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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated. WHAT THIS STUDY ADDS• As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects. AIMThis study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor. METHODSSubjects (n = 32) were stratified based on measured creatinine clearance: healthy controls (Ն80 ml min -1 ), mild (50-79 ml min -1 ), moderate (30-49 ml min -1 ) and severe impairment (<30 ml min -1 ). RESULTSRenal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONSRivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Abstract. At present, nine adrenoceptor (AR) subtypes have been identified: α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 -, and β 3 AR. In the human heart, β 1 -and β 2 AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β 1 AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β 2 AR in CHF? What is the role of increases in cardiac G i -protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of β 1 -and β 2 AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and / or might influence progression of disease. Furthermore, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β 1 AR polymorphism (the Arg389Gly β 1 AR) may affect the response to βAR-blocker treatment.

Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP Ͻ180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (Ϫ16.3 to Ϫ29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (Ϫ28.7 to Ϫ44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (Ն25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.