leukotriene-b4 and Coronary-Artery-Disease

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.. To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.. 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.. 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.. Changes in levels of biomarkers associated with risk of MI.. 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.. 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.

Topics: 5-Lipoxygenase-Activating Proteins; Aged; Biomarkers; Carrier Proteins; Coronary Artery Disease; Cross-Over Studies; Epoxide Hydrolases; Female; Humans; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Peroxidase; Polymorphism, Single Nucleotide; Prospective Studies; Quinolines; Risk Factors

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

Topics: 5-Lipoxygenase-Activating Protein Inhibitors; Animals; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Coronary Artery Disease; Dogs; Drug Discovery; Female; Humans; Leukotriene B4; Male; Molecular Structure; Pyrazoles; Rats, Sprague-Dawley; Structure-Activity Relationship

5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC

Topics: 5-Lipoxygenase-Activating Protein Inhibitors; Animals; Caco-2 Cells; Coronary Artery Disease; Cyclohexanes; Dogs; Female; Humans; Leukotriene B4; Male; Molecular Structure; Pyrazoles; Rats, Sprague-Dawley; Structure-Activity Relationship

The systemic inflammatory activity in patients with stable coronary artery disease (CAD) is associated with a dysregulated cortisol response. Moreover, an aberrant activation status of neutrophils in CAD has been discussed; and the question of glucocorticoid resistance has been raised. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1). We investigated the expression of glucocorticoid receptors (GR) and ANXA1, as well as the exogenous effects of ANXA1 on neutrophils in CAD patients and related the data to diurnal salivary cortisol. Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in a neutrophil stimulation assay. The patients showed a flattened diurnal cortisol pattern compared with healthy subjects, involving higher levels in the evening. The neutrophil expression of GR-total and GR-alpha was decreased, whereas the GR-beta expression did not differ compared with controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 impaired the leukotriene B(4)-induced neutrophil production of reactive oxygen species in patients but not in controls. Our findings indicate a persistent overactivation of the hypothalamic-pituitary-adrenal axis in CAD patients but do not give any evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The altered neutrophil phenotype in CAD may thus represent a long-term response to disease-related activation.

Topics: Aged; Angiography; Annexin A1; CD18 Antigens; Circadian Rhythm; Coronary Artery Disease; Female; Flow Cytometry; Glucocorticoids; Humans; Hydrocortisone; Leukotriene B4; Male; Middle Aged; Neutrophils; Phenotype; Reactive Oxygen Species; Receptors, Formyl Peptide; Receptors, Glucocorticoid; Receptors, Lipoxin; Saliva

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Coronary Artery Disease; Eicosapentaenoic Acid; Hemostasis; Humans; Immune System; Inflammation; Leukotriene B4; Lipids; Models, Biological; Models, Theoretical

This study compared the effect of a nitric oxide donor on limiting the size of infarct resulting from myocardial ischemia-reperfusion between atherosclerotic and nonatherosclerotic models.. Endothelial-derived relaxation in coronary arteries affected by ischemia is substantially impaired after reperfusion, and this impairment may exacerbate the myocardial ischemia-reperfusion injury. In animals with experimental atherosclerosis, release of endothelial-derived relaxing factor is also decreased, and the propagation of myocardial infarction could be exacerbated.. We examined the extent of myocardial injury induced by ischemia (30 min) and reperfusion (48 hr) in rabbits fed a cholesterol-rich (1%) or normal diet for 10 weeks. We also evaluated the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP], a nitric oxide precursor (L-arginine) or a degradation product of SNAP (N-acetylpenicillamine) on infarct size in these models.. Severity of myocardial injury was significantly exacerbated in cholesterol-fed rabbits (75.2 +/- 4.4% [mean +/- SEM]) compared with that in non-cholesterol-fed rabbits (53.2 +/- 5.2%). This exacerbation was prevented by treatment with SNAP (50.2 +/- 6.4%) but not with L-arginine (70.5 +/- 6.0%) or N-acetylpenicillamine (70.4 +/- 4.8%) in cholesterol-fed-rabbits. However, SNAP did not limit infarct size in non-cholesterol-fed rabbits (60.8 +/- 4.2%). The rate-pressure product was similar during the course of the experiment in all the groups.. Myocardial damage induced by ischemia-reperfusion was significantly exacerbated in rabbits fed a long-term cholesterol-rich diet but was effectively reversed by treatment with a nitric oxide donor. However, this agent did not limit infarct size in normal rabbits. Thus, a nitric oxide donor reduces myocardial infarct size in atherosclerotic but not in nonatherosclerotic rabbits.

Topics: Analysis of Variance; Animals; Cholesterol, Dietary; Coronary Artery Disease; Leukocytes; Leukotriene B4; Linear Models; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Penicillamine; Peroxidase; Rabbits; S-Nitroso-N-Acetylpenicillamine; Vasodilator Agents

The examination of 194 patients with coronary heart disease concurrent with clinical manifestations of angina pectoris established that the development of coronary atherosclerosis was accompanied by suppressed prostacyclin (PGI2) synthesis and increased thromboxane A2 (TxA2) leukotriene (LT) synthesis. The activation of synthesis of the vasoconstrictor and proaggregate TxA2 depended on the severity of clinical signs of angina pectoris. The imbalance of PGI2 to- TxA2 metabolite ratios was associated with dyslipidemias and the extent of coronary atherosclerosis. Bicycle ergometry testing resulted in prostanoid imbalance. The determination of the dynamics of prostanoids was used to check the efficiency of antianginal therapy. The concomitant application of inhibitors of thromboxane synthetase and LT synthesis was recommended for secondary prevention of thrombotic complications in patients with coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Coronary Artery Disease; Depression, Chemical; Drug Therapy, Combination; Humans; Leukotriene B4; Male; Middle Aged; Quercetin; Stimulation, Chemical; Thromboxane A2