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Cerovive

According to news published in 27 Oct 2006, NXY-059 Does Not Meet Efficacy Endpoints In Phase III Trial For Acute Ischemic Stroke.  August 10, 2007 — Disappointing results of the Stroke Acute Ischemic NXY-059 Trial (SAINT II), a randomized study of the investigational neuroprotectant NXY-059 ( Cerovive, AstraZeneca), show no effect of treatment vs placebo in patients with acute ischemic stroke, despite the promising results from SAINT I, a previous trial of the same agent.

NXY-059 is a free-radical–trapping agent that had been shown to be neuroprotective in animal models of stroke. SAINT I,  (Lees KR et al. N Engl J Med. 2006; 354:588-600), was a randomized trial that showed treatment with NXY-059 within 6 hours of ischemic stroke significantly improved the primary outcome of reduced disability at 90 days, although treatment did not have a significant effect on other outcomes, including neurologic function on the National Institutes of Health Stroke Scale (NIHSS).  

Current developer: AstraZeneca

1: Culot M, Mysiorek C, Renftel M, Roussel BD, Hommet Y, Vivien D, Cecchelli R, Fenart L, Berezowski V, Dehouck MP, Lundquist S. Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study. Brain Res. 2009 Oct 19;1294:144-52. Epub 2009 Jul 23. PubMed PMID: 19631615.

2: Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, Green AR; NXY-059 Efficacy Meta-analysis in Individual Animals with Stroke Investigators. Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol. 2009 Aug;157(7):1157-71. Epub 2009 Apr 27. PubMed PMID: 19422398; PubMed Central PMCID: PMC2743834.

3: Cheng YF, Jiang J, Hu P, Reinholdsson I, Guo W, Asenblad N, Nilsson D. Pharmacokinetics of 8-hour intravenous infusion of NXY-059: a phase I, randomized, double-blind (within dose panels), placebo-controlled study in healthy Chinese volunteers. Clin Ther. 2008 Dec;30(12):2342-53. PubMed PMID: 19167593.

4: Clausen F, Marklund N, Lewén A, Hillered L. The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat. J Neurotrauma. 2008 Dec;25(12):1449-57. PubMed PMID: 19118455.

5: Savitz SI. Cosmic implications of NXY-059. Stroke. 2009 Mar;40(3 Suppl):S115-8. Epub 2008 Dec 8. PubMed PMID: 19064771.

6: Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008 Oct;39(10):2824-9. Epub 2008 Jul 17. PubMed PMID: 18635842.

7: Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Shuaib A, Ashwood T, Wasiewski W, Alderfer V, Hårdemark HG, Rodichok L; SAINT I and II Investigators. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke. 2008 Jun;39(6):1751-8. Epub 2008 Mar 27. PubMed PMID: 18369171.

8: Savitz SI, Fisher M. NXY-059 for the treatment of stroke. N Engl J Med. 2007 Nov 22;357(21):2198; author reply 2198-9. PubMed PMID: 18032772.

9: Mutch NJ, Moore NR, Mattsson C, Jonasson H, Green AR, Booth NA. The use of the Chandler loop to examine the interaction potential of NXY-059 on the thrombolytic properties of rtPA on human thrombi in vitro. Br J Pharmacol. 2008 Jan;153(1):124-31. Epub 2007 Nov 5. PubMed PMID: 17982476; PubMed Central PMCID: PMC2199381.

10: Williams HE, Claybourn M, Green AR. Investigating the free radical trapping ability of NXY-059, S-PBN and PBN. Free Radic Res. 2007 Sep;41(9):1047-52. PubMed PMID: 17729123.

11: Proctor PH, Tamborello LP. SAINT-I worked, but the neuroprotectant is not NXY-059. Stroke. 2007 Oct;38(10):e109; author reply e110. Epub 2007 Aug 23. PubMed PMID: 17717310.

12: Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe U; SAINT II Trial Investigators. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007 Aug 9;357(6):562-71. PubMed PMID: 17687131.

13: Kågedal M, Nilsson D, Huledal G, Reinholdsson I, Cheng YF, Asenblad N, Pekar D, Borgå O. A study of organic acid transporter mediated pharmacokinetic interaction between NXY-059 and cefuroxime. J Clin Pharmacol. 2007 Aug;47(8):1043-8. PubMed PMID: 17660486.

14: Watabe M, Cheng YF, Nilsson D, Itoh Y, Kumagai Y. A phase 1, placebo-controlled, randomised, double-blind (within dose panels) study evaluating the safety, tolerability and pharmacokinetics of intravenous NXY-059 in Japanese subjects. Curr Med Res Opin. 2007 Aug;23(8):1849-57. PubMed PMID: 17605894.

15: Cheng YF, Strid S, Borgå O, Nilsson D, Wemer J. Active renal secretion of NXY-059, a novel neuroprotectant, is mediated via an organic acid transporter. J Clin Pharmacol. 2007 Jul;47(7):909-14. PubMed PMID: 17585119.

16: Feuerstein GZ, Zaleska MM, Krams M, Wang X, Day M, Rutkowski JL, Finklestein SP, Pangalos MN, Poole M, Stiles GL, Ruffolo RR, Walsh FL. Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J Cereb Blood Flow Metab. 2008 Jan;28(1):217-9. Epub 2007 Jun 20. Review. PubMed PMID: 17579658.

17: Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener HC, Grotta JC, Ashwood TJ, Hardemark HG, Svensson HH, Rodichok L, Wasiewski WW, Ahlberg G; CHANT Trial Investigators. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke. 2007 Aug;38(8):2262-9. Epub 2007 Jun 14. PubMed PMID: 17569876.

18: Huledal G, Nilsson D, Kågedal M, Reinholdsson I, Cheng YF, Svensson H, Borgå O, van Hout M. Effect of NXY-059, a novel neuroprotectant, on the pharmacokinetics of a single dose of digoxin in healthy subjects. Curr Med Res Opin. 2007 Jul;23(7):1531-9. PubMed PMID: 17559748.

19: Ginsberg MD. Life after cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era. Stroke. 2007 Jun;38(6):1967-72. Epub 2007 May 3. Review. PubMed PMID: 17478741.

20: Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol. 2007 May;205(1):20-5. Epub 2007 Mar 12. Review. PubMed PMID: 17408618.

21: Saver JL. Clinical impact of NXY-059 demonstrated in the SAINT I trial: derivation of number needed to treat for benefit over entire range of functional disability. Stroke. 2007 May;38(5):1515-8. Epub 2007 Mar 29. PubMed PMID: 17395871.

22: Nilsson D, Wemer J, Cheng YF, Reinholdsson I, Englund G, Egberg N, Schulman S. NXY-059 does not affect bleeding time in healthy volunteers: a randomized, double-blind, placebo-controlled, 3-period crossover phase I study. J Clin Pharmacol. 2007 Feb;47(2):264-72. PubMed PMID: 17244778.

23: Serebruany VL. Hypokalemia, cardiac failure, and reporting NXY-059 safety for acute stroke. J Cardiovasc Pharmacol Ther. 2006 Dec;11(4):229-31. PubMed PMID: 17220468.

24: Strid S, Nilsson D, Borgå O, Wemer J, Grahnén A. NXY-059 does not significantly interact with furosemide in healthy volunteers. J Clin Pharmacol. 2006 Dec;46(12):1417-25. PubMed PMID: 17101741.

25: Lees KR, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Ashwood T, Hardemark HG, Wasiewski W, Emeribe U, Zivin JA; SAINT I Investigators. Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial. Stroke. 2006 Dec;37(12):2970-8. Epub 2006 Oct 26. PubMed PMID: 17068304.

26: Wemer J, Cheng YF, Nilsson D, Reinholdsson I, Fransson B, Lanbeck Vallén K, Nyman L, Eriksson C, Björck S, Schulman S. Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects. Curr Med Res Opin. 2006 Sep;22(9):1813-23. PubMed PMID: 16968585.

27: Hess DC. NXY-059: a hopeful sign in the treatment of stroke. Stroke. 2006 Oct;37(10):2649-50. Epub 2006 Aug 31. PubMed PMID: 16946156.

28: Koziol JA, Feng AC. On the analysis and interpretation of outcome measures in stroke clinical trials: lessons from the SAINT I study of NXY-059 for acute ischemic stroke. Stroke. 2006 Oct;37(10):2644-7. Epub 2006 Aug 31. Review. PubMed PMID: 16946150.

29: Fisher M. NXY-059 for acute ischemic stroke: the promise of neuroprotection is finally realized? Stroke. 2006 Oct;37(10):2651-2. Epub 2006 Aug 31. PubMed PMID: 16946143.

30: Fisher M, Lees K, Papadakis M, Buchan AM. NXY-059: brain or vessel protection. Stroke. 2006 Aug;37(8):2189-90. Epub 2006 Jun 29. PubMed PMID: 16809574.

31: Koziol JA. NXY-059 for acute ischemic stroke. N Engl J Med. 2006 May 11;354(19):2075-6; author reply 2075-6. PubMed PMID: 16696147.

32: Serebruany V. NXY-059 for acute ischemic stroke. N Engl J Med. 2006 May 11;354(19):2075-6; author reply 2075-6. PubMed PMID: 16687726.

33: Doggrell SA. Is NXY-059 an advancement in the treatment of acute ischaemic stroke? Expert Opin Pharmacother. 2006 May;7(7):965-8. Review. PubMed PMID: 16634718.

34: Fong JJ, Rhoney DH. NXY-059: review of neuroprotective potential for acute stroke. Ann Pharmacother. 2006 Mar;40(3):461-71. Epub 2006 Feb 28. Review. PubMed PMID: 16507608.

35: Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Hårdemark HG, Wasiewski WW; Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators. NXY-059 for acute ischemic stroke. N Engl J Med. 2006 Feb 9;354(6):588-600. PubMed PMID: 16467546.

36: Green AR, Lanbeck-Vallén K, Ashwood T, Lundquist S, Lindström Böö E, Jonasson H, Campbell M. Brain penetration of the novel free radical trapping neuroprotectant NXY-059 in rats subjected to permanent focal ischemia. Brain Res. 2006 Feb 9;1072(1):224-6. Epub 2006 Jan 30. PubMed PMID: 16448628.

37: Jönsson S, Cheng YF, Edenius C, Lees KR, Odergren T, Karlsson MO. Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke. Clin Pharmacokinet. 2005;44(8):863-78. PubMed PMID: 16029070.

38: Wang CX, Shuaib A. NXY-059: a neuroprotective agent in acute stroke. Int J Clin Pract. 2004 Oct;58(10):964-9. Review. PubMed PMID: 15587776.

39: Green AR, Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord. 2005 Apr;4(2):109-18. Review. PubMed PMID: 15857295.

40: Maples KR, Green AR, Floyd RA. Nitrone-related therapeutics: potential of NXY-059 for the treatment of acute ischaemic stroke. CNS Drugs. 2004;18(15):1071-84. Review. PubMed PMID: 15581379.

41: Lapchak PA, Song D, Wei J, Zivin JA. Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores. Exp Neurol. 2004 Aug;188(2):279-85. PubMed PMID: 15246827.

42: Han M, He QP, Yong G, Siesjö BK, Li PA. NXY-059, a nitrone with free radical trapping properties inhibits release of cytochrome c after focal cerebral ischemia. Cell Mol Biol (Noisy-le-grand). 2003 Dec;49(8):1249-52. PubMed PMID: 14983994.

43: Green AR, Ashwood T, Odergren T, Jackson DM. Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059. Pharmacol Ther. 2003 Dec;100(3):195-214. Review. PubMed PMID: 14652110.

44: Lapchak PA, Araujo DM. Development of the nitrone-based spin trap agent NXY-059 to treat acute ischemic stroke. CNS Drug Rev. 2003 Fall;9(3):253-62. Review. PubMed PMID: 14530797.

45: Marshall JW, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke. 2003 Sep;34(9):2228-33. Epub 2003 Aug 14. PubMed PMID: 12920263.

46: Adis International Ltd. NXY 059: CPI 22, NXY 059G. Drugs R D. 2003;4(4):254-7. PubMed PMID: 12848592.

47: Marshall JW, Green AR, Ridley RM. Comparison of the neuroprotective effect of clomethiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histological and behavioural measures. Brain Res. 2003 May 16;972(1-2):119-26. PubMed PMID: 12711084.

48: Lees KR, Barer D, Ford GA, Hacke W, Kostulas V, Sharma AK, Odergren T; SA-NXY-0004 Investigators. Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke. 2003 Feb;34(2):482-7. PubMed PMID: 12574564.

49: Lapchak PA. NXY-059. Centaur. Curr Opin Investig Drugs. 2002 Dec;3(12):1758-62. Review. PubMed PMID: 12528313.

50: Dehouck MP, Cecchelli R, Richard Green A, Renftel M, Lundquist S. In vitro blood-brain barrier permeability and cerebral endothelial cell uptake of the neuroprotective nitrone compound NXY-059 in normoxic, hypoxic and ischemic conditions. Brain Res. 2002 Nov 15;955(1-2):229-35. PubMed PMID: 12419541.

51: Strid S, Borgå O, Edenius C, Jostell KG, Odergren T, Weil A. Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke. Eur J Clin Pharmacol. 2002 Sep;58(6):409-15. Epub 2002 Aug 10. PubMed PMID: 12242600.

52: Yoshimoto T, Kanakaraj P, Ying Ma J, Cheng M, Kerr I, Malaiyandi L, Watson JA, Siesjö BK, Maples KR. NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. Brain Res. 2002 Aug 30;947(2):191-8. PubMed PMID: 12176160.

53: Lapchak PA, Araujo DM, Song D, Wei J, Purdy R, Zivin JA. Effects of the spin trap agent disodium- [tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit Large clot embolic stroke model: combination studies with tissue plasminogen activator. Stroke. 2002 Jun;33(6):1665-70. PubMed PMID: 12053009.

54: Yoshimoto T, Kristián T, Hu B, Ouyang YB, Siesjö BK. Effect of NXY-059 on secondary mitochondrial dysfunction after transient focal ischemia; comparison with cyclosporin A. Brain Res. 2002 Apr 5;932(1-2):99-109. PubMed PMID: 11911866.

55: Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke. 2002 May;33(5):1411-5. PubMed PMID: 11988623.

56: Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol. 2002 Jan;135(1):103-12. PubMed PMID: 11786485; PubMed Central PMCID: PMC1573113.

57: Maples KR, Ma F, Zhang YK. Comparison of the radical trapping ability of PBN, S-PPBN and NXY-059. Free Radic Res. 2001 Apr;34(4):417-26. PubMed PMID: 11328677.

58: Lees KR, Sharma AK, Barer D, Ford GA, Kostulas V, Cheng YF, Odergren T. Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke. Stroke. 2001 Mar;32(3):675-80. PubMed PMID: 11239186.

59: Peeling J, Del Bigio MR, Corbett D, Green AR, Jackson DM. Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke. Neuropharmacology. 2001 Mar;40(3):433-9. PubMed PMID: 11166336.

60: Marshall JW, Duffin KJ, Green AR, Ridley RM. NXY-059, a free radical--trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke. 2001 Jan;32(1):190-8. PubMed PMID: 11136936.

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