Published online before print August 23, 2007, doi: 10.1161/STROKEAHA.107.489161
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(Stroke. 2007;38:e109.)
© 2007 American Heart Association, Inc.
Letters to the Editor |
SAINT-I Worked, But the Neuroprotectant Is Not NXY-059
Proctor Clinic, Houston, Tex
University of Texas Medical Branch, Galveston, Tex
To the Editor:
Testing AstraZeneca’s nitrone drug NXY-059 against acute stroke, the SAINT-I phase-3 trial1 showed significant neuroprotectant activity.1 Moreover, looking at hemorrhagic progression secondary to the "clot-buster" tPA (alteplase) in a parallel trial, symptomatic hemorrhage more than halved in the NXY-059-treated group, to 2.5% versus 6.4% in the controls. Likewise, the rate of asymptomatic hemorrhage was significantly lower in the treatment group (12.9% versus 20.9%). Although the subjective modified Rankin Scale used in the main trial might be open to question, it is hard to dismiss the alteplase findings, based on hard dichotomous radiological data.
Unfortunately, the second (SAINT-II) trial failed. This difference has been ascribed to unspecified methodological problems. But there is a ready alternative explanation. This is that a neuroprotectant was present in SAINT-I, but not in SAINT-II.
Phenylbutylnitrone (PBN) derivatives such as NXY-059 hydrolyze to produce the corresponding benzaldehyde plus N-t-butylhydroxylamine (NtBHA).2–7 Itself a potent radical scavenger, NtBHA readily oxidizes to its parent spintrap, MNP or "2-methyl-2-nitrosopropane", AKA, "t-nitrosobutane". In addition to trapping radicals, MNP is reduced by (say) vitamin-C or mitochondria back to NtBHA. Moreover, on exposure to light or in oxidizing conditions, MNP releases nitric oxide (NO),2–6 with antiplatelet, antioxidant, neuroprotective and vessel-dialating properties.
Such hydrolysis products might account for the success of the SAINT-I trial and their absence for the failure of SAINT-II. It had similarly proved impossible to replicate earlier results produced with "aged" PBN.4 This was later tracked down to NtBHA and MNP production during storage.
A smoking gun? AstraZeneca patent ‘5277 claims methods for inhibiting hydrolysis of NXY-059 to NtBHA and MNP. These methods include antioxidants, limiting light exposure, storage under nitrogen, pH-elevation, decreased headspace, and increasing concentrations. Otherwise, the shelf life of NXY-059 is "unacceptably short",7 hydrolyzing a few percent per year. Moreover, NXY-059 in parenteral solutions can hydrolyze up to about 1% per day.7 Postulating that the hydrolysis products are the true neuroprotectants, such normally unremarkable variables might explain the rather different results in SAINT-I and SAINT-II.
Sample scenarios: the SAINT-I trial was delayed pending animal toxicity studies. Perhaps the SAINT-I trial was thus done with "old" NXY-059 and SAINT-II with new. Likewise, perhaps the parenteral solutions of NXY-059 used in SAINT-I were not as "fresh" as in SAINT-2 or experienced more light exposure. Alternately, perhaps the differences resulted from the application of the ‘527 patent’s stabilization methodology to SAINT-II.
Most importantly, should any such prove the case, the SAINT/STAIR methodology works well. It not only showed an unexpected neuroprotectant, but also distinguished this from NXY-059. That is, human neuroprotectants are not only possible, but provable.
Acknowledgments
Disclosures
P.H.P. has patent claims in this area.
References
1. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Dienre H-C, Grotta J, Lyden P, Shuab A, Hardemark HG, Wasiewski MM. NXY-059 for acute ischemic stroke. N Engl J Med. 2006; 354: 588–600.
2. Saito K, Ariga T, and Yoshioka H. Generation of nitric oxide from spin-trapping agents under oxidative conditions. Bioscience, Biotechnology, and Biochemistry. 1998; 62: 275–279.[CrossRef]
3. Chamulitrat W, Jordan SJ, Mason RP, Saito K, Cutler RG. Nitric oxide formation during light-induced decomposition of phenyl N-tert-butylnitrone. J Biol Chem. 1993; 268: 11520–11527.
4. Atamna H, Paler-Martínez A, Ames BN. N-t-Butyl Hydroxylamine, a hydrolysis product of -Phenyl-N-t-butyl Nitrone, is more potent in delaying senescence in human lung fibroblasts. J Biol Chem. 2000; 275: 6741–6748.
5. Lapchak PA, Chapman DF, Zivin JA. Pharmacological effects of the spin trap agents N-t-Butyl- Phenylnitrone (PBN) and 2,2,6,6-Tetramethylpiperidine-N-Oxyl (TEMPO) in a rabbit thromboembolic stroke model, combination studies with the thrombolytic tissue plasminogen activator. Stroke. 2001; 32: 147–153.
6. Fredrik C. Delayed Cell Death After Traumatic Brain Injury, Role of Reactive Oxygen Species. Dissertation, Upsalla University; 2004: 46.
7. Andersson M, Andersson, Mattias, Ericksson P. Novel formulations of Alpha-2-4-disulfophenyl-N-tert-butylnitrone, US Patent application #2003/0181527. Available at: http://drproctor.com/nxy-n 059/527pat.pdf. The Swedish patent (PCT/SE01/01164) lists AstraZeneca as the applicant.
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