BACKGROUND/SYNOPSIS:Apolipoprotein (apo) B is highly predictive of coronary risk, especially in patients with high triglycerides (TG). This post hoc analysis evaluated the effects of lipid-lowering therapy on correlations between apoB and low-density lipoprotein cholesterol (apoB:LDL-C) and non-high-density lipoprotein cholesterol (apoB:non-HDL-C) in patients with TG< and ≥ 200 mg/dL. METHODS:This analysis used data from 3 randomized clinical trials in patients with primary hypercholesterolemia receiving placebo, ezetimibe (EZE), simvastatin (SIMVA) or EZE/SIMVA for 12 weeks. Simple linear regression analyses predicted LDL-C and non-HDL-C levels corresponding to apoB values (80 mg/dL) at baseline and Week 12. RESULTS:ApoB correlated with LDL-C (r ≥ 0.76) and non-HDL-C (r ≥ 0.86) at baseline. The correlations were strengthened with SIMVA and EZE/SIMVA at Week 12 (r ≥ 0.88 for LDL-C and r ≥ 0.94 for non-HDL-C). The predicted LDL-C and non-HDL-C values were lower following treatment with SIMVA or EZE/SIMVA than for placebo and EZE. For SIMVA and EZE/SIMVA, the predicted LDL-C and non-HDL-C values were closer to more aggressive LDL-C and non-HDL-C levels (i.e., 70 and 100 mg/dL, respectively). The apoB:LDL-C and apoB:non-HDL-C correlations were weaker and the predicted LDL-C values were generally lower in high TG patients than in low TG patients both at baseline and Week 12. In contrast, the predicted non-HDL-C values were generally higher in high versus low TG patients at baseline but less so at Week 12. CONCLUSION:After treatment with EZE, SIMVA, or EZE/SIMVA, a given apoB value corresponds to lower LDL-C and non-HDL-C levels than those obtained from untreated patients.

AimTo evaluate the effects of the usual starting and next higher doses of ezetimibe/simvastatin and atorvastatin on the cholesterol content of lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia.MethodsThis post hoc analysis compared the effects of treatment with ezetimibe/simvastatin 10/20 mg vs. atorvastatin 10 and 20 mg/day and ezetimibe/simvastatin 10/40 mg/day vs. atorvastatin 40 mg/day on the cholesterol content of lipoprotein subclasses in the modified intent-to-treat (mITT) population (n = 1013) and in subgroups of patients with triglyceride (TG) levels < 200 mg/dl (n = 600) and >= 200 mg/dl (2.6 mmol/l) (n = 413).ResultsEzetimibe/simvastatin significantly reduced low-density lipoprotein cholesterol (LDL-C) subclasses LDL1-C, LDL2-C and LDL3-C; real LDL-C (LDL-C-r); intermediate-density lipoprotein cholesterol (IDL-C), IDL1-C, IDL2-C; very low-density lipoprotein cholesterol (VLDL-C), VLDL3-C; and remnant-like lipoprotein cholesterol (RLP-C) from baseline more than atorvastatin at all dose comparisons (p < 0.01) in the mITT population. Significant improvements were also observed in high-density lipoprotein cholesterol (HDL-C) subclass HDL3-C at the ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg and highest dose comparisons (p < 0.001) and in VLDL1 + 2-C at the lowest and highest dose comparisons (p < 0.001). Changes in LDL4-C and LDL-C subclass patterns (A, B and I) were comparable for both treatments. Generally, similar results were observed for patients with TG levels < 200 and >= 200 mg/dl (2.3 mmol). For both treatments, notable differences between TG subgroups were that patients with elevated TGs had smaller reductions in LDL2-C, slightly smaller decreases in all IDL subclasses and greater decreases in all VLDL-C subclasses than those with lower TG levels. Frequency of pattern B was also reduced more in patients with higher TGs for both treatments.ConclusionsEzetimibe/simvastatin reduced the cholesterol content of most lipoprotein subclasses from baseline with generally similar efficacy in patients with low and high TGs. Despite the different mechanism of action of ezetimibe, the response to ezetimibe/simvastatin and atorvastatin treatment related to these lipoprotein subclasses was generally consistent with the overall effects of these therapies on the major lipid/lipoprotein classes. The clinical significance of these results awaits further study.

Synopsis: The increased CVD risk of hyperlipidemic (HL) patients is only partly quantified by the standard lipid panel (TG, cholesterol, LDL and HDL). As differences in lipoprotein composition can influence atherogenicity, assessment of the lipoprotein subclass profile may aid in risk assessment and in guiding therapy.

Objective: Evaluate the lipid-altering effects of ezetimibe added to ongoing statin therapy, statin titration, switching from statin monotherapy to a more potent statin or to ezetimibe/simvastatin. Methods: A pooled analysis of patient-level data from 17 double-blind, active or placebo-controlled studies of 8667 hypercholesterolemic adults randomized to ezetimibe 10 mg added to ongoing statins, statin titration (doubling), or switching from ongoing statins to rosuvastatin (10 mg) or to ezetimibe/simvastatin (10/20 and 40 mg). Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) was estimated by analysis of variance. Percent of patients who achieved LDL-C and other guideline-recommended targets, and target lipid levels by baseline distance to goal were evaluated. Results: LDL-C percent change from baseline was −26.0 for ezetimibe added to ongoing statin therapy, −27.6 for switching from ongoing statin to ezetimibe/simvastatin, −19.7 for switching to rosuvastatin 10 mg, and −9.7 for dose doubling of the ongoing statin. For patients within 0.8 mmol/L (30 mg/dL) of the target at baseline, LDL-C target attainment rates were 75.9% for adding ezetimibe to ongoing statin, 72.8% for switching to ezetimibe/simvastatin, 61.8% for switching to rosuvastatin, and 44.3% for statin dose-doubling. Similarly, improvements in other lipids and achievement of non-high-density lipoprotein cholesterol and apolipoprotein B targets among this patient group were largest for ezetimibe added to ongoing statins and switching to ezetimibe/simvastatin; switching to rosuvastatin 10 mg and statin dose-doubling were less effective. Conclusions: Adding ezetimibe to ongoing statin therapy appeared to be an effective option for patients who do not achieve lipid-lowering goals on statins alone.

Coexistence of thermal springs, travertine deposits and tectonic activity is a recurring feature for most geothermal areas. Although such a certainty, their relationships are debated mainly addressing on the role of the tectonic activity in triggering and controlling fluids flow and travertine deposition. In this paper, we present the results of an integrated study carried out in a geothermal area located in western Anatolia (Turkey), nearby the well-known Pamukkale area (Denizli Basin). Our study focused on the relationships among hydrothermal fluids circulation, travertine deposition and tectonic activity, with particular emphasis on the role of faults in controlling fluids upwelling, thermal springs location and deposition of travertine masses. New field mapping and structural/kinematics analyses allowed us to recognize two main faults systems (NW- and NE-trending), framed in the Neogene–Quaternary extensional tectonic evolution of western Anatolia. A geo-radar (GPR) prospection was also provided in a key-area, permitting us to reconstruct a buried fault zone and its relationships with the development of a fissure-ridge travertine deposit (Kamara fissure-ridge). The integration among structural and geophysical studies, fluids inclusion, geochemical, isotopic data and 230 Th/238 U radiometric age determination on travertine deposits, depict the characteristics of the geothermal fluids and their pathway, up to the surface. Hydrological and seismological data have been also taken in account to investigate the relation between local seismicity and fluid upwelling. As a main conclusion we found strict relationships among tectonic activity, earthquakes occurrence, and variation of the physical/chemical features of the hydrothermal fluids, presently exploited at depth, or flowing out in thermal springs. In the same way, we underline the tectonic role in controlling the travertine deposition, making travertine (mainly banded travertine) a useful proxy to reconstruct the seismological history of an area, as well as the characteristics of the parent geothermal fluids, adding an effective tool for geothermal exploration tasks.

Objectives This study evaluated the safety and lipid-altering efficacy of ezetimibe/simvastatin (E/S) coadministered with extended-release niacin (N) in patients with type IIa or IIb hyperlipidemia.Background. Current guidelines recommend consideration of combination drug therapy to achieve optimal low-density lipoprotein cholesterol (LDL-C) lowering and broader lipid-altering effects when treating hypercholesterolemic patients at high risk for atherosclerotic cardiovascular events.Methods In this 24-week multicenter, randomized, double-blind study, 1,220 type IIa or IIb hyperlipidemic patients were randomized to treatment with E/S (10/20 mg/day) + N (titrated to 2 g/day), or N (titrated to 2 g/day), or E/S (10/20 mg/day). Changes from baseline in LDL-C (primary) and other secondary variables were assessed in the completers and modified intent-to-treat populations.Results Coadministered E/S with N resulted in significantly greater reductions in LDL-C, non-high-density lipoprotein cholesterol, triglycerides, apolipoprotein B, and lipid/lipoprotein ratios, compared with either agent alone (p < 0.001). The combination increased levels of apolipoprotein A-l and high-density lipoprotein cholesterol significantly more than E/S (p < 0.001), and reduced high-sensitivity C-reactive protein levels significantly more than N (p = 0.005). A significantly greater percentage of patients discontinued the study in the N (25.0%) and E/S + N (23.3%) groups, compared with E/S (9.6%, p < 0.001) because of clinical adverse experiences (primarily flushing). Incidences of other clinical and laboratory adverse experiences (liver-, muscle-, and gastrointestinal-related) were similar for all groups.Conclusions Combination treatment with E/S plus N showed superior lipid-altering efficacy compared with N or E/S in type IIa or IIb hyperlipidemia patients and was generally well tolerated aside from N-associated flushing. This combination offers an effective, broad, lipid-altering therapy with improvements in lipid effects beyond LDL-C in these patients. (To Evaluate Ezetimibe/Simvastatin and Niacin [Extended Release Tablet] in Patients With High Cholesterol; NCT00271817).

BACKGROUND:Rofecoxib and nabumetone were developed to provide gastrointestinal benefits over traditional nonsteroidal antiinflammatory drugs (NSAIDs). However, there is limited comparative information relating to these 2 drugs. OBJECTIVE:The objective of this study was to compare rofecoxib and nabumetone, at their lower, recommended doses, in patients with osteoarthritis (OA). METHODS:Nine hundred seventy-eight patients with knee OA and a positive history of NSAID response were randomized to 12.5 mg rofecoxib per day (N=390), nabumetone 500 mg twice a day (N=392), or placebo (N=196) for 6 weeks. The primary efficacy end point was percent of patients with a "good" or "excellent" Patient Global Assessment of Response to Therapy (PGART) at week 6; PGART was also evaluated over days 1 to 6. Additional end points included investigator assessment of response, pain walking over 6 days and 6 weeks, joint tenderness, discontinuation as a result of lack of efficacy, and quality of life. Adverse experiences (AEs) were collected. RESULTS:Significantly more rofecoxib (50.4%) than nabumetone (43.3%, P=0.043) or placebo (29.5%, P<0.001) patients had a good or excellent PGART at week 6. Median time to a good or excellent PGART was significantly shorter with rofecoxib (52 hours) than nabumetone (100 hours, P=0.001) or placebo (>124 hours, P<0.001). Results for rofecoxib and nabumetone were similar in all additional end points except pain in walking over 6 days and 6 weeks, in both of which the rofecoxib treatment group demonstrated better results. There were significantly (P<0.050) more overall and serious AEs and discontinuations resulting from AEs with rofecoxib than nabumetone. Five rofecoxib and one nabumetone patients had confirmed thrombotic cardiovascular events (P=0.123). Information on thrombotic cardiovascular events from this study was included in a published, prespecified pooled analysis and is included here for completeness. CONCLUSIONS:At their recommended starting doses for OA, both agents were more effective than placebo. Rofecoxib at a dosage of 12.5 mg demonstrated significantly better efficacy in PGART than 1000 mg nabumetone in these patients known to be NSAID responders. Significantly more AEs occurred with rofecoxib than nabumetone. Considering these data and other recent safety information regarding cyclooxygenase-2 selective and nonselective NSAIDS, physicians must make risk/benefit assessments for each individual patient when considering the use of these agents, as recommended by the U.S. Food and Drug Administration.

ABSTRACT Bowel colonization with resistant bacteria can develop in patients receiving broad-spectrum antimicrobial therapy. We compared the impact of two antimicrobial regimens often used to treat intraabdominal infections on susceptibility patterns of bowel flora at the end of therapy. In a double-blind clinical trial, adults with complicated intraabdominal infection requiring surgery were randomized to receive piperacillin-tazobactam (3.375 g every 6 h) or ertapenem (1 g once a day) for 4 to 14 days. Rectal swabs were obtained at baseline and at the end of study therapy to determine the acquisition rates of Enterobacteriaceae resistant to the study drug, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli or Klebsiella species, Pseudomonas aeruginosa resistant to imipenem or piperacillin-tazobactam, and vancomycin-resistant Enterococcus faecalis or Enterococcus faecium . Treated patients were assessable for the acquisition of resistant bacteria if appropriate specimens were obtained at both time points. Enterobacteriaceae resistant to the treatment received were acquired during study therapy by 8/122 assessable piperacillin-tazobactam recipients (6.6%) compared to 0/122 assessable ertapenem recipients ( P = 0.007). Neither ESBL-producing E. coli or Klebsiella species nor P. aeruginosa resistant to piperacillin-tazobactam was isolated from patients in either treatment group. Imipenem-resistant P. aeruginosa was acquired by two of the ertapenem recipients (1.6%) versus zero of the piperacillin-tazobactam recipients ( P = 0.50). Vancomycin-resistant enterococci were acquired during therapy by 8/125 assessable ertapenem recipients (6.4%) versus 2/123 assessable piperacillin-tazobactam recipients (1.6%; P = 0.10). In this study, the acquisition of resistant Enterobacteriaceae occurred significantly more often in patients treated with piperacillin-tazobactam than in those treated with ertapenem.