Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial

2.50
Hdl Handle:
http://hdl.handle.net/2336/53793
Title:
Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial
Authors:
Hakonarson, Hakon; Thorvaldsson, Sverrir; Helgadottir, Anna; Gudbjartsson, Daniel; Zink, Florian; Andresdottir, Margret; Manolescu, Andrei; Arnar, David O; Andersen, Karl; Sigurdsson, Axel; Thorgeirsson, Gestur; Jonsson, Asgeir; Agnarsson, Uggi; Bjornsdottir, Halldora; Gottskalksson, Gizur; Einarsson, Atli; Gudmundsdottir, Hrefna; Adalsteinsdottir, Asdis E; Gudmundsson, Kolbeinn; Kristjansson, Kristleifur; Hardarson, Thordur; Kristinsson, Arni; Topol, Eric J; Gulcher, Jeffrey; Kong, Augustine; Gurney, Mark; Thorgeirsson, Gudmundur; Stefansson, Kari
Citation:
JAMA. 2005, 293(18):2245-56
Issue Date:
11-May-2005
Abstract:
CONTEXT: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES: Changes in levels of biomarkers associated with risk of MI. RESULTS: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://jama.ama-assn.org/cgi/content/abstract/293/18/2245

Full metadata record

DC FieldValue Language
dc.contributor.authorHakonarson, Hakon-
dc.contributor.authorThorvaldsson, Sverrir-
dc.contributor.authorHelgadottir, Anna-
dc.contributor.authorGudbjartsson, Daniel-
dc.contributor.authorZink, Florian-
dc.contributor.authorAndresdottir, Margret-
dc.contributor.authorManolescu, Andrei-
dc.contributor.authorArnar, David O-
dc.contributor.authorAndersen, Karl-
dc.contributor.authorSigurdsson, Axel-
dc.contributor.authorThorgeirsson, Gestur-
dc.contributor.authorJonsson, Asgeir-
dc.contributor.authorAgnarsson, Uggi-
dc.contributor.authorBjornsdottir, Halldora-
dc.contributor.authorGottskalksson, Gizur-
dc.contributor.authorEinarsson, Atli-
dc.contributor.authorGudmundsdottir, Hrefna-
dc.contributor.authorAdalsteinsdottir, Asdis E-
dc.contributor.authorGudmundsson, Kolbeinn-
dc.contributor.authorKristjansson, Kristleifur-
dc.contributor.authorHardarson, Thordur-
dc.contributor.authorKristinsson, Arni-
dc.contributor.authorTopol, Eric J-
dc.contributor.authorGulcher, Jeffrey-
dc.contributor.authorKong, Augustine-
dc.contributor.authorGurney, Mark-
dc.contributor.authorThorgeirsson, Gudmundur-
dc.contributor.authorStefansson, Kari-
dc.date.accessioned2009-03-10T13:21:42Z-
dc.date.available2009-03-10T13:21:42Z-
dc.date.issued2005-05-11-
dc.date.submitted2009-03-10-
dc.identifier.citationJAMA. 2005, 293(18):2245-56en
dc.identifier.issn1538-3598-
dc.identifier.pmid15886380-
dc.identifier.doi10.1001/jama.293.18.2245-
dc.identifier.urihttp://hdl.handle.net/2336/53793-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractCONTEXT: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES: Changes in levels of biomarkers associated with risk of MI. RESULTS: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.en
dc.language.isoenen
dc.publisherAmerican Medical Associationen
dc.relation.urlhttp://jama.ama-assn.org/cgi/content/abstract/293/18/2245en
dc.subject.meshAgeden
dc.subject.meshBiological Markersen
dc.subject.meshCarrier Proteinsen
dc.subject.meshCoronary Artery Diseaseen
dc.subject.meshCross-Over Studiesen
dc.subject.meshEpoxide Hydrolasesen
dc.subject.meshFemaleen
dc.subject.meshHumansen
dc.subject.meshLeukotriene B4en
dc.subject.meshLeukotriene E4en
dc.subject.meshLipoxygenase Inhibitorsen
dc.subject.meshMaleen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiddle Ageden
dc.subject.meshMyocardial Infarctionen
dc.subject.meshPeroxidaseen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshProspective Studiesen
dc.subject.meshQuinolinesen
dc.subject.meshRisk Factorsen
dc.titleEffects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trialen
dc.typeArticleen
dc.contributor.departmentDecode Genetics Inc, Reykjavik, Iceland. hakonh@decode.isen
dc.identifier.journalJAMA : the journal of the American Medical Associationen

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