ABSTRACT
This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin.
Subject(s)
6-Ketoprostaglandin F1 alpha/analogs & derivatives , Acetaminophen/administration & dosage , Cyclooxygenase 2 Inhibitors/administration & dosage , Indomethacin/administration & dosage , Thromboxane B2/analogs & derivatives , 6-Ketoprostaglandin F1 alpha/urine , Acetaminophen/adverse effects , Administration, Oral , Adult , Biomarkers/urine , Cross-Over Studies , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/adverse effects , Double-Blind Method , Drug Administration Schedule , Female , Healthy Volunteers , Humans , Indomethacin/adverse effects , Male , Philadelphia , Prospective Studies , Renal Elimination/drug effects , Thromboxane B2/urine , Young AdultABSTRACT
OBJECTIVE: Patients with metabolic syndrome are at increased risk of atherosclerotic coronary heart disease, often have mixed dyslipidemia, and may thus require more aggressive treatment of multiple lipid parameters. The objective of this investigation was to compare the treatment response of ezetimibe co-administered with fenofibrate in mixed dyslipidemic patients with and without metabolic syndrome. METHODS: This post hoc analysis evaluated 625 patients 18-75 years of age with mixed dyslipidemia, defined as elevated low-density lipoprotein cholesterol (LDL-C) levels (130-220 mg/dL) and elevated triglycerides (TG) levels (200-500 mg/dL). Patients were randomized in a 1:3:3:3 ratio to 1 of 4 treatments for 12 weeks: Placebo; ezetimibe 10 mg; fenofibrate 160 mg; or ezetimibe 10 mg plus fenofibrate 160 mg. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III criteria and was identified at baseline in 450 patients. RESULTS: Ezetimibe alone, fenofibrate alone, or their combination produced expected, and generally similar, lipid effects among those with or without metabolic syndrome with respect to LDL-C, apolipoprotein B (ApoB), and non-high-density lipoprotein cholesterol (HDL-C) levels. Ezetimibe alone may have resulted in greater LDL-C and ApoB lowering in the metabolic syndrome group than the non-metabolic syndrome group (P ≤ 0.05 for both). TG and high-sensitivity C-reactive protein had greater reductions in the fenofibrate and fenofibrate plus ezetimibe groups than the ezetimibe alone group (P ≤ 0.05 for both) CONCLUSIONS: In this analysis of patients with mixed dyslipidemia, the lipid effects of ezetimibe plus fenofibrate were generally similar in metabolic syndrome patients versus those without metabolic syndrome.
Subject(s)
Azetidines/administration & dosage , Dyslipidemias/complications , Dyslipidemias/drug therapy , Fenofibrate/administration & dosage , Metabolic Syndrome/complications , Metabolic Syndrome/drug therapy , Adolescent , Adult , Aged , Anticholesteremic Agents/administration & dosage , Apolipoproteins B/metabolism , Cholesterol, LDL/metabolism , Ezetimibe , Female , Humans , Hypolipidemic Agents/administration & dosage , Lipids/chemistry , Male , Middle Aged , Triglycerides/metabolismABSTRACT
This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18-79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/simvastatin 10/20 mg/day + fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with more-pronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin + fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.