available. It is known that combining lipid lowering agents with different modes of action may enhance the lipid altering effect, but the impact of the combined treatment effects on the major cholesterol balance mechanisms is only poorly understood.In addition to newer medications meant to treat hypercholesterolemia, there have been major improvements in the development of methods of measuring cholesterol balance. The use of nonradiolabeled isotope enrichment of tracer cholesterol and the nonabsorbed marker sitostanol and multiple selective ion monitoring gas chromatographymass spectroscopy (GC-MS) have made it possible to make repeated treatments within a study, whereas, previously, the number of treatments and measurements was limited by exposure to radiation and/or the ability to detect the isotopes. Numerous studies of cholesterol absorption have demonstrated that there are wide interindividual variations in the fraction of cholesterol absorbed with a range of about 15-70% in normal healthy individuals ( 1-5 ).This study investigated the infl uence of simvastatin and ezetimibe and the combination of simvastatin and ezetimibe on cholesterol balance by assessing fractional cholesterol absorption from the gastrointestinal tract by measuring the absorption of isotopic cholesterol compared with the nonabsorbed marker sitostanol ( 6 ) as well as cholesterol synthesis by mass balance ( 7 ).Simvastatin and ezetimibe are approved cholesterol lowering medications that are prescribed individually or together in patients in need of plasma cholesterol reduction. Simvastatin has been previously characterized as an inhibitor of HMG-CoA reductase and as an LDL receptor enhancer ( 8 ), and ezetimibe, an inhibitor of cholesterol absorption from the gastrointestinal tract, has been characterized as an inhibitor of the Niemann-Pick C1-Like 1 Abstract This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively ( P < 0.001 for both relative to placebo). Simvastatin did not signifi cantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively ( P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated.The decreases in net cholesterol synthesis and increased fecal sterol e...

Menadione-6,7was prepared from tetrasodium 2-methyl-l,4-naphthoquinol-6,7-3H diphosphate with specific activities to 44 Ci/mmole. Distribution of radioactivity in rats 18 hr after administration of a physiological dose (10 /¿g) of the tritiated vitamin to deficient rats showed low levels in liver, heart, kidney, carcass, and viscera while 78-83% of the administered tritium was recovered in the urine during this period. The lipophilic metabolite of menadione, menaquinone-4, ./X. study of vitamin K under conditions which relate physiological response to the vitamin with its metabolic fate has been undertaken as an approach to elucidating the function of this fat-soluble vitamin. A metabolic study under these conditions requires labeled vitamin with a specific activity higher than previously attained. The work of Andrews et al. (1962) resulted in highly radioactive vitamin K in the form of tetrasodium 2methyl-1,4-naphthoquinol-6,7-3H diphosphate.* 1 Although originally used as a cancer chemotherapeutic, this compound is easily converted to menadione-6,7-3H with specific activities much higher than the labeled preparations presently available (Lee et al., 1953;

No abstract

Metabolic syndrome (MetS) is a clustering of atherosclerotic coronary heart disease risk factors. This post-hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg in a cohort of 618 high-risk hypercholesterolaemic patients with (n=368) and without (n=217) MetS who had previously been on statin monotherapy. Patients were randomised 1:1 to double-blind ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg for 6 weeks. Least squares mean percent change from baseline and 95% confidence intervals in lipid efficacy parameters were calculated for the population and within subgroups. Treatment with ezetimibe/simvastatin was significantly more effective than rosuvastatin at lowering low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (all p<0.001). No significant differences in treatment effects were seen between the presence and absence of MetS. In this post-hoc analysis of high-risk hypercholesterolaemic patients the lipid-reducing effects of ezetimibe/simvastatin or rosuvastatin were not altered significantly by the presence of MetS.

No abstract