title: Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders.
abstract: Stroke is a leading cause of morbidity and mortality. While tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for ischemic stroke, clinical use of tPA has been constrained to roughly 3% of eligible patients because of the danger of intracranial hemorrhage and a narrow 3 h time window for safe administration. Basic science studies indicate that tPA enhances excitotoxic neuronal cell death. In this review, the beneficial and deleterious effects of tPA in ischemic brain are discussed along with emphasis on development of new approaches toward treatment of patients with acute ischemic stroke. In particular, roles of tPA-induced signaling and a novel delivery system for tPA administration based on tPA coupling to carrier red blood cells will be considered as therapeutic modalities for increasing tPA benefit/risk ratio. The concept of the neurovascular unit will be discussed in the context of dynamic relationships between tPA-induced changes in cerebral hemodynamics and histopathologic outcome of CNS ischemia. Additionally, the role of age will be considered since thrombolytic therapy is being increasingly used in the pediatric population, but there are few basic science studies of CNS injury in pediatric animals.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. armsteaw@uphs.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Kumkum
authors.initials: K
authors.lastname: Ganguly
authors.forename: J W
authors.initials: JW
authors.lastname: Kiessling
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Chen
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Smith
authors.forename: Sherman C
authors.initials: SC
authors.lastname: Stein
authors.forename: Abd A R
authors.initials: AA
authors.lastname: Higazi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.forename: Sergei
authors.initials: S
authors.lastname: Zaitsev
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000367:Age Factors; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced; D016017:Odds Ratio; D015398:Signal Transduction / Q000187:drug effects*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
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