Emmanuel Touzé1,2, Denis Vivien1, Cyrille Orset1,3, Benoit Haelewyn3, Stuart M Allan4, Saema Ansar5,6, Francesco Campos7,8, Tae Hee Cho1,9, Anne Durand9, Mohamad El Amki10, Marc Fatar11, Isaac Garcia-Yébenes12, Maxime Gauberti1, Saskia Grudzenski11, Ignacio Lizasoain12, Eng Lo13, Richard Macrez1, Isabelle Margaill10, Samaneh Maysami4, Stephen Meairs5, Norbert Nighoghossian9, Josune Orbe1,1, Jose Antonio Paramo14, Jean-Jacques Parienti15, Nancy J Rothwell4, Marina Rubio1, Christian Waeber7,16, Alan R Young1. 1. Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France. 2. Department of Neurology, CHU Côte de Nacre, Caen. 3. Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France. 4. University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom. 5. Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 6. Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden. 7. Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 8. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. 9. Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France. 10. EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. 11. Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany. 12. Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. 13. Departments of Radiology, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA. 14. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Pamplona, Spain. 15. Departments of Biostatistics and Clinical Research, Centre Hospitalier Universitaire (CHU), Caen ; EA4655 Risques Microbiens, Université de Caen Normandie, Caen, France. 16. School of Pharmacy and Dept. of Pharmacology/Therapeutics, University College Cork, Ireland.
Abstract
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 data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with 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 (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. RESULTS: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. CONCLUSIONS: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.
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 data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with 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 (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. RESULTS: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. CONCLUSIONS: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.
Authors: George W J Harston; Brad A Sutherland; James Kennedy; Alastair M Buchan Journal: J Cereb Blood Flow Metab Date: 2010-08-25 Impact factor: 6.200
Authors: Victoria E O'Collins; Malcolm R Macleod; Geoffrey A Donnan; Laura L Horky; Bart H van der Worp; David W Howells Journal: Ann Neurol Date: 2006-03 Impact factor: 10.422
Authors: Matthias Endres; Britta Engelhardt; Jari Koistinaho; Olle Lindvall; Stephen Meairs; Jay P Mohr; Anna Planas; Nancy Rothwell; Markus Schwaninger; Martin E Schwab; Denis Vivien; Tadeusz Wieloch; Ulrich Dirnagl Journal: Cerebrovasc Dis Date: 2008-02-22 Impact factor: 2.762
Authors: Cyrille Orset; Richard Macrez; Alan R Young; Didier Panthou; Eduardo Angles-Cano; Eric Maubert; Veronique Agin; Denis Vivien Journal: Stroke Date: 2007-08-16 Impact factor: 7.914
Authors: H M Vesterinen; E S Sena; K J Egan; T C Hirst; L Churolov; G L Currie; A Antonic; D W Howells; M R Macleod Journal: J Neurosci Methods Date: 2013-10-04 Impact factor: 2.390
Authors: Manuel Navarro-Oviedo; Carmen Roncal; Agustina Salicio; Miriam Belzunce; Obdulia Rabal; Estefanía Toledo; Beatriz Zandio; Jose A Rodríguez; Jose A Páramo; Roberto Muñoz; Josune Orbe Journal: Transl Stroke Res Date: 2018-07-27 Impact factor: 6.829
Authors: Jack W Scannell; James Bosley; John A Hickman; Gerard R Dawson; Hubert Truebel; Guilherme S Ferreira; Duncan Richards; J Mark Treherne Journal: Nat Rev Drug Discov Date: 2022-10-04 Impact factor: 112.288
Authors: Hiramani Dhungana; Mikko T Huuskonen; Taina Pihlajaniemi; Ritva Heljasvaara; Denis Vivien; Katja M Kanninen; Tarja Malm; Jari Koistinaho; Sighild Lemarchant Journal: Cell Death Dis Date: 2017-01-12 Impact factor: 8.469
Authors: Dmitri Nikitin; Seungbum Choi; Jan Mican; Martin Toul; Wi-Sun Ryu; Jiri Damborsky; Robert Mikulik; Dong-Eog Kim Journal: J Stroke Date: 2021-01-31 Impact factor: 6.967