Optimization of HPLC method using central composite design for estimation of Torsemide and Eplerenone in tablet dosage form

Abstract A simple, precise, accurate and robust high performance liquid chromatographic method has been developed for simultaneous estimation of Torsemide and Eplerenone in tablet dosage form. Design of experiment was applied for multivariate optimization of the experimental conditions of RP-HPLC method. A Central composite design was used to study the response surface methodology and to analyse in detail the effects of these independent factors on responses. Total eleven experiments along with 3 center points were performed. Two factors were selected to design the matrix, one factor is variation in ratio of Acetonitrile and the second factor is flow rate (mL/min). Optimization in chromatographic conditions was achieved by applying Central composite design. The optimized and predicted data from contour diagram comprised mobile phase (acetonitrile, water and methanol in the ratio of 50: 30: 20 v/v/v respectively), at a flow rate of 1.0 ml/min and at ambient column temperature. Using these optimum conditions baseline separation of both drugs with good resolution and run time of less than 5 minutes were achieved. The optimized assay conditions were validated as per the ICH guidelines (2005). Hence, the results showed that the Quality by design approach could successfully optimize RP-HPLC method for simultaneous estimation of Torsemide and Eplerenone.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design.

OBJECTIVES: In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS: One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine. CONCLUSION: This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment.

Lipid-based nano-formulation platform for eplerenone oral delivery as a potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment.

PURPOSE: Eplerenone (EPL) is a selective mineralocorticoid receptor antagonist used for treatment of chronic central serous chorioretinopathy which characterized by accumulation of subretinal fluid causing a localized area of retinal detachment. unfortunately, EPL suffers from poor oral bioavailability due to poor aqueous solubility in addition to high hepatic first pass metabolism. METHOD: Aiming to improve its oral bioavailability, EPL-loaded nanostructured lipid carriers (NLCs) were prepared by the emulsification solvent evaporation method and in-vitro evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). A D-optimal design was used for study the effect of liquid lipid to solid lipid ratio, surfactant type and percentage on PS, PDI, EE%, and for data optimization. The optimized EPL-loaded NLCs system was further evaluated using in-vitro drug release and ex-vivo permeation studies through rabbit intestine in comparison to EPL aqueous suspension. The physicochemical properties of the drug in the optimized system were further examined using FT-IR and X-ray diffraction studies. RESULTS: The resultant NLCs showed small PS (100.85-346.60 nm), homogenous distribution (0.173-0.624), negatively charged particles (ZP -20.20 to -36.75 mV), in addition to EE% (34.31-70.64%). The optimized EPL-loaded NLCs system with a desirability value of 0.905 was suggested through the Design expert® software, containing liquid to solid lipid ratio (2:1) in presence of 0.43%w/v Pluronic® F127 as a surfactant. The optimized EPL-loaded NLCs system showed a PS of 134 nm and PDI of 0.31, in addition to high EE% (76 ± 6.56%w/w), and ZP (-32.37 mV). The ex-vivo permeation study showed two-fold higher drug permeation through rabbit intestine compared to that from the aqueous drug suspension after 24 h, confirming the ability of optimized EPL-loaded NLCs system as successful oral targeting delivery carrier. CONCLUSION: Our results pave the way for a new oral nanotherapeutic approach toward CSCR treatment. In-vivo study is currently under investigation.

Blocking the Mineralocorticoid Receptor Improves Cognitive Impairment after Anesthesia/Splenectomy in Rats.

Recent mounting studies showed that neuroinflammation caused by surgery or anesthesia is closely related to postoperative cognitive dysfunction (POCD). This study investigated the effect of mineralocorticoid receptor (MR) on neuroinflammation and POCD. To detect the MR effect in an animal model, we randomly divided rats into control, anesthesia, and surgery groups. To determine whether the MR-specific blocker eplerenone (EPL) could improve cognitive dysfunction, we assigned other animals into the control, surgery and EPL treatment, and surgery groups. Cognitive function was detected using the Morris water maze. Serum cytokine levels were measured by ELISA, and the histopathological changes of hippocampal neurons were identified by hematoxylin/eosin and Nissl staining. Our research confirmed that anesthesia and surgical stimulation could lead to IL-1ß, IL-6, and TNF-α activation and hippocampal neuronal degeneration and pathological damage. MR was upregulated in the hippocampus under cognitive impairment condition. Additionally, EPL could alleviate inflammatory activation and neuronal damage by exerting neuroprotective effects. The preclinical model of sevoflurane anesthesia/splenectomy implied that MR expression is upregulated by regulating the neuroinflammation in the brain under POCD condition. Manipulating the MR expression by EPL could improve the inflammation activation and neuronal damage.

Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial.

AIM: As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial. METHODS: This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. RESULTS: A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. CONCLUSION: The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

Predictive factors of selective mineralocorticoid receptor antagonist treatment in chronic central serous chorioretinopathy.

To compare the macular morphology of good and poor responders to eplerenone treatment in chronic central serous chorioretinopathy (CSCR) patients. Thirty eyes of 29 patients with chronic CSCR were treated with 50 mg/day oral eplerenone and followed up for 1 year. The integrity of outer retinal layers at baseline was assessed using optical coherence tomography. Patients who showed complete resolution of subretinal fluid at 1 year were assigned to the good responder group (Group 1), whilst those who showed moderate or no resolution were classified as poor responders (Group 2). Ellipsoid zone interruption, ELM interruption and hyperreflective foci in outer segment (OS) and outer nuclear layer (ON layer) was significantly more frequent in Group 2 than in Group 1 (p < 0.05 for all parameteres). Outer segment elongation was significantly more frequently seen in Group 1 than in Group 2 (p < 0.05) Multivariable regression analysis showed that intact ellipsoid zone at baseline is an independent predictor of good therapeutic response, with an odds ratio of 26.00 (95% CI 3.69-183.45; p = 0.001) after controlling for the effect of hyperreflective foci and ELM integrity. There is higher chance of the resolution of subretinal fluid after eplerenone treatment in CSCR patients with intact outer retinal layers at baseline. Baseline morphologic evaluation of the outer retinal layers on OCT scans can be useful in predicting the response to mineralocorticoid antagonist therapy in these patients.

The effect of aldosterone and aldosterone blockade on the progression of chronic kidney disease: a randomized placebo-controlled clinical trial.

The progression of chronic kidney disease (CKD) cannot be completely inhibited. We first explored factors contributing to CKD progression in patients with CKD in a prospective observational study. In the next phase, we focused on the effects of aldosterone, conducting a single-blinded placebo-controlled study using the selective mineralocorticoid receptor antagonist (MRA), eplerenone (25 mg/day). We recruited patients with CKD stage 2 and 3 whose plasma aldosterone concentration was above 15 ng/dL based on the prior data of a prospective observational study. In the CKD cohort study (n = 141), baseline plasma aldosterone concentration was identified as an independent contributory factor for the future rate of change in estimated glomerular filtration rate (eGFR). When the cut-off value for aldosterone was set at 14.5 ng/dL, the decline rate was significantly higher in patients with higher plasma aldosterone concentration (- 1.22 ± 0.39 ml/min/1.73 m2/year vs. 0.39 ± 0.40 ml/min/1.73 m2/year, p = 0.0047). In the final intervention study, in the eplerenone group, eGFR dropped at 6 months after the initiation of the study, and thereafter eGFR was maintained until the end of the study. At 24 months and 36 months, eGFR was significantly higher in the eplerenone group than in the placebo group. In conclusion, MRA can be an effective strategy in preventing CKD progression, especially in patients with high plasma aldosterone.

Tratamiento del hiperaldosteronismo primario / Treatment of primary hyperaldosteronism

El hiperaldosteronismo primario (HAP) se asocia con una mayor morbimortalidad cardiovascular y renal que la hipertensión arterial (HTA) esencial, a misma edad, sexo y grado de HTA. Por ello, es esencial instaurar un tratamiento específico para aminorar los efectos deletéreos del exceso de aldosterona. Aunque se considera que la adrenalectomía es generalmente el tratamiento de elección en los casos de HAP por enfermedad unilateral, se deben tener en cuenta varios aspectos y circunstancias que pueden hacer más adecuado el tratamiento médico. Entre ellos, en esta revisión se mencionan, la limitada experiencia y eficacia, y los riesgos del cateterismo de venas adrenales; los riesgos y baja eficacia de la adrenalectomía; la elevada seguridad y eficacia del tratamiento médico y algunas situaciones especiales como el embarazo, la edad avanzada o las formas familiares, en las que el tratamiento médico se considera especialmente indicado como primera línea. También se comentan los principales estudios que comparan el tratamiento médico y quirúrgico en el HAP

Primary aldosteronism is associated with higher cardiovascular and renal morbidity and mortality than essential hypertension in age- and sex-matched patients with the same degree of blood pressure elevation. Therefore, it is essential to establish a specific treatment to avoid the deleterious effects of aldosterone excess. Although adrenalectomy is generally considered the treatment of choice in cases of primary aldosteronism due to unilateral disease, several aspects and circumstances should be taken into account that may make medical treatment more appropriate. Among them, in this review we mention the limited experience and efficacy, and the potential risks of adrenal vein sampling; the risks and low efficacy of adrenalectomy; the high safety and efficacy of medical treatment and some special situations such as primary aldosteronism during pregnancy, in patients of advanced age or hereditary forms of primary aldosteronism, in which medical treatment is considered especially indicated as the first line therapy. The main studies comparing medical and surgical treatment in primary aldosteronism are also discussed

A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.

CONTEXT: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). OBJECTIVE: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. DESIGN, SETTING, AND PATIENTS: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. RESULTS: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. CONCLUSIONS: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.

Reduced Diuretic Dose in Patients Treated With Eplerenone: Data From the EPHESUS Trial.

BACKGROUND: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status. METHODS: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. RESULTS: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; P for interaction, 0.54). CONCLUSIONS: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division.

Introduction: Mineralocorticoid receptor (MR) activation within adipose tissue, triggers inflammation and metabolic syndrome development. The pharmacological blockade of MR provides beneficial effects for adipose tissue. Our study evaluates the impact of eplerenone implantation upon obesity. Experimental approach: A group of mice with implanted placebo pellets were fed using two types of diet, a normal (ND) or a high fat (HFD) diet. Additionally, a group of mice fed HFD were implanted with an eplerenone pellet. Metabolic and biochemical parameters were assessed in each animal group. Adipocyte size and lipid accumulation were investigated in the liver and adipose tissue. We evaluated the components of renin-angiotensin-aldosterone system (RAAS) locally in adipose tissue. Key results: Eplerenone reduced HFD-induced body weight gain, fasting glucose levels, fat accumulation, HFD-induced adipocyte size and liver lipid accumulation and improved glucose tolerance. In the adipose tissue, HFD significantly increased the mRNA levels of the RAAS molecules relative to the ND group. Eplerenone lowered RAAS mRNA levels, components of lipid metabolism and markers of inflammation in HFD-fed animals. Conclusion: MR antagonism with eplerenone diminishes insulin resistance that is related to obesity partly via a reduction of RAAS activation, inflammatory progression and cytokines induction. This suggests that eplerenone should be further studied as a therapeutic option for obesity and overweight.

Oral Mineralocorticoid-Receptor Antagonists: Choroidal Parameters Changes Using OCT in Central Serous Chorioretinopathy.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy and safety of oral eplerenone in the treatment of acute and chronic central serous chorioretinopathy (CSCR). PATIENTS AND METHODS: Treatment-naïve patients with acute (< 3 months) and chronic (≥ 3 months) CSCR were enrolled in this prospective, nonrandomized, interventional, comparative case series. Patients with acute CSCR were either treated with oral eplerenone (acute case group; n = 16) or observed only (acute control group; n = 8). All chronic patients (chronic group; n = 25) were treated with oral eplerenone. Eplerenone was prescribed 25 mg twice per day for 3 months. Best-corrected visual acuity (BCVA) and optical coherence tomography measures, including subretinal fluid (SRF) height, subfoveal choroidal thickness (CT), central CT, central choroidal volume (CV), and total CV, were assessed at baseline and 3-month follow-up (FU) visit. RESULTS: BCVA improvement and SRF reduction at 3-month FU relative to baseline were observed in all three study groups. SRF was completely resolved in 13 patients (81.2%) in the acute case group, four patients (50%) in the acute control group, and eight patients (32%) in the chronic group. The acute case group showed greater SRF decrease relative to baseline compared to the chronic group (P = .009), but the resolution of SRF between acute cases and an acute control group was not statistically significant (P = .076). Subfoveal CT, central CT, total CV, and central CV were significantly reduced at the 3-month FU compared to baseline in both affected and the fellow eyes in the acute case and chronic groups, whereas no change was observed in either eyes in the acute control group. At 3 months' FU, the mean logMAR visual acuity demonstrated no significant difference among the study groups (P = .08). Eplerenone was well-tolerated, and no serious side effect was detected. CONCLUSIONS: Oral eplerenone is a safe and effective treatment option for both acute and chronic CSCR. Resolution of SRF was more significant in acute CSR cases comparative to chronic cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:726-733.].

The effect of eplerenone on the renin-angiotensin-aldosterone system of rats with thyroid dysfunction.

OBJECTIVES: This study was conducted to evaluate the effect of eplerenone on the RAAS and kidney function in rats with thyroid hormone disorders. METHODS: This study involved 30 male Wistar albino rats, divided into three groups. The first group (N = 6) served as a control. The second group involved 12 rats with experimentally induced hypothyroidism through receiving propylthiouracil (0.05% w/v) in drinking water for one month, which was divided into two subgroups of six rats each. The first subgroup served as a positive hypothyroid control, and the second subgroup received oral daily dose of eplerenone (100 mg/kg) for 14 days. The third group included 12 rats with induced hyperthyroidism with L-thyroxin (0.0012% w/v) in drinking water, and rats in this group were also divided into two subgroups. The first subgroup served as a positive hyperthyroid control, and the second subgroup received oral eplerenone 100 mg/kg. RESULTS: Eplerenone indicated a significant increase in renin and angiotensin I from 184.09 pg/ml and 178.66 pg/ml to 603.31 pg/ml and 250.88 pg/ml, respectively, meanwhile, aldosterone indicated no significant changes after inducing hypothyroidism and eplerenone administration. The induction of hyperthyroidism led to a significant increase in angiotensin I from 248.84 pg/ml to 292.22 pg/ml. Oral administration of eplerenone for 14 days caused a significant increase aldosterone from 364.23 pg/ml to 497.02 pg/ml. CONCLUSION: Eplerenone significantly increased the serum renin and angiotensin I in hypothyroid and aldosterone and angiotensin I in hyperthyroid rats. Aldosterone in hypothyroid rats was not changed by eplerenone.

Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial.

Background Duchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low-dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate-dose spironolactone versus eplerenone would provide similar cardioprotection in this first head-to-head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial. Methods and Results This was a multicenter, double-blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12-18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, -0.4 to 0.6] versus 0.2 [interquartile range, -0.2 to 0.7]; P=0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm. Conclusions In boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.

Eplerenone in patients with myocardial infarction and "mid-range" ejection fraction: An analysis from the EPHESUS trial.

BACKGROUND: Trials using mineralocorticoid receptor antagonists (MRAs) in myocardial infraction (MI) without heart failure (HF) or systolic impairment have been underpowered to assess morbidity-mortality benefit. In EPHESUS 6632 patients were included, of whom 11% had an ejection fraction (EF) of 40% and HF or diabetes. We aim to assess the potential benefit of MRAs in MI with EF of 40%. METHODS: Cox models with interaction term for EF. The primary outcome was a composite of cardiovascular death or hospitalization for cardiovascular reasons. HYPOTHESIS: Patients with an EF of 40% benefit similarly from MRA therapy to those with an EF <40%. RESULTS: In EPHESUS, 753 patients had an EF = 40% and 5864 an EF < 40%. Patients with an EF = 40% were younger (63 vs 64 years), had lower heart rate (73 vs 75 bpm), less atrial fibrillation (10% vs 14%), previous MI (21% vs 28%), HF hospitalization (5% vs 8%), and had more often reperfusion therapy and/or revascularization (55% vs 44%). The mean EF was 40.0 ± 0.3% in those with EF = 40% vs 32.2 ± 5.9% in those with EF < 40%. The primary outcome occurred in 13.3% (10 events per 100 py) of the patients with EF = 40% vs 22.9% (19 events per 100 py) in those with EF < 40%; adjusted HR for EF = 40% vs <40% = 0.65 (0.53-0.81). Eplerenone reduced the event-rate homogenously regardless of EF (interaction p EF = 40% vs EF < 40% = 0.21). Similar findings were observed for cardiovascular and all-cause death. CONCLUSION: Eplerenone reduces hospitalizations and mortality in patients with MI and EF = 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the "mid-range zone" may also benefit from MRA therapy which might help clinicians in their treatment decisions.

The Effect of Eplerenone in Chronic Central Serous Chorioretinopathy Refractory to Photodynamic Therapy.

Purpose: To evaluate the efficacy and safety of oral eplerenone in cases of central serous chorioretinopathy (CSCR) refractory to photodynamic therapy (PDT). Methods: 19 patients with chronic CSCR and persistent subretinal fluid (SRF) were treated with oral eplerenone for 6 months, starting at a dose of 25 mg/day for 4 weeks and then 50 mg/day for 5 months. All patients underwent visual acuity measurement and optical coherence tomography (OCT), while fluorescein angiography was also performed at baseline, before treatment. Resolution of SRF, changes in retinal thickness and BCVA changes at month 6 and 12 post-treatment initiation were assessed. In addition, creatinine and electrolyte test was done on each patient every month for potential complications. Results: Two out of 19 cases were excluded, since one presented with hyperkaliemia 15 days after eplerenone intake and one with skin rash one day after the treatment initiation. At month 12, 88.2% of patients exhibited visual acuity improvement and 76.4% SRF resolution, while in 11.8% of patients SRF remained stable. Conclusions: This study has shown that eplerenone is safe and effective in cases of chronic CSCR, refractory to previous PDT.

High-salt diet promotes crystal deposition through hypertension in Dahl salt-sensitive rat model.

OBJECTIVES: To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. METHODS: Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. RESULTS: A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. CONCLUSIONS: A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

Comparative efficacy and safety of mineralocorticoid receptor antagonists in heart failure: a network meta-analysis of randomized controlled trials.

The efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF) are controversial. To explore the role of MRAs in HF patients with an ejection fraction of no more than 45%, we conducted a network meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Embase, the Cochrane Library, and Clinicaltrials. RCTs involving the efficacy and/or safety of the use of MRAs in patients with HF were included. Outputs are presented as the surface under the cumulative ranking area (SUCRA) probabilities. Thirteen RCTs involving a total of 13,597 participants were included. Finerenone 10 mg was associated with the lowest probability of achieving at cardiovascular mortality (SUCRA, 5.0%), followed by finerenone 7.5 mg (SUCRA, 31.6%). In reducing N-terminal pro-B-type natriuretic peptide, finerenone 15 mg and finerenone 7.5 mg ranked the best and second best (SUCRA 68.1% and 63.8%, respectively), followed by finerenone 10 mg (SUCRA 59.2%). Spironolactone and canrenone have a higher risk of hyperkalemia and renal deterioration. Regarding the prevention of worsening renal function, finerenone 7.5 mg (SUCRA 14.3%) was the best treatment, followed by finerenone 2.5 mg (SUCRA 16.3%) and finerenone 10 mg (SUCRA 25.6%). Compared with spironolactone and eplerenone, finerenone 10 mg was associated with low risk in the occurrence of cardiovascular mortality, hospitalization, and adverse events (P < 0.01). This network meta-analysis is the first to find that finerenone 7.5-10 mg has the highest probability of being the optimal alternative among MRAs in the treatment of HF patients with an ejection fraction of no more than 45%.