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Concept: Spironolactone

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Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.

Concepts: Chronic kidney disease, Kidney, Nephrology, Blood pressure, Aldosterone, Spironolactone, Eplerenone, Renin

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QUESTION In patients with left ventricular (LV) dysfunction, what is the relative efficacy of eplerenone and other aldosterone antagonists (AAs)? REVIEW SCOPE Included studies compared eplerenone or other AAs with control (placebo, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or β-blocker) in patients > 18 years of age with symptomatic or asymptomatic LV dysfunction, had ≥ 8 weeks of follow-up, and reported ≥ 1 outcome of interest. Studies comparing AAs with each other were excluded. Outcomes were all-cause mortality, cardiovascular (CV) mortality, gynecomastia {per trial definition in individual studies}*, and hyperkalemia {serum potassium > 5.5 mEq/L}*. REVIEW METHODS MEDLINE, EMBASE/Excerpta Medica, CINAHL, and Cochrane Central Register of Controlled Trials (all to Jul 2011); reference lists; and reviews were searched for randomized controlled trials (RCTs). 16 RCTs (n = 12 505, mean age 55 to 69 y, 54% to 87% men) met selection criteria. 4 RCTs included patients after acute myocardial infarction LV dysfunction, and 12 included patients with heart failure. Study drugs were spironolactone (10 RCTs), canrenone (3 RCTs), and eplerenone (3 RCTs). Risk for bias (Cochrane criteria) was low for 8 RCTs, intermediate for 7, and high for 1. MAIN RESULTS Eplerenone and other AAs reduced all-cause mortality and CV mortality compared with no AA (Table). Eplerenone increased risk for hyperkalemia, and other AAs increased risk for gynecomastia, compared with no AA (Table). Based on an indirect comparison, other AAs reduced mortality more than eplerenone (P = 0.009). CONCLUSION Based on an indirect comparison, eplerenone is not more effective at reducing mortality for adults with left ventricular dysfunction than other aldosterone antagonists.Eplerenone or other AAs vs control in patients with left ventricular dysfunction†OutcomesNumber of trials (n)Weighted event ratesAt 2 to 24 moEplerenoneControl‡RRR (95% CI)NNT (CI)All-cause mortality2 (9369)14%16%15% (7 to 23)41 (27 to 88)CV mortality2 (9369)12%14%17% (8 to 25)42 (29 to 88)Gynecomastia2 (9361)0.49%0.66%26% (-27 to 57)NSRRI (CI)NNH (CI)Hyperkalemia3 (9489)6.1%3.8%72% (19 to 147)37 (19 to 140)Other AA§Control‡RRR (95% CI)NNT (CI)All-cause mortality12 (3569)19%25%26% (17 to 34)16 (12 to 24)CV mortality4 (2553)26%34%25% (16 to 33)12 (9 to 19)RRI (CI)NNH (CI)Gynecomastia6 (2279)5.4%0.86%526% (238 to 1057)23 (11 to 49)Hyperkalemia10 (3342)8.1%4.5%80% (-17 to 291)NS†AA = aldosterone antagonist; CV = cardiovascular; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from control event rates and risk ratios in article using a random-effects model.‡Placebo, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or β-blocker.§Other AAs were spironolactone or canrenone.

Concepts: Myocardial infarction, Hypertension, Heart failure, Spironolactone, Aldosterone antagonist, Eplerenone, ACE inhibitor, Hyperkalemia

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CONTEXT: Prevalence of Cushing’s syndrome (CS) in patients presenting with hirsutism is not well-known. OBJECTIVE: Screening of CS in patients with hirsutism. SETTING: Referral hospital PATIENTS AND OTHER PARTICIPANTS: This study was carried out on 105 patients who admitted to Endocrinology Department with the complaint of hirsutism. INTERVENTION: All the patients were evaluated with low dose dexamethasone suppression test (LDDST) for CS. MAIN OUTCOME MEASURE: Response to LDDST in patients presenting with hirsutism RESULTS: All the patients had suppressed cortisol levels following low dose dexamethasone administration excluding CS. The etiology of hirsutism were polycystic ovary syndrome in 79%, idiopathic hirsutism in 13%, idiopathic hyperandrogenemia in 6% and non-classical congenital hyperplasia in 2% of the patients. CONCLUSION: Routine screening for CS in patients with a referral diagnosis of hirsutism is not required. For the time being, diagnostic tests for CS in hirsute patients should be limited to patients who have accompanying clinical stigmata of hypercortisolism.

Concepts: Obesity, Glucocorticoid, Cortisol, Spironolactone, Polycystic ovary syndrome, Cushing's syndrome, Hirsutism, Dexamethasone suppression test

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In the presence of salt, aldosterone causes hypertension and organ damage via the mineralocorticoid receptor (MR) through various mechanisms. MR antagonists are considered to be potassium-sparing diuretics that exert their effect by blocking MR in the kidney, and they are not the first choice for treating hypertension. However, the importance and usefulness of inhibiting aldosterone in the management of hypertension have recently been revealed in both the basic and clinical fields. In Japan, both the selective MR antagonist eplerenone and the non-selective MR antagonist spironolactone are indicated for the treatment of hypertension. Although these drugs are generally used in the same manner, in some cases they require differentiation. This differentiation is divided into two types due to the differences in their features and differences in their contraindications in Japan. Based on a number of studies on MR antagonists that have been recently published, the diseases and clinical conditions targeted by MR antagonists appear to be likely to increase in the future. In Japan, we consider it necessary to carefully differentiate spironolactone from eplerenone in regard to their intended uses.Hypertension Research advance online publication, 22 November 2012; doi:10.1038/hr.2012.182.

Concepts: Hypertension, Aldosterone, Receptor antagonist, Spironolactone, Potassium-sparing diuretic, Diuretic, Aldosterone antagonist, Eplerenone

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The purpose of this study is to evaluate long-term effects of spironolactone, an affordable and widely used aldosterone receptor blocker, in patients with heart failure (HF) and mild or no symptoms.

Concepts: Aldosterone, Spironolactone, Mineralocorticoid receptor

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PURPOSE: To collect available clinical data to define the role of diuretics and lipid formulations in the prevention of amphotericin B (AmB)-induced nephrotoxicity (AIN) in human populations. METHOD: A literature search was performed in the following databases: Scopus, Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. RESULTS AND CONCLUSION: Co-administration of mannitol failed to show any clinically significant benefit in preventing AIN. Potassium-sparing diuretics, such as amiloride and spironolactone, have been shown to have beneficial effects as an alternative or adjunct to oral/parenteral potassium supplements in preventing hypokalemia due to AmB. Lipid-based formulations of AmB are clinically effective and safe in preventing AIN. However, due to their high cost and limited accessibility, these formulations are generally used as second-line antifungal therapy in cases of conventional AmB refractoriness and/or intolerance or pre-existing renal dysfunction. The potential effects of other nephroprotective agents, such as N-acetylcysteine, AIN merit further considerations and investigations.

Concepts: Hypertension, Amphotericin B, Spironolactone, Potassium-sparing diuretic, Diuretic, Aldosterone antagonist, Hypokalemia, Hyperkalemia

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Abstract The October 2010 ESHRE/ASRM polycystic ovary syndrome (PCOS) workshop concluded: (1) all combined oral contraceptives (COC) appear to have equal efficacy for PCOS, (2) addition of antiandrogens (spironolactone) to COCs has little treatment benefit and (3) metformin does not improve the live-birth rate and should only be used with impaired glucose tolerance. We compared these guidelines to current practice in the United States IMS claims-database. Time-series analyses were conducted by calendar-year in women with PCOS to evaluate prescribing preferences for COCs, concomitant use of spironolactone, and utilization of metformin. Trends were analyzed with linear regression. Our cohort included 1.6 million women taking COCs, 46 780 with a PCOS claim. Drospirenone utilization increased by 1.52% (SE:0.48%, p = 0.007) per-year more in women with PCOS (4.16%, SE:0.45%, p < 0.001) than in women without PCOS (2.64%, SE:0.17%, p < 0.001)). Concomitant use of drospirenone and spironolactone was common (14.26%) and increased by 0.75% (SE:0.15%, p = 0.002) per-year. Although plasma glucose tests were unavailable, women with PCOS were more likely to take metformin than have a diabetes claim (45.8% versus 15.2%, p < 0.001), indicating some women likely receive metformin solely for PCOS. Our data suggests further attention is needed to medication management of PCOS to bridge the gap between guidelines and practice.

Concepts: Combined oral contraceptive pill, Endocrinology, Glucose tolerance test, Metformin, Menstrual cycle, Spironolactone, Polycystic ovary syndrome, Hirsutism

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Eighty years ago a publication in this journal proved to be seminal and transformative. The report By Irving Freiler Stein and Michael Leventhal titled “Amenorrhea Associated with Polycystic Ovaries” has proven to be a remarkably lasting and influential publication. The growth in related literature has been increasing exponentially: the 50 years between 1950 and 2000 saw a little over 8000 publications on the topic, while the 15 year period between 2001 and 2015 (so far) has seen over 20,000 related publications, a greater than 8-fold increase in publication rate post-2000. As we commemorate the 80(th) anniversary year of the publication of the report by Stein and Leventhal, it is important to ask ourselves….Was this publication truly as seminal as it is generally assumed to be? And why did it gain such a strong foothold on the medical psyche? To the first question a review of the antecedent medical literature makes it clear that the report of Drs. Stein and Leventhal in 1935, while not flawless, was both seminal and transformative. In fact, it was the first report to describe a series of patients, rather than isolated cases, who demonstrated the triad of polycystic ovaries, hirsutism, and oligo/amenorrhea, connecting what had previously been disparate features of polycystic ovaries and menorrhagia, and hirsutism and oligo/amenorrhea. Secondly, the facts that Dr. Stein and his collaborators were relatively prolific writers, consistent and clear in their message and descriptions; that a possible therapy (bilateral ovarian wedge resection) had been conveniently included in the report; and that the disorder was (is) relatively prevalent, permitted what would eventually be called the Stein-Leventhal syndrome to gain a strong foothold in contemporary medical practice. Overall, we in the field of medicine have much to celebrate, as we commemorate the 80th anniversary of the publication of the report by Stein and Leventhal in 1935, for a new disorder was described, one that we know today affects, in its various forms, one in every 7 to 17 women worldwide.

Concepts: Medicine, Menstrual cycle, Gynecology, Spironolactone, Polycystic ovary syndrome, Hirsutism, Anovulation

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Resistant hypertension-uncontrolled hypertension with 3 or more antihypertensive agents-is increasingly common in clinical practice. Clinicians should exclude pseudoresistant hypertension, which results from nonadherence to medications or from elevated blood pressure related to the white coat syndrome. In patients with truly resistant hypertension, thiazide diuretics, particularly chlorthalidone, should be considered as one of the initial agents. The other 2 agents should include calcium channel blockers and angiotensin-converting enzyme inhibitors for cardiovascular protection. An increasing body of evidence has suggested benefits of mineralocorticoid receptor antagonists, such as eplerenone and spironolactone, in improving blood pressure control in patients with resistant hypertension, regardless of circulating aldosterone levels. Thus, this class of drugs should be considered for patients whose blood pressure remains elevated after treatment with a 3-drug regimen to maximal or near maximal doses. Resistant hypertension may be associated with secondary causes of hypertension including obstructive sleep apnea or primary aldosteronism. Treating these disorders can significantly improve blood pressure beyond medical therapy alone. The role of device therapy for treating the typical patient with resistant hypertension remains unclear.

Concepts: Myocardial infarction, Hypertension, Blood pressure, Sleep apnea, Spironolactone, Diuretic, Thiazide, Calcium channel blocker

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Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF.

Concepts: Pharmacology, Clinical trial, Hypertension, Randomized controlled trial, Effectiveness, Receptor antagonist, Spironolactone, Mineralocorticoid receptor