The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Toward Wisdom From Failure: Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions
Abstract
Background — Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored. Summary of Review — In part 1, we review key challenges and complexities in translational stroke research by focusing on the “disconnect” in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often been limited by inappropriately long time windows, insufficient statistical power, insensitive outcome measures, inclusion of protocol violators, failure to target specific stroke subtypes, and failure to target the ischemic penumbra. In part 2, we explore new concepts in ischemic pathophysiology that should encourage us also to think beyond the hyperacute phase of ischemia and consider the design of trials that use multiagent therapy and exploit the capacity of the brain for neuroplasticity and repair. Conclusions — By recognizing the strengths and limitations of animal models of stroke and the shortcomings of previous clinical trials, we hope to move translational research forward for the development of new therapies for the acute and subacute stages after stroke.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Tissue Plasminogen Activator for Acute Ischemic Stroke
(1995) · New England Journal of Medicine · doi:10.1056/nejm199512143332401 · Cited by 11,654
Nudo, R. J., Wise, B. M., SiFuentes, F., & Milliken, G. W. (1996) · Science · doi:10.1126/science.272.5269.1791 · Cited by 1,911
Capes, S. E., Hunt, D., Malmberg, K., Pathak, P., & Gerstein, H. C. (2001) · Stroke · doi:10.1161/hs1001.096194 · Cited by 1,824
Morshead, C. M., Reynolds, B. A., Craig, C. G., McBurney, M. W., Staines, W. A., Morassutti, D., Weiss, S., & van der Kooy, D. (1994) · Neuron · doi:10.1016/0896-6273(94)90046-9 · Cited by 1,403
The changing landscape of ischaemic brain injury mechanisms
Lee, J.-M., Zipfel, G. J., & Choi, D. W. (1999) · Nature · doi:10.1038/399a007 · Cited by 1,102
Development of a Stroke-Specific Quality of Life Scale
Williams, L. S., Weinberger, M., Harris, L. E., Clark, D. O., & Biller, J. (1999) · Stroke · doi:10.1161/01.str.30.7.1362 · Cited by 914
Burden of Disease—Implications for Future Research
Michaud, C. M. (2001) · JAMA · doi:10.1001/jama.285.5.535 · Cited by 594
Perfusion Thresholds in Human Cerebral Ischemia: Historical Perspective and Therapeutic Implications
Baron, J.-C. (2001) · Cerebrovascular Diseases · doi:10.1159/000049119 · Cited by 352
Hasbani, M. J., Schlief, M. L., Fisher, D. A., & Goldberg, M. P. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-07-02393.2001 · Cited by 208
Modulation of use‐dependent plasticity by d‐amphetamine
Bütefisch, C. M., Davis, B. C., Sawaki, L., Waldvogel, D., Classen, J., Kopylev, L., & Cohen, L. G. (2002) · Annals of Neurology · doi:10.1002/ana.10056 · Cited by 182
Cited by
Glutamate Receptor Ion Channels: Structure, Regulation, and Function
Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., & Dingledine, R. (2010) · Pharmacological Reviews · doi:10.1124/pr.109.002451 · Cited by 3,568
Can Animal Models of Disease Reliably Inform Human Studies?
van der Worp, H. B., Howells, D. W., Sena, E. S., Porritt, M. J., Rewell, S., O'Collins, V., & Macleod, M. R. (2010) · PLoS Medicine · doi:10.1371/journal.pmed.1000245 · Cited by 1,354
Chamorro, Á., Dirnagl, U., Urra, X., & Planas, A. M. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00114-9 · Cited by 1,198
Interleukin-1 and neuronal injury
Allan, S. M., Tyrrell, P. J., & Rothwell, N. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1664 · Cited by 992
Liu, Y., Wong, T. P., Aarts, M., Rooyakkers, A., Liu, L., Lai, T. W., Wu, D. C., Lu, J., Tymianski, M., Craig, A. M., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0116-07.2007 · Cited by 773
A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia
Borsello, T., Clarke, P. G. H., Hirt, L., Vercelli, A., Repici, M., Schorderet, D. F., Bogousslavsky, J., & Bonny, C. (2003) · Nature Medicine · doi:10.1038/nm911 · Cited by 658
Antioxidant Therapies for Traumatic Brain Injury
Hall, E. D., Vaishnav, R. A., & Mustafa, A. G. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2009.10.021 · Cited by 390
Abulafia, D. P., de Rivero Vaccari, J. P., Lozano, J. D., Lotocki, G., Keane, R. W., & Dietrich, W. D. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.143 · Cited by 322
Future of neuroprotection for acute stroke: In the aftermath of the SAINT trials
Savitz, S. I., & Fisher, M. (2007) · Annals of Neurology · doi:10.1002/ana.21127 · Cited by 267
Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy
Kimelberg, H. K. (2005) · Glia · doi:10.1002/glia.20174 · Cited by 257
Exciting, Radical, Suicidal: How Brain Cells Die After Stroke
Lo, E. H., Moskowitz, M. A., & Jacobs, T. P. (2005) · Stroke · doi:10.1161/01.str.0000153069.96296.fd · Cited by 246
Significance of brain tissue oxygenation and the arachidonic acid cascade in stroke
Rink, C., & Khanna, S. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3474 · Cited by 233
MicroRNAs as regulators of brain function and targets for treatment of epilepsy
Brennan, G. P., & Henshall, D. C. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0369-8 · Cited by 169
Pignataro, G., Scorziello, A., Di Renzo, G., & Annunziato, L. (2009) · The FEBS Journal · doi:10.1111/j.1742-4658.2008.06769.x · Cited by 100
Darsalia, V., Hua, S., Larsson, M., Mallard, C., Nathanson, D., Nyström, T., Sjöholm, Å., Johansson, M. E., & Patrone, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103114 · Cited by 92
Burns, T. C., Li, M. D., Mehta, S., Awad, A. J., & Morgan, A. A. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.03.021 · Cited by 79
Rewell, S. S. J., Churilov, L., Sidon, T. K., Aleksoska, E., Cox, S. F., Macleod, M. R., & Howells, D. W. (2017) · PLOS ONE · doi:10.1371/journal.pone.0171688 · Cited by 54
Warkentin, L. M., Auriat, A. M., Wowk, S., & Colbourne, F. (2010) · Brain Research · doi:10.1016/j.brainres.2009.10.058 · Cited by 50
Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins
Giuliani, D., Ottani, A., Mioni, C., Bazzani, C., Galantucci, M., Minutoli, L., Bitto, A., Zaffe, D., Botticelli, A. R., Squadrito, F., et al. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.05.025 · Cited by 44
Giuliani, D., Ottani, A., Neri, L., Zaffe, D., Grieco, P., Jochem, J., Cavallini, G. M., Catania, A., & Guarini, S. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.11.004 · Cited by 38
What the alcohol doctor ordered from the neuroscientist
Heilig, M., & Leggio, L. (2016) · Progress in Brain Research · doi:10.1016/bs.pbr.2015.07.023 · Cited by 25
Lim, S. H., Lee, J. S., Lee, J. I., Im, S., Ko, Y. J., & Kim, H. W. (2008) · Brain Research · doi:10.1016/j.brainres.2008.07.002 · Cited by 25
Modeling Risk Factors and Confounding Effects in Stroke
McColl, B., Howells, D., Rothwell, N., & Denes, A. (2010) · Neuromethods · doi:10.1007/978-1-60761-750-1_9 · Cited by 3
Metadata
- Authors
- Gladstone, D. J., Black, S. E., & Hakim, A. M.
- Venue
- Stroke
- Published
- 2002-08
- Volume
- 33
- Issue
- 8
- Pages
- 2123-2136
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W2123152434
- Cited by
- 635
- References
- 10
- Type
- journal article
- Language
- en
- Open access
- closed
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
