(Stroke. 2000;31:347.)
© 2000 American Heart Association, Inc.
Original Contributions |
Selfotel in Acute Ischemic Stroke
Possible Neurotoxic Effects of an NMDA Antagonist
From the Departments of Neurology, Royal Melbourne Hospital and University of Melbourne (Australia) (S.M.D.); University of Glasgow (Scotland) (K.R.L.); Stanford University Medical Center, Stanford, Calif (G.W.A.); University of Essen (Germany) (H.C.D.); Novartis Pharma AG (S.M., G.K.); and the University of Toronto, (Canada) (J.N.).
Correspondence and reprint requests to Prof Stephen Davis, Director of Neurology, Melbourne Neuroscience Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia 3050. E-mail sdavis{at}ariel.its.unimelb.edu.au
Background and Purpose—Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies.
Methods—Two pivotal phase 3 ischemic stroke trials tested
the hypothesis, by double-blind, randomized, placebo-controlled
parallel design, that a single intravenous 1.5 mg/kg dose
of Selfotel, administered within 6 hours of stroke onset, would improve
functional outcome at 90 days, defined as the proportion of patients
achieving a Barthel Index score of 
60. The trials were performed in
patients aged 40 to 85 years with acute ischemic hemispheric
stroke and a motor deficit.
Results—The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05).
Conclusions—Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.
Key Words: controlled clinical trials • neuroprotection • stroke, acute • stroke, ischemic
This article has been cited by other articles:
 |
|
 |
|
  H.-S. Sun, T. A. Doucette, Y. Liu, Y. Fang, L. Teves, M. Aarts, C. L. Ryan, P. B. Bernard, A. Lau, J. P. Forder, et al. Effectiveness of PSD95 Inhibitors in Permanent and Transient Focal Ischemia in the Rat Stroke, September 1, 2008; 39(9): 2544 - 2553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. N. David, B. Haelewyn, C. Rouillon, M. Lecoq, L. Chazalviel, G. Apiou, J.-J. Risso, M. Lemaire, and J. H. Abraini Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia FASEB J, April 1, 2008; 22(4): 1275 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Donnan The 2007 Feinberg Lecture: A New Road Map for Neuroprotection Stroke, January 1, 2008; 39(1): 242 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Villmann and C.-M. Becker On the Hypes and Falls in Neuroprotection: Targeting the NMDA Receptor Neuroscientist, December 1, 2007; 13(6): 594 - 615. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Cui, A. Hayashi, H.-S. Sun, M. P. Belmares, C. Cobey, T. Phan, J. Schweizer, M. W. Salter, Y. T. Wang, R. A. Tasker, et al. PDZ Protein Interactions Underlying NMDA Receptor-Mediated Excitotoxicity and Neuroprotection by PSD-95 Inhibitors J. Neurosci., September 12, 2007; 27(37): 9901 - 9915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ali, P. M.W. Bath, J. Curram, S. M. Davis, H.-C. Diener, G. A. Donnan, M. Fisher, B. A. Gregson, J. Grotta, W. Hacke, et al. The Virtual International Stroke Trials Archive Stroke, June 1, 2007; 38(6): 1905 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The Optimising Analysis of Stroke Trials (OAST) Co Can We Improve the Statistical Analysis of Stroke Trials?: Statistical Reanalysis of Functional Outcomes in Stroke Trials * OAST Supplemental Appendix I: Statistical Tests Compared (see Table I) * OAST Supplemental Appendix II: Supplementary Analyses * OAST Supplemental Appendix III: Trial Data (see Tables II and III) * OAST Supplemental Appendix IV: Results (see Table IV) Stroke, June 1, 2007; 38(6): 1911 - 1915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. MacDonald and M. F. Jackson Transient Receptor Potential Channels of the Melastatin Family and Ischemic Responses of Central Neurons Stroke, February 1, 2007; 38(2): 665 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dingley, J. Tooley, H. Porter, and M. Thoresen Xenon Provides Short-Term Neuroprotection in Neonatal Rats When Administered After Hypoxia-Ischemia Stroke, February 1, 2006; 37(2): 501 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Young, C. J. Weir, K. R. Lees, and for the GAIN International Trial Steering Committe Comparison of the National Institutes of Health Stroke Scale With Disability Outcome Measures in Acute Stroke Trials Stroke, October 1, 2005; 36(10): 2187 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Weir, M. Kaste, K. R. Lees, and for the Glycine Antagonist in Neuroprotection Int Targeting Neuroprotection Clinical Trials to Ischemic Stroke Patients With Potential to Benefit From Therapy Stroke, September 1, 2004; 35(9): 2111 - 2116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Weaver, J. Leonardi-Bee, F. J. Bath-Hextall, and P. M.W. Bath Sample Size Calculations in Acute Stroke Trials: A Systematic Review of Their Reporting, Characteristics, and Relationship With Outcome Stroke, May 1, 2004; 35(5): 1216 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. H. Danton and W. D. Dietrich The Search for Neuroprotective Strategies in Stroke AJNR Am. J. Neuroradiol., February 1, 2004; 25(2): 181 - 194. [Full Text] [PDF]
|
|
|
|
|
|
K. R. Lees, H.-C. Diener, K. Asplund, and M. Krams UK-279,276, a Neutrophil Inhibitory Glycoprotein, in Acute Stroke: Tolerability and Pharmacokinetics Stroke, July 1, 2003; 34(7): 1704 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, R. J. Adams, T. Brott, G. J. del Zoppo, A. Furlan, L. B. Goldstein, R. L. Grubb, R. Higashida, C. Kidwell, T. G. Kwiatkowski, et al. Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association Stroke, April 1, 2003; 34(4): 1056 - 1083. [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Elting, G. A. Sulter, M. Kaste, K. R. Lees, H. C. Diener, M. Hommel, M. Versavel, A. W. Teelken, and J. De Keyser AMPA Antagonist ZK200775 in Patients With Acute Ischemic Stroke: Possible Glial Cell Toxicity Detected by Monitoring of S-100B Serum Levels Stroke, December 1, 2002; 33(12): 2813 - 2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mocco, T. Choudhri, J. Huang, E. Harfeldt, L. Efros, C. Klingbeil, V. Vexler, W. Hall, Y. Zhang, W. Mack, et al. HuEP5C7 as a Humanized Monoclonal Anti-E/P-Selectin Neurovascular Protective Strategy in a Blinded Placebo-Controlled Trial of Nonhuman Primate Stroke Circ. Res., November 15, 2002; 91(10): 907 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K W Muir Magnesium in stroke treatment Postgrad. Med. J., November 1, 2002; 78(925): 641 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Aarts, Y. Liu, L. Liu, S. Besshoh, M. Arundine, J. W. Gurd, Y.-T. Wang, M. W. Salter, and M. Tymianski Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions Science, October 25, 2002; 298(5594): 846 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Huang, D. B. Agus, C. J. Winfree, S. Kiss, W. J. Mack, R. A. McTaggart, T. F. Choudhri, L. J Kim, J Mocco, D. J. Pinsky, et al. Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke PNAS, September 25, 2001; 98(20): 11720 - 11724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uchino, D. Billheimer, and S. C. Cramer Entry Criteria and Baseline Characteristics Predict Outcome in Acute Stroke Trials Stroke, April 1, 2001; 32(4): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Lees, A. K. Sharma, D. Barer, G. A. Ford, V. Kostulas, Y.-F. Cheng, and T. Odergren Tolerability and Pharmacokinetics of the Nitrone NXY-059 in Patients With Acute Stroke Stroke, March 1, 2001; 32(3): 675 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Horn, R. J. de Haan, M. Vermeulen, and M. Limburg Very Early Nimodipine Use in Stroke (VENUS) : A Randomized, Double-Blind, Placebo-Controlled Trial Stroke, February 1, 2001; 32(2): 461 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Lees, A. G. Dyker, A. Sharma, G. A. Ford, M. E. Ardron, and D. G. Grosset Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients : A Dose-Ranging Study Stroke, February 1, 2001; 32(2): 466 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Huang, J. Mocco, T. F. Choudhri, A. Poisik, S. J. Popilskis, R. Emerson, R. L. DelaPaz, A. G. Khandji, D. J. Pinsky, E. S. Connolly Jr, et al. A Modified Transorbital Baboon Model of Reperfused Stroke Editorial Comment Stroke, December 1, 2000; 31(12): 3054 - 3063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Diener, M. Cortens, G. Ford, J. Grotta, W. Hacke, M. Kaste, P. J. Koudstaal, and T. Wessel Lubeluzole in Acute Ischemic Stroke Treatment : A Double-Blind Study With an 8-Hour Inclusion Window Comparing a 10-mg Daily Dose of Lubeluzole With Placebo Stroke, November 1, 2000; 31(11): 2543 - 2551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. N. Thijs, M. G. Lansberg, C. Beaulieu, M. P. Marks, M. E. Moseley, and G. W. Albers Is Early Ischemic Lesion Volume on Diffusion-Weighted Imaging an Independent Predictor of Stroke Outcome? : A Multivariable Analysis Stroke, November 1, 2000; 31(11): 2597 - 2602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Tirilazad Mesylate in Acute Ischemic Stroke : A Systematic Review Stroke, September 1, 2000; 31(9): 2257 - 2265. [Abstract] [Full Text] [PDF]
|
|