Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.

BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES: To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS: Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS: The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.

Ocular Biodistribution of Spironolactone after a Single Intravitreal Injection of a Biodegradable Sustained-Release Polymer in Rats.

Sustained-release formulations for ocular delivery are of increasing interest given their potential to significantly improve treatment efficacy and patient adherence. The objectives of this study were (i) to develop a sustained-release formulation of spironolactone (SPL) using a biodegradable and injectable polymer, hexyl-substituted poly-lactic acid (hexPLA) and (ii) to investigate the ocular biodistribution and tolerability of SPL and its metabolites in rats in vivo over 1 month following a single intravitreal injection (IVT inj). The concentrations of SPL and its two principal active metabolites, 7α-thiomethylspironolactone and canrenone (CAN), in the different ocular compartments were determined at different time points (3, 7, and 31 days after IVT inj) using a validated ultra-high-performance liquid chromatography-mass spectrometry method. Systemic exposure following a single IVT inj of 5% SPL-hexPLA formulation was evaluated by quantifying SPL and its metabolites in the plasma. Ocular tolerability of the formulation was evaluated using in vivo retinal imaging and histology. In vitro release studies revealed a sustained release of SPL from 5% SPL-hexPLA for up to 65 days. In vivo studies showed that SPL and its metabolites were detected in all ocular tissues at 3 and 7 days post-IVT inj. At 31 days post-IVT inj, SPL and CAN were mainly detected in the retina. These results also highlighted the clearance pathway of SPL and its metabolite involving the anterior and posterior routes in the first week (days 3 and 7), then mainly the posterior segment in the last week (day 31). This study showed that a single IVT inj of 5% SPL-hexPLA in rats enabled sustained delivery of therapeutic amounts of SPL for up to 1 month to the retina without systemic exposure. This formulation may be of interest for the local treatment of diseases involving overactivation of the mineralocorticoid receptor in the chorioretina such as chronic central serous chorioretinopathy.

Antihypertensive effect of the mineralocorticoid receptor antagonist eplerenone: a pooled analysis of patient-level data from comparative trials using regulatory-approved doses.

PURPOSE: Several options are available for the treatment of hypertension; however, many treated patients are still not below blood pressure (BP) target. Eplerenone, a selective mineralocorticoid receptor antagonist, is an approved treatment option for the management of patients with hypertension in a number of countries. This patient-level pooled analysis was conducted to document the efficacy and safety/tolerability of eplerenone at the dosages approved for use in hypertension in comparison to placebo or other approved antihypertensive agents. METHODS: Seventeen Phase III studies conducted in patients with mild-to-moderate hypertension in the Eplerenone Hypertension Clinical Program were reviewed; eleven met the selection criteria. The primary endpoint was change from baseline in seated diastolic BP and seated systolic BP measured at the end of the study. RESULTS: A total of 2,698 patients were included in this per-protocol analysis. In patients treated for at least 6 weeks with a stable dose of eplerenone, doses of 50 mg daily and 100 mg daily were associated with greater reductions of seated systolic BP and seated diastolic BP compared with placebo (P<0.001) and active-controlled studies (P< 0.033). In the analysis of covariance model testing of the contribution of four factors (age, body mass index [BMI], history of cardiovascular disease, and diabetes) on the BP lowering effects of eplerenone, only BMI and age were associated with small though statistically significant changes in BP (<0.2 mmHg). Eplerenone was well tolerated; headache was the most common adverse event for patients in any group. Severe hyperkalemia (serum potassium level >6.0 mmol/L) occurred in up to 0.4% in the eplerenone groups, 0.4% in the placebo group, and 0.1% in the active-control group. CONCLUSION: This patient-level pooled analysis provides robust evidence that eplerenone, at 50 mg or 100 mg daily, was effective in lowering BP in patients with mild-to-moderate hypertension and was well tolerated.

Mineralocorticoid Receptor Blockers and Aldosterone to Renin Ratio: A Randomized Controlled Trial and Observational Data.

Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT). Patients were 1:1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or placebo for 8 weeks. Second, we measured the ARR in 4 PA patients from the Graz Endocrine Causes of Hypertension Study (GECOH) before and after MR blocker treatment. Ninety-seven participants completed the EPATH trial, and the mean treatment effect (95% confidence interval) for log(e)ARR was 0.08 (-0.32 to 0.48) ng/dl/µU/ml (p=0.694). The treatment effect was 0.71 (0.47 to 0.96; p<0.001) ng/dl for log(e)PAC and 0.64 (0.19 to 1.10; p=0.006) µU/ml for log(e)DRC, respectively. In the 4 PA patients, the ARR decreased from 11.24±3.58 at baseline to 2.70±1.03 (p=0.013) ng/dl/µU/ml after MR blocker treatment. In this study with limited sample size, MR blocker treatment did not significantly alter the ARR in pHPT patients but significantly reduced the ARR in PA patients. Diagnostic utility of ARR and its components for PA diagnostics under MR blocker treatment warrants further study.

Effect of Eplerenone on the Glomerular Filtration Rate (GFR) in Primary Aldosteronism: Sequential Changes in the GFR During Preoperative Eplerenone Treatment to Subsequent Adrenalectomy.

Objective Eplerenone (EPL) is a mineralo-corticoid receptor antagonist that is highly selective and has few side effects. This study was conducted to examine whether or not EPL treatment was able to reverse glomerular hyperfiltration, as an indicator of aldosterone renal action, in primary aldosteronism (PA) patients. Methods Changes in the estimated glomerular filtration rate (ΔGFR) were examined in 102 PA patients with EPL treatment. Furthermore, the sequential ΔGFR in 40 patients initially treated with EPL followed by adrenalectomy was examined in order to evaluate the extent of the remaining glomerular hyperfiltration in the patients treated with EPL. Results EPL decreased the GFR at 1 month after treatment. The GFR at baseline was the sole significant predictor for the ΔGFR. Patients initially treated by EPL followed by adrenalectomy showed three different ΔGFR patterns during the treatment, despite having comparable doses of EPL and comparable control of blood pressure and serum potassium levels. The urinary aldosterone excretion was significantly different among these three groups, and the group with no decrease in the GFR after EPL treatment showed greater urinary aldosterone excretion. Glomerular hyperfiltration was completely restored only in 17.5% of our unilateral PA patients after EPL treatment. Conclusion The present study revealed that blockade of aldosterone action by EPL could, at least partially, reverse glomerular hyperfiltration in PA. Whether or not these differential effects on the GFR affect the long-term outcome needs to be investigated, especially in patients with unilateral PA who do not want adrenalectomy and choose the EPL treatment option.

Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study.

BACKGROUND: Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. METHODS: Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. RESULTS: Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. CONCLUSION: Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.

Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion.

Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy. Organ protection was studied in uni-nephrectomised db/db mice and uni-nephrectomised rats administered aldosterone and high salt. Acute effects of single compound doses on urinary electrolyte excretion were tested in rats on a low salt diet. AZD9977 and eplerenone showed similar human MR in vitro potencies. Unlike eplerenone, AZD9977 is a partial MR antagonist due to its unique interaction pattern with MR, which results in a distinct recruitment of co-factor peptides when compared to eplerenone. AZD9977 dose dependently reduced albuminuria and improved kidney histopathology similar to eplerenone in db/db uni-nephrectomised mice and uni-nephrectomised rats. In acute testing, AZD9977 did not affect urinary Na+/K+ ratio, while eplerenone increased the Na+/K+ ratio dose dependently. AZD9977 is a selective MR modulator, retaining organ protection without acute effect on urinary electrolyte excretion. This predicts a reduced hyperkalemia risk and AZD9977 therefore has the potential to deliver a safe, efficacious treatment to patients prone to hyperkalemia.

Mineralocorticoid receptor antagonism protects the aorta from vascular smooth muscle cell proliferation and collagen deposition in a rat model of adrenal aldosterone-producing adenoma

The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 μg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF-Beta1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF- Beta1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition

Aldosterone is involved in the pathogenesis of obesity-related glomerulopathy through activation of Wnt/ß-catenin signaling in podocytes.

Obesity-related glomerulopathy (ORG) is morphologically characterized by glomerulomegaly with or without observable focal segmental glomerulosclerosis under light microscope, with decreased podocyte density and number, and with increased foot­process width observed under electron microscope. The severity of podocyte injury is correlated with the degree of proteinuria and renal dysfunction. However, the pathogenesis of ORG is not well understood. The aim of the present study was to explore the possible pathogenic role of aldosterone (ALDO) in ORG. In the in vivo animal experiments, body weight, Lee's obesity index, abdominal fat index, urinary protein excretion, average glomerular diameter were significantly increased, the mRNA and protein expression of podocyte­associated molecules including nephrin, podocin, podoplanin and podocalyxin were significantly reduced, and the Wnt/ß­catenin signaling pathway was activated in ORG model mice compared with the Control mice, whereas the administration of spironolactone significantly ameliorated these effects. In the in vitro experiments on cultured podocytes, the mRNA and protein expression levels of the aforementioned podocyte­associated molecules were significantly downregulated and the Wnt/ß­catenin signaling pathway was activated following ALDO stimulation, whereas eplerenone significantly attenuated all the above effects. Dickkopf­related protein 1 (DKK1), an inhibitor of Wnt/ß­catenin signaling pathway, also reduced the effects of ALDO exposure on the expression of podocyte­associated molecules. The present study hypothesized that ALDO may be involved in the pathogenesis of ORG through the activation of Wnt/ß­catenin signaling pathway in podocytes.

Eplerenone pretreatment protects the myocardium against ischaemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway in diabetic rats.

We investigated the eplerenone-induced, PI3K/Akt- and GSK-3ß-mediated cardioprotection against ischemia/reperfusion (I/R) injury in diabetic rats. The study groups comprising diabetic rats were treated for 14 days with 150 mg/kg/day eplerenone orally and 1 mg/kg wortmannin (PI3K/Akt antagonist) intraperitoneally with eplerenone. On the 15th day, the rats were exposed to I/R injury by 20-min occlusion of the left anterior descending coronary artery followed by 30 min of reperfusion. The hearts were processed for biochemical, molecular, and histological investigations. The I/R injury in diabetic rats inflicted a significant rise in the oxidative stress and apoptosis along with a decrease in the arterial and ventricular function and the expressions of PI3K/Akt and GSK-3ß proteins. Eplerenone pretreatment reduced the arterial pressure, cardiac inotropy, and lusitropy. It significantly reduced apoptosis and cardiac injury markers. The histology revealed cardioprotection in eplerenone-treated rats. Eplerenone up-regulated the PI3K/Akt and reduced the GSK-3ß expression. The group receiving wortmannin with eplerenone was deprived eplerenone-induced cardioprotection. Our results reveal the eplerenone-induced cardioprotection against I/R injury in diabetic rats and substantiate the involvement of PI3K/Akt and GSK-3ß pathways in its efficacy.

Mineralocorticoid receptor antagonism protects the aorta from vascular smooth muscle cell proliferation and collagen deposition in a rat model of adrenal aldosterone-producing adenoma.

The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 µg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF-ß1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF-ß1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition.

Multimodal retinal imaging in central serous chorioretinopathy treated with oral eplerenone or photodynamic therapy.

PurposeTo correlate function and structural optical coherence tomography (OCT) to optical coherence tomography angiography (OCT-A) measures in patients affected by central serous chorioretinopathy (CSC) and to describe their changes after treatments (ie oral eplerenone, half-fluence photodynamic therapy (PDT)).Patients and methodsTwenty eyes of 16 consecutive patients with treatment-naïve CSC undergoing either eplerenone or PDT were enrolled in this prospective, observational study. All patients underwent structural OCT and OCT-A at baseline and after therapy at months 1 and 3.ResultsEleven eyes of nine patients and nine eyes of seven patients underwent eplerenone or PDT treatment, respectively. Central macular thickness (CMT) and subretinal fluid (SRF) correlated to fovea avascular zone (FAZ) area (r=0.74 and r=0.71, P=0.01) and vessel density (r=0.77 and r=0.68, P=0.01) at deep capillary plexus (DCP). CMT (P=0.0011), SRF (P=0.0005), SFCT (P=0.0016), FAZ area at DCP (P=0.0334) improved at 3-month visit. A significant reduction of deep FAZ area was appreciated in eplerenone (P=0.0204) but not in PDT (P=0.5) group. SFCT reduction was significantly higher in PDT than eplerenone group (P=0.0347).ConclusionStructural and vascular parameters are correlated in CSC and they improve after different treatments. Both half-fluence PDT and oral eplerenone do not permanently damage choriocapillaris or other choroidal layers as evaluated by OCT-A.

Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study.

OBJECTIVE: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI). METHODS: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF ≤40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients` characteristics; (2) determinants; (3) and eplerenone effect. RESULTS: Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p < 0.05). Worse renal function was associated with increased levels of PIIINP (standardized ß ≈ 0.20, p < 0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9 ng/mL (0.13 ± 1.48 vs. -0.37 ± 1.56 ng/mL, p = 0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR = 1.95, 95% CI 1.16-3.29, p = 0.012). CONCLUSIONS: Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF.

A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROL PILOT STUDY OF EPLERENONE FOR THE TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY (ECSELSIOR).

PURPOSE: To evaluate the safety and effects of oral eplerenone in chronic central serous chorioretinopathy. METHODS: Prospective, randomized, double-blind, placebo-control study at a tertiary referral academic private practice. For a diagnosis of chronic central serous chorioretinopathy, patients must have had at least 3 months clinical follow-up demonstrating persistent symptoms, subfoveal fluid on spectral-domain optical coherence tomography, and <50% reduction in fluid thickness. Patients were randomized 2:1 (treatment:placebo) to receive eplerenone (25 mg daily for 1 week, then up to 50 mg daily for 8 weeks) or placebo once daily. RESULTS: Fifteen patients completed the study. Ten patients (15 eyes) were randomized into the eplerenone treatment arm, while the remaining 5 patients (6 eyes) received placebo. After 9 weeks of eplerenone therapy, mean logarithm of the minimal angle of resolution visual acuity improved from 0.394 (Snellen equivalent: 20/50) to 0.330 (20/43, P = 0.04). In the placebo group, the mean logarithm of the minimal angle of resolution visual acuity slightly decreased from 0.313 (20/41) to 0.342 (20/44) during the same period (P = 0.21). With respect to anatomic changes, mean maximal subretinal fluid height in the eplerenone group improved from 139.3 µm at baseline to 51.8 µm (P = 0.02), mean subfoveal fluid height improved from 121.4 µm to 29.4 µm (P = 0.01), and mean central subfield thickness improved from 366.2 µm to 283.7 µm (P = 0.02). In comparison with the placebo group, mean maximal subretinal fluid height worsened from 135.9 µm to 172.3 µm (P = 0.32), mean subfoveal fluid height worsened from 92.1 µm to 134.0 µm (P = 0.54), and mean central subfield thickness worsened from 345.0 µm to 380.0 µm (P = 0.37). No patients in either group experienced serious adverse events to result in treatment discontinuation. CONCLUSION: These findings suggest that oral eplerenone therapy is safe and potentially effective in the treatment of chronic central serous chorioretinopathy with persistent subretinal fluid.

Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling.

BACKGROUND: The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown. OBJECTIVES: This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation. METHODS: The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5). RESULTS: EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden. CONCLUSIONS: In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.

Biochemical monitoring after initiation of aldosterone antagonist therapy in users of renin-angiotensin system blockers: a UK primary care cohort study.

OBJECTIVE: To determine the frequency of biochemical monitoring after initiation of aldosterone antagonists(AA) in patients also using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB). SETTING: UK primary care. PARTICIPANTS: ACEI/ARB users who initiated AA between 2004 and 2014. OUTCOMES: We calculated the proportions with: (1) biochemical monitoring ≤2 weeks post initiation of AA, (2) adverse biochemical values ≤2 months (potassium ≥6 mmol/L, creatinine ≥220 µmol/L and ≥30% increase in creatinine from baseline) and (3) discontinuers of AA in those with an adverse biochemical value. We used logistic regression to study patient characteristics associated with monitoring and adverse biochemical values. RESULTS: In 10 546 initiators of AA, 3291 (31.2%) had a record of biochemical monitoring ≤2 weeks post initiation. A total of 2.0% and 2.7% of those with follow-up monitoring within 2 months of initiation experienced potassium ≥6 mmol/L and creatinine ≥220 µmol/L, respectively, whereas 13.5% had a ≥30% increase in creatinine. Baseline potassium (OR 3.59, 95% CI 2.43 to 5.32 for 5.0-5.5 mmol/L compared with <5.0 mmol/L) and estimated glomerular filtration rate 45-59 ml/min/1.73 m2 (OR 2.06, 95% CI 1.26 to 3.35 compared with ≥60 ml/min/1.73 m2) were independently predictive of potassium ≥6 mmol/L. Women and people with diabetes had higher odds of ≥30% increase in creatinine. CONCLUSION: Less than one-third of patients taking ACEI/ARB had biochemical monitoring within 2 weeks of initiating AAs. Higher levels of monitoring may reduce adverse biochemical events.

Irvine-Gass Macular Edema Responding to the Combination of Oral Mineralocorticoid-Receptor Antagonist With Dexamethasone Drops.

Long-lasting postoperative macular edema is a therapeutic challenge. The authors report an efficient combination therapy of oral mineralocorticoid receptor antagonists (eplerenone [Inspra; Pfizer, New York City, NY] or spironolactone, 25 mg/day to 50 mg/day) and topical dexamethasone (four times/day and progressive dose tapering) in three refractory cases following complex cataract or retinal detachment surgery. In Case 1, central macular thickness (CMT) decreased from 523 µm to 214 µm and visual acuity (VA) improved from 20/200 to 20/50 during a 6-month period. In Cases 2 and 3, CMT improved from 505 µm to 333 µm and from 438 µm to 316 µm during 5- and 3-month periods, respectively; however, VA remained unchanged (20/100 and 20/200) due to photoreceptor damage. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:936-942.].

Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists.

Mineralocorticoid-receptor antagonists (MRAs) have proven to be effective in some types of hypertension, especially in resistant hypertension (RHTN). In this phenotype of hypertension, the renin-angiotensin-aldosterone pathway plays an important role, with MRAs being especially effective in reducing blood pressure. In this review, we show the relevance of aldosterone in RHTN, as well as some clinical characteristics of this condition and the main concepts involving its pathophysiology and cardiovascular damage. We analyzed the mechanisms of action and clinical effects of two current MRAs - spironolactone and eplerenone - both of which are useful in RHTN, with special attention to the former. RHTN represents a significant minority (10%-15%) of hypertension cases. However, primary-care physicians, cardiologists, nephrologists, neurologists, and geriatricians face this health problem on a daily basis. MRAs are likely one of the best pharmacological options in RHTN patients; however, they are still underused.

Fungal biotransformation of diuretic and antihypertensive drug spironolactone with Gibberella fujikuroi, Curvularia lunata, Fusarium lini, and Aspergillus alliaceus.

Derivatives of spironolactone (1), a diuretic and antihypertensive drug, were synthesized by using fungal cells for the first time. Ten different fungi were screened for their ability to biotransform 1, four of which were able to produce metabolites 2-8. Gibberella fujikuroi produced canrenone (2), 1-dehydrocanrenone (3), Curvularia lunuta provided compound 2, and 7α-thio-spironolactone (4), Fusarium lini yielded compounds 2, 3, 1ß-hydroxycanrenone (5), 1α-hydroxycanrenone (6), 1-dehydro-15α-hydroxycanrenone (7), and 15α-hydroxycanrenone (8), while Aspergillus alliaceus was able to produce all the seven metabolites. Metabolites 5, 6, and 7 were identified as new compounds. Their structures were elucidated by using different spectroscopic techniques. Substrate 1 and its metabolites 2, 3, and 5-8 were also evaluated for α-glucosidase inhibitory activity in vitro. Substrate 1 was found to be strongly active with IC50 = 335 ±â€¯4.3 µM as compared to the standard drug acarbose IC50 = 840 ±â€¯1.73 µM, whereas all of resulting metabolites were found to be inactive.