HHS Public Access Author manuscript Author Manuscript
Stroke. Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Stroke. 2016 May ; 47(5): 1312–1318. doi:10.1161/STROKEAHA.116.012238.
Efficacy of Alteplase® in a mouse model of acute ischemic stroke: a retrospective pooled analysis
Author Manuscript
Cyrille Orset, PhD.1,2, Benoit Haelewyn, PhD.2, Stuart M. Allan, PhD.3,#, Saema Ansar, PhD. 4,12,#, Francesco Campos, PhD.5,13,#, Tae Hee Cho, MD.1,6,#, Anne Durand, MD.6,#, Mohamad El Amki, PhD.7,#, Marc Fatar, MD.8,#, Isaac Garcia-Yébenes, PhD.9,#, Maxime Gauberti, PhD.1,#, Saskia Grudzenski, PhD.8,#, Ignacio Lizasoain, MD.9,#, Eng Lo, MD.10,#, Richard Macrez, PhD.1,#, Isabelle Margaill, PhD.7,#, Samaneh Maysami, PhD.3,#, Stephen Meairs, MD.4,#, Norbert Nighoghossian, MD.6,#, Josune Orbe, PhD.1,#,1, Jose Antonio Paramo, MD.11,#, Jean-Jacques Parienti, PhD.14,#, Nancy J. Rothwell, PhD.3,#, Marina Rubio, PhD.1,#, Christian Waeber, PhD.5,15,#, Alan R. Young, PhD.1,#, Emmanuel Touzé, PhD.#1,16, and Denis Vivien, PhD.#1 1
Author Manuscript Author Manuscript
Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France. 2 Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France. 3 University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom. 4 Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 5 Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 6 Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France. 7 EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. 8 Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany. 9 Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. 10 Departments of Radiology, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA. 11 Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Pamplona, Spain. 12 Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden 13 Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 14 Departments of Biostatistics and Clinical Research, Centre Hospitalier Universitaire (CHU), Caen ; EA4655 Risques Microbiens, Université de Caen Normandie, Caen, France 15 School of Pharmacy and Dept. of Pharmacology/Therapeutics, University College Cork, Ireland. 16 Department of Neurology, CHU Côte de Nacre, Caen. #
These authors contributed equally to this work.
Correspondence to: D. VIVIEN, Bvd Henri Becquerel, GIP Cyceron, 14074 CAEN, France; phone (+33.2.31.47.01.66), fax (+33.2.31.47.02.22) or ([email protected]).. #Alphabetical order Disclosures The authors declare no competing financial interests.
Orset et al.
Page 2
Abstract Author Manuscript
Background and purpose—The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods—We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (
Stroke. Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Stroke. 2016 May ; 47(5): 1312–1318. doi:10.1161/STROKEAHA.116.012238.
Efficacy of Alteplase® in a mouse model of acute ischemic stroke: a retrospective pooled analysis
Author Manuscript
Cyrille Orset, PhD.1,2, Benoit Haelewyn, PhD.2, Stuart M. Allan, PhD.3,#, Saema Ansar, PhD. 4,12,#, Francesco Campos, PhD.5,13,#, Tae Hee Cho, MD.1,6,#, Anne Durand, MD.6,#, Mohamad El Amki, PhD.7,#, Marc Fatar, MD.8,#, Isaac Garcia-Yébenes, PhD.9,#, Maxime Gauberti, PhD.1,#, Saskia Grudzenski, PhD.8,#, Ignacio Lizasoain, MD.9,#, Eng Lo, MD.10,#, Richard Macrez, PhD.1,#, Isabelle Margaill, PhD.7,#, Samaneh Maysami, PhD.3,#, Stephen Meairs, MD.4,#, Norbert Nighoghossian, MD.6,#, Josune Orbe, PhD.1,#,1, Jose Antonio Paramo, MD.11,#, Jean-Jacques Parienti, PhD.14,#, Nancy J. Rothwell, PhD.3,#, Marina Rubio, PhD.1,#, Christian Waeber, PhD.5,15,#, Alan R. Young, PhD.1,#, Emmanuel Touzé, PhD.#1,16, and Denis Vivien, PhD.#1 1
Author Manuscript Author Manuscript
Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France. 2 Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France. 3 University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom. 4 Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 5 Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 6 Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France. 7 EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. 8 Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany. 9 Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. 10 Departments of Radiology, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA. 11 Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Pamplona, Spain. 12 Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden 13 Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 14 Departments of Biostatistics and Clinical Research, Centre Hospitalier Universitaire (CHU), Caen ; EA4655 Risques Microbiens, Université de Caen Normandie, Caen, France 15 School of Pharmacy and Dept. of Pharmacology/Therapeutics, University College Cork, Ireland. 16 Department of Neurology, CHU Côte de Nacre, Caen. #
These authors contributed equally to this work.
Correspondence to: D. VIVIEN, Bvd Henri Becquerel, GIP Cyceron, 14074 CAEN, France; phone (+33.2.31.47.01.66), fax (+33.2.31.47.02.22) or ([email protected]).. #Alphabetical order Disclosures The authors declare no competing financial interests.
Orset et al.
Page 2
Abstract Author Manuscript
Background and purpose—The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods—We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (
