Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Stroke

@article{Cramer2013SafetyPA,
  title={Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Stroke},
  author={Steven C. Cramer and Bams Abila and Nicola E Scott and Monica Simeoni and Lori A. Enney},
  journal={Stroke},
  year={2013},
  volume={44},
  pages={1337–1342}
}
Background and Purpose— Restorative therapies have the potential to improve function and reduce disability after stroke with a wide therapeutic window. The current study evaluated GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule myelin-associated glycoprotein and also protects oligodendrocytes. Methods— Patients with mild-moderate stroke were randomized to intravenous GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts of 8–9 subjects) versus… Expand
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References

SHOWING 1-10 OF 28 REFERENCES
First‐Time‐in‐Human Study With GSK249320, a Myelin‐Associated Glycoprotein Inhibitor, in Healthy Volunteers
TLDR
GSK249320, a monoclonal antibody directed against myelin‐associated glycoprotein (MAG), is being developed for the enhancement of recovery of function poststroke and was well tolerated at all doses, with AUC showing dose linearity. Expand
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
TLDR
As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; altePlase was more frequently associated with symptomatic intracranial hemorrhage. Expand
The Beta-hCG+Erythropoietin in Acute Stroke (BETAS) Study: A 3-Center, Single-Dose, Open-Label, Noncontrolled, Phase IIa Safety Trial
TLDR
Results support the safety of this sequential, 2-growth factor therapy initiated 24 to 48 hours after stroke onset, and in several instances, domain-specific end points provided greater insight into impairments as compared with global outcome measures. Expand
Identification of Neuroprotective Properties of Anti-MAG Antibody: A Novel Approach for the Treatment of Stroke?
  • E. Irving, M. Vinson, +9 authors A. A. Parsons
  • Medicine
  • Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2005
TLDR
The novel finding that an anti-MAG monoclonal antibody not only possesses the ability to neutralise the inhibitory effect of MAG on neurons but also directly protects oligodendrocytes from glutamate-mediated oxidative stress-induced cell death is reported here. Expand
Repairing the human brain after stroke. II. Restorative therapies
TLDR
Considerations for clinical trials of restorative therapies are provided, emphasizing both similarities and points of divergence with acute stroke clinical trial design. Expand
Targeting the Nogo-A Signalling Pathway to Promote Recovery Following Acute CNS Injury
TLDR
In vivo findings provide a sound basis for the development of an effective treatment for acute CNS injuries in humans and significantly enhance axonal regeneration and neuroplasticity leading to improved functional recovery in animal models of acute CNS injury. Expand
Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury.
TLDR
In vivo findings have been shown to significantly enhance axonal regeneration and neuroplasticity leading to improved functional recovery in animal models of acute CNS injury, providing a sound basis for the development of an effective treatment for acute CNS injuries in humans. Expand
Differences in psychometric properties, cut-off scores, and outcomes between the Barthel Index and Modified Rankin Scale in pharmacotherapy-based stroke trials: systematic literature review
  • S. Balu
  • Medicine
  • Current medical research and opinion
  • 2009
TLDR
Despite the lack of uniformity in the cut-off points used in the trials, the follow-up time after administration of therapy, and the amount of time within which treatment is initiated after onset of stroke symptoms, the MRS seems to be more sensitive and responsive as compared to the BI in measuring stroke disability. Expand
Experimental models for analysis of oligodendrocyte pathophysiology in stroke
  • K. Arai, E. Lo
  • Medicine
  • Experimental & Translational Stroke Medicine
  • 2009
TLDR
This mini-review aims at summarizing current knowledge on experimental systems for analyzing the role of white matter injury relevant to stroke by analyzing the molecular and cellular pathways underlying OLG/OPC damage and demyelination in cell, tissue and whole-animal platforms. Expand
The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents.
TLDR
It is proposed that the use of modality-specific outcome measures may be best suited as primary end points in clinical trials of stroke recovery-promoting agents and may result in a more selective labeling of strokes recovery treatments. Expand
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