Ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg in high cardiovascular risk patients with primary hypercholesterolemia: a randomized, double-blind, active-controlled, multicenter study

<p>Abstract</p> <p>Background</p> <p>A considerable number of patients with severely elevated LDL-C do not achieve recommended treatment targets, despite treatment with statins. Adults at high cardiovascular risk with hypercholesterolemia and LDL-C ≥ 2.59 and ≤ 4.14 mmol/L (N = 250), pretreated with atorvastatin 20 mg were randomized to ezetimibe/simvastatin 10/40 mg or atorvastatin 40 mg for 6 weeks. The percent change in LDL-C and other lipids was assessed using a constrained longitudinal data analysis method with terms for treatment, time, time-by-treatment interaction, stratum, and time-by-stratum interaction. Percentage of subjects achieving LDL-C < 1.81 mmol/L, < 2.00 mmol/L, or < 2.59 mmol/L was assessed using a logistic regression model with terms for treatment and stratum. Tolerability was assessed.</p> <p>Results</p> <p>Switching to ezetimibe/simvastatin resulted in significantly greater changes in LDL-C (-26.81% vs.-11.81%), total cholesterol (-15.97% vs.-7.73%), non-HDL-C (-22.50% vs.-10.88%), Apo B (-17.23% vs.-9.53%), and Apo A-I (2.56% vs.-2.69%) vs. doubling the atorvastatin dose (all <it>p </it>≤ 0.002), but not HDL-C, triglycerides, or hs-CRP. Significantly more subjects achieved LDL-C < 1.81 mmol/L (29% vs. 5%), < 2.00 mmol/L (38% vs. 9%) or < 2.59 mmol/L (69% vs. 41%) after switching to ezetimibe/simvastatin vs. doubling the atorvastatin dose (all <it>p </it>< 0.001). The overall safety profile appeared generally comparable between treatment groups.</p> <p>Conclusions</p> <p>In high cardiovascular risk subjects with hypercholesterolemia already treated with atorvastatin 20 mg but not at LDL-C < 2.59 mmol/L, switching to combination ezetimibe/simvastatin 10/40 mg provided significantly greater LDL-C lowering and greater achievement of LDL-C targets compared with doubling the atorvastatin dose to 40 mg. Both treatments were generally well-tolerated.</p> <p>Trial registration</p> <p>Registered at clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00782184">NCT00782184</a></p

Application of Lie theory to optical resonators: The two dimensional master equation

The goal of this dissertation is the derivation of a differential equation that describes the evolution of an electromagnetic field in a stable cavity that has no axial symmetry (a toroidal system). The approach uses concepts from the theory of Lie groups and Lie algebras. Since the mathematics may be unfamiliar to the general reader, before the derivation for toroidal systems is executed, the differential equation for an optical system with radial symmetry will be derived using the general mathematical approach. After some of the theorems and formalisms associated with toroidal systems are presented, a description of general toroidal systems and their actions on electromagnetic fields will be presented. The action of systems on electromagnetic fields will be shown to be a linear representation of a group (locally). Having established the preliminaries, the differential equation can be derived. The desired differential equation is derived in three steps. In the first step, a set of differential operators that appear in a simplified equation are derived by recognizing them as the basis of a Lie algebra representation associated with the local linear representation on electromagnetic fields. In the second step, coefficients for the reduced problem are derived. Finally, the complete differential equation is presented. Algorithms that allow one to implement the above results will be presented. These algorithms will be used to execute a computation in a numerical example. By way of verification, it will be shown that the results of this dissertation subsume previous work in several ways including the structure of modes in stable toroidal cavities and the prediction of angular momentum

A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes

Abstract Objective: To examine the efficacy and general safety of rivoglitazone, a novel thiazolidinedione, as a treatment for type 2 diabetes in a dose-ranging study over a period of up to 6 months. Research design and methods: A 26-week, randomized, double-blind, double-dummy, placebo- and active comparator (pioglitazone 45 mg)-controlled study designed to evaluate the efficacy and safety of once-daily rivoglitazone 1, 2, or 3 mg in subjects with type 2 diabetes. The study was conducted in adults with type 2 diabetes (glycated hemoglobin [HbA1c] 7.0% and <10.5%) who were either naïve to prior antidiabetes drug treatment or discontinued pre-study antidiabetes medications and were switched to study medication. A total of 441 subjects were randomized, using an equal allocation schedule to one of five treatment arms, including placebo. The primary efficacy measurement was the change in HbA1c from baseline to week 26 in the intent-to-treat population (last observation carried forward), for drug treatments minus placebo (placebo-subtracted). Clinical Trial Registration: ClinicalTrials.gov Identifier NCT00143520 Results: The incidence of early discontinuations was >50%, with most cases being related to a lack of efficacy (highest on placebo) or adverse experiences (highest on rivoglitazone 3 mg). Rivoglitazone 1, 2, and 3 mg and pioglitazone 45 mg were more effective than placebo in reducing HbA1c from baseline to week 26 (placebo-subtracted change from baseline: −0.55% [p = 0.0034], −0.99% [p < 0.0001], −1.10% [p < 0.0001], and −0.59% [p = 0.0016], respectively). In general, all treatments were safe. The most common drug-related adverse events reported with rivoglitazone were peripheral edema and weight gain; incidences increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg. Conclusions: Rivoglitazone is a potent thiazolidinedione agent with demonstrated glycemic benefits over a 6-month period in subjects with type 2 diabetes. Once-daily doses of 1, 2, and 3 mg rivoglitazone demonstrated HbA1c reduction similar or superior to those observed for pioglitazone 45 mg. Limitations in generalizing from this study include a modest sample size and a high rate of discontinuation prior to the last scheduled visit

Prospecting for new bacterial metabolites:a glossary of approaches for inducing, activating and upregulating the biosynthesis of bacterial cryptic or silent natural products

Over the centuries, microbial secondary metabolites have played a central role in the treatment of human diseases and have revolutionised the pharmaceutical industry. With the increasing number of sequenced microbial genomes revealing a plethora of novel biosynthetic genes, natural product drug discovery is entering an exciting second golden age. Here, we provide a concise overview as an introductory guide to the main methods employed to unlock or up-regulate these so called ‘cryptic’, ‘silent’ and ‘orphan’ gene clusters, and increase the production of the encoded natural product. With a predominant focus on bacterial natural products we will discuss the importance of the bioinformatics approach for genome mining, the use of first different and simple culturing techniques and then the application of genetic engineering to unlock the microbial treasure trove.PostprintPeer reviewe