The selective mineralocorticoid receptor antagonist eplerenone is protective in mild anti-GBM glomeru-lonephritis

Background: Growing evidence suggests that blockade of the aldosterone-receptor may preserve kidney function by anti-inflammatory effects independent of the blood pressure. We hypothesized that the selective aldosterone-receptor antagonist eplerenone has a profound anti-inflammatory effect in the autologous phase of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Methods: Mice received ≈200mg/kg body wt/day eplerenone via supplemented chow diet or standard chow starting at the day of immunization with rabbit IgG. Three days later the anti-GBM antibody was injected and the experiments were stopped at day 7 and 14. Results: Mice receiving eplerenone showed significantly decreased albuminuria and glomerular sclerosis at day 7 and 14 after induction of anti-GBM GN. Eplerenone treatment significantly inhibited the infiltration of CD4+, CD8+ T cells and macrophages into the kidneys. Circulating levels and glomerular deposition of autologous IgG were comparable in both groups. At day 7 the pro-inflammatory cytokines MCP-1 and IL-6 were found to be significantly decreased in regional draining lymph nodes of eplerenone-treated mice, whereas the anti-inflammatory cytokine IL-10 was significantly upregulated. In line, splenocytes from eplerenone-treated nephritic mice produced significantly increased IL-10. Conclusion: Aldosterone-receptor blockade by eplerenone effectively attenuated proteinuria, kidney damage and the inflammatory response in anti-GBM GN by significantly decreasing pro-inflammatory cytokines in the regional draining lymph nodes of the kidney. Our results suggest that this selective aldosterone receptor antagonist is a possible additional tool in the treatment of GN.     

LC MS/MS快速测定血浆中依普利酮浓度及其人体药动学研究

 目的研究依普利酮片在中国健康受试者体内单次及多次给药的药动学特征。方法12名受试者（男、女各半）,按3×3拉丁方设计分别交叉口服依普利酮片25,50,100 mg,进行单次给药药动学研究;10名受试者（男、女各半）连续给药6 d,每天1次,每次50 mg,进行多次给药药动学研究。血药浓度用LC MS/MS快速测定。结果12名受试者单次给药25,50,100 mg依普利酮后,ρmax分别为(4502±1462)、(7652±2582)、(1 262±428)μg·L-1,tmax分别为(171±033)、(206±101)、(279±148) h,t1/2分别为(250±039)、(269±055)、(284±053) h,AUC0 24 h分别为(2 410±778)、(4 403±1 522)、(8 202±2 398)μg·h·L-1,AUC0 ∞分别为(2 429±774)、(4 426±1 523)、(8 246±2 407)μg·h·L-1;10名受试者单次给药50 mg和多次给药50 mg依普利酮达到稳态后,tmax分别为（340±127）和(265±100)h,t1/2分别为（303±066）和(322±062)h,ρmax和ρSSmax分别为(6907±2074)和(7432±1923)μg·L-1,ρSSmin为(1281±964)μg·L-1,ρSSav为(2190±596)μg·L-1,AUCSS为(5 256±1 431) μg·h·L-1。结论口服给药剂量范围在25~100 mg时,依普利酮在人体内具有线性药动学特征;依普利酮按每日给药1次,每次口服50 mg,连续给药6 d在人体内不会产生蓄积。     

依普利酮在健康志愿者体内代谢物依普利酮酸的药代动力学研究

目的对单次给药后,依普利酮在健康志愿者体内代谢物依普利酮酸的药代动力学进行研究。方法健康志愿者单次服用不同剂量依普利酮片后,采用液相色谱串联质谱法测定依普利酮的代谢物依普利酮酸的浓度,用DAS2.0药动学软件计算药动学参数。结果单次口服25、50、100mg依普利酮片的主要药代动力学参数：t1/2分别为（4.2±1.6）、（4.5±2.3）、（5.1±1.3）h;Cmax分别为（151.5±38.36）、（203.9±60.49）、（543.0±139.8）ng/ml;AUC（0-30）分别为（756.7±300.4）、（1103±363.0）、（2660±638.0）μg.h/L。结论在25～100mg给药剂量范围内,依普利酮片在体内呈现线性药代动力学特征。     

选择性醛甾酮拮抗药在高血压治疗中的应用

醛甾(固)酮与其受体结合后通过增加水钠潴留加重高血压。醛甾酮拮抗药分为选择性和非选择性2 大类。醛甾酮受体拮抗药不仅有助于降低血压,而且可减少醛甾酮对心血管系统的不利作用,减少心室肥厚和心血管事件的发生率。     

The role of aldosterone in heart failure and the clinical benefits of aldosterone blockade

Aldosterone has a variety of detrimental effects on the heart and vasculature and is increasingly recognized as an important target in chronic heart failure, as illustrated by the Randomized Aldactone Evaluation Study. In this article, the evidence supporting the cardiovascular effects of aldosterone in humans and the proven benefits of aldosterone-receptor antagonists in heart failure shall be discussed.     

Oral eplerenone for the management of chronic central serous chorioretinopathy

AIM: To examine eplerenone (Inspra, Pfizer), a mineralocorticoid receptor antagonist, as a treatment option for chronic central serous chorioretinopathy (CSCR). METHODS: A retrospective consecutive case series was conducted for patients receiving oral eplerenone for chronic CSCR. At baseline and each follow-up visit, spectral domain optical coherence tomography (SD-OCT) imaging was performed, including manual measurements of the height and diameter size of subretinal fluid. The primary outcome measure was the reduction in subretinal fluid following initiation of therapy. RESULTS: A total of 17 eyes of 13 patients treated with 25 and 50 mg of oral eplerenone per day were identified. Subretinal fluid (SRF) decreased over time following eplerenone therapy (P= 0.007 and P = 0.002, diameter and height respectively). Maximum SRF height decreased from a mean of 131.5 μm at baseline to 15.3 μm at day 181+. SRF diameter decreased from an average of 2174.4 μm at baseline to 46.9 μm at day 181+. LogMAR visual acuity improved from 0.42 (Snellen equivalent: 20/53) at baseline to 0.29 (Snellen equivalent: 20/39) at day 181+ (P = 0.024). Central subfield thickness (CST) decreased from 339.5 μm at baseline to 270.3 μm at day 181+ (P = 0.029). CONCLUSION: Eplerenone therapy resulted in significant anatomic and visual improvements in eyes with chronic CSCR.     

Neurohormonal Intervention to Reduce Sudden Cardiac Death in Heart Failure: What is the Optimal Pharmacologic Strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension

We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.     

Aldosterone-Sensitive Nucleus Tractus Solitarius Neurons Regulate Sensitivity of the Baroreceptor Reflex in High Sodium–Loaded Rats

We examined the role of aldosterone-sensitive neurons in the nucleus tractus solitarius (NTS) in the arterial baroreceptor reflex (baroreflex) function. Baroreflex sensitivity was induced by phenylephrine in high sodium–loaded rats and was significantly reduced. This baroreflex sensitivity was reversed by microinjection of the mineralocorticoid receptor (MR) antagonist eplerenone into the NTS. 11β-Hydroxysteroid dehydrogenase type 2 neurons and MR were also identified in the NTS. These data suggest that the aldosterone-sensitive neurons in the NTS may have an important role in baroreflex function.