Translational Stroke Research Using a Rabbit Embolic Stroke Model: A Correlative Analysis Hypothesis for Novel Therapy D
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REVIEW ARTICLE
Translational Stroke Research Using a Rabbit Embolic Stroke Model: A Correlative Analysis Hypothesis for Novel Therapy Development Paul A. Lapchak
Received: 11 January 2010 / Revised: 28 January 2010 / Accepted: 11 March 2010 / Published online: 2 April 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract Alteplase (tissue plasminogen activator, tPA) is currently the only FDA-approved treatment that can be given to acute ischemic stroke (AIS) patients if patients present within 3 h of an ischemic stroke. After 14 years of alteplase clinical research, evidence now suggests that the therapeutic treatment window can be expanded 4.5 h, but this is not formally approved by the FDA. Even though there remains a significant risk of intracerebral hemorrhage associated with alteplase administration, there is an increased chance of favorable outcome with tPA treatment. Over the last 30 years, the use of preclinical models has assisted with the search for new effective treatments for stroke, but there has been difficulty with the translation of efficacy from animals to humans. Current research focuses on the development of new and potentially useful thrombolytics, neuroprotective agents, and devices which are also being tested for efficacy in preclinical and clinical trials. One model in particular, the rabbit small clot embolic stroke model (RSCEM) which was developed to test tPA for efficacy, remains the only preclinical model used to gain FDA approval of a therapeutic for stroke. Correlative analyses from existing preclinical translational studies and clinical trials indicate that there is a therapeutic window ratio (ARR) of 2.43-3 between the RSCEM and AIS patients. In conclusion, the RSCEM can be used as an effective translational tool to gauge the clinical potential of new treatments.
Introduction
Keywords Neuroprotection . Embolism . Acute ischemic stroke . Clinical . Behavior . Toxicity . Translational science . Antioxidant . Laser . Radicut . NXY-059 . Thrombolytic . Penumbra
1. Cardioembolic stroke in which the embolism arises from a cardiac source such as atrial fibrillation with intra-atrial thrombus, congestive heart failure, myocardial infarction, valve disease, and aneurysm surgery; 2. Atheroembolic stroke which can be associated with narrowing of a cervicocephalic artery (i.e., large artery to artery stroke) including the carotid, vertebral, basilar, middle cerebral, anterior cerebral, or posterior cerebral artery; and
P. A. Lapchak (*) Department of Neurology, Cedars-Sinai Medical Center, 8730 Alden Drive, Thalians E216, Los Angeles, CA 90048, USA e-mail: [email protected]
Stroke Incidence AIS is the third leading cause of death and the leading cause of adult disability in the USA [1] with an estimated cost of $68.9 billion. According to the current 2009 USA stroke statistics [2], each year, approximately 795,000 people suffer a stroke (one every 40 s with one mortality every 3 min), 75% of which are first strokes and the remainder recurren
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