Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial
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Authors
Hakonarson, HakonThorvaldsson, 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
Issue Date
2005-05-11
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JAMA. 2005, 293(18):2245-56Abstract
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
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http://jama.ama-assn.org/cgi/content/abstract/293/18/2245ae974a485f413a2113503eed53cd6c53
10.1001/jama.293.18.2245
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