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Prostate cancer: metastatic
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
Endothelin-1 antagonists:23,24Endothelin-1 (ET-1), a vasoconstrictor and cell growth modulator, stimulates osteoblasts and growth of bony lesions in patients with metastatic prostate cancerAtrasentan is a selective ETA receptor antagonist which decreases median time to disease progression, incidence of bone pain, and median time to bone painCurrently in phase 3 trialsPotential adverse effects: headache, rhinitis, and peripheral edema.
Recent advances in drug discovery for diabetic kidney disease
Published in Expert Opinion on Drug Discovery, 2021
Chhanda Charan Danta, Andrew N. Boa, Sunil Bhandari, Thozhukat Sathyapalan, Shang-Zhong Xu
Selective endothelin receptor A (ETA) blockers have shown some promising results by decreasing albuminuria, hypertension, fibrosis, structural injury, and the maintenance of podocyte integrity in experimental models of DKD, and therefore, blockage of ETA has become an attractive line of approach for the treatment of DKD. Currently, atrasentan, a selective ETA antagonist, is in phase III clinical trials. Atrasentan has an antialbuminuric effect which may be due to the possible mechanism of restoring glomerular endothelial glycocalyx barrier and improving endothelial function, which were confirmed by the increase of NO concentrations, the decrease of glomerular heparinase expression, and inflammation [91]. However, despite a 40% decrease in albuminuria, clinical studies on avosentan in combination with RAAS blockers for DKD has been terminated early due to high rates of cardiovascular adverse effects. These included edema, heart failure, and cardiovascular deaths, which was thought to be due to high dose of avosentan that blocks both ETA and the endothelin receptor B (ETB) [92]. Therefore, it may be assumed that selective inhibitors of ETA could be a potential approach for DKD treatment.
Novel avenues for drug discovery in diabetic kidney disease
Published in Expert Opinion on Drug Discovery, 2018
Matthew D. Breyer, Matthias Kretzler
Similarly, atrasentan faces safety challenges due to renal sodium retention, congestive heart failure (CHF), and edema [34,35]. While avosentan, another endothelin receptor antagonist, reduced albuminuria in patients with diabetic nephropathy, its development was discontinued due to increased incidence of CHF [34]. To mitigate CHF in the atrasentan phase 3 trial, patients with a history of edema, CHF, or a BNP level >200 pg/mL are specifically excluded [36]. In addition, before participating in the randomized, double-blind, placebo-controlled portion of the trial, all eligible patients receive open-label atrasentan for 6 weeks to confirm they can tolerate the drug. Patients who show signs of fluid retention are excluded from the blinded chronic treatment phase of the study. This may significantly restrict its use in patients with diabetic nephropathy given the propensity of renal impaired patients for fluid retention and the high coexistence of CHF [15,37]. Another potential treatment for DKD is the ARB/neprilysin inhibitor class. While not in clinical development for DKD, clinical trials in heart failure patients demonstrate potential protection by ARB/neprilysin of renal failure events [38].
Diabetic nephropathy: newer therapeutic perspectives
Published in Journal of Community Hospital Internal Medicine Perspectives, 2018
Krishna C. Keri, Naga S. Samji, Samuel Blumenthal
Atrasentan, a highly selective ET-A antagonist, was studied next. Fluid retention was thought to be mediated mainly via ET-B receptor and atrasentan showed less of these side effects in animal models [42,43]. 211 participants were randomized to receive atrasentan 0.75 mg/day, 1.25 mg/day, or placebo and followed for 12 weeks. Compared to placebo, both doses of atrasentan caused at least 35% reduction in UACR. Estimated GFR changes between the groups were not significant. Fluid retention was not noted in the low-dose group, but atrasentan 1.25 mg/day significantly increased the body weight compared to placebo.