Spironolactone

Spironolactone is a potent antagonist of the androgen receptor with IC50 of 77 nM.

Signal Enhancement in the HPLC-ESI-MS/MS analysis of spironolactone and its metabolites using HFIP and NH4F as eluent additives.[Pubmed:28224249]

Anal Bioanal Chem. 2017 May;409(12):3145-3151.

This paper describes an LC-MS/MS method to determine the concentration of Spironolactone and its metabolites 7-alpha-methylthioSpironolactone and canrenone in blood plasma samples. The resulting assay is simple (using protein precipitation for sample preparation) and sensitive (the lower limit of quantification is close to 0.5 ng/ml) while requiring only 50 mul of plasma, making it especially suitable for analyzing samples obtained from pediatric and neonatal patients where sample sizes are limited. The sensitivity is achieved by using ammonium fluoride as an eluent additive, which in our case amplifies the signal from our analytes in the plasma solution on average about 70 times. The method is fully validated according to the European Medicines Agency's guideline and used for the measurement of pediatric patients' samples in clinical trials for evaluating oral Spironolactone's and its metabolites' pharmacokinetics in children up to 2 years of age.

Anti-Fibrosis Effect of Relaxin and Spironolactone Combined on Isoprenaline-Induced Myocardial Fibrosis in Rats via Inhibition of Endothelial-Mesenchymal Transition.[Pubmed:28245473]

Cell Physiol Biochem. 2017;41(3):1167-1178.

BACKGROUND: The effect of relaxin and Spironolactone combined on myocardial fibrosis has not been reported. Thus, we investigated the effect of the combined therapy on isoprenaline-induced myocardial fibrosis and the mechanism. METHODS: Rats were injected subcutaneously with isoprenaline to induce myocardial fibrosis and underwent subcutaneous injection with relaxin (2 microg.kg-1.d-1) and given a gavage of Spironolactone (30 mg.kg-1.d-1) alone or combined for 14 days. In vitro, the endothelial-mesenchymal transition was induced with transforming growth factor beta (TGF-beta) in human umbilical vein endothelial cells (HUVECs) pretreated with relaxin, 200 ng/ml, and/or Spironolactone, 1uM. RESULTS: Relaxin and Spironolactone used alone or combined improved cardiac function and decreased cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; decreased the expression of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1), and increased the expression of cluster of differentiation-31 (CD31) in rats with isoprenaline-induced myocardial fibrosis. In vitro, compared with TGF-beta treatment, relaxin and Spironolactone used alone or combined with TGF-beta decreased cell mobility, alpha-SMA and vimentin levels but increased vascular endothelial cadherin (VE-cadherin) and endothelial CD31levels. Especially, combined therapy had more remarkable effect than relaxin and Spironolactone used alone both in vitro and in vivo. CONCLUSION: Relaxin and Spironolactone combined affected isoprenaline-induced myocardial fibrosis in rats that the mechanism might be inhibition of the cardiac endothelial-mesenchymal transition.

Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction: From the TOPCAT Trial.[Pubmed:28359411]

JACC Heart Fail. 2017 Apr;5(4):241-252.

OBJECTIVES: The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects Spironolactone. BACKGROUND: Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. METHODS: The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] >/=100 pg/ml or N-terminal proBNP >/=360 pg/ml) to Spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT. RESULTS: Higher levels of NPs were independently associated with an increased risk for TOPCAT's primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of Spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles. CONCLUSIONS: Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of Spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Effect of spironolactone on the risks of mortality and hospitalization for heart failure in pre-dialysis advanced chronic kidney disease: A nationwide population-based study.[Pubmed:28363684]

Int J Cardiol. 2017 Jul 1;238:72-78.

BACKGROUND: Spironolactone has been shown to reduce cardiovascular death in patients with mild-to-moderate chronic kidney disease (CKD), but its risks and benefits in advanced CKD remain unsettled. We aimed to assess whether Spironolactone reduces cardiovascular mortality and morbidity in pre-dialysis stage 5 CKD patients. METHODS: Using Taiwan's National Health Insurance Research Database from January 2000 to June 2009, we enrolled 27,213 pre-dialysis stage 5 CKD adult patients, in whom 1363 patients were treated with Spironolactone (user) and 25,850 were not (nonuser). Outcomes were all-cause mortality, hospitalization for heart failure (HHF) and major adverse cardiac event (MACE, the composite of acute myocardial infarction and ischemic stroke). Patients were followed up till December 31, 2009. RESULTS: Over 85,758 person-years of follow-up, Spironolactone users had higher incidence for all-cause mortality (24.7/100 person-years vs. 10.6/100 person-years), infection-related death (4.4/100 person-years vs. 1.7/100 person-years) and HHF (4.0/100 person-years vs. 1.4/100 person-years). Multivariable Cox hazards model showed that Spironolactone users were associated with higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.24-1.46), infection-related death (aHR 1.42, CI 1.16-1.73) and HHF (aHR 1.35, CI 1.08-1.67) as compared to nonusers. The risks for cardiovascular mortality, MACE and hyperkalemia-associated hospitalization were similar between two groups. After matching users and nonusers (1:3 ratio) by propensity scores, the results were consistent in matched cohort and across subgroups. CONCLUSIONS: Spironolactone may be associated with higher risks for all-cause and infection-related mortality and HHF in pre-dialysis stage 5 CKD patients. Spironolactone should be used with caution in advanced CKD patients.

Contrasting effects of eplerenone and spironolactone on adrenal cell steroidogenesis.[Pubmed:18819053]

Horm Metab Res. 2009 Jan;41(1):35-9.

Spironolactone and eplerenone are widely used as mineralocorticoid antagonists. Spironolactone has several nonspecific actions including inhibition of androgen receptor and steroid hormone biosynthesis. While studies have shown that eplerenone does not exhibit nonspecific actions on androgen receptor, its effects on steroid hormone production have not been reported. Herein, the effects of eplerenone (0.1-30 microM) and Spironolactone (0.1-30 microM) on steroid production were examined in human adrenocortical H295R cells. Spironolactone inhibited basal production of cortisol (91%) and aldosterone (53%). Treatment of H295R cells with angiotensin II (Ang II) for 24 h increased aldosterone production by 11-fold. Spironolactone inhibited Ang II stimulation of aldosterone production by 80%. Addition of pregnenolone increased aldosterone (9-fold) and cortisol (3-fold) production. Spironolactone inhibited pregnenolone metabolism to aldosterone (67%) and cortisol (74%). The inhibitory effects of Spironolactone occurred at concentrations far higher than those needed to block mineralocorticoid receptor, suggesting an action directly on the enzymes involved in steroid production. In contrast, eplerenone did not inhibit basal, Ang II, forskolin, pregnenolone-stimulated cortisol, or aldosterone production. Together, these data demonstrate that opposed to Spironolactone, pharmacologic concentrations of eplerenone do not inhibit adrenal cell aldosterone or cortisol production.

A comparison of the aldosterone-blocking agents eplerenone and spironolactone.[Pubmed:18404673]

Clin Cardiol. 2008 Apr;31(4):153-8.

Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, Spironolactone and eplerenone. A Medline search identified clinical studies assessing Spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between Spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for Spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; Spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with Spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.

Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology.[Pubmed:10760075]

Kidney Int. 2000 Apr;57(4):1408-11.

For more than 30 years after the discovery of aldosterone, scientists believed that its sole site of action was at epithelial tissues, most notably the kidney, where it mediated the transport of Na and K. It was soon recognized aldosterone contributed to several diseases by causing edema. Armed with this information, scientists set out more than 30 years ago to develop an antagonist of the mineralocorticoid receptor for the treatment of edematous states. From this effort, Spironolactone (Aldactone was discovered. Spironolactone acts functionally as a competitive inhibitor of the mineralocorticoid (aldosterone) receptor, and although Spironolactone is an effective mineralocorticoid receptor antagonist, it is not without limitations. These limitations include unwanted progestational and antiadrogenic side effects that limit its use in the chronic treatment of disease. In addition to its actions at the collecting tubule, aldosterone can participate in pathophysiology by actions at the heart, vasculature, and kidney, and it is likely that the most significant contributions to cardiovascular disease are due to actions at these sites rather than those related to Na and water retention. This is underscored by the recent clinical results from the RALES-004 Trial in which treatment with Aldactone demonstrated a significant benefit on mortality in patients with severe heart failure. The limited utility of Spironolactone owing to the aforementioned steroid-related side effects has been especially frustrating, given the newly recognized role of aldosterone in cardiovascular disease. To obviate these limitations, eplerenone is currently being developed by Searle. Eplerenone is a competitive antagonist of the mineralocorticoid receptor that takes advantage of replacing the 17alpha-thoacetyl group of Spironolactone with a carbomethoxy group, conferring excellent selectivity for the mineralocorticoid receptor over other steroid receptors. The pharmacological profile of eplerenone positions it to be an effective and selective mineralocorticoid receptor antagonist.