsectarian research university based in New York City. NYU's main campus is situated in the Greenwich Village section of Manhattan...

 reported that free radicals, especially reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

, play a key role in the progression of brain injury due to ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

 from stroke. They likewise reported that much of this process occurs outside the brain at the level of the blood vessel lining or endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

. They and subsequent researchers enlarged upon and extended these two key discoveries and the general role of free radicals in the ischemic cascade
Ischemic cascade
The ischemic cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia . This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the...

.

NXY-059 was expected to be a practical application of this work. First, both NXY-059, its parent PBN and their hydrolysis/oxidation 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-oxidant
Pro-oxidant
Pro-oxidants are chemicals that induce oxidative stress, through either creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues...

s. Finally, the negatively-charged sulfate groups of NXY-059 limits penetration of the drug into the brain, resulting in a low volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...

 and a primary site of action at the level of the vascular endothelium.

This rationale appeared to be confirmed in small trials with both animals and humans. However, in large-scale Phase III clinical trials the first (Saint-1) clinical trial worked, while, inexplicably, the second (Saint-2) trial failed. AstraZeneca then terminated development of the drug.

The failure of the Saint-2 trial in the face of the success of the Saint-1 trial raises numerous questions. Something similar had previously been seen with the parent drug, PBN. "Aged" PBN would show pharmacological activity in one study and not in another done with newly-prepared PBN. This was later traced to hydrolysis and oxidation during storage of PBN to t-Butylhydroxylamine (NtBHA) and its parent spintrap, 2-methyl-2-nitrosopropane
2-Methyl-2-nitrosopropane
2-Methyl-2-nitrosopropane can be prepared by catalytic oxidation of 3CNH2 using hydrogen peroxide and sodium tungstate. Depending on the temperature and solvent, it is either dimeric and colorless or monomeric and blue. It can be used as a spin trap...

(MNP), which proved to be the active agents.

One interpretation is that the Saint-1 trial reflected the presence of such a neuroprotectant, while the failure of the Saint-2 trial merely established that this neuroprotectant is not NXY-059. The difference could have arisen by subtle, perhaps even deliberate, changes in the storage and administration of the agent between the two trials.

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