Nueva evidencia en el tratamiento de la enfermedad renal diabética: ¿qué aporta la finerenona?

Contexto: la enfermedad renal diabética (ERD) es la primera causa a nivel mundial de enfermedad renal crónica (ERC) e impacta directamente en el riesgo cardiovascular y mortalidad de los pacientes con diabetes mellitus (DM). La finerenona, un antagonista selectivo del receptor mineralocorticoide (ARM), ha sido descrito en diversos estudios recientes como un fármaco que contribuye a la reducción de la progresión de la ERD y la disminución del riesgo cardiovascular, con un adecuado perfil de seguridad. Objetivo: realizar una revisión de la literatura sobre el impacto de la finerenona en la progresión del daño renal y el riesgo cardiovascular en los pacientes con ERD. Metodología: se realizó una búsqueda sistemática en diversas fuentes: PubMed (Medline, Biblioteca del Congreso de los Estados Unidos), Science Direct, Scopus, Embase y Lilacs; la búsqueda fue restringida a referencias en idioma español e inglés, sin límites en la fecha de publicación. Se utilizaron las siguientes palabras clave en el idioma inglés: diabetic renal disease, chronic kidney disease, diabetes mellitus, spironolactone, eplerenone, finerenone, mineralocorticoid receptor antagonist y sus correspondientes versiones en español. Resultados: Las referencias encontradas en la búsqueda fueron revisadas entre los diferentes autores para, posteriormente, proceder a realizar la elaboración del documento. Conclusiones: la finerenona es un medicamento que brinda cardio y nefroprotección en pacientes con ERD de fenotipo albuminúrico.

Background: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) worldwide and has a direct impact on cardiovascular risk and mortality in patients with diabetes mellitus (DM). Finerenone, a selective mineralocorticoid receptor (MRA) antagonist, has been described in several recent studies as a drug that contributes to slowing the progression of CKD and reducing cardiovascular risk, with an adequate safety profile. Purpose: To carry out a review of the literature on the impact of finerenone on the progression of renal damage and cardiovascular risk in patients with DKD. Methodology: A systematic search were carried out in various sources: PubMed (Medline, United States Library of Congress), Science Direct, Scopus, Embase and Lilacs; the search was restricted to references in Spanish and English, with no limits on publication date. The following keywords in the English language were used: diabetic renal disease, chronic kidney disease, diabetes mellitus, spironolactone, eplerenone, finerenone, mineralocorticoid receptor antagonist and their corresponding Spanish versions. Results: The references found in the search were reviewed among the different authors to subsequently proceed to prepare the document. Conclusions: Finerenone is a drug that provides cardio and nephroprotection in patients with DKD albuminuric phenotype.

Reappraising the Role of Eplerenone in the Management of Heart Failure

Background: In India, the prevalence of heart failure (HF) is increasing at 1.2/1,000 people according to a study in northern India, and the mortality rate at 1 year (INTERnational Congestive Heart Failure [INTER-CHF]) is 37%. Due to the diverse phenotypes of HF, nonadherence to guideline-directed medical therapy (GDMT), resistance to uptitration of medication and underuse of mineralocorticoid receptor antagonists (MRAs), such as eplerenone, a uniform management approach may not be feasible. This review is aimed at assessing the burden of HF, reasons for underutilization of MRAs in treatment, evaluating the evidence and reappraising the disease-modifying role of eplerenone in HF management. Methods: An electronic database search was performed to identify relevant literature. Results: The review details various studies that demonstrate the role of MRA eplerenone as a disease-modifying agent in patients with mild-to-moderate hypertension and those with acute myocardial infarction (MI) complicated by left ventricular dysfunction and HF. It also outlines different patient profiles for eplerenone use and ways to handle minor side-effects. Conclusions: Eplerenone shows a promising effect in selectively blocking aldosterone receptors to suppress fibrosis and reverse cardiac remodeling.

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.

Pulsatile Chronotherapeutic Drug Delivery for Controlling Early Morning Surge in Blood Pressure; Effect of Coating on Eplerenone In-vitro, In-vivo Release and Urinary Na/K Ratio

Abstract The objective of the present study was to develop time delayed chronotherapeutic formulation of Eplerenone (Ep) to provide rapid drug release after a pre-determined lag time for the treatment of early morning hypertension. Cyclodextrin complexation was used to prepare fast release Ep core tablets. The developed core tablets were then coated with different rate-controlling polymers using compression coating technique. The developed tablets were evaluated for hardness, friability, drug content and swelling index. The in-vitro drug release was carried out to study the effect of different coating materials on drug release and lag time. Tablets selected for stability study were those showing lag time of 5-7 hours followed by complete drug release; F2, F3, F7, F8, and F12. The in-vivo study was carried out on tablets with the highest t90 as compared to commercial tablets after being administered to healthy human volunteers where plasma Ep and urinary Na/K ratio were determined. Results suggested that this approach was able to provide delayed release Ep formulations that will be useful for patients with morning surge in blood pressure.

Efficacy and Safety of Eplerenone in the Treatment of Essential Hypertension ：Reevaluation of Systematic Review/Meta-analysis / 中国药房

OBJECTIVE：To reeval uate the systematic review/Meta-analy sis of efficacy and safety of eplerenone in the treatment of essential hypertension. METHODS ：Retrieved from PubMed ，Embase，Cochrane Library ，Web of Science ，Wanfang database，CNKI，VIP，systematic review/Meta-analysis about eplerenone in the treatment of essential hypertension were collected from the inception to June 24th，2021. After literature screening and data extraction ，the quality of included literatures were evaluated with PRISMA statement ；methodology quality of included literatures were evaluated with AMSTAR 2 scale；GRADE method was adopted to evaluate the evidence quality of outcome measures. Efficacy and safety index evaluation of included literatures were summeried. RESULTS ：A total of 8 systematic reviews/Meta-analyses were included ，involving 5 systematic reviews and 3 Meta-analysis，including 73 outcome indicators. PRISMA scores ranged from 7.5 to 23.5，including 6 literatures （75.0％）with≤15 points，1（12.5％）with ＞15-＜21 points and 1（12.5％）with ≥21 points. The results of AMSTAR 2 evaluation indicated that the methodological quality of 2 studies was low ，and that of 6 studies was very low . GRADE quality evaluation results showed that there were 3 high quality indicators ，24 medium quality indicators and 46 low or very low quality indicators；the factors contributed to downgrading evidence quality were limitation ，inconsistency，imprecision and publication bias. In terms of efficacy ，compared with placebo ，eplerenone could significantly reduce clinical blood pressure （CBP）and 24-hour ambulatory blood pressure （ABP）. Its effect in reducing CBP was significantly better than other antihypertensive drugs or equivalent to other antihypertensive drugs. The effects of eplerenone on reducing clinical systolic blood pressure was not as good as spironolactone and enalapril ，or bett er than calcium channel blocker ，enalapril and angiotensin receptor antag onist，or equivalent to calcium channel blocker and enalapril ；the effect of eplerenone on reducing clinical diastolic blood pressure was not as good com as spironolactone ，calcium c hannel blocker and enalapril ，or as good as enalapril ，but better than angiotensin receptor antagonist. In terms of safety ，there was no significant difference in the incidence of ADR ，serious ADR or hyperkalemia caused by eplerenone ，compared with placebo ，or the incidence of ADR was higher than that of placebo. There was no statistical significance in the incidence of ADR or serious ADR ，compared with other antihypertensive drugs. CONCLUSIONS ：Efficacy and safety of eplerenone in the treatment of essential hypertension was good ，but in view of the poor methodological quality of systematic reviews or Meta-analysis and the low or very low level of outcome indicator evidence ，the authenticity and effectiveness of the conclusion will be reduced ，so that those indcaters should be interpreted carefully.

Antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica / Mineralocorticoid receptor antagonists in chronic central serous chorioretinopathy

INTRODUCCIÓN: La coriorretinopatía central serosa consiste en la filtración de fluido desde la coroides y su acumulación en el espacio subretinal. Su forma crónica se asocia a pérdida visual permanente. Los antagonistas de mineralocorticoides son una alternativa de tratamiento para esta patología, aunque no existe evidencia clara sobre su efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron 22 estudios primarios, de los cuales, cuatro corresponden a ensayos aleatorizados. Concluimos que el uso de antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica probablemente resulta en poca o nula diferencia en la agudeza visual corregida. No es posible establecer con claridad si su uso disminuye el grosor del fluido subretinal, debido a que la certeza de la evidencia ha sido evaluada como muy baja. Además, esta intervención podría resultar en poca o nula diferencia en la aparición de efectos adversos, pero la certeza de la evidencia es baja.

INTRODUCTION: Central serous chorioretinopathy consists of the leakage of fluid from the choroid and its accumulation into the subretinal space. Its chronic form is associated with permanent vision loss. Mineralocorticoid receptor antagonists are an alternative treatment for this condition, although there is no clear evidence about their effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including 22 studies overall and four of them are randomized trials. We concluded that in chronic central serous chorioretinopathy, mineralocorticoid receptor antagonists probably make little or no difference to best-corrected visual acuity. We are uncertain whether this intervention reduces subretinal fluid height because the certainty of the evidence is very low. Furthermore, this intervention may make little or no difference in terms of adverse effects, but the certainty of the evidence is low.

Inhibition of mineralocorticoid receptor activation by eplerenone to reduce autophagy in obstructive nephropathy / 中国药理学通报

Aim To observe the effect of mineralocorticoid receptor blocker eplerenone on autophagy in obstructive nephropathy and its mechanism. Methods Totally 36 male Wistar rats were randomly divided into sham-operation group, model group and eplerenone group. The animal models were established with unilarteral urteral obstruction ( UUO). The rats in eplerenone group were treated with eplerenone (100 mg • kg"1 • d"1). The obstructed kidneys were collected lOd after UUO. The expression of NR3C2 was detected by laser confocal microscopy, the expression of serum and glucocorticoid-induced protein kinase 1 ( SGK-1), phosphorylated mammal target of rapamycin (p-mTOR) , autophagy associated gene 5 (Atg5) , Be-clin-1 and microtubular-associated protein 1 light chain 3 (LC3) were detected by immunohistochemistry and Western blot. Results The expression of NR3C2 was detected in cytoplasm of renal tubular distal epithelial cells, but not in nucleus in sham-operation group with laser confocal microscopy. The expression of NR3C2 was enhanced significantly in model group, mainly in nucleus but significantly inhibited in eplerenone group. The immunohistochemistry and Western blot showed that the expressions of SGK-1, Atg5, Beclin-1 and the ratio of LC3 11/I in model group were up-regulated and down-regulated by eplerenone treated group. The expression of p-mTOR was down-regulated in model group compared with sham-operation group and up-regulated in eplerenone group. Conclusions Eplerenone plays a role in reducing autophagy in obstructive nephropathy via inhibiting the activation of mineralocorti-coid receptor.

An unusual case of multifocal central serous chorioretinopathy with low serum cortisol managed using eplerenone

In this report, we describe a rare case of a 44-year-old Asian male with acute central serous chorioretinopathy (CSC) with bullous exudative retinal detachment. Endocrinology evaluation revealed hypothalamic–pituitary–adrenal axis suppression with low serum cortisol. Furthermore, neuroimaging revealed the presence of a pituitary microadenoma. He was treated with systemic eplerenone and hydrocortisone. After 12 weeks, bullous detachment completely resolved. Our case is a unique description of acute CSC with underlying low serum cortisol levels that responded to treatment with mineralocorticoid antagonist. This case highlights the various endocrine abnormalities other than the raised serum cortisol that can occur in patients with CSC.

Effect of RNA interfering Kvl. 3 channel expression on regulatory T lymphocytes in rats / 中国药理学通报

To investigate the changes in activation and proliferation of Tregs after targeted RNA inter-ference of Kvl. 3 channel genes and in vitro administration of eplerenone (EPL). Methods After lenti-virus vector was transfected to regulatory T cells (Tregs) of rats, qPCR and whole-cell patch-clamp methods were used to detect gene knockout efficiency, and EOSA method was used to detect cytokine secretion IL-10 and TGF-p levels of Tregs group,Tregs + EPL group,RNAi-Tregs group,and RNAi-Tregs + EPL group. Results Lentivirus vector was successfully transfected into Tregs cells, and the mRNA level and current density of Kvl. 3 channel was 78% and 71.3% respectively; compared with Tregs group, extracellular and intracellular TGF-p levels in RNAi-Tregs group were significantly reduced (P < 0. 01), and extracellular and intracellular TGF-(3 levels in Tregs + EPL group were also reduced (P < 0. 05 ) ; compared with RNAi-Tregs group, extracellular and in-tracellular TGF-fJ levels in RNAi-Tregs + EPL group showed no change. However, IL-10 levels in Tregs group,Tregs + EPL group, RNAi-Tregs group, RNAi-Tregs + EPL group showed no significant change. Conclusions Kvl.3 channel mediates the activation and proliferation of Tregs cells, while EPL can reduce the activation and proliferation of Tregs cells by directly inhibiting Kvl.3 channel and reducing the secretion of TGF-fi levels, further indicating that EPL is a specific blocker of Kvl. 3 channel.

Management of chronic central serous chorioretinopathy

New treatment modalities for the management of central serous chorioretinopathy (CSC) now exist. While acute CSC generally resolves without the requirement for intervention, chronic CSC has been associated with persistent disruption in visual function. Current treatment approaches include photodynamic therapy, oral aldosterone antagonism and subthreshold multifocal laser. There has also been further investigation into a number of new treatments including antivascular endothelial growth factor treatment. Further investigation using developing optical coherence tomography imaging is helping to determine biomarkers of CSC activity, potential indicators of treatment response and indications of chronicity of disease activity. Further comparative study is required to determine the effectiveness of different forms of treatment in a range of patients with varied demographics, aetiology and chronicity of disease.

Antagonization of eplerenone on proliferation of cardiac fibroblasts induced by co-cultured Treg cells based on inhibition of Kv1.3 channel of Tregs / 中国药理学通报

Aim To establish a co-incubation system in cardiac fibroblasts of SD neonatal rats and spleen CD4+ CD25 + regulatory T lymphocytes (Tregs) of normal adult SD rats,and to investigate the effects of eplerenone(EPL) on the interaction of two cells and the relationship with the Kvl.3 channel on Tregs cell membrane.Methods The spleen Tregs of normal adult SD rats were sorted by immunomagnetic bead sorting,and the myocardial fibroblasts of SD rats were isolated by differential adherence method.The experiment was conducted in the following groups:CFs,CFs + Tregs,CFs + Tregs + EPL,Tregs.The proliferation of CFs was detected by CCK-8 method.The expression levels of type Ⅰ collagen,type m collagen and matrix metalloproteinase 2 (MMP-2) secreted by CFs were detected by ELISA.The mRNA expression levels of Kv1.3,KCa3.1 on Tregs cell membrane and intracellular CRAC channel were detected by RT-qPCR technique.Tregs cell membrane Kvl.3 channel protein expression levels were determined by In-Cell Western blot.Results After 48 h incubation of the co-culture system,the cell proliferation was stable.CFs proliferation was marked(P ＜0.01),which could be inhibited by EPL(P ＜0.01).The type Ⅰ,type Ⅲ collagen and MMP-2 secreted by CFs increased (P ＜ 0.01).The expression levels of Kv1.3,KCa3.1 and CRAC channel mRNA in Tregs increased by 6.95,1.99 and 1.53 fold (CFs + Tregs vs Tregs,P ＜0.01),EPL decreased the mRNA level of each channel (CFs +Tregs + EPLvs CFs + Tregs,P＜0.01),and the decrease of Kv1.3 channel was the most significant (P ＜ 0.01).The Kv1.3 channel protein of Tregs increased by 67.9％ (CFs + Tregs vs Tregs,P ＜0.01),which could be inhibited by EPL(P ＜ 0.01).Conclusions Tregs cultured with CFs after 48 h can significantly promote the proliferation of CFs,and EPL can down-regulate the Kv1.3 channel expression on the Tregs membrane and inhibit the activation/proliferation of Tregs,indirectly inhibiting myocardial fibrosis.

Inhibitory effects of Huoxue Jiedu decoction on cellapoptosis via down-regulating 8-OhdG in obstructive nephropathy rats / 中国药理学通报

Aim To observe the effect of eplerenone(EPL) and Chinese decoction on cell apoptosis in obstructive nephropathy rats.Methods Sixty male Wistar rats were randomly divided into sham group, UUO group, EPL group and ZY group(n=15).Except sham group, the rats in the other groups were ligated with unilateral ureteral obstruction(UUO) for renal interstitial fibrosis model.The rats were treated with eplerenone at 100 mg·kg-1·d-1 added to diet in EPL group, and orally 13.7 g·kg-1·d-1 decoction of Chinese medicine in ZY group.The kidneys were harvested on 14th day, the number of renal cell apoptosis were detected by TUNEL, and serum aldosterone and 8-OhdG were detected with radioimmunoassay and ELISA.Caspase-12, caspase-9, Bax and Bcl-2 were examined by immunohistochemistry and Western blot.Results The levels of serum aldosterone, serum and urine 8-OhdG and the number of positive apoptotic cells increased significantly in UUO rats compared with Sham group.The overexpression of caspase-9, caspase-12 and Bax and down-regulated Bcl-2 were obvious in UUO group(P<0.01).The level of 8-OhdG, expression of caspase-9, caspase-12 and Bax were down-regulated, and Bcl-2 expression was up-regulated in eplerenone and Chinese decoction treated rats(P<0.01).Conclusion Eplerenone and Chinese decoction could inhibit cell apoptosis induced by oxidative damage after UUO via caspases and(or) Bax pathway.

Eplerenone partly reverses thyroid hormone induced myocardial electrical remodeling / 中国病理生理杂志

AIM:To investigate the effects of eplerenone (Epl) on thyroid hormone (T3) induced myocardial electrical remodeling .METHODS:The ventricles of 1~3 d neonatal rats were digested with 0.125%trypsin and 0.08%collagenase type 2.The cell suspension was replated for 90 min to reduce the proportion of non-myocardial cells.The isola-ted cardiomyocytes were randomly divided into control group , T3 group, Epl group and T3+Epl group.The cardiomyocytes were identified by immunofluorescence staining .The viability of the cardiomyocytes was measured by CCK-8 assay.The ex-pression of Kv1.5, Kv4.3, Cav1.2, connexin 40 (Cx40) and Cx43 at mRNA and protein levels was determined by immu-nofluorescence staining , real-time PCR and Western blot .RESULTS:The results of the cell immunofluorescence labeling conformed that the cultured cells were cardiomyocytes with more than 95%positive staining of sarcomeric α-actinin.Com-pared with control group , the mRNA and protein levels of Kv1.5, Kv4.3, Cav1.2 and Cx40 were increased, but the ex-pression of Cx43 was decreased in T3 group.The mRNA and protein levels of Kv1.5, Kv4.3, Cav1.2 and Cx40 were de-creased, but the expression of Cx43 was increased in Eplerenone group .Compared with T3 group, the mRNA and protein expression levels of Kv1.5, Kv4.3, Cav1.2 and Cx40 were decreased, but the expression of Cx43 was increased in T3+Epl group.CONCLUSION:Eplerenone partly reverses T3-induced myocardial electrical remodeling .

Effective High Dose Multi-Drug Treatment Regimen Favours Event Free Survival Rate in DCMP Patients.

Background: To study the effect of multidrug treatment regimen in the patient of DCMP (Dilated cardiomyopathy) compared to single drug/ low dose multi drug regimen. Methods: A total of 40 patients diagnosed with DCMP (both ischemic and non-ischemic) in the last 5 years attending to Cardiology OPD/ Inpatients in National Institute of Medical sciences, Jaipur were enrolled in the study. Out of 40 patients, 20 were kept on routine treatment regimens like diuretics, beta-blockers, angiotensinogen converting enzyme inhibitor/ Angiotensin receptor blockers (ACEI/ARB), either of them or all three of them in low dose. The other 20 patients were started on mineralocorticoid receptor antagonists (MRA’s), beta-blockers, ACEI all together with gradual increments of doses to a higher level. Both these groups were followed for 2 years and we found that patient groups with effective high dose multi drug regimen has good event free survival rate compared to traditional single drug /low dose multiple regimen. Tests of statistical significance were done using Chi-square Test. Results: Out of 20 patients in normal (routine treatment regimen) 12 patients presented with congestive cardiac failure (CCF) ,15 with dyselectrolemia ,10 with hypotensive episodes and 6 deaths were seen compared to 5 patients with CCF, 5 with dyselectrolemia, 8 with hypotension and 2 deaths were seen in high dose multi drug regimen. Out of this episodes of CCF (p=0.002), dyselectrolemia (p=0.001) are statistically significant. Conclusion: High dose MDR is preferable for event free survival rate in patients of DCMP.

Inhibitory effects of eplerenone on cell proliferation via down-regulated SGK-1 pathway in rats with unilateral ureteral obstruction / 中国药理学通报

Aim To observe the effect of mineralocor-ticoid receptor blockade eplerenone on cell proliferation in obstructed kidney of rats. Methods Renal intersti-tial fibrotic animals were made with unilateral ureteral obstruction (UUO) and treated with eplerenone100 mg · kg - 1 · d - 1 . The kidneys were harvested on the 10th day and proliferating cell nuclear antigen ( PC-NA ), serum and glucocorticoid induced kinase-1 (SGK-1 ) and transforming growth factor-β1 ( TGF-β1 ) were detected with immunohistochemistry and Western blot. Results Renal histopathology showed large quantities extracellular matrix (ECM) accumula-tion in kidney with UUO, large numbers of inflammato-ry cells infiltrated in renal interstitium, renal tubular expansion and exfoliation of epithelial cells . The cell proliferation and ECM accumulation were inhibited in eplerenone treated rats significantly. Immunohisto-chemistry and Western blot showed that expressions of PCNA,SGK-1 and TGF-β1 were significantly up-regu-lated with UUO and down-regulated by eplerenone. Conclusion Eplerenone plays the role in inhibiting the cell proliferation and reducing ECM accumulation by down-regulating expression of SGK-1 pathway in rats with unilateral ureteral obstruction.

RP-HPLC determination of eplerenone and its related substances / 中国药学杂志

OBJECTIVE: To establish an RP-HPLC method for determination of the contents of eplerenone and its related substances. METHODS: A RP-HPLC method was developed by using a C18 column (Agilent Poroshell, 4.6 mm×100 mm, 2.7 μm), the mobile phase consisted of H2O-CH3CN-MeOH (64:18:18), the flow rate was 1.0 mL·min-1, and the detection wavelength was set at 240 nm. The diluent was H2O-CH3CN-MeOH (50:25:25). RESULTS: Eplerenone was well separated from the impurities. For the determination of related substances, the LODs of eplerenone, its intermediate (III and IV) and related substances (A-E) were 0.03, 0.13, 0.25, 0.05, 0.05, 0.26, 0.07 and 0.12 ng, and the LOQs were 0.12, 0.42, 0.84, 0.18, 0.18, 0.86, 0.22 and 0.41 ng, respectively. The calibration curves of eplerenone and related substances (A-E) had good linear relationship within 0.13-1.53, 0.25-3.03, 0.25-2.99, 0.13-1.61, 0.14-1.63, and 0.13-1.54 μg·mL-1 (r=0.9999, n=1), and the correction factors of the related substances (A-E) were all in the range of 0.90-1.10. The average recoveries of the related substances (A-E) were all within 95.0%-105.0% (n=9). For the content determination of eplerenone, the validation test showed good linearity over the range of 12.60-75.63 μg·mL-1 (r=0.999 6, n=6) with good repeatability (RSD=0.19%, n=6). CONCLUSION: The developed method proves to be simple, accurate, specific and reliable. It can be applied to the determination of eplerenone and its related substances.

Uso de antagonistas de aldosterona para detener la progresión de la enfermedad renal: de las bases fisiológicas a la aplicación clínica / Clinical use of aldosterone antagonists for slowing progression of chronic kidney disease: From the physiological basis to clinical application

La aldosterona, sintetizada en la zona glomerulosa de la corteza suprarrenal, es la principal hormona reguladora del metabolismo de sodio y potasio y del volumen extracelular. A través del receptor de mineralocorticoides, actúa como la señal endocrina final del sistema renina-angiotensina-aldosterona sobre el epitelio del túbulo renal y del colon distal, que estimula la reabsorción de sodio y la secreción de potasio. El agua se reabsorbe, vía ósmosis, favoreciendo la expansión del volumen circulante y, por ende, incrementando la presión arterial. Recientemente, se ha centrado el interés en las acciones no clásicas de la aldosterona sobre el endotelio vascular, corazón y riñón. Existe evidencia de que la aldosterona está involucrada en la remodelación vascular, la función endotelial y la formación de colágena, y que contribuye a la progresión de la insuficiencia cardiaca, así como del daño renal. Se revisa la evidencia clínica y experimental que fundamenta el uso de bloqueadores de aldosterona para detener la progresión del daño renal en diferentes modelos.

Aldosterone is synthesized in the adrenal cortex and is the main regulator of sodium and potassium metabolism and the extracellular volume. Acting through the mineralocorticoid receptor, it is the final endocrine signal of the renin-angiotensin-aldosterone system with effects on the renal tubular epithelium and distal colon stimulating sodium reabsorption and potassium secretion. Water is absorbed by osmosis favoring expansion of circulating volume and increasing arterial blood pressure. Recently there has been great interest in the non-classical actions of aldosterone on the vascular endothelium, heart and kidney. There is evidence suggesting that aldosterone participates in vascular remodeling, endothelial function and collagen deposition, contributing to heart failure progression and kidney damage. Clinical and experimental evidence supporting the use of aldosterone blocking agents in different models of kidney damage is reviewed.

¿Con qué drogas deben ser asociados los antialdosterónicos?

El bloqueo de los efectos adversos del sistema renina-angiotensina-aldosterona (SRAA) ha sido un foco importante en el desarrollo de drogas para el tratamiento de la enfermedad cardiovascular en los últimos 30 años. Los niveles plasmáticos de aldosterona disminuyen en forma transitoria luego del inicio del tratamiento con inhibidores de la enzima convertidora de angiotensina (IECA) y se ha demostrado que la aldosterona ejerce efectos adversos sobre el sistema cardiovascular en forma independiente de la angiotensina II. En dos reuniones consecutivas 50 líderes de opinión se reunieron para discutir en forma crítica la evidencia actualmente disponible. El presente documento sintetiza las conclusiones que surgieron por consenso de la mesa: "¿Con qué drogas deben ser asociados los antialdosterónicos?" El tratamiento farmacológico de la insuficiencia cardíaca congestiva ha cambiado significativamente en los últimos años. Sin embargo, muchos efectos adversos han sido reportados con las diferentes asociaciones utilizadas en la actualidad, no sólo para el tratamiento de la disfunción sistólica ventricular izquierda; sino también, para el tratamiento de la hipertensión arterial sistémica refractaria. Entre ellos el más importante es la hiperkalemia al modificar farmacológicamente el eje neurohumoral del SRAA. En la actualidad, asociaciones farmacológicas positivas y negativas son observadas en el grupo de fármacos antialdosterónicos, pudiéndose clasificar las interacciones con fármacos cardiovasculares y no cardiovasculares.

What drugs should be associated antialdosterone drugs? Blocking the adverse effects of the rennin-angiotensin system has been a major focus of drug development for the treatment of cardiovascular disease over the last 30 years. Plasma aldosterone levels are only transiently decreased suppressed after the initiation of angiotensin-converting enzyme (ACE) inhibitors treatment and has been shown that aldosterone causes adverse effects on the cardiovascular system independent of angiotensin II. In two consecutive meetings, 50 experts critically reviewed the available evidence. The present document reflects the consensus of the subject: "What drugs should be associated antialdosterone drugs?" Pharmacological treatment of congestive heart failure has changed significantly in recent years. However, many adverse effects have been reported with different associations currently used not only for the treatment of left ventricular dysfunction, but also for the treatment of refractory arterial hypertension. Among them the most important is the hyperkalemia to modify pharmacologically neurohumoral axis of the renin-angiotensin-aldosterone system. At present positive and negative drug associations are observed in a group of drugs aldosterone can be categorized interactions with cardiovascular and non-cardiovascular drugs.

¿O que as drogas devem ser associados os antialdosterónicos? O bloqueio dos efeitos adversos do sistema renina-angiotensina-aldosterona (SRAA) tem sido o foco principal no desenvolvimento de drogas para o tratamento de doença cardiovascular nos últimos 30 anos. Os níveis plasmáticos da aldosterona temporariamente diminuem depois de início do tratamento com inibidores da enzima conversora da angiotensina (IECA) e tem mostrado-se que a aldosterona ter efeitos adversos sobre o sistema cardiovascular independente da angiotensina II. Em duas reuniões consecutivas, 50 líderes de opinião se reuniram para discutir criticamente as evidências atuais. O presente documentoreflete o consensosobre o assunto: "O que as drogas devem ser associados os antialdosterónicos?" O tratamento farmacológico da insuficiência cardíaca congestiva mudou significativamente nos últimos anos. No entanto, muitos efeitos adversos têm sido relatados com diferentes associações atualmente utilizados não só para o tratamento da disfunção ventricular esquerda, mas também para o tratamento de hipertensão refratária. Entre eles, o mais importante é o hiperkalemia ao modificar farmacologicamente eixo neuro-humoral do SRAA. Atualmente, as associações de drogas positivas e negativas são observadas num grupo de drogas de aldosterona pode ser categorizadas interações com drogas cardiovasculares e não cardiovasculares.

Possible Contribution of Mineralocorticoid Receptor Activation on Glucocorticoid-Induced Left Ventricular Remodeling in Adrenalectomized Rat.

Background: Chronic glucocorticoid treatment induces the development of renal injury via mineralocorticoid receptor (MR) activation in bilaterally adrenalectomized rats. It has been hypothesized that glucocorticoid contributes to the development of left ventricular (LV) remodeling through MR activation in bilaterally adrenalectomized rats (ADX).Methods: ADX rats were maintained with 1%NaCl in drinking water and randomly treated as follows for 8 weeks: vehicle (n=7), bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO) (5 mg/kg/day, subcutaneous, n=7), and ADX + HYDRO + eplerenone (0.125% in chow; approximately 75 mg/kg/day, n=7). An osmotic minipump was implanted subcutaneously for continuous infusion of HYDRO. Results: As compared with control vehicletreated uninephrectomized rats, ADX+HYDRO treatment for 8 weeks significantly increased systolic blood pressure, LV weight, collagen content and mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and collagen type 1 and III. These changes were associated with increase in LV thiobarbituric acid reactive substances content, dihydroethidium fluorescence and mRNA levels of NADPH oxidase subunits. Treatment with a selective MR antagonist, eplerenone significantly attenuated HYDRO induced changes in LV parameters. HYDRO-induced increases in mRNA and protein levels of serum and glucocorticoid-regulated kinases 1 were prevented by eplerenone. Conclusion: These data suggest that chronic glucocorticoid treatment induces LV tissue remodeling through MR dependent mechanism in bilateral adrenalectomized rats.

Monitoreo del bloqueo aldosterónico / Monitoring of aldosterone blockade / Monitorização do bloqueio da aldosterona

El bloqueo de los efectos adversos del sistema renina-angiotensina-aldosterona ha sido un foco importante en el desarrollo de drogas para el tratamiento de la enfermedad cardiovascular en los últimos 30 años. Los niveles plasmáticos de aldosterona disminuyen en forma transitoria luego del inicio del tratamiento con inhibidores de la enzima convertidora de angiotensina. En dos reuniones consecutivas 50 líderes de opinión se reunieron para discutir en forma crítica la evidencia actualmente disponible. El presente documento sintetiza las conclusiones que surgieron por consenso de la mesa: "Monitoreo del bloqueo aldosterónico". En la última década, se ha demostrado que la aldosterona ejerce efectos deletéreos sobre el sistema cardiovascular, disfunción endotelial, hipertrofia, fibrosis e inflamación cardiovascular, cuyos efectos son independientes de la angiotensina II. Para monitorear los diferentes efectos de los fármacos antialdosterónicos, debemos considerar un algoritmo, donde conste: evaluación inicial pretratamiento, evaluación intratratamiento, contraindicaciones y efectos adversos. La búsqueda de la respuesta clínica y el monitoreo farmacológico mediante la utilización de marcadores biológicos, nos permitirá valorar la evolución del paciente y el efecto deseado del fármaco.

Blocking the adverse effects of the renin-angiotensin-aldosterone system has been a major focus in the development of drugs for the treatment of cardiovascular disease in the last 30 years. Plasma aldosterone levels transiently decrease after initiation of treatment with inhibitors of angiotensin converting enzyme. In two consecutive meetings, 50 opinion leaders met to discuss critically the current evidence. The present document reflects the consensus of the subject: "Monitoring of aldosterone blockade." In the last decade, it has been shown that aldosterone have detrimental effects on the cardiovascular system, endothelial dysfunction, hypertrophy, fibrosis and cardiovascular inflammation, the effects are independent of angiotensin II. To monitor the different effects of aldosterone drugs, we must consider an algorithm, stating: pretreatment baseline assessment, intra-treatment assessment, contraindications and adverse effects. The search for clinical response and drug monitoring using biomarkers will allow us to assess the evolution of the patient and the desired effect of the drug.

O bloqueio dos efeitos negativos do sistema renina-angiotensina-aldosterona tem sido um foco importante no desenvolvimento de medicamentos para o tratamento de doença cardiovascular, nos últimos 30 anos. Transitoriamente os níveis de aldosterona no plasma diminuem após a iniciação do tratamento com inibidores da enzima conversora da angiotensina. Em duas reuniões consecutivas, 50 líderes de opinião se reuniram para discutir criticamente as evidências atuais. O presente documento reflete o consenso sobre o assunto:" Monitorização do bloqueio da aldosterona" Na última década, tem sido demonstrado que a aldosterona ter efeitos prejudiciais sobre o sistema cardiovascular, a disfunção endotelial, hipertrofia e fibrose inflamação cardiovascular, os efeitos são independentes de angiotensina II. Para monitorar os diferentes efeitos das drogas aldosterona, devemos considerar um algoritmo, afirmando: avaliação pré-tratamento de linha de base, a avaliação intra-tratamento, contra-indicações e efeitos adversos. A busca de resposta clínica e vigilância da droga utilizando biomarcadores permitirá avaliar a evolução do paciente e o efeito desejado do medicamento.