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. Abstract: To determine the effect of an inhibitor of ...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. Abstract: 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.展开更多
文摘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. Abstract: 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.
