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  • br ET Antagonist for the Future Macitentan


    ET Antagonist for the Future: Macitentan and Atresentan Macitentan is an insurmountable antagonist, resulting from structure-activity studies to improve the efficacy and tolerability of bosentan, and gained approval in the United States in 2013 for the treatment of PAH. Actelion describes the compound as a dual antagonist, but on the basis of their own data measuring inhibition of [125I]–ET-1 binding to human-expressed receptors it displays approximately 800-fold selectivity for the ETA subtype. However, plasma ET-1 concentrations were increased significantly (two-fold at the highest dose tested), suggesting blocking of ETB occurs at the dose used. A metabolite of macitentan, ACT-132577, is active pharmacologically, albeit with a lower potency, but reaches higher plasma concentrations and has a longer half-life than macitentan.76, 77, 78, 79 Key pharmacologic parameters suggest macitentan will have the potential for greater efficacy and safety than bosentan. Macitentan has a much longer receptor occupancy (17 minutes compared with 70 seconds for bosentan), probably as a result of interaction with different amino Lonafarnib residues in the ET receptors and is an order of magnitude more potent than bosentan, measured by in vitro assays. Pharmacokinetic benefits include fewer interactions with other drugs, with no requirement to alter doses in patients with renal (or hepatic) impairment. Crucially, the compound has improved hepatic safety and reduced edema/fluid retention compared with bosentan.79, 80 A number of clinical trials are actively recruiting, however, these do not yet include chronic kidney disease patients. Clinical trials also recently were reported on an investigational ETA-selective antagonist: atrasentan (ABT 627). The aim of the double-blind study performed in parallel at two centers was to determine whether albuminuria was reduced further when atrasentan was administered at two different doses, with inhibitors of the renin-angiotensin system, to patients with type 2 diabetic nephropathy. Atrasentan reduced albuminuria at both doses tested, and reduced blood pressure, cholesterol, and triglyceride levels, with unwanted side effects being more manageable at the lower dose. These promising results lead to the initiation of a phase 3 multicenter trial (Study Of Diabetic Nephropathy With Atrasentan) with 4,000 patients.
    Perspectives After more than 25 years since the discovery of ET, the peptide remains the most powerful and long-lasting constrictor of the human vasculature including the kidney described to date. In pathophysiological conditions, ET-1 contributes to vascular remodeling, proliferation of mesangial cells, and extracellular matrix production mainly through binding to ETA. Beneficial actions of ET-1 on sodium and water regulation are mainly ETB-mediated. These findings suggest an ETA-selective antagonist would have a therapeutic advantage over a mixed antagonist in renal disease, and indeed the small number of acute studies directly comparing the peptide antagonists BQ123 versus BQ788 suggest ETA blockade, sparing ETB, may be beneficial. However, this is balanced by the possible greater prevalence of side effects such as edema reported for small-molecule, orally active ETA antagonists compared with mixed antagonists, although the latter also have their limitations because of liver toxicity. In addition, head-to-head studies in patients comparing orally active ETA antagonists with mixed antagonists have not been performed. The renal ET system remains a compelling target: will new therapies be clinically relevant in the future? This question may be answered by the next generation of ET antagonists.
    Introduction Recruitment and activation of neutrophils (PMN) [1] are characterized by liberation of intracellular granules. Myeloperoxidase (MPO), stored in primary granules of PMN, is among the principal enzymes released. Of note, increased levels of circulating MPO can be also detected in patients with coronary artery disease, unstable angina and acute myocardial infarction [2], [3], [4], [5] and indicate adverse outcome [6], [7]. Also, MPO plasma levels are predictive of outcome in patients presenting in the early phase after onset of chest pain [8], [9] and correlate with an impaired left-ventricular function [10].