Acute anti-inflammatory approaches to ischemic stroke.
In preparation for designing and undertaking trials of strategies that can modulate "innate inflammation" to improve outcomes of ischemic injury, consideration of approaches that have managed cellular inflammation in ischemic stroke are instructive. Robust experimental work has demonstrated the efficacy (and apparent safety) of targeting PMN leukocyte-endothelial cell interactions in the early moments following focal ischemia onset in model systems. Four clinical trial programs were undertaken to assess the safety and efficacy of inhibitors to PMN leukocyte interactions with the endothelial cell during ischemic stroke. Experiences in those clinical trial programs indicate specific limitations that halted progress in this line of investigation before an adequate hypothesis test could be achieved. Although innate inflammation is a central part of injury evolution following focal ischemia, great care in the translation from experimental studies to Phase I/II clinical safety assessments and to the design and conduct of Phase III trials is needed.
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA. grgdlzop@u.washington.edu
Gregory J
GJ
del Zoppo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D002545:Brain Ischemia / Q000276:immunology / Q000628:therapy*; D018821:CD18 Antigens / Q000187:drug effects; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000502:physiology; D020521:Stroke / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018821:CD18 Antigens; C474712:enlimomab; D018799:Intercellular Adhesion Molecule-1; C115464:rovelizumab