Minocycline is a safe and well-tolerated antibiotic with excellent blood-brain barrier penetration. Recent evidence demonstrates that minocycline is a promising neuroprotective agent and is effective in animal models of global and focal ischemia. Minocycline has anti-inflammatory and anti-apoptotic effects and also inhibits the matrix metalloproteinases. Moreover, minocycline is neuroprotective in a rodent model of temporary focal ischemia at serum concentrations that are likely to be achievable in humans. Minocycline is presently in clinical trial in Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This proposal is a phase Ib/lla clinical trial of minocycline in acute ischemic stroke. The central hypothesis is that minocycline will be safe and tolerable in acute ischemic stroke patients when administered in a dose, route, and time window associated with neuroprotection in animal models. We plan to test our central hypothesis and accomplish the overall objective of this application by performing a dose-finding study using an open label, non-randomized, dose escalation design with a novel statistical method for stroke trials, the modified continual reassessment method.
The specific aims are: 1.) Determine the maximally tolerated dose (MTD) of intravenous minocycline in patients with acute ischemic stroke. 2.) Determine the pharmacokinetics of minocycline in patients with ischemic stroke 3.) Determine the effect of different doses of minocycline on plasma MMP-9 activity 4.) Gather preliminary data of the effect of different doses of minocycline on functional outcome This proposal will generate data that is critical to the development of a later phase ll/lll study of minocycline in acute ischemic stroke. There is a desperate need for a safe and effective neuroprotective agent that could be given to a diverse group of stroke patients. Since it is a safe drug and may also have activity against intracerebral hemorrhage, minocycline has excellent potential to become a """"""""field drug"""""""", administered by ambulance crews and in rural hospitals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055728-03
Application #
7591163
Study Section
Special Emphasis Panel (ZNS1-SRB-G (06))
Program Officer
Janis, Scott
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$512,316
Indirect Cost
Name
Georgia Regents University
Department
Neurology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Switzer, Jeffrey A; Hess, David C; Ergul, Adviye et al. (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42:2633-5
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Hess, David C; Fagan, Susan C (2010) Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Pharmacotherapy 30:55S-61S

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