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dc.contributor.advisorMacleod, Malcolm
dc.contributor.advisorHowells, David
dc.contributor.authorSena, Emily Shamiso
dc.date.accessioned2011-02-15T10:37:35Z
dc.date.available2011-02-15T10:37:35Z
dc.date.issued2010
dc.identifier.urihttp://hdl.handle.net/1842/4824
dc.description.abstractIschaemic stroke is responsible for substantial death and disability and creates a huge financial burden for healthcare budgets worldwide. At present there are few effective treatments for acute stroke and these are urgently required. Increased understanding of the ischaemic cascade has generated interest in neuroprotection for focal cerebral ischaemia. However, treatment effects observed in of over 500 interventions in animal models have yet to be translated to the clinic. Systematic review and meta-analysis allows unbiased identification of all relevant data for a given intervention, gives a clearer view of its true efficacy and the limitations to its therapeutic potential. Understanding the reasons for this bench-to-bedside failure and providing quantitative explanations may help to address these discrepancies. Random effects weighted mean difference meta-analysis of six interventions (tirilazad, tPA, NXY-059, Hypothermia, Piracetam and IL1-RA) reported study quality to be consistently low. In some instances, potential sources of bias were associated with overestimations of efficacy. Likewise, clinical trials have tested interventions in conditions where efficacy was not observed in animals. Cumulative meta-analysis suggests that for tPA the estimate of efficacy is stable after the inclusion of data from 1500 animals; hypothermia and FK506 are the only other interventions to have been tested in at least 1500 animals. Meta-regression suggests biological rather methodical factors are better predictors of outcome; a major limitation of these data is the impact of publication bias, and this work suggests effect sizes from met-analyses are inflated by about 31% because 16% of studies remain unpublished. The systematic review and meta-analysis of hypothermia was used to plan experiments investigating the possible impact of pethidine, a drug used to prevent shivering. This in vivo experiment, in which potential sources of bias were minimised, suggests that pethidine does not influence the observed efficacy of hypothermia in an animal model of ischaemic stroke. This thesis reports that animal studies of ischaemic stroke are often not conducted with sufficient rigour. Both minimising potential sources of bias in individual experiments and using meta-analysis to summarise data from a number of experiments may be helpful in improving the translation of neuroprotective efficacy in ischaemic stroke.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionHowells DW, Porritt MJ, Rewell SS, O'Collins V, Sena ES, van der Worp HB, Traystman RJ, Macleod MR. (2010) Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. Journal of Cerebral Blood Flow & Metabolism 30(8):1412-31.en
dc.relation.hasversionvan der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O'Collins V, Macleod MR. (2010) Can animal models of disease reliably inform human studies? PLoS Medicine 30; 7(3):e1000245.en
dc.relation.hasversionSena ES, van der Worp HB, Bath PMW, Howells DW, Macleod MR. (2010) Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biology 8 (3): e1000245en
dc.relation.hasversionJerndal M, Forsberg K, Sena ES, Macleod MR, O’Collins VE, Linden T, Nilsson M, Howells DW. (2009) Systematic review and meta-analysis of erythropoietin in experimental stroke. Journal of Cerebral Blood Flow & Metabolism 18(4):269-276.en
dc.relation.hasversionBanwell V*, Sena ES*, Macleod MR. (2009) Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. Journal of Stroke and Cerebrovascular Diseases 8(4):269-76. (*joint first author)en
dc.relation.hasversionMacleod MR, Fisher M, O'Collins V, Sena ES, Dirnagl U, Bath PM, Buchan A, van der Worp HB, Traystman R, Minematsu K, Donnan GA, Howells DW (2009), Good Laboratory Practice. Preventing Introduction of Bias at the Bench. Stroke 40(3):e50-2. Reprinted in: Journal of Cerebral Blood Flow & Metabolism 29(2):221-3 International Journal of Stroke 4(1):3-5.en
dc.relation.hasversionMacleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA (2008) Evidence for the Efficacy of NXY-059 in Experimental Focal Cerebral Ischaemia Is Confounded by Study Quality. Stroke 39(10):2824-9.en
dc.relation.hasversionCrossley NA, Sena E, Goehler J, Horn J, van der Worp B, Bath PM, Macleod M, Dirnagl U (2008) Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke 39(3):929-34.en
dc.relation.hasversionWheble PC, Sena ES, Macleod MR (2008) A systematic review and meta-analysis of the efficacy of piracetam and piracetam-like compounds in experimental stroke. Journal of Cerebrovascular Diseases 25(1-2):5-11.en
dc.relation.hasversionSena E, van der Worp HB, Howells D, Macleod M (2007) How can we improve the preclinical development of drugs for stroke? Trends in Neuroscience 30(9):433-9.en
dc.relation.hasversionvan der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR (2007) Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 130(Pt 12):3063-74.en
dc.relation.hasversionSena E, Wheble P, Sandercock P, Macleod M (2007) Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke 38(2):388-94.en
dc.relation.hasversionPerel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS (2007) Comparison of treatment effects between animal experiments and clinical trials: systematic review. British Medical Journal 27; 334(7586):197.en
dc.subjectmeta-analysisen
dc.subjectstrokeen
dc.subjectanimal modelsen
dc.titleSystematic review and meta-analysis of animal models of acute ischaemic strokeen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dcterms.accessRightsRestricted Access


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