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Michelle J Pena, Dick de Zeeuw, Dennis Andress, John J Brennan, Ricardo Correa-Rotter, Blai Coll, Donald E Kohan, Hirofumi Makino, Vlado Perkovic, Giuseppe Remuzzi, Sheldon W Tobe, Robert Toto, Hans-Henrik Parving, Shoba Sharma, Tom Corringham, Kumar Sharma, Hiddo Jl Heerspink
We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, four of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and six were reduced in patients with eGFR <60 ml/min/1...
December 25, 2016: Diabetes, Obesity & Metabolism
Richard Larivière, Alexandra Gauthier-Bastien, Roth-Visal Ung, Julie St-Hilaire, Fabrice Mac-Way, Darren E Richard, Mohsen Agharazii
OBJECTIVE: Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD. METHODS: CKD was induced in Wistar rats by renal mass ablation...
February 2017: Journal of Hypertension
Sergei I Petrykiv, Dick de Zeeuw, Frederik Persson, Peter Rossing, Ron T Gansevoort, Gozewijn D Laverman, Hiddo J L Heerspink
AIMS: Albuminuria-lowering drugs have shown different effect size in different individuals. Since urine albumin levels are known to vary considerably from day-to-day, we questioned whether the between-individual variability in albuminuria response after therapy initiation reflects a random variability or a true response variation to treatment. In addition, we questioned whether the response variability is drug dependent. METHODS: To determine whether the response to treatment is random or a true drug response, we correlated in six clinical trials the change in albuminuria during placebo or active treatment (on-treatment) with the change in albuminuria during wash-out (off-treatment)...
December 21, 2016: British Journal of Clinical Pharmacology
T-M Lee, Nen-Chung Chang, Shinn-Zong Lin
Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase (GSK)-3β signal has been implicated in the regulation of NGF. We investigated whether selective ET receptor blockers attenuated cardiac sympathetic reinnervation through restoring PI3K/Akt/GSK-3β activity. After ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, atrasentan (an ETA receptor antagonist) or A-192621 (an ETB receptor antagonist) for 4 weeks...
December 19, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Hiddo J L Heerspink, Hirofumi Makino, Dennis Andress, John J Brennan, Ricardo Correa-Rotter, Blai Coll, Justin W Davis, Ken Idler, Donald E Kohan, Mohan Liu, Vlado Perkovic, Giuseppe Remuzzi, Sheldon W Tobe, Robert Toto, Hans-Henrik Parving, Dick de Zeeuw
AIMS: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0...
December 15, 2016: Diabetes, Obesity & Metabolism
R F Claudino, D F Leite, A F Bento, J G Chichorro, J B Calixto, G A Rae
OBJECTIVE AND DESIGN: This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors...
October 24, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Suzanne A Nasser, Ramzi Sabra, Ahmed I Elmallah, Mahmoud M Mohy El-Din, Mohamed M Khedr, Mahmoud M El-Mas
AIMS: Cyclosporine (CSA) elevates blood pressure (BP) and alters arterial baroreflex sensitivity (BRS) and vasoreactivity. In this study we determined whether the renin-angiotensin system (RAS) interplays with other vasopressor pathways in mediating the CSA actions. MATERIALS AND METHODS: Whole animal and isolated vascular preparations were employed to determine the effects of pharmacologic interruption of angiotensin II (Ang II), endothelin (ET), or thromboxane (TXA2) signaling on the adverse cardiovascular effects of CSA...
October 15, 2016: Life Sciences
Margien G S Boels, M Cristina Avramut, Angela Koudijs, Martijn J C Dane, Dae Hyun Lee, Johan van der Vlag, Abraham J Koster, Anton Jan van Zonneveld, Ernst van Faassen, Hermann-Josef Gröne, Bernard M van den Berg, Ton J Rabelink
Atrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-to-creatinine ratios by 26...
August 2016: Diabetes
Duygu Batu Demir, Mark E Cooper
PURPOSE OF REVIEW: The purpose of this review is to provide an overview of recent preclinical and clinical studies, which demonstrate new insights for the treatment of diabetic kidney disease (DKD) and to outline future directions with respect to novel therapies. RECENT FINDINGS: Positive findings with respect to new glucose-lowering agents such as sodium-dependent glucose transporter 2 inhibitors may lead to a change in the way we treat diabetic individuals with or at risk of DKD...
July 2016: Current Opinion in Nephrology and Hypertension
Susan J Allison
No abstract text is available yet for this article.
June 2016: Nature Reviews. Nephrology
Wen-Ling Kang, Gao-Si Xu
Atrasentan is a promising therapy for treating diabetic nephropathy (DN). Here we evaluated whether atrasentan down-regulated the miR-199b-5p expression, thereby increasing klotho and preventing renal tubular injury in DN. One-hundred patients with type 2 diabetes mellitus (T2DM) and 40 healthy subjects were included. A DN mice model was established by an injection of streptozotocin (STZ). Human renal proximal tubular epithelial HK-2 cells were exposed to high glucose (20 mmol/L). Treated the mice and HK-2 cells with atrasentan, and we then investigated whether and how miR-199b-5p and Klotho were involved in preventing renal tubular injury in DN...
January 27, 2016: Scientific Reports
Ivana Vaněčková, Lenka Řezáčová, Jaroslav Kuneš, Josef Zicha
AIMS: Chronic endothelin receptor A (ETA) blockade lowered blood pressure (BP) by decreasing angiotensin-dependent vasoconstriction and attenuating calcium influx. We tested whether the addition of ETA blockade to renin-angiotensin system (RAS) blockade would have further effects on the principal vasoactive systems contributing to BP maintenance in Ren-2 transgenic rats (TGR). METHODS: Four-week-old TGR rats were fed with normal-salt diet and given either different renin-angiotensin system (RAS) blockers [angiotensin receptor blocker losartan, angiotensin converting enzyme inhibitor captopril, direct renin inhibitor aliskiren], or ETA blocker (atrasentan) alone, or a combination of atrasentan with RAS blockers for 4weeks...
August 15, 2016: Life Sciences
Kohei Kaku
The trend of new drug development in the field of diabetes mellitus is overviewed. The hypoglycemic drugs such as glucagon receptor antagonists, glucokinase activators, and GPR agonists and oral medication of GLP-1 receptor agonist are under phase 2 trial in Japan. As for therapeutic medicines for diabetic nephropathy, atrasentan as an endothelin A receptor antagonist is in phase 3 trial, and bardoxolone methyl as Nrf2 activator in phase 2 in Japan. Canagliflozin, a SGLT2 inhibitor, is in phase 3 study to obtain new indication of diabetic nephropathy...
December 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
Suttira Intapad, Norma B Ojeda, Elliott Varney, Thomas P Royals, Barbara T Alexander
The renal endothelin system contributes to sex differences in blood pressure with males demonstrating greater endothelin type-A receptor-mediated responses relative to females. Intrauterine growth restriction programs hypertension and enhance renal sensitivity to acute angiotensin II in male growth-restricted rats. Endothelin is reported to work synergistically with angiotensin II. Thus, this study tested the hypothesis that endothelin augments the blood pressure response to acute angiotensin II in male growth-restricted rats...
December 2015: Hypertension
Michael A Carducci, Judith Manola, Suresh G Nair, Glenn Liu, Steven Rousey, Janice P Dutcher, George Wilding
BACKGROUND: Atrasentan, an oral endothelin receptor A antagonist, demonstrated phase 1 activity in patients with renal cell carcinoma (RCC). A phase 2 study was undertaken in patients with measurable or bone-only metastatic RCC in the pre-VEGF/TKI era. METHODS AND MATERIALS: Patients were stratified by disease status and prior immunotherapy. Eligible patients had no prior chemotherapy, 0 to 1 prior immunotherapies, and an Eastern Cooperative Oncology Group performance status of 0 to 2...
December 2015: Clinical Genitourinary Cancer
Maria Vanessa Perez-Gomez, Maria Dolores Sanchez-Niño, Ana Belen Sanz, Catalina Martín-Cleary, Marta Ruiz-Ortega, Jesus Egido, Juan F Navarro-González, Alberto Ortiz, Beatriz Fernandez-Fernandez
Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways...
June 18, 2015: Journal of Clinical Medicine
Bauke Schievink, Dick de Zeeuw, Paul A Smink, Dennis Andress, John J Brennan, Blai Coll, Ricardo Correa-Rotter, Fan Fan Hou, Donald Kohan, Dalane W Kitzman, Hirofumi Makino, Hans-Henrik Parving, Vlado Perkovic, Giuseppe Remuzzi, Sheldon Tobe, Robert Toto, Jarno Hoekman, Hiddo J Lambers Heerspink
BACKGROUND: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes...
May 2016: European Journal of Preventive Cardiology
Ping Qi, Ming Chen, Li-xiu Zhang, Rui-xia Song, Zhen-hua He, Zhi-ping Wang
BACKGROUND: Endothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC...
2015: PloS One
Donald E Kohan, Hiddo J Lambers Heerspink, Blai Coll, Dennis Andress, John J Brennan, Dalane W Kitzman, Ricardo Correa-Rotter, Hirofumi Makino, Vlado Perkovic, Fan Fan Hou, Giuseppe Remuzzi, Sheldon W Tobe, Robert Toto, Hans-Henrik Parving, Dick de Zeeuw
BACKGROUND AND OBJECTIVES: Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs...
September 4, 2015: Clinical Journal of the American Society of Nephrology: CJASN
M Agharazii, A Gauthier-Bastien, R V Ung, F Mac-Way, D Richard, R Lariviere
OBJECTIVE: Increased risk of cardiovascular disease in patients with chronic kidney disease (CKD) has been related to vascular stiffness and isolated systolic hypertension as a result of vascular calcification due to mineral metabolism abnormalities. Using a rat model of CKD with vascular calcification, we found a marked increase in endothelin-1 (ET-1) production in the media of calcified vessels suggesting a role for ET-1. This study was designed to investigate the effect of the ETA receptor antagonist atrasentan on vascular calcification and hemodynamic parameters in CKD rats with mineral metabolism abnormalities...
June 2015: Journal of Hypertension
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