title: Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats.
abstract: Recombinant tissue plasminogen activator (r-tPA) is the only FDA-approved drug treatment for ischemic stroke and must be used within 4.5h. Thrombolytic treatment with r-tPA has deleterious effects on the neurovascular unit that substantially increases the risk of intracerebral hemorrhage if administered too late. These therapeutic shortcomings necessitate additional investigation into agents that can extend the therapeutic window for safe use of thrombolytics. In this study, combination of r-tPA and APT102, a novel form of human apyrase/ADPase, was investigated in a clinically-relevant aged-female rat embolic ischemic stroke model. We propose that successfully extending the therapeutic window of r-tPA administration would represent a significant advance in the treatment of ischemic stroke due to a significant increase in the number of patients eligible for treatment. Results of our study showed significantly reduced mortality from 47% with r-tPA alone to 16% with co-administration of APT102 and r-tPA. Co-administration decreased cortical (47 ± 5% vs. 29 ± 5%), striatal (50 ± 2%, vs. 40 ± 3%) and total (48 ± 3%vs. 33 ± 4%) hemispheric infarct volume compared to r-tPA alone. APT102 improved neurological outcome (8.9±0.6, vs. 6.8 ± 0.8) and decreased hemoglobin extravasation in cortical tissue (1.9 ± 0.1mg/dl vs. 1.4 ± 0.1mg/dl) striatal tissue (2.1 ± 0.3mg/dl vs. 1.4 ± 0.1mg/dl) and whole brain tissue (2.0 ± 0.2mg/dl vs. 1.4 ± 0.1mg/dl). These data suggest that APT102 can safely extend the therapeutic window for r-tPA mediated reperfusion to 6h following experimental stroke without increased hemorrhagic transformation. APT102 offers to be a viable adjunct therapeutic option to increase the number of clinical patients eligible for thrombolytic treatment after ischemic stroke.
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA.
authors.forename: Xinlan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26505, USA.
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Lucke-Wold
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26505, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: DiPasquale
authors.affiliation: APT Therapeutics Inc, St. Louis, MO 63108, USA.
authors.forename: Soon Soeg
authors.initials: SS
authors.lastname: Jeong
authors.affiliation: APT Therapeutics Inc, St. Louis, MO 63108, USA.
authors.forename: Ridong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26505, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA. Electronic address: crosen@hsc.wvu.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001081:Apyrase / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000150:complications / Q000517:prevention & control; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000517:prevention & control*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D001081:Apyrase
keywords: APT102/apyrase; Acute ischemic stroke; Hemorrhagic transformation; Infarction size; Recombinant tissue plasminogen activator