Astrazeneca Stroke nxy-059 Saint

AstraZeneca, Stroke, NXY-059--the Saint-2 = trial

Failure of the NXY-059 Saint-II stroke trial

The Saint-1 trial showed a neuroprotectant. The Saint-2 trial demonstated that this neuroprotectant is not NXY-059.

Unfortunately, after very promising results in AstraZeneca's first clinical trial (Saint-1) testing NXY-059 for the amelioration of stroke-induced = injury and disability, the second NXY-059 trial (Saint-2) failed.

It seems improbable that an agent which produced significant neuroprotection in a stroke trial involving 1700 patients should so utterly fail in a second neuroprotection trial involving almost double that number. Moreover, a second parallel trial, looking at prevention of hemorrhagic stroke secondary to the use of the clot-buster tPA, gave even more striking results in Saint-1, with a value of .005. Further, this was on the basis of objective radiological data and not some "soft" measure of function such as the Modified Rankin Scale.

Likely, some hidden variable caused the second (Saint-II) stroke neuroprotection trial to fail. For example, the antioxidant status of blood in stroke victims plays a key role in the eventual outcome. In fact, the uniquely high level of certain antioxidants (such as uric acid) in humans is likely one reason antioxidant drug results in experimental animals often do not directly translate to humans.

However, The most likely explaination of the strikingly different outcomes was some material difference in the drug formulations used in the two trials. The probable culprit-- PBN derivatives such as NXY-059 (PBN-disulfonate) are somewhat unstable. During storage, they spontaneously hydrolyze to produce the appropriate benzaldehyde and N-t-butylhydroxylamine ("NtBHA" or "MNP-OH"). For more technical details, go here. As the last name implies, NtBHA is in redox equilibrium with its corresponding nitroso spintrap,MNP.*=20

NtBHA scavenges radicals significantly better than PBN. In doing so = it=20 oxidizes back to MNP. In addition to scavenging radicals itself, MNP can = be=20 reduced by (say) vitamin-C back to NtBHA. MNP releases nitric = oxide=20 (NO) . Nitric oxide is a natural messenger substance with antiplatelet, antioxidant, neuroprotective and blood-vessel-dialating properties.

Ignoring other products, these reactions are roughly as follows:

1. PBN derivatives (e.g., NXY-059) hydrolyzes to make NtBHA

2. NtBHA oxidizes to MNP, which then does any or all of the following:

3. Vitamin-C or mitochondria (e.g.) reduce MNP back to NtBHA, or

4. MNP makes Nitric Oxide (NO), which dialates blood vessels, = scavenges=20 radicals, etc., or

5. MNP forms a spin adduct with a free radical, neutralizing = it.

All this cycling, SODase-activity, etc. is rather similar to what happens = with spin labels such as TEMPO. Interestingly, such spin labels have a = pharmacological=20 spectrum rather similar to spin traps such as PBN. See for example, this paper and the papers citing it. Incidentally, this writer earlier pointed out the connection between the spin traps and nitric oxide.=20

Such neuroprotective hydrolysis products might account for the clear efficacy found in the Saint-I trial and their absence for the failure of the Saint-II trial. This occurred in previous studies with PBN, in which it similarly proved impossible to replicate earlier results produced with "aged" PBN.

One possible scenario: Shortly before it was scheduled to start, The Saint-1 trial was suspended pending more animal toxicity studies. Perhaps, as a result of this months-long delay the Saint-1 trial was done with "Old" NXY-059 and Saint-2 with new. NtHBA and its air oxidation product MNP might have been produced during storage, as they are during storage of the parent PBN. Similarly, NtHBA is used in the synthesis of NXY-059, raising the possibility of contamination.

For some refs, go here = and here and = follow to=the citing papers.

Significantly, the possibility of NtHBA, MNP, etc. contributing to = the action of NXY-059 was broached in Swedish PhD dissertation (warning--large file). With respect to this very issue, on Page 46 the author Clausen notes "According to AstraZeneca representatives there is no evidence of any in vivo decomposition of S-PBN or NXY-059 (personal communication)...". Note the "in vivo" limitation--- The issue here is decomposition in vitro during storage, as with other PBN derivatives.

Thus, statements that neuroprotective agents are impossible are = premature--on the basis of the Saint-1 trial such clearly exist. Further, it may be possible to salvage a very promising stroke drug. On paper at least, the NtHBA-MNP couple is a designer neuroprotectant, both scavenging radicals and,unlike other NO-donors, releasing NO specifically at sites of oxidative stress, but not much elsewhere. This is because circulating MNP is normally in its reduced form NtHBA. This may be what it took to get a clinically-effective antioxidant neuroprotectant in humans.

Neuroprotection and Me

Disclosure: I own certain patent claims to MNP and its reduction products.

Phone: 713-960-1616 or mailto:home@drproctor.com

Peter H. Proctor, PhD, MD

* MNP is also known as "2-methyl-2 nitrosopropane", "t-nitrosobutane" = or=20 "t-NB".





Engine fodder: NXY-059 astrazeneca stroke renovis saint-1 saint-2 organic semicoductors hair regrwoth 2-methyl-2-nitrosopropane butylhydroxylamine hydrolysisNtBHA organic semiconductors.



















This link is moot, at least=20 at the moment. I leave it in because search engines like it. Ignore it=20 otherwise.