Document Detail


Neuroprotection for ischemic stroke: past, present and future.
MedLine Citation:
PMID:  18308347     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safety-feasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6h therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials. This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized.
Authors:
Myron D Ginsberg
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Publication Detail:
Type:  Journal Article; Review     Date:  2008-03-04
Journal Detail:
Title:  Neuropharmacology     Volume:  55     ISSN:  0028-3908     ISO Abbreviation:  Neuropharmacology     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-15     Completed Date:  2008-10-23     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  363-89     Citation Subset:  IM    
Affiliation:
Department of Neurology (D4-5), University of Miami Miller School of Medicine, Miami, FL 33101, USA. mginsberg@med.miami.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain Ischemia / complications,  drug therapy*,  therapy*
Clinical Trials as Topic
Excitatory Amino Acid Antagonists / therapeutic use
Fibrinolytic Agents / therapeutic use
Humans
Hypothermia, Induced
Magnesium / therapeutic use
Neuroprotective Agents / therapeutic use*
Stroke / drug therapy*,  etiology,  therapy*
Grant Support
ID/Acronym/Agency:
R01 NS040406-03/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Excitatory Amino Acid Antagonists; 0/Fibrinolytic Agents; 0/Neuroprotective Agents; 7439-95-4/Magnesium
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