prostaglandin-d2 and Hypercholesterolemia

Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low).. After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks.. ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled.. The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.

Topics: Adult; Aged; Aged, 80 and over; Cholesterol, HDL; Cholesterol, LDL; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Prostaglandin D2; Treatment Outcome; Young Adult

Laropiprant, an antagonist of the PGD(2) receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD(2) has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B(2) (11-dTxB(2)), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB(2) levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB(2) levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Platelets; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Epoprostenol; Female; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Niacin; Platelet Activation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Thromboxane B2; Young Adult

Inflammation plays an integral role in the development of abdominal aortic aneurysms (AAAs), and the expression of cyclooxygenase (COX)-2 is increased in aneurysmal tissue compared with normal aorta. Nonsteroidal anti-inflammatory drugs, which inhibit the activity of COX-1 and COX-2, decrease AAA expansion in humans and animal models of the disease. In the current study, we investigated the effectiveness of selective inhibition of COX-1 or COX-2 in attenuating AAA formation.. Eight-week-old male apolipoprotein E-deficient mice were treated with selective inhibitors of COX-1 or COX-2, SC-560 (approximately 25 mg.kg(-1).day(-1)), or celecoxib (approximately 125 mg.kg(-1).day(-1)), respectively. COX inhibitors were administered 1 week before angiotensin II (Ang II; 1000 ng.kg(-1).min(-1)) or saline infusion and throughout the time course of the experiment. COX-1 inhibition had no effect on incidence (control: 90% [9:10] versus SC-560: 89% [8:9]) or severity of Ang II-induced AAA formation. In contrast, celecoxib decreased the incidence (control: 74% [22:30] versus celecoxib: 11% [2:19]; P<0.001) and severity (P=0.001) of AAA formation. Celecoxib also decreased the incidence and severity of AAAs in nonhyperlipidemic mice.. COX-2-derived prostanoids play a fundamental role in the development of Ang II-induced AAAs in both hyperlipidemic and nonhyperlipidemic mice.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Prostaglandin D2; Pyrazoles; Sulfonamides

1. A sensitive and specific negative ion chemical ionization mass spectrometric assay for the major urinary metabolite of PGD2 has been developed employing a chemically synthesized [18(0)4]-labelled internal standard. 2. The finding that increased urinary excretion of this metabolite occurs in a number of clinical situations suggests that the assay may prove to be a valuable tool to explore the role of PGD2 in the pathophysiology of human disease.

Topics: Asthma; Bronchoalveolar Lavage Fluid; Histamine; Humans; Hydroxyprostaglandin Dehydrogenases; Hypercholesterolemia; Indicator Dilution Techniques; Mass Spectrometry; Mastocytosis; Niacin; Prostaglandin D2; Prostaglandins D